Jon D. Blumenfeld John H. Laragh
|
Overview, 1465 |
||
|
Epidemiology, 1466 |
||
|
Physiology of Blood Pressure Homeostasis, 1478 |
||
|
Pathophysiology of Hypertension, 1481 |
||
|
Human Hypertensive Disorders As a Spectrum of Abnormal Plasma Renin and Sodium-Volume Products, 1486 |
||
|
Two Forms of Vasoconstriction in Primary Hypertension, 1505 |
||
|
Evaluation and Treatment of the Individual Patient, 1506 |
||
|
Recapitulation and Summary, 1516 |
OVERVIEW
Hypertension is a leading risk factor for heart disease, stroke, and kidney failure.[1] As hypertension is the most common primary diagnosis in the United States, affecting an estimated 50 million or more people, it is not surprising that blood pressure (BP) measurement is one of the most common reasons for a visit to the doctor's office and antihypertensive medications are among the most commonly written prescriptions. [2] [3] [4] [5] Nevertheless, only about 30% of all hypertensive patients in this country have their BP adequately controlled ( Table 42-1 ). [1] [5]
TABLE 42-1 -- Trends Awareness, Treatment, and Control of High Blood Pressure in Adults
|
|
NHANES II (1976–1980) |
NHANES III (Phase 1) (1988–1991) |
NHANES III (Phase 2) (1991–1994) |
NHANES (1999–2000) |
|
Awareness |
51 |
73 |
68 |
70 |
|
Treatment |
31 |
55 |
54 |
59 |
|
Control |
10 |
29 |
27 |
34 |
From Chobanian AV, Bakris GL, Black HR, et al: Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 42:1206–1252, 2003.
|
Data are percentages of adults ages 18 to 74 years with systolic blood pressure ≥140 mm Hg, diastolic pressure ≥90 mm Hg, or taking antihypertensive medication.[1] NHANES, National Health and Nutrition Examination Survey. |
In Europe, the age- and sex-adjusted prevalence of hypertension is 44% compared with 28% in the United States and Canada. The risk of cardiovascular disease (CVD) and stroke are also commensurately high. [6] [7] Despite these sobering facts, national guidelines for treating high BP have had a limited impact on antihypertensive drug selection by practicing physicians, as indicated by their decreased use of recommended drugs, including diuretics or β-blockers. [8] [9] [10] [11] Even though the proportion of patients with controlled hypertension has increased over the past few decades, the rates of decline in deaths due to coronary heart disease (CHD) and stroke have slowed.[1]Moreover, the prevalence and hospitalization rates due to heart failure (HF), which is preceded by hypertension in a majority of patients, have continued to increase.
The factors contributing to the difficulties in the diagnosis and treatment of hypertension are complex. However, a key factor is the widely held misconception that essential hypertension, referred to as primary hypertension in this chapter, is a discrete entity that can be addressed with a monolithic approach that does not consider pathophysiologic mechanisms. In this chapter, we focus on the concept that primary hypertension is a heterogeneous disorder in which patients can be stratified by pathophysiologic characteristics that have a direct bearing on the efficacy of targeted antihypertensive medications, on the detection of potentially curable secondary forms of hypertension, and on the risk of cardiovascular complications. Secondary hypertension is often considered separately from primary hypertension. However, because these disorders share common pathophysiologic mechanisms, they are considered together in this chapter.
The phenomenon of hypertension was first characterized at the turn of the previous century, when Riva-Rocci[12] developed the prototype of the modern sphygmomanometer and so allowed the routine measurement of BP. Korotkov[13] then perfected the sphygmomanometric technique by describing the sounds heard over the brachial artery as the pressure in the cuff is reduced. In general, the upper limits of normal BP in older persons had been considered to be a systolic value of 140 mm Hg and a diastolic value of 90 mm Hg. These figures have been adjusted downward to the point that readings in excess of 120/80 mm Hg may be considered abnormal.[1] Population studies suggest that BP is a continuous variable, with no absolute dividing line between normal and abnormal values.[14] This situation has resulted in an inevitable continuous debate over borderline readings that focus on whether people with such pressures are normal and on what, in fact, constitutes normalcy. [15] [16] Moreover, studies using 24-hour monitoring techniques and home BP measurements indicate that significant fractions of patients who appear hypertensive in the office setting do not have hypertension at other times, whereas some patients who appear normotensive in the office are hypertensive in other settings. [17] [18] [19]
Early on, however, life insurance studies indicated that relatively higher BPs that are casually recorded, even those that are within the normal range, are statistically associated with increased mortality from cardiovascular complications. [20] [21] [22] Through a subsequent trial of therapy (principally with diuretics), the Veterans Administration established that antihypertensive treatment could provide a significant degree of protection against such complications—notably congestive heart failure (CHF), renal failure, and stroke, but not coronary artery disease. [23] [24] From such demonstrations sprang the concept of a medical obligation to treat all cases of hypertension.
Nonetheless, the risks of death and disability associated with hypertension are increased only in the broad statistical sense; a large majority of patients with clearly elevated BP have normal longevity and health. [25] [26] Not only are the risks variable from one person to another, but also great variability has been found among hypertensive patients in their responses to antihypertensive treatments, a phenomenon that also suggests no single cause. Thus, risks are apparently not distributed randomly but are concentrated in subgroups, in many cases that have been difficult to identify. For these and other reasons, hypertension cannot yet be considered a discrete disease entity but must rather be considered a marker common to the course of perhaps several pathologic developments. Thus, hypertension is a physical sign and a risk factor to be assessed in conjunction with other physiologic and environmental factors.
Variant patterns may be recognized. Hypertension may be purely systolic and accompanied by normal or even lowered diastolic pressure. Systolic hypertension usually occurs in the elderly and may be a manifestation of atherosclerosis, the increased systolic pressure resulting from increased arterial stiffness. [3] [27] [28] Often in the elderly, diastolic pressure is either normal or low, which suggests less arteriolar vasoconstriction and a different pathophysiologic process involving changes in the large vessels rather than in the arterioles.[29]
Imprecise terms have been applied to describe patients with high BP. In an attempt to clarify the nomenclature, recent guidelines from the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC7) have designated a classification system for BP for adults as normal (systolic < 120 or diastolic < 80 mm Hg), prehypertension (systolic 120-139 or diastolic 80-89 mm Hg), stage 1 (systolic 140-159 mm Hg or diastolic 90-99 mm Hg) and stage 2 (systolic ≤ 160 or diastolic ≤ 100 mm Hg).[1] However, there is a continuous relationship between blood pressure and cardiovascular risk; thus, any discrete numeric criteria for the classification of hypertension should be considered arbitrary.[30]
Some causes of hypertension can be identified, and some are curable ( Table 42-2 ). By definition, these are designated secondary hypertension. Although aspects of the pathophysiology of hypertension can be identified in many patients, the cause is unknown in approximately 90% of the hypertensive population. Members of this group are classified as having primary hypertension or essential hypertension. Thus, primary hypertension is a diagnosis (if indeed a confession of ignorance can be called a diagnosis) reached only after known causes of hypertension have been excluded. The diagnostic exclusion process is of vital importance, however, because cure or effective treatment is available for some of the known causes.
TABLE 42-2 -- Known Causes of Hypertension
|
||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||
|
Pheochromocytoma (adrenal medullary or extraadrenal chromaffin tumors secreting norepinephrine or epinephrine) |
||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||
|
Toxemias of pregnancy |
||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||
|
From Blumenfeld JD, Mann SJ, Laragh JH: Clinical evaluation and differential diagnosis of the individual hypertensive patient. In Laragh JH, Brenner BM (eds): Hypertension Pathophysiology, Diagnosis, and Management, 2nd ed. New York, Raven Press, 1995, pp 1897–1911.
Even when known causes have been excluded, the enormous residue defaulted as primary hypertension suggests etiologic variability, reflected by heterogeneity not only in morbidity and mortality but also in the response, or lack of it, to different classes of drugs. [31] [32] [33] Moreover, much of this considerable variability is not well correlated with the BP level. [25] [26] Converging clinical and pharmaceutical research is providing clues to physiologic mechanisms that might explain this variability. In this chapter, we discuss this evidence and its implications for diagnosis and treatment.
EPIDEMIOLOGY
Genetic Epidemiology
A report in 1923 of several families with two generations of hypertension sparked an intense debate regarding the inherited basis of hypertension. Was hypertension a distinct disorder that was inherited as a mendelian trait or was hypertension an extreme expression of a continuous trait determined by several BP-raising alleles? In fact, both positions have proved to be correct. Several monogenic hypertensive disorders, although quite rare, have been identified and their genetic and molecular characteristics have been defined.[34] However, for the vast majority of patients with essential hypertension, the inherited basis of hypertension is polygenic, with complex gene-gene and gene-environment interactions contributing to the hypertensive phenotype.[35]
During the past decade, several strategies have begun to address the genetic basis of primary hypertension. One approach has been to seek variants in candidate genes and associate them with the risk of hypertension or a quantitative effect on BP.[36] Although these approaches have provided plausible evidence for involvement of variants in several genes, they are restricted to known variants and cannot identify previously unsuspected genes. [36] [37] These limitations have led to the use of genome-wide scans that employ anonymous, highly polymorphic markers distributed across the genome.[36] These markers can identify the location of genes that influence the susceptibility to hypertension or to BP regulation by exploiting familial relationships. Excess sharing of alleles among affected siblings should occur for markers near genes that influence the risk of hypertension. Most reports have indicated nominal (i.e., significant P-value) or suggestive linkages (i.e., occurring once at random in a genome scan), although a few studies have reported significant linkages. [38] [39] [40] [41] [42] [43]
The Family Blood Pressure Program is the largest genome scan effort, comprising four networks consisting of more than 12,000 individuals genotyped for more than 380 markers (GenNet,[38] GENOA,[39] HyperGEN,[40] and SAPPHIRE[41]). Suggestive linkages (log of the odds score [LOD]) >1) were reported for hypertension in a meta-analysis of these populations.[42] The strongest linkage evidence was apparent in the region of 2p14 (LOD 1.91). However, there was no locus achieving genome-wide significance (LOD >2). Another recent meta-analysis of genome scans has also identified linkage in this region (2p12-q22).[43]
The ability to detect a locus depends on many factors including the number of families studied, their genetic homogeneity, the strength of the effect of that locus, and the linkage disequilibrium between the marker tested and that locus.[36] Another major factor that influences the sensitivity of this method is the heterogeneity of the primary hypertension phenotype, highlighted throughout this chapter, which can be demonstrated by (1) epidemiologic differences in vascular complications, (2) differential response to sodium restriction and to antihypertensive agents (e.g., diuretic, angiotensin receptor blocker [ARB]), (3) pathophysiologic, and (4) pathologic differences.[44] Failure to fully define the hypertensive phenotype restricts the optimal use of genotypic data.[45]
Gene polymorphisms of the components of the renin-angiotensin system (RAS) have been the focus of intense interest. Angiotensin-converting enzyme (ACE) I/D gene polymorphisms alone have been the subject of more than 1000 citations relating to topics as diverse as hypertension, left ventricular hypertrophy (LVH), Alzheimer's disease, and rheumatoid arthritis.[35] However, after controlling for racial background, no associations have been found between ACE genotypes and cerebrovascular disease history or cardiovascular risk factors, including baseline BP.[46] In a study of more than 5600 patients, the ACE genotype was not associated with the long-term risks of stroke, cardiac events, mortality, dementia, or cognitive decline, and the ACE genotype did not predict the BP reduction during ACE inhibitor treatment.[46] Moreover, there was no evidence that the ACE genotype modified the relative benefits of ACE inhibitor-based therapy over placebo. Altogether, these negative findings indicate that ACE gene polymorphisms are not a guide for predicting cardiovascular risk or antihypertensive drug treatment with an ACE inhibitor.
The angiotensinogen T174M and M235T polymorphisms are in linkage disequilibrium with a variant in the gene's promoter. These variants have been reported to influence BP. In a study of more than 10,000 individuals with elevated BP, ischemic heart disease, and ischemic cerebrovascular disease, Sethi amd co-workers[47] found that individuals with -6AA, 174TT, or 235TT in the angiotensinogen gene had increased plasma angiotensinogen levels and, in women moderately increased risk of elevated BP. However, there were no corresponding increments in BP examined as a continuous variable, or risk of ischemic heart disease and ischemic cerebrovascular disease. A meta-analysis of 127 trials encompassing more than 45,000 individuals found that the angiotensinogen M235T genotype was associated with a stepwise increase in angiotensinogen levels in white subjects and a corresponding increase in risk of hypertension in both white and Asian subjects.[48]
Prevalence
The most recent National Health and Nutrition Examina-tion Survey (NHANES 1999-2000) found that almost 29% of the adult noninstitutionalized U.S. population, an estimated 58.5 million individuals, had hypertension, when the criteria included systolic BP of 140 mm Hg or higher, diastolic BP of 90 mm Hg or higher, or current treatment for hypertension with prescription medication[5] (see Table 42-1 ). The prevalence of hypertension increased by 3.7% compared with the previous NHANES data from 1988 to 1991.[3]
Systolic BP increases during adulthood.[1] Although the mean systolic BP tends to be lower in younger women, after age 60 years it increases at a greater rate and is at least as high as the corresponding values for men ( Fig. 42-1 ). Diastolic BP increases until age 50 years, when it plateaus and then decreases with advancing age. Consequently, there is an age-related increase in pulse pressure, the numeric difference between systolic and diastolic BP, for both men and women. [27] [49] After age 45 years, systolic BP becomes an increasingly important determinant of cardiovascular risk compared with diastolic BP, although both measurements provide relevant information in this assessment (see Defining the Risk of Hypertensive Complications, later in this chapter).[50]
|
|
|
|
|
|
|
FIGURE 42-1 Systolic and diastolic blood pressure distribution stratified by gender, age, and race. See text. (From Burt VL, Whelton P, Roccella EJ, et al: Prevalence of hypertension in the U.S. population: Results from the Third National Health and Nutrition Examination Survey, 1988–1991. Hypertension 25:305–314, 1995.) |
|
NHANES (1999–2000) found that 65% of individuals age 60 years or older were hypertensive, a significantly greater proportion than reported earlier.[5] By contrast, the prevalence of hypertension in younger individuals did not increase during this period. Data from the Framingham population[51] indicate that BP remains in the normal range in only 6.9% of individuals older than 80 years. This is underscored by the finding that, even for those who remain free of hypertension at age 65 years, the risk of developing hypertension thereafter is approximately 90%.[52]
There is a significant association between race/ethnicity and the age-adjusted prevalence of hypertension. Non-Hispanic blacks have the highest prevalence (33.5%) compared with non-Hispanic whites (28.0%) and Mexican Americans (20.7%).[5] Of the demographic characteristics evaluated in the NHANES reports, non-Hispanic black race/ethnicity accounted for 0.4% of hypertension prevalence.
Metabolic Syndrome.
Several cardiovascular risk factors commonly cluster together. This phenomenon has been designated the metabolic syndrome. The National Cholesterol Education Program's Adult Treatment Panel III (ATP-III) has identified six components of the metabolic syndrome that relate to CVD.[53] These include abdominal obesity (waist circumference: men > 40 inches, women > 35 inches), atherogenic dyslipidemia (high-density lipoprotein [HDL]: men ≤ 40 mg/dL, women < 50 mg/dL; triglycerides ≤ 150 mg/dL), raised BP (≤130, ≤85 mm Hg) insulin resistance (fasting glucose > 110 mg/dL), proinflammatory state (elevated C-reactive protein level) and prothrombotic state (increased plasma activator inhibitor I [PAI-I]). According to the ATP-III guidelines, the metabolic syndrome exists when three or more of these abnormalities are present. Variations on these guidelines have been proposed by other organizations. For example, the World Health Organization has included microalbuminuria (urinary albumin excretion rate ≤ 20 mg/min or albumin-to-creatinine ratio ≤ 30 mg/g) as a criterion.[53]
The Framingham study[54] followed more than 3300 middle-aged individuals for 8 years and found that, in those without CVD or type 2 diabetes mellitus at baseline, the prevalence of the metabolic syndrome was 26.8% in men and 16.6% in women. It was associated with an increased risk for CVD and type 2 diabetes in both sexes and accounted for up to one third of CVD in men and approximately half of new type 2 diabetes during the follow-up period. The components of the metabolic syndrome have also been implicated in the marked increase in the prevalence of chronic kidney disease (CKD). [55] [56] [57] Results of several clinical drug treatment trials have suggested that pharmacologic inhibition of the RAS, using an ACE inhibitor or ARB, may exert favorable metabolic effects capable of preventing type 2 diabetes in high-risk individuals. [56] [58] [59]
Obesity is a predominant component of the metabolic syndrome. In the United States, approximately two thirds of all adults are overweight (body mass index [BMI] 25-29.9 kg/m2) and more than 30% are obese (≤30 kg/m2).[60]BMI is independently associated with higher prevalence of hypertension after adjusting for age, sex, and race/ethnicity.[5] The increase in BMI (from 26.1 to 27.8 kg/m2) that occurred from 1988 to 2000 accounted for more than one half of the 3.6% increase in hypertension prevalence reported during that period. An analysis of lipid profiles was not included in that report. However, in a cohort of more than 3100 nondiabetic, nonobese, middle-aged men who were free of hypertension, CVD, and cancer, there was an association between the presence of dyslipidemias and the subsequent development of hypertension.[61]
Obesity is associated with an increased risk of target organ damage. In the Framingham study,[62] elevated BMI was independently associated with an increased risk of HF, without evidence of a threshold. However, the effect of BMI on the risk of HF in subjects with hypertension was less than that in normotensive subjects. This reduced effect probably indicates a decreased contribution of obesity to the risk of HF in the presence of hypertension, a predominant independent risk factor for HF. The prevalence of CKD is also increased significantly in obese subjects, partly reflecting concurrent diabetes and hypertension.
Awareness, Treatment, and Control
Awareness.
Hypertension awareness improved significantly from 1976 to 2001[5] (see Table 42-1 ). However, the awareness level has not increased since 1988 in any age group or sex. Therefore, the increased prevalence of hypertension is unlikely to be due to increased awareness. However, there is racial disparity, with 77.7% of non-Hispanic blacks and 70.4% whites aware of their diagnosis.[5] This racial difference is most striking among black women, who have an 84% awareness rate that is significantly greater than that in white women (73.5%).[63]
Treatment.
Although awareness has not increased since 1988, in the NHANES,[5] the overall treatment rate was 58.4% in the most recent survey, representing a 6% rise. This change occurred predominantly in men, although women remained more likely to receive treatment. Both non-Hispanic black and white groups had significant improvements in treatment rates during this period, but no change occurred in the Mexican American group.[5]
In the Framingham study,[51] the overall treatment rate was 69%, increasing from 56% among those younger than age 60 years to about 73% in the older age groups. However, the number of antihypertensive medications did not differ with increasing age, with 60% using one drug, 30% using two drugs, and 10% using three or more drugs. Patterns of drug use were related to age. Thiazide diuretic use was more prevalent in older patients, with 23% of men and 38% of women older than 80 years using these agents compared with fewer than 20% of those younger than age 60 years.[51] By contrast, ACE inhibitor use declined progressively with age to 33% in the oldest age group. Nevertheless, the prevalence of use of β-blockers, calcium channel blockers, or ACE inhibitors each exceeded thiazide diuretic use regardless of patient age. These findings suggest that the JNC7 treatment recommendations are not being followed.
Control.
Despite the increased rate of hypertension awareness and treatment, only about one third of all patients have their BP controlled to less than 140/90 mm Hg.[5] However, during the period from 1988 to 2000, the proportion of patients with controlled hypertension increased by about 6%. Comparable, or even poorer response rates have been reported in European studies.[64]
Patient noncompliance with medical therapy accounts, at least partly, for the failure to control high BP. It has been estimated that 50% of hypertensive patients fail to keep follow-up appointments and only 60% follow their prescribed medication regimens.[65] These problems are even more prevalent among the inner-city poor populations in which the 1-year compliance rate for hypertensive patients was 6.2% in the California Medicaid program. The potential causes of noncompliance include lack of awareness; asymptomatic nature of the disease; and complexity, cost, and adverse effects of antihypertensive medication.
The failure to control BP is not solely a problem of patient noncompliance or lack of access to medical care. In a recent analysis of practice patterns at the Veterans Affairs hospitals, more than 45% of patients were reported to have BP of 160/95 mm Hg or higher and fewer than 25% had BP less than 140/90 mm Hg.[66] Physicians in that study frequently failed to increase the dose of medications or to try new treatments in those with poorly con-trolled BP even though patients were monitored relatively frequently.
Sodium Intake
Hypertension and its complications have been attributed to high sodium (Na) and chloride (Cl) intake, whereas some primitive tribal societies have low Na intake and a low prevalence of hypertension with aging. [67] [68] [69] [70] In the International Cooperative Cardiovascular Diseases and Alimentary Comparison (CARDIAC) Study,[71] a multicenter study designed to investigate the epidemiologic relationship of dietary factors to BP and major CVDs, across-center, simple regression analysis found that systolic and diastolic BP were significantly correlated with 24-hour urinary Na excretion in men and in postmenopausal (but not premenopausal) women. Moreover, in a study of farmers migrating to an urban community where they increased salt intake and decreased potassium (K) intake, BP increased during a 6-month follow-up period.[72] However, the Intersalt study[68] found no correlation between Na intake and BP or prevalence of high BP in 48 centers around the world. These disparate observations most likely reflect the heterogeneity in the pathophysiologic mechanisms in patients with primary hypertension.[73] This is supported by the observation that approximately 30% of hypertensive patients will decrease their BP when dietary Na restriction is markedly reduced, whereas in the majority, pressure either is unchanged or may even increase.[74]
The potential impact of Na restriction on hypertensive target organ damage was illustrated by the studies of Kempner,[75] utilizing a rice diet composed of less than 0.6 g Na, 5 g of fat, and 20 g of protein. Of 500 hypertensive patients, 62% had a decrease in BP of at least 20 mm Hg, 18% showed a change in electrocardiographic (ECG) T wave appearance from inverted to upright, and some had an improvement in severe retinopathy. Moreover, there is evidence that dietary Na restriction can lead to regression of LVH and reduction of urinary albumin excretion.[76] However, the rice diet was less effective in those with renal disease.
The effect of dietary composition on BP was evaluated in the Dietary Approaches to Stop Hypertension (DASH) Study. [77] [78] In that study, the effects on BP of either a diet rich in fruits, vegetables, and low-fat dairy products were compared with a control diet typical of intake in the US. In addition, dietary Na intake on each diet ranged from high (150 mmol/day), intermediate (100 mmol/day), to low (50 mmol/day). The DASH diet significantly lowered systolic BP at each level of Na intake and reduced BP at high and intermediate levels of Na intake by (systolic/diastolic): 5.9/2.9 mm Hg (high-Na diet), 5.0/2.5 mm Hg (intermediate-Na diet), and 2.2/1.0 mm Hg (low-Na diet). These statistically significant BP effects were observed in both black and white subjects and were comparable in obese and nonobese subjects.[79] Although this study demonstrated BP reduction by dietary intervention, the impact of these findings on cardiovascular risk in hypertensive patients has not been defined because the follow-up period in these studies was only 30 days.
The NHANES I Epidemiologic Follow-up Study,[80] a prospective cohort study, found that among overweight individuals, a 100-mmol higher Na intake was associated with significantly higher risk of stroke and mortality from stroke, CHD, CVD, or death from all causes. These findings were independent of baseline systolic BP. However, the associations between Na intake and risk of these adverse outcomes were not found in nonobese subjects. The issue is complicated further by two reports that have linked Na restriction with higher rates of myocardial infarction (MI) and of death from cardiovascular and other causes. [70] [81]
Defining the Risk of Hypertensive Complications
Practice guidelines for the treatment of hypertension are traditionally based on the premise that a discrete cut-point value separates normotension and hypertension. During the past 5 decades, antihypertensive treatment strategies have produced improvement in cardiovascular health. However, their impact is limited by their use in patients with BP that exceeds some arbitrary threshold, even though their risk of stroke and CVD may be very small.[82] For example, in the Medical Research Center (MRC) treatment trial of mild hypertension, [26] [83] enrollment of many low-risk patients occurred because mildly elevated BP was required for inclusion (diastolic pressure 90-109 mm Hg). This probably accounted for the finding that only one stroke was prevented for every 850 patients treated for 1 year. [26] [83] This modest benefit comes at a cost because antihypertensive drug treatment, per se, has risk, particularly electrolyte disturbances and glucose intolerance that occur with first-line agents such as diuretics and β-blockers. [84] [85] [86] [87] [88]
There is a continuous, graded, and independent relationship between the height of the BP and the incidence of CVD and stroke [26] [89] ( Fig. 42-2 ). Observational studies involving more than 1 million individuals have shown that death from both ischemic heart disease and stroke increases progressively and linearly from BP levels as low as 115 mm Hg systolic and 75 mm Hg diastolic upward. [1] [89] The increased risks are present in ages ranging from 40 to 89 years. This conclusion is supported by the observation from the Framingham population[90] that prehypertension was associated with a significant increased risk of MI and coronary artery disease.
|
|
|
|
|
|
|
FIGURE 42-2 Ischemic heart disease (IHD) mortality in each decade of age versus usual systolic (A) and diastolic (B) blood pressure (BP) at the start of that decade. Rates are plotted on a floating point absolute scale and each square has area inversely proportional to the effective variance of the log of the mortality rate. For diastolic BP, each age-specific regression line ignores the left-hand point (i.e., at slightly less than 75 mm Hg) for which the risk lies significantly above the fitted regression (as indicated by the broken line below 75 mm Hg). (From Lewington S, Clarke R, Qizilbash N, et al: Age-specific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 360:1903–1913, 2002.) |
|
However, BP is not the sole determinant of cardiovascular risk.[91] Only some hypertensive individuals will have a heart attack or stroke even at the highest end of the BP range. For example, during 15 years of follow-up in the Framingham study, [26] [92] fewer than one third of patients whose only risk factor was systolic BP exceeding 195 mm Hg had a heart attack or stroke. Conversely, lower BP does not necessarily protect against a cardiovascular event—more than half of all heart attacks and almost one half of all strokes occur in persons with normal BP[26] Thus, there is no threshold BP that distinguishes patients who will have a heart attack or stroke.
To determine the likelihood that treatment will lead to a decrease in risk of CHD or stroke, one must quantify the probability that an event will occur. Relative risk describes the increase (or decrease) in the likelihood of an event in one population compared with a reference population—it is a ratio that provides no information about the absolute incidence of events. Absolute risk is a term that describes the expected incidence of events and the actual odds for a person to have an event.[26]
By defining absolute risk, one can identify the prognostic differences between patients with identical BP ( Fig. 42-3 ). For example, the risk for CHD is significantly greater at every level of BP for a 55-year-old male smoker with LVH than for a 55-year-old male nonsmoker without cardiac enlargement. [26] [93] The relative risk of CVD increases with increasing BP among persons with higher or lower absolute risk. However, the absolute hazard is dramatically different in this example. Persons with lower absolute risk (even those with systolic BP >195 mm Hg) are only one tenth as likely to have an event as those of the same age and gender with systolic BP 105 but at high absolute risk (46 vs. 372/1000 patient-years).[26]
|
|
|
|
|
|
|
FIGURE 42-3 Absolute and relative risk for a cardiovascular disease event in a high- and low-risk 55-year old man by systolic blood pressure. See text. (From Lewington S, Clarke R, Qizilbash N, et al: Age-specific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 360:1903–1913, 2002.) |
|
In the Framingham cohort[94] from 1990 to 1995 found to have BP of 130/85 or greater, 2.4% had high normal or stage 1 hypertension without other risk factors or other target organ damage; 59.3% were hypertensive with other cardiovascular risk factors except diabetes mellitus, but did not have target organ damage; and 38.2% had hypertension with CVD. In recognition of this complex interaction between BP, cardiovascular risk, and the presence of genetic, biologic, and behavioral factors that modify it, the BP threshold for antihypertensive treatment has been lowered when other cardiovascular risk factors are present.[1]
Complications of Hypertension
Cardiovascular Disease
Life insurance statistics have established that hypertensive individuals, as a population, have shortened survival and that this vulnerability correlates broadly with increasing levels of arterial BP.[95] The Framingham Heart Study [91] [93] confirmed these findings and demonstrated that high BP is a leading risk factor predisposing to stroke, HF, heart attack, and kidney failure. Whether and how soon these complications occur in a specific hypertensive patient appears to be strongly determined by the concurrence of other risk factors, such as LVH, glucose intolerance, smoking, hypercholesterolemia, and obesity. Sleep-disordered breathing is also a relatively common, although often unrecognized, factor that is independently associated with hypertension and its cardiovascular complications. [96] [97] [98] [99] [100] [101]
The relative importance of systolic, diastolic, and more recently, pulse pressure components of BP as predictors of cardiovascular risk have been analyzed. [49] [50] [102] Under age 50 years, diastolic BP is the strongest predictor. Between ages 50 and 59 years, all three BP components are comparable predictors. However, from age 60 years onward, diastolic pressure is negatively related to CHD risk at any given systolic pressure of 120 mm Hg or higher, so that both systolic BP and pulse pressure are significant predictors of cardiovascular morbidity and mortality. [103] [104] [105] [106] This finding is especially relevant in the elderly, in whom 65% to 75% of hypertension is of the isolated systolic type[25] and is effectively treated with antihypertensive medication. [107] [108]
There have been reports of excess mortality due to CHD at both low and high levels of diastolic pressure, referred to as a J-curve relationship. [25] [109] In both sexes, a statistically significant excess of CVD events was observed at a diastolic BP less than 80 mm Hg only when accompanied by a systolic BP greater than 140 mm Hg. That relationship persisted after adjustment for age and associated CVD risk factors.[110] Increments in mortality risk have also been reported for end-stage renal disease (ESRD) patients treated with either hemodialysis or peritoneal dialysis (PD). [111] [112] By contrast, in healthy people, there was a linear, graded effect of both systolic and diastolic BPs to the occurrence of CHD.[25]
LVH is a common manifestation of hypertension that carries with it an ominous prognosis. ECG evidence of LVH (ECG-LVH) is present in about 3% to 8% of hypertensive individuals.[113] When ECG-LVH is identified, clinical manifestations of CVD occur at a rate that is about threefold higher than that in the general population. Moreover, the risks of stroke and HF associated with ECG-LVH are actually greater than those following the appearance of ECG changes of MI. Data from the Framingham population[114] illustrate this strong association between BP and LVH. In that cohort, effective antihypertensive drug treatment was associated with decreased prevalence of ECG-LVH. During the period from 1959 to 1989, antihypertensive drug use increased from 2.3% to 24.6% among men and 5.7% to 27.7% among women. As antihypertensive treatment became more prevalent, the age-adjusted prevalence of more severe hypertension (i.e., >160/100 mm Hg) decreased from 18.5% to 9.2% among men and from 28.8% to 7.7% among women. This reduction in BP was accompanied by an age-adjusted decrement in the prevalence of ECG-LVH (men: 4.5%–2.5%; women 3.6%–1.1%).
Echocardiography is a more sensitive measure of left ventricular (LV) mass.[113] Thus, about 12% to 30% of relatively unselected hypertensive adult patients will have echocardiographic increases in LV mass. LV mass index is more closely related to 24-hour ambulatory BP (ABP) than to casual office BP measurements, although increased daytime pulse pressure and office BP are associated with increased prevalence of LVH. [115] [116] Treated hypertensive subjects in whom ABP is higher than predicted from office BP are more likely to develop LVH.[117] Moreover, there is a significant association between the prevalence of hypertensive target organ damage (e.g., LVH) and the magnitude difference in casual and ambulatory BP, referred to as a white coat effect. [118] [119]
Echocardiographic LVH is a powerful predictor of morbidity and mortality in hypertensive patients.[120] In a study of patients with initially uncomplicated essential hypertension, LV mass index greater than 125 g/m2 strongly predicted all-cause mortality and cardiac death.[121] Compared with hypertensives with normal LV geometry, those with concentric LVH (increased LV mass and relative wall thickness) had about 10-fold greater total mortality and about 5-fold higher rate of cardiovascular events. Subsequent modifications in the criteria for LVH have been established (LV mass/body surface area >116 (men), >104 (women) g/m2). Other methods for LV indexation to identify LVH have been proposed.[121a]
Higher peripheral resistance results in LVH by increasing systemic BP and LV systolic pressure.[122] The predominant stimulus to myocyte hypertrophy is systolic LV wall stress, which is increased when BP is elevated, leading to a corresponding increase in LV mass. High peripheral vascular resistance may be accompanied by a reduced stroke volume, reduced LV chamber volume, and thus, elevated relative wall thickness. Several mechanisms may contribute to this increased cardiovascular risk, including increased total myocardial oxygen demand of the hypertrophied ventricle and induction of electrophysiologic abnormalities that may predispose to arrhythmias. Aldosterone excess appears to participate in the pathogenesis of LVH, as LV mass index was significantly greater in subjects with either primary aldosteronism or renovascular hypertension than in those with essential hypertension. [124] [125]
Hypertensive black individuals are at greater risk for ESRD, HF, coronary artery disease, and stroke than their white counterparts. [1] [123] However, the degree to which race may influence LV structure in hypertensive individuals is not well established. In a study of black and white hypertensive participants free of valvular or coronary disease, both LV mass and relative wall thickness were higher in blacks than in whites after controlling for clinical and hemodynamic parameters.[122] In that study, the risk of having LVH, whether indexed by height or by body surface area, was almost twice as high for blacks as for whites. Early concentric remodeling of the left ventricle in black patients may be partly mediated by hemodynamic influences, including a greater peripheral vascular resistance and a smaller nocturnal decline in BP.[125] In addition, in Afro-Caribbean but not in white subjects, LV mass index was independently correlated with plasma aldosterone, although the mean renin level was lower than in whites.[126] The increase in the ratio of plasma aldosterone to plasma renin activity (PRA) suggests that aldosterone production was less dependent on renin in the black hypertensive patients.[124] A role for Na-volume mediated hypertension is supported by the finding that LV mass has also been positively correlated with urinary Na excretion, a marker of Na intake.[127]
There is evidence that inappropriately high LV mass is associated with relevant LV abnormalities independent of the traditional definition of LV hypertrophy (i.e., LV mass index >116 g/m2 in men and >104 g/m2 in women). Inappropriately high LV mass was independently associated with indices of reduced systolic and diastolic myocardial function apart from LV hypertrophy and other covariates.[128] These findings suggest that there is a continuous relationship between LV mass and abnormalities of cardiac function in hypertensive individuals.
Heart Failure.
Hypertension is the most common condition antedating HF, with a two- to threefold higher risk than for normotensive subjects and with a graded increase in risk at higher pressure. [130] [131] In the Framingham population,[129] more than 90% of patients with symptomatic HF had a history of hypertension. Systolic, diastolic, and pulse pressures were related to the risk of HF in the Framingham cohort,[130] but the relation was strongest for systolic and pulse pressures. This risk is amplified further when ECG-LVH or echo-LVH are present (see earlier). Although MI is a principal cause of systolic dysfunction, fewer than half of hypertensive patients in the Framingham cohort had a history of MI. Therefore, diastolic dysfunction may have played an important role in the pathogenesis of HF in that hypertensive population.
Treatment of hypertension decreases the risk of HF, with an approximately 50% reduction in the occurrence of HF in hypertensive patients who received medication compared with those who received placebo. [131] [132]
Plasma Renin Activity.
Several lines of evidence suggest that excess activity of the renin system plays an important role in the pathogenesis of CVD: (1) Angiotensin II (Ang II) infusion causes MI in experimental animal models,[132] (2) drugs that block renin secretion (b-blockers), Ang II formation (ACE inhibitors), or Ang II binding (type 1 Ang II receptor [AT1] blockers) decrease the risk of CVD and stroke in hypertensive individuals and prevent myocardial reinfarction and prolong survival in patients with CHD and HF, [87] [134] [135] [136] and (3) the risks of MI and stroke in hypertensive patients were greater in those with medium or high plasma renin levels than in those with a low renin level.[135]Alderman and colleagues[136] measured the pretreatment PRA level in more than 1700 patients with mild hypertension and then followed them during antihypertensive treatment for approximately 8 years. Despite the comparable level of BP control in the high-, medium-, and low-renin groups, there was a greater incidence of MI in patients with medium or high pretreatment renin levels ( Fig. 42-4 ). This association of cardiovascular risk and a high PRA was especially striking in those without other cardiovascular risk factors—an MI was seven times more likely to occur with a high PRA level than with a normal or low pretreatment PRA level. In fact, when all other cardiovascular risk factors were absent, no MI occurred in patients with low PRA levels.[136] Thus, there is a strong independent association between PRA and the incidence of MI in hypertensive patients.
|
|
|
|
|
|
|
FIGURE 42-4 Association between plasma renin activity (PRA) level and future myocardial infarction in patients with mild hypertension. The incidence of myocardial infarction is related to baseline, pretreatment PRA among 1717 patients with mild hypertension. Back row represents the 997 patients who had one or more known cardiac risk factors (hypercholesterolemia, diabetes, cigarette use). Front row indicates heart attack rates for patients with no known risk factors. Plasma renin level, prior to antihypertensive treatment, is a powerful, continuous risk factor that increased the heart attack rate by more than threefold among those who had other risk factors, and by more than sevenfold among those without other risk factors. No heart attacks occurred in 241 patients with low renin levels, suggesting that renin is a continuous variable. These data are further supported by animal studies describing myocardial, cerebral, and renal lesions after injection of renin or angiotensin. (From Alderman MH, Madhavan S, Ooi WL, et al: Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension [see comments]. N Engl J Med 324:1098–1104, 1991.) |
|
This association between PRA and MI was confirmed and extended in a study of both normotensive and hypertensive patients evaluated in an emergency department for suspected MI.[137] The mean PRA level was threefold higher in patients found to have an MI compared with those in whom MI was ruled out. Furthermore, there was a strong association between PRA and MI that was independent of other cardiac risk factors and medication use. Altogether, this evidence suggests a causal role for excess renin system activity in the pathogenesis of MI.
The distribution of PRA levels is very wide among hypertensive patients.[138] A high-renin patient is more likely to be young, non-African American, and male, whereas a low-renin patient is more likely to be African American. However, the magnitude of these differences is relatively small and does not provide the means to predict renin status by demographic characteristics. Moreover, diabetic hypertensive patients have a distribution of PRA that is indistinguishable from the hypertensive patients overall, with 30% of diabetic hypertensive patients in the low-renin category.[138] Contrary to the common belief that older hypertensive patients have low PRA, the majority (60%) of patients aged 55 years have medium renin, 8.4% have high renin, and 31.5% had low renin status, similar to the levels in the general hypertensive population. [137] [140] These observations are especially relevant for antihypertensive drug selection, considering the efficacy of drugs that interrupt the renin system (e.g., ACE inhibitors and type 1 angiotensin II receptor antagonists) for the treatment of diabetic nephropathy and hypertensive CVD.[87]
Stroke
Stroke is the third most common cause of death in the United States and is the most feared and devastating complication of hypertension. Hypertension is characterized by microaneursyms, lipohyalinosis, and fibrinoid necrosis of the penetrating arteries that supply the basal ganglia, cerebral deep white matter, and pons.[139] In the Systolic Hyperten-sion in the Elderly Program (SHEP) and other sources, ischemic strokes predominate in hypertensive individuals, accounting for 80% of all strokes, followed by the hemorrhagic type. [108] [141]
There is a direct, graded, positive association between BP and stroke risk, down to at least 115 mm Hg systolic BP and 75 mm Hg diastolic BP, below which there is little evidence. [89] [142] In the Framingham study,[140] definite hypertension (≤160/95 mm Hg) was associated with a 2.5-fold higher relative risk of stroke, after adjustment for other known cardiac risk factors. A study of more than 12,000 European hypertensive patients found that BP control rates were poor and that the 10-year risk of stroke (>20%) was predicted in more than 50% of those not treated with an antihypertensive medication and 25% of those who were treated.[7]
Chronic Kidney Disease
Hypertension is both a consequence and a cause of CKD. [143] [144] It is estimated that 3% of the U.S. adult population has an elevated serum creatinine level and that 70% are hypertensive.[142] Data from NHANES III[142] showed that the prevalence of hypertension is reciprocally related to glomerular filtration rate (GFR), with stage 1 or higher hypertension occurring in approximately 75% of those with GFR less than 30 mL/min/1.73 m2 ( Fig. 42-5 ). As in the general population, BP control rates are low in CKD. Although 75% of individuals in NHANES III[142] with decreased kidney function received treatment, only 11% with both hypertension and elevated serum creatinine had BP less than 130/85 mm Hg and only 27% had BP less than 140/90 mm Hg. Risk factors associated with the presence of hypertension in CKD patients include GFR, BMI, black race, increasing age, male gender, diabetes, hypertriglyceridemia, and proteinuria. [143] [145]
|
|
|
|
|
|
|
FIGURE 42-5 Prevalence of high blood pressure by level of glomerular filtration rate (GFR), adjusted to age 60 years in NHANES III. GFR was estimated using the abbreviated Modification of Diet in Renal Disease (MDRD) Study equation. Hypertension was defined as Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC) stage 1 or 2. 95% confidence intervals are shown at selective levels of estimated GFR. (From National Kidney Foundation: K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease. Am J Kidney Dis 43:S1–S290, 2004.) |
|
CKD is associated with an increased risk of CVD, and as in the general population, cardiovascular complications cause 40% to 50% of deaths in those with CKD. [144] [146] The magnitude of this problem is underscored in the dialysis population, in whom the risk of CVD mortality is 50 to 500 times higher than in age-matched individuals in the general population. This led to the National Kidney Foundation Task Force on Cardiovascular Disease in Chronic Renal Failure to conclude that CKD is the “highest risk group” for CVD events.[145] Several factors contribute to this increased risk. Traditional cardiovascular risk factors are highly prevalent in this population.[146] In addition, both reduced GFR and albuminuria are associated with CVD outcomes in CKD.[142] Although the relative contribution of each of these CVD risk factors is not well defined in CKD, hypertension plays an important role because it contributes to the progression of both CKD and CVD.
Microalbuminuria
Microalbuminuria, defined as urinary albumin excretion between 30 and 299 mg/mg creatinine, is the earliest sign of nephropathy.[146a] It occurs in approximately 6% to 40% of individuals with primary hypertension, with the prevalence increasing with age and duration of hypertension. [150] [151] After adjustment for other factors in a longitudinal study of more than 4500 American Indians, microalbuminuria was associated with a significantly greater risk of developing hypertension.[149] Microalbuminuria is a well-defined marker for increased risk of CVD in patients with diabetes (see Chapter 36 ). However, large-scale, prospective studies in general populations have also found that microalbuminuria is associated with all-cause mortality and that this relationships extends to urinary albumin excretion rates that are in the normal range. [151] [153] [154] Moreover, in a study of more than 11,000 nondiabetic individuals with hypertension, the presence of microalbuminuria was associated with a significantly higher prevalence of LVH, coronary artery disease, MI, hyperlipidemia, and peripheral vascular disease.[152] These findings relating albumin excretion with adverse outcomes in nondiabetic subjects have been reported in other large-population studies. [151] [156]
There is a link between hypertensive heart disease and changes in the glomerular hemodynamic profile in primary hypertension. Patients with essential hypertension and LVH reportedly have higher GFR and filtration fraction than those without ventricular hypertrophy.[154] Although albumin excretion was not measured in that study, these findings suggest that glomerular hyperfiltration in patients with hypertension is related to cardiac remodeling and, perhaps, more generalized vascular adaptation. In the Losartan Intervention for Endpoint study (LIFE), a large prospective study of patients with hypertension, ECG-LVH, and plasma creatinine below 1.9 mg/dL, microalbuminuria was found in 23% and macroalbuminuria was found in 4% of patients.[155] It was less prevalent in white subjects (22%) than African American (35%), Asian (36%), or Hispanic subjects (37%). Excess albumin excretion was significantly more prevalent in diabetics than in nondiabetics, although the association between LV mass and albumin excretion was independent of coexisting diabetes, systolic BP, age, serum creatinine and race. Moreover, urinary albumin-to-creatinine ratio predicted cardiovascular complications and cardiovascular death independently of LV mass.[156]
Effective reduction in BP with antihypertensive medication can decrease the urinary excretion of albumin (see Chapters 36 and 54 ).[157] Although there is evidence that ACE inhibitors may be more effective in accomplishing this goal, this effect has been reported with several different classes of antihypertensive agents.[154] It has not been established whether the treatment-related reduction in albumin excretion, per se, is associated with a decline in cardiovascular risk in patients with essential hypertension, or whether this change simply reflects the decline in BP.
Hypertension in the Dialysis Population
Hypertension is highly prevalent in the ESRD population, affecting approximately 60% to 85% of those on hemodialysis and 50% treated by PD in the United States. Several studies have shown that predialysis hypertension is indicative of hypertension during the interdialytic period and is associated with increased risk of death. [111] [161] CVDs are the most common cause of death in patients with ESRD, and within the 1st year of dialysis, 55% of nondiabetics with hypertension carry a diagnosis of CVD (see earlier and Chapter 48 ). Elevated BP in dialysis patients has been associated with LVH, HF, and ischemic heart disease.[159] High postdialysis systolic BP and diastolic BP are associated with an elevated mortality risk.[111] Moreover, the severity of cerebral atrophy is correlated with both predialytic BP values and the duration of hypertension in hemodialysis patients.[160]
Hypertension in the Renal Transplant Population
Post-transplantation hypertension is highly prevalent and is a significant predictor of reduced long-term graft survival and cardiovascular morbidity and mortality. [164] [165] [166] Data from 30,000 patients in the Collaborative Transplant Study, who underwent cadaveric renal transplantation from 1987 to 1995, showed that systolic and diastolic BPs at 1 year after transplantation were associated with an increased risk of graft failure during the following 6 years[161] ( Fig. 42-6 ). More than half of patients in that study had systolic BP over 140 mm Hg, indicative of the inadequate rate of BP control.
|
|
|
|
|
|
|
FIGURE 42-6 Relationship between systolic BP and graft survival. Association of systolic BP at end of year 1 with subsequent graft survival in recipients of cadaver kidney ransplants. Ranges of systolic BP values (mm Hg) and number of patients in the subgroups are indicated. The association of systolic BP with graft survival at year 7 was significant (P < .0001). (From Opelz G, Wujciak T, Ritz E: Association of chronic kidney graft failure with recipient blood pressure. Collaborative Transplant Study. Kidney Int 53:217–222, 1998.) |
|
A retrospective analysis of renal transplant recipients found that 44.5% had a systolic BP greater than 140 mm Hg.[164] Moreover, of the patients with a functioning allograft at 1 year, only 12.4% had normal BP, 36.3% had prehypertension, 34.2% had stage 1, and 17.1% had stage 2 hypertension by JNC7 criteria. Those with pretransplant bilateral nephrectomy had the lowest BP after transplantation. Remarkably, the rate of BP control was comparable during the period 1976 to 1992 when compared with the rate during 1993 to 2002, despite the marked increase in antihypertensive drug use during the latter period. As in the Collaborative Transplant Study, systolic BP was associated with graft failure, death-censored graft failure, and death, even after adjusting for acute rejection, estimated GFR, and other recipient, donor, and transplantation variables.[164] However, mean arterial pressure (MAP) was the BP variable most closely related to graft outcomes. This adverse, independent impact of BP on graft failure was found to precede the graft failure by at least 5 years.
The predictive value of BP on cadaveric allograft failure has been confirmed by others.[165] For each 10 mm Hg increment in systolic, diastolic, and MAP, there were reductions of 15%, 27%, and 30%, respectively, in the rate of allograft survival. No relationship was detected between allograft survival and exposure to ACE inhibitor or calcium channel blocker treatment within 3 to 12 months after transplantation.
Although hypertension has a negative impact on post-transplant renal allograft survival and patient morbidity and mortality, effective BP control during the post-transplant period reduced the risk for these adverse outcomes. In the Collaborative Transplant Study, 24,000 cadaver transplant recipients who had a systolic BP greater than 140 mm Hg at 1 year post-transplantation and that decreased to 140 mm Hg or less by year 3 had significantly improved graft and patient survival rates when compared with those with sustained elevations in BP. [165] [166]
Natural History of Untreated Essential Hypertension
In the 1950s, Perera[166] observed 500 untreated patients, 150 from before the onset of their hypertension until their death and another 350 from the uncomplicated phase until their death. The mean survival of these patients after discovery of their hypertension was 20 years. The height of the casually obtained BP had little prognostic value. Some patients with readings above 200 mm Hg systolic survived untreated for more than 35 years. The disease process included an uncomplicated phase lasting about 15 years followed by a phase in which organ complications, largely arteriolosclerotic and atherosclerotic, became apparent. Of these complications, 74% were cardiac, 42% were renal, and 32% were retinal. More than half the subjects died of heart disease (principally CHF), 10% to 15% died of cerebral accidents, and about 10% died of renal failure. Malignant hypertension occurred in fewer than 5% of these patients.
Benefits and Limitations of Treatment
The Veterans Administration Cooperative Trial of the 1960s was the first major American effort to evaluate the impact of antihypertensive therapy in a group of patients with essential hypertension. [23] [24] Compliant veterans were randomly assigned to placebo or medication, and treatment was rapidly found to result in great improvement of cardiovascular morbidity and mortality in patients with diastolic BPs of 115 to 129 mm Hg. A statistically favorable outcome was shown after 3.3 years of follow-up in the treated group in whom diastolic BP was between 105 and 115 mm Hg. The benefit was manifested by a reduced frequency of strokes, CHF, and dissection of the aorta but not of ischemic cardiac events. The benefits of treating patients with moderate to severe hypertension were thus clearly shown.
No benefit was achieved, however, among the patients with diastolic BP below 105 mm Hg. Furthermore, the major benefit in the group with diastolic BPs between 105 and 115 mm Hg was realized by those patients who had evidence of preexisting CVD on entering the study or who were 50 years of age or older. Among patients who had no preexisting end-organ disease or who were younger than 50 years, no difference in benefit was found between the treated and the untreated groups.
One of the first attempts to address some of the issues left unresolved by the original Veterans Administration study was undertaken by the U.S. Public Health Service Hospital Study Group.[167] Although the study was inconclusive—largely because it involved a small sample of subjects whose diastolic BP was below 104 mm Hg and who had shown no evidence of target organ disease—no difference in mortality rates were found between the two groups. Increased BP levels and LVH were evident in the untreated control subjects. The study's chief value was its demonstration that BP levels in a general population could be controlled.
The benefits of treatment were studied in the early 1970s by the National Institutes of Health[168] in a far broader population (approximately 11,000 subjects screened from 158,000 in 14 communities), which included women and a higher proportion of asymptomatic patients. In this Hypertension Detection and Follow-up Program (HDFP) study, patients were randomly allocated to “stepped-care” intervention or to “referred care.” The stepped-care group received drug treatment without cost, whereas patients in the referred group were simply referred to their own physicians. Diastolic BP was substantially reduced in both groups but to a significantly greater degree, with a difference of 5 mm Hg, in the stepped-care group. Because the study did not control for such factors as compliance, distinguishing the benefits of the nature and quality of medical care from the benefits of specific pharmacologic therapy is difficult. The fact that the stepped-care group had a 17% reduction in mortality from all causes (e.g., a significant reduction in cancer mortality was found) supports the notion that aspects of care other than antihypertensive treatment, such as consistent, enthusiastic, and cost-defrayed general care, may have contributed to the observed outcome. Death rates in both groups were extremely low and the incremental gain realized by intervention was limited. One reason for these results may have been that most subjects had only mild (90–104 mm Hg diastolic) hypertension.
Based on the reduction in mortality achieved by antihypertensive treatment in patients with malignant hypertension and in severe diastolic hypertension, several randomized controlled treatment trials were performed during the past 4 decades to assess the efficacy of treatment in patients with more modestly elevated BP. Until the late 1980s, entry criteria included diastolic rather than systolic BP, reflecting the perceptions of cardiovascular risk at that time. Diuretics and β-blockers were the primary drugs tested, and most studies done before the mid-1980s used high doses of diuretics.[169] Moreover, patients enrolled in those studies were younger, approximately 50 to 60 years old. In a metaanalysis of 18 antihypertensive treatment trials including over 48,000 patients with follow-up averaging 5 years, Psaty and associates[170] analyzed separately the controlled trials that involved high-dose diuretics (≤50 mg hydrochlorothiazide) from those in which lower doses were used. Whereas stroke protection occurred regardless of the drug doses used, risk of CHD was not decreased by high doses of diuretics and β-blockers.
The clinical impact of diuretic-induced hypokalemia on CHD and stroke risk was highlighted in a recent analysis of data from the SHEP study. After 1 year of treatment with a low-dose diuretic, patients randomized to active treatment were more likely to be hypokalemic (serum K < 3.5 mEq/L) than those randomized to placebo (7.2% vs, 1.0%; P < .01). After adjustment for known risk factors, those who received active treatment and who experienced hypokalemia had a similar risk of cardiovascular events, coronary events, and stroke as those randomized to placebo. By contrast, for those in the active treatment group who had normal serum K levels, the risk of these events was 51%, 55%, and 72% lower, respectively, among those who had normal serum potassium levels compared with those who experienced hypokalemia. Although renin-angiotensin-aldosterone system (RAAS) activity was not measured in this study, diuretic stimulation of aldosterone often occurs during diuretic therapy[171] (see later).
Since 1985, several large, randomized, placebo-controlled treatment trials have been performed in elderly patients with isolated systolic hypertension. A meta-analysis of more than 15,000 patients found that antihypertensive treatment (mean BP 10.4/4.1 mm Hg) predominantly with diuretics and β-blockers, significantly reduced all-cause (13%) and cardiovascular (18%) mortality during a 3.8-year follow-up[172] Furthermore, there were significant reductions in cardiovascular morbidity (23%) and stroke (28%) when compared with placebo. These benefits were greater in male patients with higher baseline risk status, such as prior cardiovascular complications. Accordingly, to prevent one cardiovascular event, treatment for 5 years would be required in the following: 18 men versus 38 women; 19 patients age 79 versus 39 patients age 60 to 69; 16 patients with prior cardiovascular complications versus 37 patients without. In a more recent meta-analysis of treatment trials encompassing 80,000 patients, prevention of coronary heart disease was attributed primarily to the reduction in systolic BP and to ACE inhibitor use, whereas prevention of stroke was most closely associated with systolic BP reduction and calcium channel blocker use.[173]
Left Ventricular Hypertrophy
Regression of echocardiographic LVH has been reported during treatment with several classes of antihypertensive medication. In a randomized controlled trial, ACE inhibitor treatment with ramipril reduced LV mass to a greater extent than hydrochlorothiazide, even though 24-hour ABP was reduced to a lower level during diuretic treatment.[174] In that study, plasma Ang II decreased to undetectable levels during ramipril treatment but increased with hydrochlorothiazide. The dissociation of BP reduction from this marker of hypertensive heart disease (i.e., LV mass) during diuretic therapy may represent a pathophysiologic mechanism for the well-recognized limited reduction in cardiovascular risk during diuretic treatment.[175] This finding suggests that, in addition to the absolute level of BP, Ang II is also a determinant of LV geometry.[174] These results support the finding of an earlier meta-analysis that specific drug class was an important determinant of the extent of LV regression (ACE inhibitor > β-blockers = calcium channel blockers = diuretics[154]). Moreover, results of the Heart Outcomes Prevention Evaluation Study (HOPE), in which high-risk patients were randomized to treatment with ramipril or placebo, showed that ramipril decreases the development of ECG-LVH and causes its regression. These changes were independent of BP and were associated with reduced risk of death, MI, and CHF.[176]
These findings suggest that Ang II is important in the pathogenesis of LVH and related cardiovascular complications. This hypothesis was tested in the LIFE study (see earlier).[87] Compared with atenolol, losartan treatment was associated with a significant (13%) reduction in the primary composite end point (death, MI, or stroke), attributable to a 25% relative risk reduction for stroke. In that study, sustained BP reduction with either atenolol or losartan caused decrements in echocardiographic LV mass index, with the proportion of subjects with normal LV mass index increasing to 45% after the 1st year of treatment and to 68% after 5 years.[177] Antihypertensive treatment with losartan, plus hydrochlorothiazide and other medications when needed for BP control, resulted in greater LVH regression than conventional atenolol-based treatment.[178] Individuals without LVH during treatment were 42% less likely to have cardiovascular complications that those with persistent LVH. The LIFE study [180] [182] also found that lower ECG measures of LVH were associated with reduced rates of morbidity and mortality in the entire LIFE population. Thus, concordant findings with two different determinants of LV mass indicate that regression or prevention of LVH during antihypertensive therapy, compared with persistence or development of hypertrophy, is associated with a reduced rate of major cardiovascular events. These findings are consistent with results of the HOPE trial, which found that an ACE inhibitor also protects against stroke, after adjusting for BP, in high-risk patients.[180]
Heart Failure
Median survival after the diagnosis of HF in the Framingham cohort[129] was 1.4 years in men and 2.5 years in women. Reports from controlled treatment trials indicate that survival is prolonged by drugs that interrupt renin system activity, including ACE inhibitors and AT1 blockers, β-blockers and mineralocorticoid receptor antagonists. [184] [185] [186] [187] [188] Moreover, patients with the highest pretreatment levels of Ang II are most likely to derive benefits in ventricular function, functional class, and prolonged survival during treatment with an ACE inhibitor.[186]
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT: see Limitations of Antihypertensive Drug Treatment Trials, below), a randomized, double-blind active-controlled clinical trial, reported that hypertensive patients with at least one other cardiovascular risk factor, when treated with doxazosin (an α1-adrenergic receptor blocker), were twice as likely to develop HF (8.13% vs. 4.45%) than patients treated with chlorthalidone.[187] There was no difference in the primary outcome, fatal or nonfatal MI. Several factors make it difficult to judge whether the CHF rate in the doxazosin group was different than expected in an untreated, comparable group of hypertensive patients, including: (1) absence of a placebo control group, (2) greater adherence to drug treatment in the chlorthalidone group, and (3) slightly higher mean systolic pressure (2–3 mm Hg) in the doxazosin group.
Previous studies lend support to the view that α1-adrenergic receptor blockade may not reduce the risk of CHF. In the Treatment of Mild Hypertension Study, LV mass was reduced in the chlorthalidone group but not in the doxazosin group.[188] In patients with preexisting HF, mortality benefit for combination therapy was reported with isosorbide-dinitrate and hydralazine but not for prazosin, an α1-receptor blocker.[189] However, based upon data from the SHEP trial, a 3-mm Hg systolic BP could account for a 10% to 20% increase in CHF risk but is unlikely to explain the doubling of this risk that occurred in ALLHAT.[190]
Ischemic Stroke
BP rises during acute stroke in previously treated hypertensive and even in previously normotensive patients.[191] When left untreated during an ischemic stroke, BP decreases to baseline level within 1 to 4 days. By contrast, during intracerebral hemorrhage, BP tends to increase to a higher level and does not usually decline as predictably as in ischemic stroke. Data from a stroke registry, which included more than 2000 patients, showed that a U-shaped relationship occurred between admission BP levels (both systolic and diastolic BP) and mortality rate within 30 days in ischemic stroke patients.[192] The poorest outcomes occurred in patients at the lowest BP level (systolic BP < 130 mm Hg or diastolic BP < 70 mm Hg). For patients with brain hemorrhage, there was a J-shaped relationship between BP and mortality, with the poorest outcomes in those with the highest BP.[192] In that study, the BP range associated with the most favorable prognosis was systolic 150 to 169 mm Hg and diastolic 100 to 110 mm Hg, which is comparable with that reported by the International Stroke Trial that included data on more than 17,000 patients.[196] [197] A J-shaped relationship was also identified between diastolic BP and the incidence of stroke in treated hypertensive patients participating in the Rotterdam Study,[194] a prospective population-based cohort study. The adjusted stroke risk increased at diastolic BP levels below 65 mm Hg when compared with a reference range 65 to 74 mm Hg. This observation persisted after patients with isolated systolic hypertension were excluded from the analysis. By contrast, in patients untreated for hypertension, there was a continuous increase in stroke incidence with increasing systolic and diastolic BP.
A study of hypertensive patients who were otherwise healthy found that autoregulation of cerebral blood flow is reset to a higher level.[195] This has led to the questionable recommendation that MAP can be safely lowered by 25% with antihypertensive drug treatment within the first 24 hours of onset of an acute ischemic stroke.[196] To the contrary, cerebral autoregulation is disrupted during acute ischemic stroke and marked decrements in cerebral blood flow can occur with reductions in BP of that magnitude. [201] [202]
Although severe hypertension during an ischemic stroke has been reported to auger a poor prognosis, there is no convincing evidence to support the acute pharmacologic reduction in BP in this setting. [197] [201] [203] [204] [205] In a study of ischemic stroke patients in a community hospital, two thirds were treated with an antihypertensive medication—within the first 2 days after hospitalization, more than 40% had their regimen intensified and about one third had drug treatment initiated.[202] In that study, relative hypotension (systolic < 120 or MAP < 85 mm Hg) occurred on the days of treatment in about 60% who had their antihypertensive treatment either intensi fied or newly initiated. Moreover, 75% of untreated patients had at least one episode of relative hypotension.
Randomized, controlled clinical trials indicate that antihypertensive drug treatment during an ischemic stroke does not improve clinical outcome and, in fact, may worsen it. For example, a large (N = 624), randomized, placebo-controlled trial of treatment with antihypertensive medication (i.e., labetalol, nitroprusside) and recombinant tissue plasminogen activator (rt-PA) during ischemic stroke evaluated the potentially greater risk of intracerebral hemorrhage in hypertensive stroke patients.[200] The study found that, in hypertensive patients randomized to receive treatment with rt-PA, antihypertensive treatment after randomization was associated with a fourfold greater risk of death and chronic neurologic impairment when compared with rt-PA patients who did not receive antihypertensive medication after randomization. Furthermore, in patients who were randomized not to receive treatment with rt-PA, antihypertensive therapy after randomization provided no benefit in neurologic recovery or death rate. The rt-PA group treated with antihypertensive drugs was more likely to have a more abrupt decline in BP than those who were not treated with antihypertensive medication. The adverse impact of antihypertensive treatment could not be attributed to other patient characteristics (e.g., age, stroke severity, or severity of hypertension), which were similar in the rt-PA and non-rt-PA treatment groups. This important trial highlights that, during ischemic stroke: (1) There is no demonstrable benefit of antihyperten-sive treatment regardless of whether concurrent rt-PA is employed, and (2) concurrent treatment with rt-PA and antihypertensive medication appears to have a detrimental effect on clinical outcomes, including neurologic recovery and survival.[200]
Precipitous declines in BP during treatment with direct vasodilators (e.g., nitroprusside, nifedipine, hydralazine) may cause catastrophic consequences. This has led to the discontinuation of short-term calcium channel blockers, especially short-acting nifedipine, in this setting.[203]
Because acute antihypertensive treatment holds the potential for harm and is of unproven benefit, it should be avoided and BP should be allowed to decrease spontaneously during the first few days after an ischemic stroke. [142] [201]Antihypertensive treatment is indicated when a concurrent medical condition exists, such as acute aortic dissection or MI. A single target BP is unlikely to apply for all patients and will likely depend upon the extent of the stroke and the size of the penumbral zone. This pathophysiologic variability will undoubtedly complicate the management of patients with nonhemorrhagic strokes for whom thrombolytic therapy is being considered (see later).
Hemorrhagic Stroke
Hypertension occurs commonly in the early period following intracerebral hemorrhage. It is more severe and, in contrast to the BP elevation during ischemic stroke, is less likely to spontaneously improve during the first few days after presentation.[191]
Severe hypertension is a common feature of subarachnoid hemorrhage. [201] [208] Nimodipine, a dihydropyridine calcium channel blocker, significantly improves outcome in patients with subarachnoid hemorrhage. However, transient hypotension is a relatively common side effect of nimodipine, particularly when it is administered intravenously. [209] [210] Although the fall in BP usually responds to hydration, approximately 30% of patients also require treatment with vasoconstrictors (e.g., dopamine, phenylephrine, norepinephrine) to reverse its vasodilating effect. These offsetting therapeutic strategies have unpredictable consequences, particularly now that surgery for ruptured aneurysms is done in older patients with concomitant coronary artery disease.[205]
Treatment with a dihydropyridine calcium channel blocker during the early period after intracerebral or subarachnoid hemorrhage has a significant effect on cerebral hemodynamics.[207] Within 30 minutes after a single dose of short-acting nifedipine, MAP falls by 20%, mean intracerebral pressure rises by 40%, and consequently, cerebral perfusion pressure falls by 40%. Patients with higher pretreatment intracerebral pressures (i.e., ≤40 mm Hg) have more marked reductions in cerebral perfusion pressure. This means that nifedipine promotes cerebral edema, reduction in cerebral perfusion pressure and, hence, impairs autoregulation of cerebral blood flow.[207] However, the long-term clinical impact of these results cannot be interpreted fully because the neurologic outcomes of these patients were not reported.
The adverse hemodynamic responses of dihydropyridine calcium channel blockers may account for their limited therapeutic efficacy reported in some treatment trials. For example, The Cooperative Aneurysm study, a large (N = 906), randomized, controlled trial in patients with aneursymal subarachnoid hemorrhage compared high-dose intravenous nicardipine with a control group treated with volume expansion. In that study, hypotension occurred twice as frequently in the nicardipine group (34.5% vs. 17.5%).[208] Overall neurologic outcome and survival were similar in these two groups at 3-month follow-up, even though the incidence of symptomatic vasospasm was greater in the control group than in the nicardipine group.
In summary, data from these controlled studies of antihypertensive drug therapy on acute stroke are limited but useful when considering treatment options. The evidence indicates that, in ischemic stroke, BP spontaneously falls to prestroke levels within a few days.[191] There is no evidence from clinical trials to support the use of antihypertensive treatment during acute stroke in the absence of other concurrent disorders (e.g., aortic dissection, HF; see later). Moreover, data from laboratory and clinical studies strongly suggest that antihypertensive treatment may adversely affect cerebral autoregulation in acute stroke. In particular, dihydropyridine calcium channel blockers and other direct vasodilators promote inconsistent changes in cerebral hemodynamics that might be detrimental. Although the favorable effect of nimodipine in patients with acute subarachnoid hemorrhage has been established, treatment-induced hypotension may limit its efficacy.
White Coat and Masked Hypertension
There is significant variability in the measurement of BP. This is most apparent when casual BP is measured by the physician, in which differences may be as much as 25 mm Hg from one office visit to the next in healthy individuals.[209] Furthermore, for the majority of hypertensive subjects, the daytime ABP level is lower than the casual office BP level. This phenomenon, referred to as the white coat effect, can be reduced when multiple office BP measurements are obtained with a stationary oscillometric device over 15 to 20 minutes in a quiet environment.[17] Twenty-four-hour ABP monitoring is a method for identifying patients for whom casual office measurements are not representative of their BP levels during routine daily activities. This information has clinical relevance because ABP studies have provided prognostic information concerning CVD and stroke, after adjusting for other traditional cardiovascular risk factors. [214] [215] [216] [217] [218]
When measured by ABP monitoring, nighttime (asleep) BP usually drops by 10% or more from daytime (awake) BP, referred to as a dipping pattern.[17] A nondipping pattern, in which the reduction in BP from day to night is less than 10%, appears to be associated with an increased risk of BP-related complications. [215] [219] [220]
With ABP monitoring, it has become possible to characterize patients according to their BP levels, as follows:
White Coat Hypertension.
Approximately 15% to 20% of patient with stage 1 hypertension have BP elevations in the presence of a physician or other health care worker, but not during other activities including work.[17] When this occurs in patients not taking antihypertensive medication, it is referred to as white coat hypertension (WCH). The criteria for WCH are persistently elevated office BP greater than 140/90 mm Hg and an average awake BP less than 135/85 mm Hg. Active drug treatment reduces ABP and casual BP in patients with sustained hypertension, but only casual BP is lowered in those with nonsustained hypertension.[217]
Individuals with WCH are at lower risk of BP-related complications than are subjects with sustained BP elevations. [17] [221] [222] In a study of stage 1 hypertension at relatively low risk (i.e., without LVH, CVD, renal disease, or diabetes), those with WCH had a significantly lower risk of cardiovascular complications, despite less frequent and intensive drug therapy, than subjects with sustained hypertension.[120] In that study, the predictive value of WCH was not significantly different from normal BP. Moreover, individuals with resistant hypertension (i.e., high clinic BP and ABP despite antihypertensive drug treatment) were at higher risk of cardiovascular complications than were those with elevated clinic BP and normal ABP.[219] However, the issue of whether the risk of CVD in WCH exceeds that of nonhypertensive subjects is unresolved.
Masked Hypertension.
Approximately 5% to 10% of individuals are found by ABP or home BP monitoring to have BP that is normal during clinic visits but elevated at other times. This phenomenon has been referred to as isolated ambulatory hypertension or masked hypertension.[17] Several factors have been implicated in the pathogenesis of masked hypertension (e.g., cigarette smoking, coffee consumption, work stress, abnormal baroreflexes), although the mechanism is not clearly defined. [213] [223] Those with masked hypertension are at greater risk of target organ damage and cardiovascular complications than are subjects with normal clinic and ABP. [19] [223] [224] [225] [226] In addition, during antihypertensive treatment, patients with masked hypertension are at greater cardiovascular risk than are those with BP that is maintained within the normal range. [19] [223]
ABP monitoring can provide information that is useful for the diagnosis, risk stratification, and management of the hypertensive patient. However, it is not feasible for use in all patients and certainly not for repeated use in the individual patient. Similarly, repeated office BP measurements are limited by inconvenience and the white coat effect. The ideal BP measurement modality, or the best compromise between convenience and clinical relevance, has not been established. However, home BP devices are available that are accessible and accurate and provide information that may be useful for identifying patients at increased risk for BP-related complications.
PHYSIOLOGY OF BLOOD PRESSURE HOMEOSTASIS
Before proceeding with a discussion of the pathophysiology of hypertension, it is necessary to briefly review the factors that control BP homeostasis. BP is defined as
where BP = blood pressure, CO = cardiac output, HR = heart rate, SV = stroke volume, and TPR = total peripheral resistance.
Body volume varies directly with total body Na content because Na is the predominant extracellular solute that retains water within the extracellular space. One primary function of the kidneys is to regulate Na and water excretion, and consequently, they also provide a dominant role in the long-term control of BP. To achieve this goal, two important renal mechanisms are utilized. One mechanism regulates extracellular fluid volume by coupling increases or decreases in urinary excretion of salt and water, and the related changes in blood volume and cardiac output, to changes in renal perfusion pressure. This phenomenon has been referred to as pressure natriuresis. [227] [228] The second mechanism employs the RAAS, which directly controls peripheral vascular resistance and renal reabsorption of Na and water. Accordingly, the renin system normally functions as a long-term regulator of BP homeostasis. [73] [229]
Pressure Natriuresis
Pressure natriuresis is the increase in urinary excretion of Na and water that occurs when arterial pressure increases. As a consequence of this compensatory renal response, BP is maintained within the normal range.[223] For example, when an experimental animal is infused rapidly with approximately 40% of its own blood volume, cardiac output and urine output increase dramatically. However, only a minor increase in BP occurs because peripheral vascular resistance declines. The subsequent increase in urine flow restores blood volume to normal and so BP is reduced and urinary excretion then falls back to the baseline level. This feedback allows the kidney to regulate BP. Accordingly, the kidney functions as a servocontroller of arterial pressure and exhibits an infinite negative feedback gain for the long-term regulation of arterial pressure by adjusting blood volume.[226]
The quantitative characteristics of pressure natriuresis can be illustrated by examining the relationship between MAP and the relative intake and output of Na ( Fig. 42-7 ). The BP and urinary Na values are obtained after the experimental subject has eaten a diet containing a fixed level of Na for several days so that salt intake and excretion are equal. This situation is referred to as Na balance. One striking characteristic of the normal salt-loading renal function curve is that BP remains remarkably constant despite the wide range of Na intake, even in amounts exceeding 15 times above normal. This illustrates the capability of the renal-fluid volume mechanism for returning BP back to a normal level regardless of any initial deviation. Using a term applied to negative feedback systems, this characteristic is referred to as infinite gain. The kidney regulates the excretion of water and electrolytes through the tightly controlled balance of glomerular filtration, tubular reabsorption, and secretion. These processes are governed by biophysical characteristics such as transcapillary pressure gradients (see Chapter 3 ) and by a variety of hormones (see later) and locally acting vasoactive substances (see Chapter 10 ).
|
|
|
|
|
|
|
FIGURE 42-7 Pressure natriuresis relationship. BP is maintained at relatively constant level despite 15-fold changes in dietary Na intake. Renin-angiotensin dependency of BP normally occurs at low Na intake, whereas Na-volume dependency of BP occurs during high Na intake. These are salt-loading renal function curves in three dog models: (1) normal, (2) during angiotensin-converting enzyme (ACE) inhibitor treatment (SQ-14,225), and (3) during continuous infusion of angiotensin II. The numbers in parentheses represent the calculated levels of circulating angiotensin II, with 1.0 as the normal level. (From Guyton A, Hall J, Coleman T, et al: The dominant role of the kidneys in long-term arterial pressure regulation in normal and hypertensive states. In Laragh JH, Brenner BM (eds): Hypertension: Pathophysiology, Diagnosis, and Management, Vol 2. New York, Raven Press, 1995, pp 1311-1326.) |
|
Autoregulation of renal blood flow and GFR prevent increases in renal perfusion pressure from being transmitted to the glomerular or peritubular capillaries (see Chapter 3 ). Therefore, some of the mechanisms promoting pressure natriuresis appear to inhibit tubular reabsorption in the absence of an intrarenal hemodynamic signal.[227] This conclusion is supported by the observation that, in experimental models of acute and chronic hypertension, increments in urine flow and lithium clearance are associated with a redistribution of the apical proximal tubule Na+-H+ exchanger (NHE3) from the microvilli to endosomal stores.[228] A concurrent decrease in Na+,K+-ATPase activity occurs together with the internalization of apical NHE3.
Increments in renal interstitial hydrostatic pressure (RIHP) occur with elevated renal perfusion pressure, even in the absence of increased GFR and renal blood flow.[229] Pressure natriuresis can be attenuated, but not abolished, by preventing the rise in RIHP by renal decapsulation during increasing renal artery pressure.[230] Blood flow and pressure are not autoregulated in the renal medullary circulation of volume-expanded rats.[231] Vasa recta capillary pressure and RIHP increase, whereas pressure in peritubular capillaries in the renal cortex is unchanged. The rise in vasa recta capillary pressure leads to increased RIHP and, consequently, attenuates reabsorption of medullary tubular fluid. Other factors contribute to the pressure natriuresis phenomenon, including the effect of high medullary pressure and flow to wash out the medullary solute gradient, although these effects may be modest. [230] [236]
In addition to these biophysical factors, it clear that several endocrine and paracrine factors contribute to the pressure natriuresis phenomenon and, hence, to the regulation of BP.
Renin-Angiotensin-Aldosterone System
The ability to maintain normal BP at Na intakes ranging from levels well below to those far above normal is a direct effect of the circulating levels of renin-Ang II. The kidneys secrete the enzyme renin from the juxtaglomerular cells in response to a variety of normal or abnormal phenomena that reduce arterial BP, renal perfusion, or Na chloride load to the macula densa (MD).[73] These include changes in posture or effective circulating fluid volume (i.e., Na depletion, hemorrhage, HF, nephrotic syndrome, cirrhosis). Baroreceptors in the afferent arterioles, chloride-sensitive receptors in the MD and juxtaglomerular apparatus, and efferent renal sympathetic nerve activity all participate in this feedback control. [237] [238] In this way, circulating renin levels are tightly regulated and subject to constant physiologic adjustment. [239] [240] [241] [242]
Cellular transduction mechanisms have been identified for these physiologic stimuli.[239] Inhibition of renin secretion in response to an increase in NaCl at the MD requires adenosine 1 receptors (A1AR) and therefore appears to be adenosine-dependent.[240] Moreover, A1AR mediate the inhibition of renin secretion by an increase in renal perfusion pressure, suggesting that formation and action of adenosine are responsible for baroreceptor-mediated inhibition of renin release.[241] In contrast, the stimulation of the renin system by a low BP appears to follow different pathways. Cyclooxygenase-2 and neuronal nitric oxide (NO) synthase (NOS) both participate in regulation of renin secretion, and in their absence, renin secretion is suppressed. [246] [247]
Renin is an aspartyl protease that is synthesized in the juxtaglomerular cell as prorenin, its inactive proenzyme, which contains an additional 43-amino acid N-terminal fragment. Prorenin is converted to renin by cleavage of this prosegment by a proconvertase exclusively within the juxtaglomerular cell.[244] The kidney secretes renin into the peripheral circulation and, thus, it has characteristics of both an enzyme and a hormone.[225] The half-life of renin in the circulation is about 15-20 minutes, with its metabolism occurring primarily in the liver. The rate of disappearance from the blood after bilateral nephrectomy suggusts a longer half-life, reflecting the accumulation of renin in extravascular fluids. Clearance of renin can also be delayed when hepatic function is impaired. Under normal circumstances, changes in the biosynthesis and renal secretion of renin are the primary determinants of plasma Ang II formation. Thus, renin secretion is the rate-limiting step in the regulation of the renin-angiotensin system[225] ( Fig. 42-8 ). Renin cleaves the inactive decapeptide, Ang I, from angiotensinogen (renin substrate). Ang I is then converted to the octapeptide, Ang II by ACE, located on the endothelial surface and in the circulation.
|
|
|
|
|
|
|
FIGURE 42-8 Regulation of the renin-angiotensin-aldosterone system. Renin, secreted in response to reduced arterial pressure or reduced renal tubule Na+, cleaves angiotensin I from circulating angiotensinogen (renin substrate). ACE then converts angiotensin I to angiotensin II. Angiotensin II raises pressure, by direct arteriolar vasoconstriction, and stimulates adrenal aldosterone secretion; together, aldosterone and angiotensin II cause renal Na+ retention. The resultant fluid accumulation leads to improved flow. These pressure and volume effects in turn lead to suppression of renin release. Dashed line indicates negative feedback. (From Laragh JH, Letcher RL, Pickering TG: Renin profiling for modern diagnosis and treatment of hypertension. JAMA 241:151–156, 1979. Copyright 1979, American Medical Association.) |
|
Prorenin is secreted constitutively by the juxtaglomerular cell, maintaining plasma levels that are approximately 10-fold higher than those of renin. Although prorenin is secreted by the kidney and is also synthesized by extrarenal tissues, PRA is undetectable following bilateral nephrectomy.[73] Moreover, during infusion of recombinant prorenin in cynomolgous monkeys, conversion of prorenin to renin was not observed.[244a] These findings, together with a lack of evidence of renin synthesis by other organs, lead to the conclusion that renin of renal origin determines the plasma renin level.[244b] However, Nguyen et al have identified a 350-amino acid protein with a single transmembrane domain located on mesangial and vascular smooth muscle cells that binds both prorenin and renin with equal affinity. [248] [251] This (pro)renin receptor promotes: (i) nonproteolytic activation of prorenin due to a conformational change of prorenin without cleavage of the prosegment, facilitating catalytic activity and the conversion of angiotensinogen to Ang I, (ii) a 5-fold increase in the catalytic efficiency of angiotensinogen conversion to Ang I by renin bound to the receptor compared with renin in the soluble phase, and (iii) rapid activation of ERK1/2 and transforming growth factor beta (TGFb-1) via an Ang II-independent pathway.[244] An 8.9 kDa fragment of the (pro)renin receptor, referred to as M8-9, co-precipitates with a vacuolar proton-ATPase (V-ATPase).[244d] V-ATPases participate in acidification of intracellular compartments and provide a potential link to the previously described property of nonproteolytic acid activation of prorenin.
Ichihara et al found that infusion of a decoy peptide, which mimics the pentameric handle-region of prorenin, prevented prorenin binding to its receptor and normalized Ang I and Ang II levels in the kidneys of a hypertensive rat model (stroke-prone SHR [SHRsp]) without lowering blood pressure or circulating levels of these hormones.[244e] Moreover, the development and progression of proteinuria and glomerulosclerosis were attenuated in that model. If confirmed, these findings would have substantial implications for our understanding of the biology of the renin system and the pathophysiology and treatment of diseases associated with excess renin system activity.
Ang II is the first effector hormone of the system. It increases BP in several different ways, each of which is mediated by the AT1. First, it exerts powerful, direct, and immediate vasoconstriction and, thus, increases peripheral vascular resistance. [73] [254] [255] [256] Second, it rapidly stimulates Na reabsorption via NHE3 at the proximal nephron and by NHE3 and bumetanide-sensitive cotransporter 1 (BSC-1) at the medullary thick ascending limb that are inhibitable by ACE inhibitors and Ang II receptor blockers [257] [258] [259] (see Chapters 6 , 10 , and 12 ). Third, and at a slower pace, Ang II stimulates aldosterone biosynthesis and secretion by the adrenal zona glomerulosa. The regulation of aldosterone secretion occurs in two distinct phases. In an initial, rapid phase the increased release of aldosterone reflects the increased transfer of cholesterol to the mitochondria, where it is acted upon in the inner mitochondrial membrane by the cytochrome P-450 (CYP) side chain cleavage.[251] This transfer is mediated by the steroidogenic acute regulator (StAR) protein. Subsequently, Ang II stimulates an increase in transcription and expression of the rate-limiting enzyme in the biosynthesis of aldosterone, CYP aldosterone synthase.[252] Ang II receptors in the glomerulosa cell surface activate intracellular signaling pathways (mainly Ca2-/protein kinase C [PKC]) that cause up-regulation of several genes, including transcription factors, steroidogenic enzymes, and StAR, ultimately leading to an increase in aldosterone production.[251]
Aldosterone stimulates electrogenic reabsorption of Na by principal cells in the collecting duct and by mineralocorticoid responsive tissue in the colon and sebaceous and salivary glands (see later). Retained Na is responsible for increased extracellular fluid volume that increases BP hydraulically and also heightens vascular sensitivity to Ang II and other vasoconstrictors. [67] [229] Together, these multiple effects combine to raise BP and to restore fluid volume to the point at which the initial signals for renin release (i.e., low BP and renal perfusion pressure) are attenuated or abolished.
In the normotensive individual, when salt intake is increased, circulating renin-Ang II levels decrease and BP remains within the normal range. Conversely, when Na intake decreases, renin-Ang II levels increase without a significant deviation in BP.[253] Thus, BP is kept relatively constant, even when Na intake is varied from 10 to 1500 mEq/day, because of the reciprocal change in Ang II levels and body Na content[223] (see Fig. 42-7 ). By contrast, when the plasma Ang II concentration is fixed at a relatively high level by a constant infusion of exogenous hormone, then increases in Na intake result in marked increases in BP (see Fig. 42-7 ). [227] [228] [263] When the renin system is blocked (e.g., ACE inhibition), then the salt-loading renal function curve is shifted to the left so that BP decreases profoundly at low levels of Na intake. However, BP remains normal in the absence of Ang II as long as Na intake is sufficient.[73]
The concept that long-term control of arterial BP is determined by the degree of vasoconstriction of the arterial bed located between the aortic valve and the capillaries and by the volume of fluid filling this bed has been referred to as the vasoconstriction-volume hypothesis.[73] Accordingly, it has been well established that renin-mediated vasoconstriction, as reflected by the height of the plasma renin value, is a major factor for sustaining the increased arteriolar tone. In contrast, when plasma renin levels are suppressed in normal subjects who are Na replete, then arteriolar tone is supported by a renin-independent, Na-related support of arteriolar tone.
The dynamic reciprocation between these two forms of vasoconstriction has been demonstrated in several experimental models. For example, the BP response to upright tilt, before and after renin suppression, was examined during high and then low dietary Na. [73] [227] [264] Normally, PRA levels increase significantly during upright posture ( Fig. 42-9 ). However, when renin secretion is blocked by pretreatment with a β-adrenergic receptor blocker during a high Na diet, tilting produced no reduction in BP.[255] This indicates that a renin-independent mechanism of vasoconstriction was enabled by dietary Na. When the study was repeated during a low Na diet, baseline PRA levels were higher and increased further during upright tilt, while BP was maintained. However, when the tilt test was repeated during both concurrent low Na intake and pretreatment with a β-blocker to suppress renin secretion, all subjects became hypotensive during upright tilt. This study illustrates that Na-mediated vasoconstriction does not require participation of the renin system and that renin-dependent vasoconstriction does not require Na. However, when both renin-mediated and Na-mediated mechanisms are inactivated, hypotension occurs.
|
|
|
|
|
|
|
FIGURE 42-9 Interaction of Na balance and renin system activity on BP. Four patients with uncomplicated hypertension were studied twice—first after ingesting a high Na diet (300 mEq/day; left panel) for 5 days and then again after ingesting a low Na diet (10 mEq/day; right panel) for 5 days. On the high Na diet (left panel), BP did not change in response to head-up tilt but the mean renin level increased. However, the defense of BP was independent of the renin level, which was suppressed by intravenous propranolol (0.12 mg/kg) that was administered prior to the second tilt study. On the low Na diet (right panel), baseline plasma renin levels were significantly higher than during the high Na diet and increased markedly during head-up tilt, although BP was maintained. After propranolol, plasma renin was suppressed and head-up tilt caused severe hypotension. Thus, after removal of both the Na and the renin mechanisms, BP could not be sustained during tilt. See references 255 and 693. (Adapted from Morganti A, Lopez-Ovejero JA, Pickering TG, Laragh JH: Role of the sympathetic nervous system in mediating the renin response to head-up tilt. Their possible synergism in defending blood pressure against postural changes during sodium deprivation. Am J Cardiol 43:600–604, 1979.) |
|
The Ang II-mediated events described previously occur through its interaction with the AT1, which has been localized to the brain, peripheral blood vessels, adrenal gland, heart, and kidney. [256] [265] [266] Compared with the AT1 receptor, the function of the type 2 Ang II receptor (AT2) is less well understood. AT2 mRNA expression decreases with age, disappearing after the neonatal period, although the receptor has been identified at a reduced level in mature rats.[258] It has been proposed that the AT2 receptor mediates actions of Ang II that are opposed to those transduced by the AT1 receptor, such as vasoconstriction and cell growth and proliferation.[259] Bradykinin, NO and cyclic guanosine monophosphate (cGMP) have been reported to mediate the AT2-receptor actions.
Cytochrome P-450–Dependent Metabolites of Arachidonic Acid
Arachidonic acid is metabolized primarily by CYP enzymes in the brain, lung, kidney, and peripheral vasculature to 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs).[260] EETs, which are derived from endothelial cells, promote vasodilatation by activating K+ channels and hyperpolarizing vascular smooth muscle cells. By contrast, 20-HETE vasoconstricts vascular smooth muscle cells by reducing the open-state probability of Ca2+-activated K+ channels.[260] Both EETs and 20-HETEs play an important role in renal vascular tone and Na excretion, and thus, it has been proposed that they participate in the pressure natriuresis relationship. Pretreatment of rats with CoCl2, an inducer of heme oxygenase activity that reduces the formation of EETs and 20-HETE, blocks the inhibitory effects of elevated perfusion pressure on Na+,K+-ATPase activity and proximal tubule Na transport.[261] Inhibitors of the formation of 20-HETE normalize the elevated renal medullary vascular resistance in a hypertensive rat model, suggesting that 20-HETE may contribute to resetting of the pressure natriuresis relationship and the development of hypertension by elevating renal vascular resistance and tubuloglomerular feedback (TGF) responses.[260] These metabolites have been found to contribute to pressure natriuresis by inhibiting Na+,K+-ATPase activity and promoting internalization of NHE3 protein from the brush border of the proximal tubule.[262]
Nitric Oxide
There is considerable evidence that NO participates in the regulation of BP, with important influences on BP and renal hemodynamics.[226] Renal medullary blood flow plays a central role in the maintenance of BP homeostasis. NO regulates medullary renal vascular resistance, natriuresis, and diuresis and, therefore, contributes importantly to the pressure natriuresis relationship. [272] [273] Deep vasa recta respond to vasoconstrictors (e.g., Ang II, arginine vasopressin [AVP], endothelin) and vasodilators (e.g., bradykinin, prostaglandin E2 [PGE2], adenosine) and can be controlled independently from the cortical circulation in response to endogenously released vasoactive substances.[265] The renal medulla is the major source of NO production in the rat kidney,[265] with NOS levels that are 26 times higher in the medulla than in the cortex.[266] Renal interstitial infusion of an NOS inhibitor causes a sustained reduction in medullary blood flow, but not cortical blood flow, with a concomitant decrease in Na excretion[267] (see later).
There is considerable evidence that NO serves an important counterregulatory role within the renal medullary circulation. Infusion of Ang II, norepinephrine, or vasopressin at subvasoconstrictor levels provokes a significant increase in medullary tissue NO levels. When this NO response is prevented by pretreatment with an NOS inhibitor, medullary blood flow and tissue Po2 decrease by 30%.[268] These findings indicate that the effects of vasoconstrictors on medullary blood flow are buffered by the increased production of NO.[265]
Pressure natriuresis appears to be mediated by renal interstitial cGMP via protein kinase G in response to high renal perfusion pressure independently of changes in GFR.[269] The related increase in cGMP and Na excretion could be prevented by blockade of soluble guanylate cyclase, NOS, or protein kinase G (PKG). These results suggest that an NO-cGMP pathway involving the interstitial compartment is required for pressure natriuresis and that cGMP action to promote natriuresis at high renal perfusion pressure is mediated by PKG.
There appears to be differential regulation of NOS in response to salt intake. Dietary salt restriction in normal rats increases the expression of nNOS in the kidney cortex and MD but decreases the production of all NOS isoforms in the inner medulla.[270]
Other vasoactive factors, including endothelin ( Chapter 10 ), vasopressin ( Chapters 10 and 13 ), arachidonic acid metabolites ( Chapter 11 ), and atrial natriuretic peptide ( Chapter 10 ) influence the pressure natriuresis relationship and, hence, BP regulation to varying degrees.[226]
PATHOPHYSIOLOGY OF HYPERTENSION
The central role of the kidneys in BP phenomena was pointed out in 1826, when Richard Bright[271] called attention to a group of patients who had bounding pulse and edema and, at autopsy, demonstrated hardened, contracted kidneys and cardiac hypertrophy. Tigerstedt and Bergmann in 1898[272] identified a humoral substance, which they called renin, in saline extracts of rabbit kidneys. This substance had a powerful capacity to raise BP when injected into another rabbit. Goldblatt's landmark experiment in 1934,[273] in which hypertension similar to the human form was produced hemodynamically by constricting the renal artery of the dog, further documented the kidney's vital role. The organ's importance in physiologic and pathologic BP events was reconfirmed by studies in the 1960s that showed renin and aldosterone to be key elements in a normal servocontrol system that simultaneously regulates electrolyte balance and BP. [283] [284] [285]
Several lines of evidence further support the conclusion that the kidney plays an essential role in the pathogenesis of hypertension. First, in human hypertension and virtually all experimental models of hypertension, the ability to excrete Na is impaired at normal BP. [227] [228] [230] This phenomenon has been demonstrated in renal artery stenosis, aortic coarctation, mineralocorticoid hypertension, surgical reduction of renal mass, glomerulonephritis, long-term infusion of vasoconstrictors,[277] and all genetic rat models of hypertension (see later). Second, when renal excretory function is dampened by infusion of Na- and water-retaining hormones (e.g., vasopressin, Ang II, aldosterone), an increase in renal perfusion pressure is required to restore Na and volume homeostasis (see later). Third, all effective antihypertensive drugs shift the pressure natriuresis relationship back to control levels.[277] Fourth, the BP level in a human or experimental animal renal transplant recipient is directly related to the BP of the kidney donor. For example, to maintain a similar BP level in renal transplant recipients without familial hypertension, a kidney received from a hypertensive donor determines a 10-fold larger increase in the required dose of antihypertensive therapy than the transplantation of a kidney from a normotensive donor.[278]
Vascular Remodeling and Pathologic Changes
In primary hypertension, the column of blood in the arterial tree between the aortic valves and the capillaries moves at abnormally high pressure throughout the cardiac cycle of contraction and relaxation. However, cardiac output is usually normal or close to normal. Thus, the main determinant of the sustained elevated BP is an increase in peripheral resistance. The increase in vascular resistance, a cardinal characteristic of diastolic hypertension, is commonly related to excessive vasoconstriction of arteriolar smooth muscle, although it can also result, at least in part, from structural changes in these arterioles, from increased blood viscosity, or even perhaps from increased extravascular (interstitial) pressure.[279]
Physiologic and pathologic renal changes in primary hypertension often precede changes identifiable in other organs, but whether they precede or follow the onset of the hypertension itself has not been fully determined. Early hypertensive patients may exhibit no renal structural changes observable by light microscopy. [289] [290] [291]
Renal vein catheterization data also indicate that the earliest physiologic lesion of essential hypertension is vascular: GFR is maintained, whereas total renal blood flow is reduced (increased filtration fraction). [292] [293] This pattern may be explained by diffuse, predominantly efferent, but also afferent vasoconstriction of all nephrons or, alternatively, by selective afferent vasoconstriction with diversion of blood away from some nephrons to maintain near-normal GFR. That renal vasoconstriction can be reversible is shown by the depressor response to pyrogens or to antihypertensive drugs.
This process is unlike that of malignant hypertension, in which gross pathologic change is accompanied by major disruption of renal function.[285] Renal blood flow and GFR may be greatly reduced, and the renal vasculature in malignant hypertension, unlike that in essential hypertension, may no longer respond to vasodilators. Indeed, in the more advanced forms of hypertensive disease, Na deprivation may be contraindicated, because it may further reduce renal blood flow by provoking renal vasoconstriction.[286]
Under normal circumstances, peripheral resistance is determined predominantly by the precapillary vessels with a lumen diameter of approximately 100 to 300 mm. [296] [297] In human hypertension and in experimental animal models of hypertension, structural changes in these resistance vessels are commonly observed. In primary hypertension, the outer diameter and lumen of these vessels are smaller, the media-to-lumen ratio is greater, but the cross-sectional area of the media is not different from that of age- and sex-matched normotensive subjects. This pathologic alteration is termed eutrophic remodeling.[288]
The LaPlace relationship illustrates that these characteristic vascular changes provide an adaptive function by reducing wall tension as follows:
where T = tension per unit wall layer, P = transmural pressure, r = radius, and w = wall thickness.
It is apparent from this relationship that, when the P increases, T remains constant only if the ratio of radius to wall thickness (r/w) decreases proportionately by w thickening and/or r decreasing. When this alteration of vascular structure occurs within the resistance axis, located from the aortic valve up to and including the glomerular capillary membrane, then it contributes to the long-term elevation in BP.[223]
In human essential hypertension, increasing evidence supports the view that vascular remodeling, rather than growth, is the predominant change occurring in resistance vessels. The increase in media-to-lumen ratio of the resistance vessels occurs by the addition of material to either the outer or the inner surfaces of the blood vessel wall.[287] For this to occur, a reduction in the external diameter of the blood vessel is required. Restructuring of the vessel wall is the consequence of several events, which appear to include increased vasoconstriction, increased matrix deposition, increased apoptosis in the periphery of the vessel with enhanced growth toward the lumen, and changes in motility of smooth muscle cells. [298] [299] [300]
Ang II stimulates vascular smooth muscle cell hypertrophy and hyperplasia, extracellular matrix production, and collagen degradation, which contribute to the remodeling of resistance vessels.[288] Ang II, via NAD(P)H oxidase, also has significant proinflammatory actions in the vascular wall, stimulating the production of reactive oxygen species, such as superoxide (O22-) and H2O2, cytokines, adhesion molecules, and activation of redox-sensitive inflammatory genes. [279] [297] [301] Vascular O22- and H2O2 influence redox-sensitive signaling molecules that regulate the vascular smooth muscle cell responses involved in remodeling.[288]
The signficance of Ang II in the pathogenesis of vascular remodeling was reinforced in studies of human hypertension in which treatment with an ACE inhibitor or ARB, but not a β-blocker, corrected the structure and improved the function of small arteries.[288] This response appeared to be independent of the BP, which was equivalent in each treatment group. Activation of peroxisome proliferator-activated receptors (PPARs), which participate in the regulation of cell growth and migration, oxidant stress, and inflammation in the cardiovascular system[293] may also attenuate Ang II-mediated vascular remodeling. [302] [303]
The hallmark renal vascular lesion in patients with uncomplicated primary hypertension is afferent arteriolar narrowing. [289] [304] This abnormality is characterized by a spectrum of histologic changes including focal spasm of the otherwise normal afferent arterioles, endothelial edema, vascular smooth muscle hypertrophy, widening of the internal elastic lamina with deposition of periodic acid-Schiff (PAS)–positive material, and degenerative changes and hyalinization with focal luminal narrowing. In addition, juxtaglomerular cells are hyperplastic, signifying increased renin biosynthesis. However, it should be emphasized that these renal vascular changes are focal, with relatively few obsolescent glomeruli being present, thereby supporting the clinical observation that significant nephron loss and overt renal insufficiency are not major contributing factors in the pathogenesis of uncomplicated essential hypertension.
The relevance of this renal lesion to the pathogenesis of essential hypertension is supported by the finding that when the luminal diameter of the distal afferent arteriole is decreased in young spontaneously hypertensive rats (SHR), hypertension subsequently develops.[296] Moreover, when young SHR rats were treated with an ACE inhibitor, the lumen diameter of the afferent arterioles was increased, the media-to-lumen ratio decreased in a dose-dependent manner, and the BP remained low even after the drug was discontinued. By contrast, other agents that had no effect on afferent arteriolar structure did not cause a sustained reduction in BP.[297] These findings support the hypothesis that a subpopulation of nephrons with narrowed afferent arterioles can contribute to the pathogenesis of sustained hypertension. Tracey and co-workers[298] have shown that there is a direct relationship between the severity of interlobular artery fibrointimal changes and the magnitude of BP elevation that occurs in patients with primary hypertension, raising the possibility that other renal vascular abnormalities may also contribute to nephron heterogeneity.
Thus, an increase in the ratio of preglomerular-to-postglomerular resistances described previously may cause hypertension by (1) impeding transmission of pressure to the glomerulus, thereby reducing pressure natriuresis and promoting Na retention, (2) enhancing renin-angiotensin-aldosterone secretion by stimulating the MD and juxtaglomerular baroreceptor, thereby increasing vasoconstriction and Na reabsorption, and (3) promoting Ang II-enhanced TGF, thereby amplifying the signal whereby distal tubular Na delivery stimulates afferent arteriolar constriction. [227] [305] [308] [309]
Our research indicates that there are two functionally abnormal nephron populations in essential hypertension: (1) a minor subgroup of ischemic hypofiltering nephrons with impaired Na+ excretion and with unabated renin secretion that is not turned off by Na feeding; and (2) a larger subgroup of normal but adapting, hyperfiltering nephrons that excrete the added Na+ burden and exhibit chronically suppressed renin secretion with increased GFR and distal Na+supply.[295] The two populations thus resemble the interaction between the two kidneys in the two-kidney one-clip Goldblatt model of hypertension.
With this nephron heterogeneity, natriuresis by the normal nephrons is blunted by excessive renin-angiotensin production by the neighboring ischemic nephrons. This internephron discord causes excess total body Na+ in the face of unsuppressed plasma renin levels—a hallmark hypertensive situation in which total GFR and mean renal renin secretion remain normal. Yet, blockade of this “normal” plasma renin level by ACE inhibitors normalizes Na balance and BP.[295]
Functional evidence for heterogeneity of nephron function in essential hypertension, comparable with that described in experimental hypertension, derives from data demonstrating the abnormal responses of renin secretion to Na loading. The natriuretic response to saline infusion in hypertensive patients is more immediate than in normotensive subjects.[301] This response is attenuated when BP is reduced, indicating high arterial pressure is a prerequisite. Furthermore, the magnitude of this natriuresis is inversely related to the baseline PRA, with a consistent reciprocal relationship between the extent of PRA suppression and the fractional excretion of Na during acute infusion of saline. The magnitude of natriuresis was reportedly greatest in patients with primary aldosteronism in whom renin secretion was completely suppressed and PRA levels were the lowest.
Impaired Pressure Natriuresis
Disruption of the pressure natriuresis relationship is a fundamental aspect of human hypertension and all experimental models of hypertension (see earlier). The relevance of the renal-fluid volume mechanism and the RAAS in the pathogenesis of hypertension can be clearly seen from the results of a series of studies done by Guyton and co-worker. [227] [228] [311] [312] These investigators devised an experimental model in which an electronically controlled hydraulic constrictor was placed around the aorta above the renal arteries in awake animals. With this technique, the renal artery pressure could be maintained at a normal level even though the systemic BP was increased by the simultaneous infusion of vasoactive hormones. When aldosterone was infused at a constant rate for 2 weeks, during which the renal perfusion pressure was maintained at normal baseline levels, Na retention occurred and the systemic pressure rose significantly. By the end of the infusion period, signs of volume overload, including pulmonary edema, were apparent. The rise in systemic pressure was caused initially by Na retention owing to the direct renal effects of aldosterone and then was sustained by the impaired pressure natriuresis owing to the inability to transmit the elevated pressure to the renal circulation. When the suprarenal constriction was relieved and the renal perfusion pressure allowed to increase to the level of the systemic pressure, a brisk natriuresis and diuresis occurred and systemic pressure decreased. Similar responses were also observed when other vasoactive salt- and water-retaining hormones (e.g., Ang II, vasopressin) were infused and a rise in renal perfusion pressure prevented. [227] [228] [312]
Medullary Circulation and Hypertension
Cowley and associates [230] [274] [276] have elucidated the role of the renal medullary circulation in the normal pressure natriuresis relationship and in the pathogenesis of hypertension in a variety of experimental animal models (see earlier). Using laser Doppler flowmetry, these investigators found that, although superficial and deep cortical blood flow are autoregulated when renal perfusion pressure is raised above 100 mm Hg, blood flow to the inner and outer medulla are poorly autoregulated in volume-expanded rats.[226] Accordingly, increases in medullary blood flow and pressure in the vasa recta capillaries result in parallel increases in renal interstitial hydrostatic pressure, loss of the medullary osmotic gradient, and consequently, increased natriuresis. [230] [276] [313]
The following vasoactive substances contribute to these hemodynamic effects in the renal medulla (see Chapters 10 and 11 ).
Nitric Oxide
In animal models, impaired NO production or responsiveness plays an important role in the pathogenesis of Na-sensitive hypertension. Normally, high salt intake increases NO concentrations and NOS expression and activity in the renal medulla. [274] [314] Inhibition of NOS within the medulla causes Na-dependent hypertension independent of changes in GFR or renal perfusion pressure. Medullary administration of L-arginine, the substrate for NOS, prevents the reduction in medullary blood flow and salt-mediated increase in BP in Dahl S rats.[306]
In healthy human subjects, inhibition of NO synthase by Nw-monomethyl-L-arginine (L-NMMA) acutely increases BP, peripheral vascular resistance, and fractional excretion of Na.[307] NO is tonically active in the medullary circulation, so that reducing NO production, or vascular responsiveness to it, reportedly enhances the pressure natriuresis response followed by reductions in papillary blood flow, RIHP, and Na excretion by almost 30%, without corresponding changes in total or cortical renal blood flow or GFR.[226] This mechanism may contribute to the blunted pressure natriuresis reported in experimental models (see later).
Angiotensin II
This direct vasodilating effect of NO on the renal medullary circulation appears to have an important role in the defense of BP against elevated levels of circulating vasoconstrictors. Ang II can shift the pressure natriuresis relationship to abnormally high levels of arterial pressure. However, there are substantial differences in this response among different species—dogs and human are highly sensitive, whereas rat models are less sensitive to its renal medullary vasoconstrictor effects.[304] This relative insensitivity of rats to long-term elevations of circulating Ang II has been attributed to counterregulatory effects of the NO system within the renal medulla. [274] [279] Specifically, neither BP nor blood flow to the renal cortex or medulla was altered in rats infused with Ang II. By contrast, the same dose of Ang II, when administered after a threshold dose of a NO synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) that did not affect renal blood flow or BP, decreased medullary blood flow by 30% and subsequently increased BP by approximately 20 mm Hg. Thus, renal NO production buffers the effects of Ang II on the renal medullary circulation and, in turn, blunts a related shift in the pressure natriuresis relationship.[308]
Vasopressin
Vasopressin is a powerful vasoconstrictor that significantly reduces medullary blood flow and blunts natriuresis.[304] However, these effects are not sustained during a chronic vasopressin infusion, and consequently, chronic hypertension does not occur. The transient response to vasopressin reflects the divergent effects of the V1 and V2 receptors.[309] Infusion of a selective V1R agonist reduces medullary blood flow and increases BP. By contrast, V2R stimulation promotes medullary NO production. When renal medullary NOS is inhibited by a suppressor dose of NG-nitro-l-arginine methyl ester, then vasopressin produces a sustained elevation in BP. Endothelial NOS expression is significantly increased in the inner medulla during prolonged vasopressin infusion. Thus, AVP stimulation of NO production in the renal medulla attenuates the V1R-mediated vasoconstrictor effects. As with Ang II, this local counterregulatory response blunts the increase in BP that would otherwise occur during conditions in which vasopressin levels are elevated.[309]
Endothelin-1
Renal endothelin-1 (ET-1) production and receptor expression localizes predominantly to the medulla, with the inner medulla collecting duct (IMCD) producing up to 10-fold more ET-1 than any other nephron segment.[310]Normally, renal medullary ET-1, via the ETB receptor, is an important regulator of systemic BP. The IMCD, and to a lesser extent the medullary thick ascending limb and vasa recta, release ET-1 under conditions that stimulate a natriuresis or diuresis. ET-1 acts as an autocrine factor, activating the basolateral ETB receptor, and stimulating NO- and PGE2-mediated vasodilation and, possibly, natriuretic or diuretic effects.[310]
In studies of a collecting duct ET-1 receptor knockout mouse model, which have impaired ability to excrete a salt load, systolic BP is 15 mm Hg higher than in controls on a normal salt intake.[311] On a high-salt diet, BP was 35 mm Hg higher in the knockout model. This Na-induced increase in BP was attenuated by amiloride. These effects of Na loading were not observed in an ETA receptor knockout mouse model and are, thus, mediated by ETB.[312]Hypertensive animal models (e.g., Dahl-S, Sprague rats) have decreased medullary ET-1 content and, in studies of small numbers of patients with salt-sensitive hypertension, urinary ET-1 excretion was reduced. [319] [322] These findings suggest a role for impaired medullary ET-1 production in the pathogenesis of salt-sensitive hypertension.
Sympathetic Nervous System
A popular belief is that hypertension may arise from persistent vasomotor alarm reactions. [323] [324] Hypertensive patients have been reported to respond to such noxious stimuli as mental arithmetic and psychic trauma with increased BP, visceral and skin vasoconstriction, and increased blood flow to muscles. The hemodynamic pattern resembles that occurring after exercise, and investigators believe that it reflects an abnormal conditioned reflex arising in the central nervous system, which suggests that hypertension is an expression of a central nervous system disorder. In apparent support of this view are animal studies demonstrating severe hypertension with renal damage in a strain of mice subjected to the psychosocial stress of overcrowding.[315] Hypertension has been induced by operant conditioning in primates and dogs, although this type of hypertension is not severe and tends to subside when the stimulus is withdrawn. The beneficial effects of tranquilizers, anesthetics, autonomic blocking drugs, and sympathectomy are well recognized. Moreover, tumors of chromaffin tissue (pheochromocytoma), which secrete excessive norepinephrine or epinephrine, constitute a surgically curable cause of hypertension (see later).
In experimental models, bilateral destruction of the nucleus tractus solitarius can produce acute fulminant hypertension that is sustained in a milder form resembling buffer nerve hypertension.[316] Similar bilateral lesions in dogs have been shown to result in only transient hypertension associated with a sustained increase in peripheral resistance.[317]
Recent studies in a rat model have demonstrated that prolonged infusion with phenylephrine, at a dose sufficient to elevate BP, can cause renal microvascular and tubulointerstitial injury.[318] When the phenylephrine infusion was withdrawn, BP returned to normal. However, hypertension developed when those animals were fed a high Na diet. These findings support the possibility that excess sympathetic nervous system (SNS) activity may lead to chronic hypertension by inducing renal injury, thereby disrupting the normal pressure natriuresis relationship.[319] Similar observations have also been reported in animal models, whereby renal injury caused by infusion of other vasoconstrictors (e.g., Ang II, cyclosporine) has culminated in Na-sensitive hypertension. These observations fit with the general hypothesis that heterogeneity of nephron structure and function plays a key role in the pathogenesis of hypertension.[295]
The inability to precisely quantitate human SNS activity has been a limitation in identifying its contribution to the pathogenesis of hypertension. Measurement of urinary norepinephrine (NE) secretion is no longer used for this purpose, whereas the assay of plasma NE has two major limitations: (1) It is dependent on the rate of removal from plasma, not only sympathetic tone and release, and (2) there are regional differences in SNS activity that can be detected only by techniques that assess organ-specific sympathetic function.[320] Clinical microneurograhphy and measurement of NE spillover, which together provide useful information for studying regional SNS activity, have demonstrated high SNS activity and decreased neuronal reuptake in patients with primary hypertension.[320] Thus, the possibility that a central or peripheral disorder of neural behavior may be involved in established human hypertension, although still unproved, remains an extremely attractive subject. The characterization of an interaction of this rapidly acting, centrally controlled system with other, more prolonged pressor mechanisms, such as the renin system, may be fundamental to a complete understanding of BP regulation and the pathogenesis of hypertension.[321]
Several studies suggest that patients with primary hypertension have impaired circulatory homeostasis with abnormal vascular reactivity. When monitored for 24 hours, these patients generally show a resetting of their diurnal BP profile to a higher level, with somewhat wider than normal fluctuations in BP.[322] They may also have a wider BP response to various psychic or physical stimuli. They may exhibit abnormal responses (fainting) to venous occlusion of the legs and can exhibit such other vasomotor phenomena as increased flushing, tachycardia, and sweating in response to various stimuli.[323] These phenomena are not necessarily or consistently related to the hypertension itself. They may reflect a relative instability of the individual's circulation compared with that of normotensive people, whose BP level is closer to the midpoint of defensive buffering systems that protect against assaults on the circulation.
Pathogenesis of Obesity Hypertension
The initial renal abnormality in obesity hypertension is increased tubular Na reabsorption, which promotes a rightward shift of the pressure natriuresis relationship, expansion of extracellular fluid volume, and elevation in BP.[324]Several mechanisms have been implicated in this abnormal response. Increased renal and muscle SNS activity have been associated with body fat levels in obesity. [329] [333] [334] [335]
Leptin influences cardiovascular and renal function through SNS-mediated mechanisms. It is the product of the OB gene, synthesized by adipocytes, and acting mainly on the hypothalamus. The central effects of leptin include reduction of appetite and augmentation of renal sympathetic activity and BP that are mediated by the ventromedial and dorsomedial hypothalamus. [334] [336] [337] Leptin resistance causes obesity and increased sympathetic outflow to the kidney and peripheral vasculature.
Insulin resistance and hyperinsulinemia, components of the metabolic syndrome, have been implicated in the pathophysiology of hypertension. However, this causal link has been challenged, and if present, this mechanism does not appear to be mediated by the SNS.[324]
Despite Na retention, several components of the renin system are elevated in obesity hypertension, including PRA, angiotensinogen, ACE, and Ang II. In animal models of obesity, treatment with an Ang II antagonist or ACE inhibitor blunts Na retention and volume expansion and attenuates the rise in BP, thus suggesting a significant role for Ang II in the pathophysiology of obesity hypertension. [228] [338] [339]
Wave Reflection and Systolic Hypertension
Although the left ventricle ejects only a single jet of blood with each contraction, a second waveform can normally be observed in the arterial pressure pulse.[331] This secondary wave is caused by wave reflections that occur at peripheral sites where large-diameter arteries with low resistance branch and narrow into vessels with high resistance. Reflected waves can be identified beyond the high frequency notch associated with aortic valve closure[28] ( Fig. 42-10 ). These waves have their greatest amplitude at their origin in the peripheral vasculature and their lowest amplitude in the central thoracic aorta. This behavior accounts for the observation that the systolic and pulse pressures are higher in the peripheral vasculature than in the aorta.
|
|
|
|
|
|
|
FIGURE 42-10 Aortic pressure wave synthesized from the measured radial artery pressure wave (applanation tonometry) using a generalized transfer function. Pd, minimum diastolic pressure; Pi, an inflection point that indicates the beginning upstroke of the reflected pressure wave; Ps, peak systolic pressure; Dtp, round-trip travel time of the forward (or incident) wave from the ascending aorta to the major reflecting site and back; Dtr, systolic duration of the reflected pressure wave. Pulse pressure is (Ps - Pd) = (Pi - Pd) + (Ps - Pi). Augmentation index (AIa) = (Ps - Pi)/(Ps - Pd) and wasted LV pressure energy (Ew) = 2.09Dtr (Ps - Pi). (From Nichols WW: Clinical measurement of arterial stiffness obtained from noninvasive pressure waveforms. Am J Hypertens 18:3S–10S, 2005.) |
|
Under normal conditions, wave reflection is coordinated to return to the ascending aorta from the periphery after ventricular ejection has ceased. [28] [340] This is advantageous because the rise in aortic pressure caused by the reflected wave occurs in diastole rather than in systole. As a consequence, diastolic pressure is increased, perfusion pressure to the coronary arteries is augmented, and LV afterload is reduced. However, for the reasons described previously, this favorable response is associated with amplification of the systolic BP in the periphery above that in the thoracic aorta and left ventricle. The degree of amplification can differ widely between individuals based upon features of the vessel wall (see later). Thus, brachial artery cuff BP is not always a reliable measure of ascending aorta pressure and, thus, can be an unreliable predictor of LV mass index and cardiovascular risk. [28] [341]
Pulse wave velocity (PWV) is dependent upon the characteristics of the conduit artery wall.[333] It is directly related to wall stiffness and inversely related to vessel caliber. PWV is determined by tonometry, whereby the delay in upstroke between a proximal and a distal sensor is measured by placing a Doppler probe directly over the artery and dividing the value by the distance traversed. The pulse waveforms obtained with this noninvasive method are similar to those recorded by intra-arterial catheter.[332]
The contour of the pulse wave is dependent on the incident wave generated by LV stroke volume, the reflected waves that originate at arterial branch points and in the microcirculation, the viscosity of blood, and the structure and tone of various segments of the arterial vasculature. [28] [342] Figure 42-10 illustrates the pulse pressure or amplitude determined by the incident wave ejected from the left ventricle (Pi - Pd) and a late-arriving reflected wave (Ps - Pi) from the lower body.[28] The augmentation index, defined as the ratio of the central augmented pressure wave to the central pulse pressure, is related to properties of the arterial wall. Increased arterial wall stiffness causes the increase in PWV and an early return of the reflected wave (Dtp decreases) during systole while the left ventricle is still ejecting blood. As Dtp decreases, both reflected wave amplitude (Ps - Pi) and systolic duration (Dtr) increase.[28]Consequently, aortic systolic and pulse pressures are amplified. However, the additional energy (2.09 Dtr[Ps - Pi]) that is expended by the left ventricle to overcome this reflected wave-associated increase in pressure is wasted, as it does not contribute to the ejection of blood, but instead increases cardiac afterload and myocardial oxygen consumption.
Progressive increases in pulse pressure and PWV occur with aging (see earlier). [29] [102] Arterial stiffening occurs because of the decreased elastic fiber content in the vessels.[333] A similar stiffening of the vessels and the concomitant increase in PWV can also occur in younger individuals with hypertension because wall stress caused by the high BP is transferred from the elastic fibers to collagen fibers, which are less distensible. The magnitude of this increase in systolic BP can be substantial, averaging over 20 mm Hg in normotensive adults and up to 50 mm Hg in hypertensive patients. The related increases in systolic, augmentation index, and pulse pressure have been associated with an increased risk of cardiovascular events.[332]
Acute reduction in augmentation index can be achieved by drugs that actively dilate muscular arteries and by the passive effects on elastic arteries. [28] [341] Vasodilator drugs (e.g., calcium channel blockers, ACE inhibitors, Ang II receptor blockers) decrease arterial stiffness and PWV, delay return of the reflected wave, and thus, decrease its amplitude and systolic duration. This reduction in wasted energy leads to the regression of LVH. The effects of vasodilator drugs on brachial and radial artery systolic and pulse pressures are much less pronounced than their effects on central artery pressure.[28]
The disproportionately greater reduction of LV and aortic pressure than brachial and radial pressures during vasodilator drug treatment has led some investigators to challenge the claims that ACE inhibitors and Ang II receptor blockers have direct cardiac benefits that extend “beyond BP lowering.” [28] [341] [343] Accordingly, they argue that the greater reduction in risk of cardiovascular complications and stroke observed in an Ang II receptor blocker treatment group compared with a β-blocker group, despite the equivalent reduction in BP, is due to the greater reduction in central BP and afterload in the losartan group. Several studies support this hypothesis: (1) Reduction in LV mass for 12 months with a perindopril/indapamide combination, but not with atenolol, lowered aortic and LV systolic pressure as measured from the calibrated carotid or convolved radial waveforms,[335] (2) for identical reductions in diastolic BP during treatment with either atenolol or ramipril, central systolic and pulse pressures were reduced by 5 mm Hg more than was measured in the brachial artery,[336] and (3) a study of more than 2000 patients randomized either to atenolol (with or without a thiazide) or amlodipine (with or without perindopril) found that, despite similar brachial systolic BP in both groups, central aortic pressure was lower in the amlodipine group.[337] In the latter study, central pulse pressure was significantly associated with a post hoc-defined composite outcome of total cardiovascular events/procedures and development of renal impairment.[337] These findings suggest that brachial BP is not always a good surrogate for the effects of antihypertensive drugs on arterial hemodynamics and that central pressure measurements estimated by radial tonometry are predictors of cardiovascular risk.
HUMAN HYPERTENSIVE DISORDERS AS A SPECTRUM OF ABNORMAL PLASMA RENIN AND SODIUM-VOLUME PRODUCTS
An important contribution to the modern understanding of hypertension was the discovery of the involvement of the renin system in high BP states.[73] Clinical studies in normal volunteers demonstrated that prolonged infusion of Ang II for 10 days or more could produce sustained hypertension with Na+ retention.[275] Moreover, this effect could be achieved with diminishingly small doses of Ang II. Neither the sustained hypertension nor the Na+ retention could be produced by NE infusion. These studies established that Ang II, which was effective at low concentrations, was unique among known pressor agents in that it could produce and sustain chronic hypertension that was indistinguishable from human primary hypertension. By contrast, NE infusions do not produce sustained hypertension in normal humans. This research indicated that the renin system, like other endocrinologic control systems, did not function in isolation but was reactive to other forces, both internal and external, affecting BP and electrolyte balance. Just as a normal level of serum insulin may be defined only in relationship to the concurrent influence of glucose, so a normal level of plasma renin may be defined only in relationship to the concurrent influence of Na+.
This point was demonstrated by the development of a protocol of renin-Na+ profiling, in which plasma renin levels were indexed to the current state of Na intake as determined by a 24-hour Na+ excretion analysis. [137] [138] [347] [348] The nomogram obtained from normal subjects ( Fig. 42-11 , values inside dotted lines) indicates that the PRA levels are inversely related to Na intake. At high levels of Na intake, PRA is suppressed, whereas at low Na intake, PRA is markedly elevated. Despite these wide ranges of Na intake, BP remains constant. These data indicate that, at low Na intake, normal BP is maintained by renin-Ang II-mediated vasoconstriction, whereas at high Na intake, BP is maintained in the normal range by Na-volume-mediated vasoconstriction. The dynamic reciprocation of these two forms of vasoconstriction is essential to maintain normal BP homeostasis across a wide range of dietary Na intakes (Normal Blood Pressure Homeostasis, earlier). With this index of normalcy, the role of the renin system in the various types of hypertension can be examined with the potential for stratifying patients pathophysiologically according to their renin system patterns. This is evident with the observation that, although the reciprocal relationship of Na intake and PRA is similar in hypertensive patients and normotensive subjects, renin levels are distributed over a much broader range in hypertensive patients.
|
|
|
|
|
|
|
FIGURE 42-11 Relation of the noon ambulatory plasma renin activity (left) and the corresponding daily urinary aldosterone excretion (right). The dashed lines define the normal channel derived from the study of normotensive people. A total of 219 patients with untreated essential hypertension were studied, some on several occasions at different levels of Na intake. Closed triangles, low renin; open circles, normal renin; closed squares, high-renin essential hypertension. Three major subgroups are defined by the appropriateness or normalcy of the PRA to the rate of Na+ excretion, which is used as an index of dietary intake and of Na+ balance. Additional normal subgroups are defined when aldosterone (right) is included in the analysis. PRA results are expressed as nanograms angiotensin I formed per milliliter per hour. Multiply these PRA values by 0.65 to conform to the National Bureau of Standards angiotensin I reference standard used by The Cardiovascular Center Laboratory at New York Presbyterian Hospital-Weill Medical College and by Quest Laboratories. (From Brunner HR, Laragh JH, Baer L, et al: Essential hypertension: Renin and aldosterone, heart attack and stroke. N Engl J Med 286:441, 1972.) |
|
The pathophysiologic relevance of this finding is illustrated in Figure 42-12 , in which the most commonly encountered forms of hypertension are stratified according to their renin-Na profile. The higher renin states (see Fig. 42-12, top four disorders ) have the most severe vascular disease, with damage to the heart, brain, and kidneys. By contrast, the Na+-retaining, high-volume forms of hypertension, such as low-renin essential hypertension (see Fig. 42-12, bottom two disorders ) have suppressed renin secretion associated with Na+-volume excess and lower risk of cardiovascular complications. [137] [138] [349] The intermediate types of hypertension, with mixed renin-Na excess, develop intermediate degrees of cardiovascular damage. Bilateral renal artery stenosis and aortic coarctation have Na-volume retention, which only partially suppresses renin secretion. Consequently, these disorders are manifested by pulmonary edema when Na+-volume is in excess (see Pressure Natriuresis, earlier). [227] [350]
|
|
|
|
|
|
|
FIGURE 42-12 The spectrum of hypertensive disorders stratified according to their renin-sodium relationship. Normal subjects, as indicated by the equation at the bottom of the figure, maintain and defend normotension by curtailing renal renin secretion in reaction to a rise in sodium intake or autonomic vasoconstriction or by proportionally increasing renin secretion in the face of either Na+ depletion or hypotension from fluid or blood loss or a neurogenic fall in BP. Hypertensive subjects sustain their higher BPs by renal secretion of too much renin for their Na+-volume states or by renal retention of too much Na+ (volume) for their renin level, which often fails to fully turn off as it does in normal subjects. High-renin hypertensive patients are proportionately more vasoconstricted with poorer tissue perfusion and therefore most susceptible to cardiovascular tissue ischemic damage (see text). |
|
Renin-Dependent Forms of Hypertension
Malignant Hypertension
Malignant hypertension is characterized clinically by severe accelerating hypertension with neuroretinopathy or papilledema and by evidence of renal damage.[342] Clinically, it is almost always associated with massive oversecretion of renin and aldosterone and is strikingly relieved by binephrectomy or antirenin drugs but not by total adrenalectomy.[276] On pathologic examination, it is characterized by fibrinoid and necrotizing arteriolitis. This syndrome can occur de novo, but most often, it follows preexisting milder forms of hypertension. Malignant hypertension may occur as a complication of primary hypertension and of virtually every form of secondary hypertension, with the notable exception of coarctation of the aorta, a condition in which the renal circulation is protected from the high pressures that occur proximally to the coarctation.[14] Accelerated hypertension is a term often used synonymously with malignant hypertension, but sometimes only to imply a significant increase in the pace or severity of the hypertensive process.
The process of malignant hypertension begins with a critical degree of renal microvascular injury due to causes that are not always clear but are generally associated with severe hypertension. [283] [352] [353] [354] Renal hypoperfusion triggers a massive release of renin. In its joint vasoconstrictor and Na+-retaining effects, systemic pressure increases markedly. The rise in pressure normally suppresses renin production through feedback inhibition (see earlier). However, in malignant hypertension, this regulatory mechanism is impaired and renin secretion continues unabated. A vicious circle results whereby more renin secretion causes more hypertension, causing more renal and systemic arteriolar necrosis, which again causes more renin secretion. In addition, renal Na excretion is further impaired by the hypersecretion of aldosterone, which is stimulated by high levels of renin and Ang II. This process is referred to as secondary hyperaldosteronism.
This description of the pathogenesis of malignant hypertension is supported by several observations. Diffuse vasculitis and death result within 1 or 2 days in rats overloaded by simultaneous injections of renin and aldosterone.[346]Moreover, the experience in dialysis patients shows that the BP of patients with malignant hypertension can be lowered to virtually normal values and their arteriolar necrosis improved by bilateral nephrectomy.[347]
An equally convincing demonstration of the causal role of the renin system can be made by its pharmacologic blockade.[348] Drugs that interrupt the RAS (e.g., propranolol, captopril) can normalize and maintain the BP in patients with malignant hypertension, including those in encephalopathic crises. [358] [359] [360] [361] In other such patients, the addition of diuretics to antirenin therapy may be required for normalization of BP, illustrating the joint participation of renin and Na+ retention.
Unilateral Renovascular Hypertension (see Chapter 43 )
An experimental analog of human unilateral renovascular disease can be found in the two-kidney Goldblatt model, in which one renal artery of the animal is clipped and the other is left intact. [282] [362] [363] In general, PRA levels are significantly elevated. The affected kidney, with its decreased renal perfusion pressure beyond a stenotic renal artery, reacts to the situation as if there were systemic hypotension and, thus, releases renin. High levels of Ang II result in systemic vasoconstriction, which raises BP through an AT1-mediated mechanism.[355] The elevated systemic BP and increased circulating Ang II level suppress renin release by the contralateral kidney but not by the ipsilateral kidney, in which ischemia and reduced filtration continue beyond the arterial stenosis.
Excess Ang II promotes inappropriate Na retention in the contralateral kidney by enhancing proximal tubule Na+ reabsorption and also by increasing afferent arteriolar resistance by the TGF mechanism. [126] [304] [308] [365] Thus, complete suppression of renin in the contralateral kidney does not counterbalance the uncontrolled release of renin in the affected kidney, because the contralateral kidney is exposed to high circulating Ang II levels from the ischemic kidney. At some point, Ang II activates additional mechanisms that may be responsible for sustained increased BP, including Na retention, endothelial dysfunction, and vasoconstriction related to production of reactive oxygen species.[357]
The renin system is so clearly involved in unilateral renovascular hypertension that it provides the basis for definitive diagnosis and management. The renin dependency can be demonstrated in animals or in patients by a prompt depressor response to renin system blockade. An acute, marked increase in peripheral renin following a single dose of captopril, an ACE inhibitor, is highly suggestive and provides sound reason for pursuing the possibility of curable renovascular hypertension.[358] Renal vein renin sampling after the administration of captopril provides even greater sensitivity, because ACE inhibition produces a pronounced increase in renin release from the ischemic kidney.[368] [369] Normally, each renal vein renin level is about 25% higher than the renal arterial level, and this determines the normal peripheral level.[361] With renin secretion suppressed by the contralateral kidney in unilateral renal disease, the ischemic kidney must produce at least a 50% increment to sustain the peripheral renin level. This response suggests that hypertension may be curable and renal function may be maintained after revascularization.
The ability to use these relatively safe, sensitive, and specific diagnostic tests to define curable renovascular hypertension, together with the development of percutaneous renal angioplasty and stent placement as an alternative to surgery, has helped in identifying patients with curable renovascular disease. [368] [371] Many patients, now cured by an outpatient procedure, would previously have been labeled as having primary hypertension by default and might have been given lifelong antihypertensive drug treatment.
Pheochromocytoma
Pheochromocytoma (PHEO) is a catecholamine-producing tumor arising from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia.[363] The hemodynamic and metabolic manifestations of PHEO are caused by catecholamine excess. However, high plasma renin levels that are a consequence of catecholamine-induced renal ischemia and direct stimulation of β-adrenergic receptors located on the juxtaglomerular cell contribute importantly to the pathogenesis of hypertension in this disorder.[364]
Epidemiology.
PHEO is an uncommon cause of hypertension, although its prevalence is not well established. In the general population of Olmstead, Minnesota, it was diagnosed in 1 per 100,000 adults per year.[365] However, reports from other sources suggest that the prevalence is higher. Autopsy studies have found that the prevalence of PHEO is approximately 0.05% and that the diagnosis is usually unsuspected clinically. [375] [376] [377] In hypertension referral clinics, the prevalence is approximately 0.5%. [378] [379]
Clinical Presentation.
Many of the signs and symptoms of PHEO are related to the direct actions of catecholamines. However, the failure to diagnose or even to suspect the diagnosis of PHEO reflects the nonspecific nature of the associated signs and symptoms. Although the classic triad of headache, paroxysmal sweating, and tachycardia in a hypertensive patient has a diagnostic sensitivity and specificity exceeding 90%, fewer than 10% of patients present in this way.[371] In a Mayo Clinic study of autopsy-proven cases,[368] only 54% were hypertensive; headaches (27%), diaphoresis (17%), and palpitations (17%) were much less common than in patients who were diagnosed before death.
Metabolic effects include hyperglycemia, lactic acidosis, and weight loss. [372] [381] Diabetes was diagnosed in 35% of patients with PHEO, exceeding that of a control population with primary hypertension.[372] Moreover, there was an 18-fold higher likelihood of the diagnosis of PHEO than primary hypertension in hypertensive diabetic patients younger than 51 years with a BMI less than 25 kg/m2. Although weight loss can occur, the majority of patients in one autopsy study were overweight.[367] Very rarely, PHEO may secrete adrenocorticotropic hormone (ACTH) and cause Cushing's syndrome.[373]
Although hypertension is usually present, BP may be quite variable. Sustained hypertension with paroxysmal increases is relatively common and may be associated with a hypertensive crisis. [383] [384] The appearance of sudden and severe hypertension during induction of anesthesia or prolonged hypotension immediately after a surgical procedure may herald PHEO. [374] [376] Asymptomatic patients, including those with persistently normal BP, are being identified with increasing frequency now that adrenal tumors are discovered incidentally during abdominal imaging. [385] [386] The occurrence of unexplained orthostatic hypotension in patients with sustained hypertension is a clue that PHEO may be present. [387] [388] Hypotension and shock may be the presenting clinical signs.[380]
PRA measured supine, standing, and after walking for 1 hour was higher in subjects with PHEO than in those with primary hypertension or in healthy controls.[364] In all three situations, PRA was closely correlated with NE levels in those with PHEO but not in the primary hypertension or control subjects. Pharmacologic interruption of the renin system with either a β-blocker or an ACE inhibitor significantly lowered BP. These findings indicate that high PRA accompanies hypertension in PHEO and that renin release is stimulated in response to NE. The decreased BP in response to β-blockade and captopril provides indirect support that renin-dependent mechanisms are involved in the hypertension of PHEO. In addition, Ang II receptors have been identified on PHEO cells, and Ang II perfusion increased the in vitro release of NE and neuropeptide-Y by the PHEO cells, suggesting a mutually reinforcing, pathophysiologic relationship between these hormonal systems in this disease.[381]
Cardiovascular complications are common, most notably atrial and ventricular fibrillation, myocarditis with dilated cardiomyopathy, vasospastic coronary artery disease, and cardiogenic or noncardiogenic pulmonary edema. [384] [391] During pregnancy, PHEO can cause severe hypertension, with cardiovascular and neurologic complications.[383] The diagnosis of PHEO during pregnancy is associated with maternal mortality of 4% and fetal loss of 11%.[384]It can mimic preeclampsia when it occurs during the 3rd trimester, although related complications may occur at any time during the pregnancy. In early pregnancy (i.e., before 24 wk), both tumor resection and medical treatment are associated with good fetal outcome. In later pregnancy, elective cesarean delivery followed by tumor resection results in favorable maternal and fetal outcomes.[384]
Genetics.
A high prevalence of PHEO occurs in certain familial syndromes. Germline mutations in five genes have been identified to be responsible for familial PHEOs: the von Hippel-Lindau gene (VHL), which causes von Hippel-Lindau syndrome; the RET gene leading to multiple endocrine neoplasia type 2; the neurofibromatosis type 1 gene (NF1), which is associated with von Recklinghausen's disease; and the genes encoding the B and D subunits of mitochondrial succinate dehydrogenase (SDHB and SDHD), which are associated with familial paragangliomas and pheochromocytomas. [372] [394] PHEO is not usually the initial presenting sign in patients, who more commonly present with other benign or malignant neoplasms.[363]
Recent evidence indicates that a hereditary basis for this tumor can also be identified in approximately 25% of patients for whom no evidence or family history of these syndromes can be found.[386] Younger age, multifocal tumors, and extra-adrenal tumors were significantly associated with the presence of a mutation. More than 90% of the patients with mutations were identified solely by molecular testing of VHL, RET, SDHD, and SDHB; these patients had no associated signs and symptoms at presentation.[386] These findings have raised the issue of whether all patients with PHEO should undergo genetic testing because (1) syndromic hereditary forms are associated with other neoplasms, which may benefit from early tumor screening, and (2) those with germline mutations are more likely to have multiple PHEOs and recurrent tumors, so that more stringent clinical follow-up is indicated throughout life.[363]
Laboratory Tests.
All patients with suspected PHEO should undergo biochemical evaluation. Indications for testing include (1) episodic headaches, tachycardia, diaphoresis (regardless of whether hypertension is present), (2) family history of PHEO, (3) history, signs, or symptoms of a multiple endocrine neoplasia (MEN) syndrome (e.g., medullary thyroid carcinoma [MTC]), (4) incidentally discovered adrenal mass, (5) hypertension with equivocal increases in catecholamine production, and (6) markedly elevated BP or hemodynamic instability, especially during induction of anesthesia or surgical procedure. [5] [26] [27]
Plasma and Urinary Free Metanephrines.
Catechol-N-methyltransferase (COMT) catalyzes the metabolism of epinephrine and NE to their free (unconjugated) metabolites metanephrine and norepinephrine, respectively.[387] Plasma concentrations of free metanephrines are relatively independent of renal function and are, therefore, more suitable for screening patients with concurrent kidney disease.[388]
COMT is not present in sympathetic nerves and is found exclusively in non-neuronal sources, including chromaffin cells of the adrenal medulla. By contrast, monoamine oxidase (MAO), the enzyme that catalyzes the deamination of NE and epinephrine to 3,5-dihydroxyphenolglycine (DHPG), is located within both sympathetic nerves and adrenal chromaffin cells. Intratumoral metabolism of catecholamines within PHEO leads to the production and release of high plasma levels of metanephrines and normetanephrine. Relatively small increases in the levels of these metabolites, compared with the parent amines, occur during paroxysmal attacks or tumor manipulation in patients with PHEO.[389] Moreover, these levels far exceed those of normal individuals during stress.
The high rates of production of the catecholamine metabolites in PHEO compared with those in normal individuals provide the basis for these metabolites in screening. Plasma free metanephrines and normetanephrines have a diagnostic sensitivity exceeding 95% and specificity of approximately 85%. [372] [399] [400] [401] In comparison, 24-hour urinary total metanephrines and catecholamines have a sensitivity of 90% and specificity of 98%. The higher specificity of the urinary measurements yield fewer false-positive results and, thus, may be preferable for screening low-risk patients.[392]
Urinary vanillylmandelic acid levels are often normal in patients with PHEO and lack sufficient sensitivity to be used as a screening test for this disorder. [372] [402]
Catecholamines.
There is no relationship between the height of the BP and the plasma catecholamine levels.[382] Therefore, plasma catecholamine levels can have diagnostic value regardless of whether the patient is symptomatic or hypertensive at the time the sample is obtained. Resting plasma catecholamine levels (sum of norepinephrine and epinephrine) are abnormal when elevated above 2000 pg/mL and are normal below 500 pg/mL. PHEO is very unlikely to be present when catecholamine levels are normal in the patient with a markedly elevated BP. Values between 500 and 2000 pg/mL are equivocal and the sampling should be repeated.
Levels of catecholamines and metanephrines provide complementary information because the pattern of catecholamine excretion can reflect tumor size. Specifically, tumors weighing less than 50 g have rapid turnover rates and predominantly release unmetabolized catecholamines, whereas larger tumors mainly excrete catecholamine metabolites.
Clonidine Suppression Test.
In most cases of PHEO, catecholamine and plasma free metanephrine level are markedly elevated. However, when equivocal levels of plasma catecholamines and/or plasma metanephrines are found, then further evaluation with a clonidine suppression test is indicated. Clonidine is a centrally acting α2-adrenergic receptor agonist that normally suppresses neurally mediated plasma catecholamine levels. In supine, resting patients with primary hypertension, plasma total catecholamine levels fall below 500 pg/mL and by at least 50% below the baseline level within 3 hours after clonidine 0.3 mg is given orally. Failure to suppress plasma catecholamine levels after acute clonidine administration is highly predictive of PHEO, with both false-positive and false-negative rates of 2%.[394] In addition, failure of clonidine to suppress the plasma normetanephrine level by less than 40% below the elevated baseline level of 112 ng/L was associated with a diagnostic sensitivity and specificity exceeding 97%.[395]
BP decreases after clonidine is given, and significant bradycardia may also occur regardless of whether a PHEO is present. To reduce these risks, antihypertensive medications, particularly β-blockers, should be withdrawn prior to the test. In addition, an indwelling intravenous catheter should be in place so that, if hypotension occurs, normal saline can be infused.
False-Positive Biochemical Test Results.
Several relatively common disorders, including HF, stroke, autonomic dysfunction, alcohol withdrawal, cocaine use, clonidine withdrawal, and vasodilator therapy are associated with increased activity of the SNS and increased levels of catecholamines and their metabolites and, thus, can lead to a false-positive screening test for PHEO.[363] Sampling blood after an overnight fast while the patient is supine, after resting for at least 30 minutes, can eliminate the confounding effects of diet and physical exercise. Urinary collections should include creatinine measurements to ensure that an adequate sample is provided. Medications are a major factor that leads to false-positive biochemical test results. Certain drugs can interfere with the assay method or influence the pharmacologic disposition of catecholamines and their metabolites.[363]
Phenoxybenzamine and tricyclic antidepressants account for 41% to 45% of all elevated plasma levels of normetanephrine and NE in patients without PHEO.[395] Patients taking these types of drugs have plasma concentrations or urinary outputs of normetanephrine or NE that are approximately twice that of patients not taking these medications. Moreover, the likelihood of false-positive results is up to 7.7-fold higher in patients treated with these drugs.[395]Buspirone, an anxiolytic drug, is known to falsely elevate urinary metanephrines, but not plasma levels, by interfering with the high-pressure liquid chromatography (HPLC) analysis of this analyte. [404] [405]
β-Adrenergic receptor blockers (b-blockers), including the combined α1- and β-blocker labetalol, have been associated with 60% of all false-positive elevations of plasma metanephrines.[395] Although these drugs are not associated with an increased frequency of false-positive elevations of plasma normetanephrine, NE, or epinephrine when HPLC-based analytical methods are used. Moreover, β-blockers are associated with a significantly greater frequency of false-positive elevations of urinary epinephrine, normetanephrine, and metanephrine.
Calcium channel blockers have been associated with a significantly higher prevalence of false-positive elevations of plasma and urinary NE levels as well as the urinary epinephrine level.[395] By contrast, other antihypertensive agents, including ACE inhibitors, ARBs, and diuretics, had little influence on the frequency of false-positive biochemical results of these plasma and urinary analytes.
Sympathomimetic drugs (e.g., pseudoephedrine) are highly likely to cause false-positive elevations of urinary normetanephrine and metanephrines, and false elevations of plasma levels of these analytes can also occur, although apparently with lower prevalence.[395]
Tumor Localization.
To avoid unnecessary radiographic procedures, tumor localization should be attempted only after the diagnosis of PHEO has been confirmed by biochemical testing. Age and the presence of family history are important considerations when determining the type and location of PHEOs. Adrenal tumors are prevalent in patients older than 60 years, are rarely associated with extra-adrenal tumors, and may be bilateral in patients with familial syndromes.[365] By contrast, extra-adrenal tumors are more prevalent in younger patients and are more likely to be multifocal. Most tumors (95%) are found within the abdomen. The most common extra-adrenal locations are the superior and inferior paraortic areas (75% of extraadrenal tumors), the bladder (10%), the thorax (10%), and the head, neck, and pelvis (5%).[397] Although the traditional teaching has been that 10% of all PHEOs are at extra-adrenal sites, this is an underestimation. Extra-adrenal PHEOs probably represent up to 15% of adult and 30% of childhood PHEOs. [372] [406]
The average diameter of PHEO, whether discovered incidentally or during the evaluation of symptomatic patients, is about 5 cm.[398] Magnetic resonance imaging (MRI) with gadolinium enhancement and computed tomography (CT) scans identify lesions with a diameter greater than 0.5 cm with diagnostic sensitivities approaching 100% and specificities ranging from 70% to 80%. However, MRI is superior for detecting extra-adrenal PHEO.[399] Moreover, MRI provides additional information including (1) a characteristic bright T2-weighted image that, although not unique to this tumor, is useful in narrowing the differential diagnosis, and (2) the ability to obtain sagittal and coronal images that define anatomic relationships between the tumor, surrounding vasculature, and draining venous channels. Moreover, MRI avoids exposure to radiation and iodinated contrast and is preferable in the valuation of children and during pregnancy.[383] Therefore, MRI is the initial imaging procedure utilized at our center.
Other imaging modalities may enhance the diagnostic accuracy of CT and MRI, especially in patients with multifocal lesions or large adrenal tumors (>5 cm) that may be malignant and be associated with metastases. [372] [408] 123I-Metaiodobenzylguanidine (MIBG) and 131I-MIBG scintigraphy employs radioisotopes with chemical similarities to NE that allow it to enter the metabolic pathway into and out of storage granules. However, false-negative MIBG scan results can occur when patients are also treated with drugs that block the catecholamine transport mechanism (e.g., tricyclic antidepressants, guanethidine, phenylpropranolamine). 18F-Fluorodopamine positron-emission tomography (PET) reportedly has greater diagnostic sensitivity than 131I-MIBG scintigraphy for detecting metastases.[400] When radiographic imaging does not identify the source of catecholamine overproduction, selective venous sampling at sites along the inferior and superior vena cava is required. [410] [411]
Medical Treatment
Surgical resection of PHEO is the definitive treatment. The goal of preoperative treatment is to optimize the patient's cardiovascular status and, thus, prevent perioperative complications. Prospective clinical trials of various drug treatment regimens have not been performed. However, we utilize the following preoperative medical regimen in patients with PHEO:
α-Adrenergic Receptor Blockade.
In our experience, phenoxybenzamine is the α-blocker of choice because it is a noncompetitive antagonist, thereby preventing drug displacement from the α-adrenergic receptors by marked increases in catecholamines that occur during surgery, unlike competitive α-blockers (e.g., prazosin, doxazosin, terazosin). Treatment with phenoxybenzamine is begun 2 to 4 weeks prior to surgery, with an initial dose of 20 mg/day, increasing to 40 to 100 mg daily as necessary. Postoperative hypotension during α-blockade is a problem in hypovolemic patients with inadequate preoperative hydration. This can cause hemodynamic instability during surgery. Therefore, when postural hypotension occurs preoperatively during treatment with phenoxybenzamine, dietary intake of Na and water should be liberalized (≤200 mEq/day), and in the immediate preoperative period, saline infusion is provided. Another side effect of α-blockade is nasal congestion, although this symptom is not a reliable marker of treatment efficacy. Although single-center, retrospective, nonrandomized studies of small numbers of patients comparing phenoxybenzamine with competitive α-receptor blockers (e.g., doxazosin, prazosin) found no differences in perioperative BP or volume replacement, the methodologic limitations render them inconclusive.[403]
-Adrenergic Blockade.
β-Blockers are usually not required and should not be given prophylactically for tachycardia or arrhythmias.[32] β2-Adrenoceptors normally mediate vasodilation, and in PHEO, β-blockade can increase vascular resistance owing to unopposed α-adrenergic-mediated vasoconstriction if concurrent α-blockade is inadequate. β-Blockade is indicated for patients with cardiac complications, such as atrial tachyarrhythmias and myocardial ischemia, that do not respond to α-blockade. It is essential that (1) effective α-blockade is established before treatment with a β-blocker is started, and (2) a β1-selective blocker (e.g., metoprolol, atenolol) is used at the lowest dose that is effective. In fixed-dose combinations of α- and β-blockers (e.g., labetalol), the β-blocking effect is often predominant. Furthermore, α1-blockade with these agents is competitive, unlike that of phenoxybenzamine. Therefore, combined α-/b-blockers limit the ability to carefully titrate adrenergic blockade and, thus, should not be used routinely in patients with PHEO.
α-Methylparatyrosine.
This is a competitive inhibitor of the rate-limiting step of catecholamine biosynthesis, the conversion of tyrosine to 3,4-dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase. [413] [414] Doses of α-methylparatyrosine (a-MPT) of 250 to 1000 mg every 6 hours decrease catecholamine synthesis by 36% to 79%. Retrospective studies have reported that (1) preoperative treatment with the combination of α-metyrosine and α-blockade results in better BP control and less need for use of antihypertensive medication or pressors during surgery compared with single-agent adrenergic blockade[406] and (2) metyrosine treatment resulted in less intraoperative blood loss and volume replacement than occurred without metyrosine.[407] Thus, it is likely that metyrosine can facilitate perioperative management, although its benefits have been most clearly demonstrated in catecholamine-induced cardiomyopathy.[408] Therefore, α-MPT is indicated for use with α-blockade in patients with (1) HF or other cardiovascular complications, (2) very high levels of catecholamine production that are refractory to adrenergic blockade, and (3) inoperable multifocal or metastatic tumors with very high levels of catecholamine.[409] Side effects of α-MPT, which occur more commonly at daily doses over 2 g, include tremor (which is probably related to dopamine deficiency), nausea, diarrhea, and sedation. Adequate hydration should be maintained because crystalluria occurs when urinary concentration exceeds 1 mg/mL, although kidney stone formation has not been reported.
Angiotensin-Converting Enzyme Inhibition.
Compared with patients with primary hypertension, those with PHEO have higher PRA levels and the PRA levels are strongly correlated with plasma catecholamine levels in PHEO but not in primary hypertension.[364] Furthermore, treatment with captopril acutely reduces BP in association with a marked rise in the PRA level, suggesting that renin-angiotensin participates in the pathophysiology of hypertension in PHEO. Indications for ACE inhibitor treatment include (1) hypertension that is resistant to α-blockade, particularly when the PRA level is high, and (2) HF due to systolic dysfunction.[16]
Calcium Channel Blockade.
Calcium channel blockade, either with or without concurrent α-blocker, has been recommended for the treatment of PHEO. [419] [420] However, in these retrospective studies, calcium channel blockade without concurrent α-blockade was associated with complications including greater perioperative fluid requirements and uncontrolled hypertension. [419] [420] Dihydropyridine calcium channel blockers with short durations of action have been associated with cardiovascular complications and have no role in the treatment of hypertension, ischemic heart disease, or HF.[203] However, those with longer duration of action are safe for the treatment of primary hypertension and, in combination with α-blockade, appear to be a useful adjunct. Long-acting forms of verapamil and diltiazem can be effective for controlling atrial tachyarrhythmias that are refractory to α-blockade and subsequent β-blockade, but we do not use these agents as first-line antihypertensive agents in PHEO.
Hypertensive Crisis.
Catastrophic presentation with multisystem organ failure can occur as a consequence of hemorrhagic necrosis of a PHEO. [383] [384] Prompt treatment with an α-blocker is required while the patient is monitored in an intensive care unit. Phentolamine infusion (50–100 mg in 500 mL 5% dextrose) enables rapid, controlled reduction of BP. The initial rate of infusion should be 1 to 5 mg/min. This is preferable to a rapid bolus injection of phentolamine 5 mg, which can cause a precipitous fall in BP and promote myocardial and cerebral ischemia. Affected patients are also likely to be markedly volume depleted and require aggressive volume repletion. Central venous monitoring is usually required to optimize fluid management.
In the hemodynamically stable patient with a PHEO, preoperative adrenergic blockade for several weeks is indicated to optimize BP, volume status, and other metabolic or cardiac complications that may be present.[412] By contrast, PHEO crisis is an indication for emergency resection of the tumor. In this case, hypovolemia should be corrected for 24 hours prior to operation, in addition to concurrent α-blockade, to minimize the risk of postoperative hypotension.
Bilateral Renovascular Hypertension (see Chapter 43 )
In the patient with bilateral renovascular disease, peripheral renin levels are either “normal” or even slightly reduced.[361] This finding also prevails in the experimental one-kidney Goldblatt model, in which one kidney is clipped and the other removed. When both kidneys are ischemic, the perfusion defect initially stimulates renin production, but at the same time, it limits excretion of Na+ and water, so BP rises. The result is total body Na+ and volume accumulation to the point at which renal perfusion pressure is restored beyond the stenosis. Renin production is thus depressed to normal or even subnormal levels. This restoration of equilibrium in bilateral renovascular disease is accomplished at the cost of volume expansion and systemic hypertension. Because total GFR and nephron number are seriously compromised, the BP elevation is sustained predominantly by Na+ retention rather than by Ang II. [363] [371] [422] [423] Acute pulmonary edema is more common in patients with bilateral disease than it is in unilateral disease[341] (see Pressure Natriuresis, above, and Chapter 12 ). This phenomenon reflects impaired pressure natriuresis, as indicated by the natriuresis that occurs after angioplasty. [227] [424]
Infusion of an Ang II blocker produces no fall in BP in the one-kidney one-clip model when dietary salt is elevated. [423] [425] Similarly, Na depletion does not produce a fall in BP because the PRA level increases sharply, converting Na-dependent hypertension to renin-dependent hypertension. However, during Na restriction, antirenin system drugs lower BP significantly. Thus, in one-kidney one-clip Goldblatt hypertension and in patients with bilateral renal artery stenosis, elevated BP is maintained by whatever mechanism is available, based upon the body Na content—either renin-Ang II when body Na is reduced or Na-volume when body Na is replete or in excess. The behavior of the renin system provides an important clue to the underlying mechanism.
Patients with bilateral renovascular disease show a marked decrease of BP and exacerbation of azotemia when treated with an ACE inhibitor, especially when volume depleted by concurrent diuretic treatment. [371] [426] Furthermore, renal vein renin patterns may be similar to that of unilateral disease, with lateralization of renin secretion to the predominantly ischemic kidney.[360] Thus, these patients may also have renin-dependent hypertension.
In summary, the pathogenesis of bilateral renovascular hypertension is characterized by the participation of both renin and volume factors. The predominant mechanism will reflect the total body Na content and, potentially, the use of drugs that interrupt the renin system (e.g., ACE inhibitor, Ang II receptor blocker).
Sodium-Dependent Forms of Hypertension
The extracellular Na+ content determines body volume, as Na+ constitutes the major osmotic factor regulating the amount of water in the bloodstream and extracellular space. Plasma protein and red blood cell mass are also key elements in determining circulating whole blood volume, but these factors appear normal and fixed in most patients with uncomplicated hypertension. Accordingly, Na contributes crucially to the volume factor that is involved to some extent in all BP phenomena. Thus, when cardiac performance is normal, arteriolar vasoconstriction and the arterial filling volume become two dynamic final determinants of BP.[73]
The mechanism by which Na retention exerts its pressor effects is still not completely understood. More than one pathway to the source of low-renin hypertension has become apparent. The first of these indications is that Ca2+channel blocking drugs lower BP in low-renin patients with primary hypertension.[418] Serum Ca2+ concentration is directly related to PRA, whereas serum Mg2+ concentration is inversely related to PRA. [428] [429] A high-salt diet has also been demonstrated to reduce plasma Ca2+, possibly because of cellular influx, to levels similar to those seen in low-renin primary hypertension. Salt restriction has been shown to have the opposite effect on cellular Ca2+.[421] Therefore, the influence of dietary Na on BP may be mediated by changes in the concentration or activity of divalent cations. Recent studies using selective Na/Ca2+ exchanger (NCX) inhibitors and genetically engineered mice support the hypothesis that salt-sensitive hypertension is triggered by Ca2+ entry through NCX type 1 in arterial smooth muscle.[422] Moreover, the antihypertensive efficacy of Ca2+ blockers is greater among those with low-renin hypertension and the antihypertensive efficacy of Ca2+ channel blockade is apparently not augmented by Na+ depletion and may actually be enhanced by the concurrent liberalization of salt intake.[423]
Na may also affect peripheral resistance through its interaction with endothelium-derived vasoactive substances. In rats, dietary Na loading stimulates the production of NO from the MD.[424] Vasodilatation of the afferent arteriole counteracts the vasoconstriction generated by the TGF response. When NOS is inhibited, MAP and renal vascular resistance rise; greater increases occur during adaptation to a high Na intake when compared with low Na intake. [316] [434] These responses appear to be independent of renin system activity. Other mechanisms may also contribute to these effects, including autoregulation-induced changes in arteriolar constriction or changes in the transport or distribution of Na+ across cell membranes and between the intravascular and the interstitial compartments.
Primary Hyperaldosteronism
The term primary hyperaldosteronism (PAL) was originally coined by Conn[212] to describe the clinical syndrome characterized by hypertension, hypokalemia, hypernatremia, alkalosis, and periodic paralysis caused by an aldosterone-secreting adenoma. As diagnostic tests for quantifying the components of the RAAS have become available, the syndrome PAL is now identified by hypertension, suppressed PRA, and high urinary and plasma aldosterone levels. However, several unresolved issues remain related to the diagnosis and management of this disorder. For example, what is the prevalence of primary aldosteronism and which diagnostic screening tests should be used? Moreover, the term PAL encompasses a family of adrenal disorders, including variants that cannot be cured by adrenalectomy. [435] [436] [437] Which diagnostic tests are most likely to identify patients with surgically remediable subtypes?
Pathophysiology
When aldosterone is secreted in amounts that are inappropriately high for the state of Na balance, Na reabsorption is augmented by the distal nephron. [438] [439] [440] [441] Extracellular Na content is increased and is accompanied by water so that isotonicity is maintained as body volume increases. Na accumulation is usually gradual and is dependent on its availability and on the magnitude of aldosterone excess. After a gain of about 1.5 kg of extracellular fluid, however, there is diminished renal Na reabsorption. This phenomenon, which accounts for the absence of edema in this disorder and is referred to as mineralocorticoid escape, enables the kidney to overcome the Na-retaining effects of mineralocorticoid excess and, consequently, maintain Na balance. [442] [443] Aldosterone-induced increases in GFR and fractional excretion of Na are required for mineralocorticoid escape, and thus, it is a manifestation of the pressure natriuresis phenomenon.[435] In addition, atrial natriuretic peptide participates in this response.[436] More recently, dynamic regulation of Na transport by the distal nephron has been shown to contribute importantly to this adaptation to high levels of aldosterone.[437] For example, increased excretion of Na during mineralocorticoid escape is associated with a major decrease in the abundance of the thiazide-sensitive Na-Cl cotransporter (NCC) in the distal nephron.[433]
As the understanding of adrenal physiology, biochemistry, histopathology, molecular biology, and genetics has advanced, it has become evident that there are distinct subsets of PAL. Reports from several centers indicate that the majority of patients with PAL can have hypertension and metabolic abnormalities ameliorated by unilateral adrenalectomy. [447] [448] [449] Patients who are most likely to respond favorably to surgery are those in whom aldosterone production is highly autonomous from renin[426] (see Diagnostic Studies). Among the features that identify autonomy are (1) limited effect on aldosterone production by maneuvers that either increase the Ang II level (e.g., angiotensin II infusion or postural stimulation) or decrease it (e.g., Na infusion, fludrocortisone administration, ACE inhibition), (2) increased levels of aldosterone biosynthetic precursors (e.g., 18-hydroxycorticosterone-to-cortisol ratio), (3) elevated levels of “hybrid” steroids (e.g., urinary C-18 cortisol methyloxygenated metabolites [18-hydroxycortisol and 18-oxocortisol]), [449] [450] and (4) lateralization of aldosterone secretion to one adrenal gland. [448] [449] [451] [452] Identifying patients with these diagnostic features has important implications for determining clinical management and for predicting the response to treatment (see Treatment, later).
The response of PRA to aldosterone-induced Na retention and BP elevation is the cornerstone of early diagnosis of PAL. Accordingly, the normal renal juxtaglomerular responses to increased BP and the increased distal delivery of Na chloride result in suppression of PRA. [73] [243] [453] Moreover, PRA remains low even in the presence of Na depletion or acute furosemide administration.[445] This observation is in marked contrast to the elevated PRA seen in patients with secondary aldosteronism, whereby oversecretion of aldosterone is the consequence of excess production of renin and Ang II, usually caused by renal arterial or parenchymal disease.[73]
In contrast with healthy subjects, in patients with PAL, the oversecretion of aldosterone is not suppressed by Na loading. [435] [454] Conversely, with ambulation, patients with an aldosterone-producing adenoma (APA) do not exhibit the characteristic rise in aldosterone secretion found in normal subjects. [455] [456] These observations highlight the autonomous secretion that is present in patients with APA and identify differences in the pathophysiology of APA and other subtypes of PAL. [452] [456] [457]
In a subset of APAs, aldosterone production is stimulated by the RAAS, as determined by Ang II infusion and postural stimulation.[449] In this case, Ang II infusion no longer stimulates aldosterone release shortly after ipsilateral adrenalectomy, suggesting that the adenoma is the sole source of aldosterone. This variant, referred to as Ang II-responsive (Ang II-R) APA, has other unique biochemical and histologic features.[449] In contrast to the typical APA, which is unresponsive to angiotensin (Ang II-U APA) and in which there is overproduction of cortisol C-18-oxygenated metabolites (i.e., 18-oxocortisol, 18-hydroxycortisol), Ang II-R APA is not associated with increased levels of these hybrid steroids. In addition, plasma cortisol levels are suppressible in Ang II-U APA but not in Ang II-R APA. These findings indicate that overproduction of cortisol occurs from some APAs.[449a] These heterogeneous biochemical responses are consistent with the histologic characteristics: Ang II-U APAs consist predominantly of fasciculate-like cells, whereas Ang II-R APA are primarily composed of glomerulosa-like cells. A reciprocal relationship between the increment in plasma aldosterone during Ang II infusion and the percentage of fasciculate-type cells in the adenoma has been reported, indicating that the aldosterone responsiveness to Ang II was related to the predominant tumor cell type.[449]
Biglieri and co-workers [460] [461] and others [448] [449] have characterized a subset of patients with autonomous aldosterone production in whom an adrenal adenoma could not be identified. This variant has been referred to as primary adrenal hyperplasia (PAH). The adrenal glands in PAH are hyperplastic, frequently with a dominant nodule. As in patients with Ang II-U APAs, aldosterone production in patients with PAH is autonomous.[448] Furthermore, correction of the metabolic abnormalities and hypertension in this subset occurs after unilateral adrenalectomy.
Adrenal carcinoma (ACC) is an extremely rare cause of PAL. [462] [463] Of 141 patients with ACC presenting to the Mayo Clinic for surgery, 15 were identified with aldosterone-secreting ACC.[454] Isolated aldosterone hypersecretion was present in 10 patients, and mixed hormonal secretion was detected in 5. Mean tumor size and weight were 10.8 cm and 453 g, respectively. The perioperative mortality was 20% and the disease recurrence rate was 70%, with a median interval of 17 months, and 5-year survival was 52%. Patients with aldosterone-secreting ACC had an increased risk of perioperative mortality compared with those with an adrenal carcinoma that did not secrete aldosterone (20% vs. 5%).
Glucocorticoid-Remediable Aldosteronism.
The pathogenesis of idiopathic hyperaldosteronism associated with bilateral adrenal hyperplasia remains uncertain. However, a systemic stimulus other than Ang II or ACTH seems to be responsible. Less common disorders associated with bilateral adrenal hyperplasia and hyperaldosteronism have been identified and characterized (see PAH, earlier). Glucocorticoid-remediable aldosteronism (GRA), also termed familial hyperaldosteronism type 1 (FH-1), is an autosomal dominant disorder in which aldosterone biosynthesis is regulated by ACTH rather than by the RAAS. [463] [465] [466] [467] [468] The exaggerated aldosterone responsiveness to ACTH in GRA can be corrected by glucocorticoid treatment. [437] [467] Clinical features include a strong family history of hypertension, early-onset hypertension, and an increased risk of intracerebral hemorrhage or aortic dissection.
The most common, routine laboratory finding is a low PRA level; however, other biochemical evidence of aldosterone excess may be absent (e.g., hypokalemia). [469] [470] A key diagnostic feature is the overproduction of C-18 cortisol-aldosterone structural hybrids, 18-hydroxycortisol and 18-oxocortisol, which are formed when cortisol is accepted by aldosterone synthase as a substrate for methyloxidation.[461] Normally, this enzyme is expressed predominantly in the adrenal glomerulosa zone. [472] [473] Based on these biochemical features and the associated hyperplasia of the zona fasciculata, Ulick and associates [450] [471] proposed that the fascicular zone acquires aldosterone synthase activity, thereby abrogating the normal zonation of adrenal function. This hypothesis was supported by the finding that GRA is caused by a chimeric gene duplication resulting from unequal crossing over between the highly homologous 11-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes, which are located in close proximity on chromosome 8. [466] [474] This chimeric gene represents a fusion of the 5′ ACTH-responsive promoter region of the 11-hydroxylase gene and 3′ coding sequences of the aldosterone synthase gene. It results in ectopic expression of aldosterone synthase activity in the cortisol-producing zona fasciculata that is stimulated by ACTH instead of Ang II. Furthermore, because of its aberrant expression in the fascicular zone, the enzymatic product of this chimeric gene uses cortisol as a substrate for C-18 oxidation to the cortisol-aldosterone hybrid steroids.[441] Treatment of this syndrome with low doses of exogenous glucocorticoid inhibits ACTH secretion, suppresses aldosterone production, thereby promoting natriuresis, normalizes PRA, and consequently reduces BP and corrects metabolic abnormalities caused by mineralocorticoid excess.
Although GRA is a rare disorder, several previously undiagnosed patients were discovered when elevated urinary levels of 18-hydroxycortisol and 18-oxocortisol were used to screen the relatives of a proband with GRA.[459] All affected adults were hypertensive before age 20 years and had lower PRA than their unaffected family members. Surprisingly, none of those affected was hypokalemic, and their urinary aldosterone excretion overlapped with the unaffected group. An attenuated aldosterone response to K+ in GRA has been described in association with a sharp diurnal decline in aldosterone in this ACTH-regulated syndrome.[460] It has been proposed that these pathophysiologic responses in GRA cause milder clinical and laboratory manifestations of hyperaldosteronism compared with other forms of primary aldosteronism, thereby producing volume expansion with minimal renal K+wasting.[460]
The preferred diagnostic test for GRA is direct genetic analysis to identify the chimeric CYP11B1/CYP11B2 gene. Other tests include 24-hour urine collection demonstrating overproduction of cortisol C-18 oxidation metabolites (i.e., 18-hydroxycortisol, 18-oxocortisol), and the dexamethasone suppression test.[464] Although C-18 hybrid steroids are also present in APA, the chimeric CYP11B1/CYP11B2 gene has not been identified in these tumors.[465]
Familial Hyperaldosteronism Type II (FH II).
Gordon and colleagues [476] [477] have described another familial form of primary aldosteronism termed FH-2, distinct from GRA (FH-1), in which aldosterone production is not suppressed by glucocorticoid treatment. The inheritance pattern of FH-2 has not been completely determined, and there is no common histologic presentation, encompassing family members with Ang II-R APA, Ang II-U APA, and bilateral hypersecretion of aldosterone.
Apparent Mineralocorticoid Excess.
Apparent mineralocorticoid excess (AME) is characterized by hypertension, low PRA, low urinary aldosterone excretion rate, and increased urinary excretion of metabolites of cortisol rather than cortisone (ratio of free cortisol-to-cortisone and tetrahydrocortisol-to-tetrahydrocortisone). [437] [478] [479] Normally, the mineralocorticoid receptor in vitro binds cortisol and aldosterone with equal affinity, whereas cortisone binding is less avid. [479] [480] Although the serum concentration of cor-tisol is normally 1000-fold greater than aldosterone, cortisol is inactivated by conversion to cortisone (which has a re-latively low affinity for the mineralocorticoid receptor) by 11β-hydroxysteroid dehydrogenase at mineralocorticoid responsive tissues. This allows aldosterone, rather than cortisol, to gain access to the mineralocorticoid receptor. Thus, it is 11β-hydroxysteroid dehydrogenase rather than the mineralocorticoid receptor, per se, that confers tissue specificity for aldosterone. Hypothalamic-pituitary-adrenal axis responsiveness is normal in AME, and the serum cortisol is normal and does not aid in the diagnosis.
Treatment options in AME include (1) blockade of either the mineralocorticoid receptor (e.g., spironolactone) or the renal apical Na channel (amiloride), or (2) suppression of endogenous cortisol production with dexamethasone, which has a low affinity for the mineralocorticoid receptor. In patients with Cushing's syndrome, cortisol can become the active mineralocorticoid, especially in the ectopic ACTH syndrome in which cortisol secretion is extremely high. [481] [482] In this disorder, mechanisms of cortisol inactivation are overwhelmed, allowing it to gain access to the mineralocorticoid receptor.
Licorice ingestion can cause hypertension with features that are similar to AME. [482] [483] [484] [485] Glycerrhyzic acid and its hydrolytic product (glycyrrhytenic acid) are the active ingredients of licorice that inhibit 11β-hydroxysteroid dehydrogenase and thereby allow cortisol to gain access to the mineralocorticoid receptor. Aldosterone receptor antagonism normalizes BP, prevents up-regulation of vascular ET-1, and restores NO-mediated endothelial function in an animal model of glycyrrhizic acid-induced hypertension.[476]
Liddle's syndrome is an autosomal dominant condition characterized by low renin hypertension, hypokalemia, renal potassium wasting, and low levels of aldosterone.[477] The genetic defects responsible for this syndrome are deletion mutations in the C-terminus of the b/g subunits of the renal epithelial Na channel (ENaC). [488] [489] [490] [491] These gain of function mutations lead to constitutive activation of ENaC, resulting in electrogenic Na reabsorption and kaliuresis. Amiloride, which blocks the apical Na channel, is effective treatment. By contrast, mineralocorticoid receptor blockade (e.g., spironolactone) is ineffective because renin, Ang II, and aldosterone levels are all suppressed by the Na-dependent hypertension.
MRL810 Mutation.
An autosomal dominant form of hypertension is caused by a mutation in the ligand-binding domain of the mineralocorticoid receptor (MRL810).[482] Carriers of this mutation are hypertensive before age 20, and aldosterone secretion is suppressed. Normally, steroids with 17-keto groups (estradiol, testosterone) and those lacking 21-hydroxyl groups (progesterone) are mineralocorticoid receptor antagonists because they bind but do not activate it. However, these steroids are potent activators of the MRL810 receptor, with progesterone-stimulating mineralocorticoid activity that is indistinguishable from aldosterone. The aberrant nature of MRL810 is underscored by the finding that spironolactone, the drug used because of its efficacy as a mineralocorticoid receptor antagonist, instead activates the MRL810 receptor.
Progesterone levels normally increase 100-fold during pregnancy, and thus, the MRL810 mutation may have particular relevance as a cause of gestational hypertension. Pregnant patients have been reported with an exacerbation of hypertension, hypokalemia, renal potassium wasting, and undetectable aldosterone levels.[482] The agonist activity of progesterone has been attributed to the alteration by the MRL810 mutation of van der Waals interactions within the ligand binding domain that eliminates the requirement for a 21-hydroxyl group for receptor activation.[34]
Epidemiology
PAL has traditionally been considered a rare form of hypertension, affecting 1% to 2% of hypertensive patients, with APA the most prevalent diagnostic subset. [449] [454] [493] However, results of screening efforts at several large centers, which rely primarily on the use of the ratio of plasma aldosterone to PRA (see Aldosterone-to-Renin Ratio [ARR], later), suggest that the prevalence of PAL is substantially higher than previously believed. After ARR was introduced as a screening strategy, the reported prevalence of PAL increased by 5- to 15-fold at five medical centers, with detection rates of PAL ranging from 3% to 32% of all hypertensive patients. [447] [494] This screening strategy has also uncovered a higher proportion of PAL patients with milder laboratory abnormalities, accounting for the observation that hypokalemia was found in only 9% to 37% of patients. Moreover, a dramatic change in the prevalence of diagnostic subsets of PAL has been reported. Whereas APA was reported as the cause of PAL in two thirds of patients prior to the use of ARR screening, [449] [454] [493] since ARR was introduced, a marked increase in the proportion of patients with bilateral adrenal hyperplasia has been reported and the prevalence of patients with APA has decreased to a range of 9% to 50%. [447] [448] [451] [494] However, the use of ARR as the cornerstone for PAL screening has been challenged and the validity of this apparent dramatic shift in the epidemiology of PAL questioned [495] [496] (see later).
Clinical Characteristics
The clinical findings in patients with this syndrome are primarily due to the increased total body Na content and deficit in total body potassium.[487] Symptoms include nocturia and urinary frequency, reflecting the urinary concentrating defect induced by the potassium deficit, although the patient may not be aware of these symptoms, and thus, the history may have to be elicited. In patients with more severe hypokalemia and other manifestations, muscular weakness, frontal headaches, polydipsia, paresthesias, visual disturbances, temporary paralysis, cramps, and tetany may occur. If the patient is normokalemic, these characteristic symptoms are usually mild or absent.
Patients with PAL are not edematous because Na retention in this syndrome is limited by the mineralocorticoid escape phenomenon[488] (see earlier). Patients with an adenoma, however, usually have more extensive manifestations of mineralocorticoid excess than those with hyperplasia, including more severe hypertension. [449] [499] The physical examination is not usually distinguishable from primary hypertension, unless hypokalemia is severe.
Hypertension is present in virtually all patients with PAL although malignant hypertension occurs rarely. The prevalence of PAL is reportedly higher in patients with more severe hypertension. Of patients evaluated for PAL at primary care centers in Chile, PAL prevalence was 2% in those with BP 140 to 159/90 to 99 mm Hg, 8% in those with BP 160 to 179/100 to 109 mm Hg, and 13.2% in those with BP higher than 180/110 mm Hg.[490]
At our center, after withdrawal of antihypertensive medication, patients with an adenoma had significantly higher systolic (184 vs. 161 mm Hg) and diastolic (112 vs. 105 mm Hg) levels than those with adrenal hyperplasia.[440]Systolic BP was 175 mm Hg or greater in 66% with adenoma, compared with only 15% with hyperplasia. Diastolic pressure was 114 mm Hg or greater in 50% of patients with adenoma, compared with only 19% of those in the hyperplasia group. There was a direct correlation (r = 0.58) between the urinary aldosterone excretion rate and the MAP among the adenoma patients.
In contrast to the escape from Na retention that occurs in this syndrome, aldosterone-mediated renal secretion of potassium is persistent and causes total body potassium deficit, hypokalemia, nephrogenic diabetes insipidus, and related symptoms.[487] In the Cornell study,[440] serum potassium levels were significantly lower in the adenoma patients (3.0 vs. 3.5 mEq/L). Levels below 2.8 mEq/L occurred in 44% of the adenoma group compared with only 6% of the group with hyperplasia. The profound hypokalemia that occurs in patients with an adenoma contributes to its marked metabolic alkalosis. Conversely, 18% of the hyperplasia group had a serum potassium concentration above 3.5 mEq/L compared with only 6% of those with an adenoma. Several previous studies have also reported normal serum potassium levels in approximately 20% of patients with PAL, [451] [493] [494] [500] [501] [502] [503] most commonly in patients with adrenal hyperplasia. Because severe hypokalemia occurs less frequently in patients with restricted dietary Na intake, we do not recommend screening patients for this syndrome unless they are adequately Na loaded (see under Diagnostic Studies).
Although case reports and other studies with relatively few patients illustrate that cardiovascular complications can occur in patients with PAL, there is little information about their prevalence. [504] [505] [506] [507] [508] [509] [510]However, a recent case-control study identified 124 patients with PAL (APA in 52%) from a rigorously screened population of 5500 patients referred for evaluation of hypertension.[501] Compared with the control group of 465 patients with primary hypertension, those with PAL were at significantly greater risk of atrial fibrillation, MI, stroke, and LVH during a mean follow-up period of 13.6 months. BP was reportedly controlled during follow-up by either unilateral adrenalectomy or antihypertensive drug treatment. The risk of complications was not preferentially associated with either diagnostic subtype of PAL. The cardiovascular complication rates reported in that study were unusually high, and those results will have to be confirmed in subsequent studies. However, treatment with mineralocorticoid receptor blockade (i.e., spironolactone, eplerenone) in patients with severe HF, which is commonly associated with secondary hyperaldosteronism, improves survival and decreases the risk of cardiovascular complications. [187] [188] Although there is a temptation to relate the cardiovascular impact of secondary hyperaldosteronism in HF with that of PAL, this comparison has obvious limitations. Nevertheless, whether the dramatically high prevalence of cardiovascular complications reported can be generalized to all patients with PAL will require further investigation.
Diagnostic Tests
The diagnostic tests described later are designed to (1) screen the large hypertensive population for PAL and (2) identify patients with surgically remediable subtypes of PAL.
Unprovoked hypokalemia is the hallmark of hyperaldosteronism, but as already discussed, serum K+ levels between 3.5 and 4.0 mEq/L are relatively common in patients subsequently proven to have PAL. Moreover, patients with primary hypertension may exhibit hypokalemia, especially during treatment with thiazide and loop diuretics. Monitoring serum K+ following salt loading is required to identify the entity of normokalemic PAL. [447] [449] [454]
Plasma Renin Activity.
The first breakthrough followed the ability to accurately determine PRA levels. In 1964, Conn and associates[502] demonstrated the suppression of PRA in patients with PAL. Until that time, a major diagnostic dilemma was distinguishing patients with PAL from those with excessive secretion of aldosterone that was the consequence of high levels or renin secretion due to primary renal parenchymal or renovascular diseases (secondary hyperaldosteronism). This problem was solved by the accurate measurement of PRA. [73] [513]
The JNC7 report erroneously recommends the measurement of 24-hour urine aldosterone as the preferred screening test for primary aldosteronism.[1] This is an inadequate and incorrect choice because 24-hour urine aldosterone levels are elevated in disorders of both primary and secondary hyperaldosteronism and, thus, would fail to discriminate them.[344] Measurement of PRA is an essential diagnostic test and should precede the measurement of either plasma or urine aldosterone. Primary aldosteronism would be an extremely unlikely diagnosis in the absence of a low PRA level, although it may occur in patients with concurrent kidney disease.[504] Nevertheless, screening patients with a 24-hour urine aldosterone measurement in the absence of a PRA level will not resolve this issue and is not indicated.
Two methods are now commonly used to measure plasma renin. The PRA enzyme kinetic assay quantifies the amount of Ang I generated during incubation of plasma. PRA is expressed as the hourly rate of Ang I generation (as ng/mL/hr). It reflects the net capacity of the blood to generate Ang II because ACE is not normally rate limiting unless it is pharmacologically blocked.[505] This is the most sensitive method available for quantifying the low levels of renin activity that are characteristic of PAL. The direct renin assay is an alternative method that is based upon a chemiluminescence assay (expressed as microU/mL). Unlike the PRA measurement by the enzyme kinetic assay, the direct renin method does not measure Ang I generation and lacks its sensitivity.[505]
Although approximately one-third of patients with primary hypertension also exhibit low PRA,[135] with an increased prevalence of low renin primary hypertension among black patients,[138] these patients are normokalemic and have normal aldosterone responses to changes in posture, Na depletion, and saline loading.
Aldosterone-to-Renin Ratio.
An elevated ARR is an indicator of autonomous aldosterone secretion that is now widely used as a screening test for PAL. [436] [451] [494] [516] ARR greater than 40 (aldosterone [ng/dL]-to-PRA [ng/mL/hr]) was initially shown to successfully identify untreated patients with APA.[506] Since then, investigators from several centers have used ARR cutoff values ranging from 14 to 50 [448] [449] [494] [500] and, consequently, have identified PAL in significantly higher proportions of patients with previously diagnosed primary hypertension. However, a precise partition value for the ARR has not been established in the diagnosis of PAL. Furthermore, ARR is not a useful index for differentiating these diagnostic subsets or the potential for surgical cure.[440]
Several factors can have an impact on the measurements of PRA and aldosterone and, thus, influence the interpretation of the ARR. When the PRA is less than 1 ng/mL/hr, which is a characteristic finding in patients with PAL, then the ARR is disproportionately affected by small changes in the PRA.[507] For example, a patient with primary hypertension with a PRA 0.6 ng/mL/hr and a serum aldosterone level 8 ng/dL (ARR = 13) would be misdiagnosed with PAL if the result of PRA was erroneously reported as 0.2 ng/mL/hr (ARR = 40). The risk of a false-positive screening test, and hence, the likelihood of an incorrect diagnosis of PAL, is amplified because the accuracy of the PRA measurement in limited at these low levels. The large intra- and interpatient variations in plasma aldosterone, PRA, and ARR levels in patients with APA highlight this problem. In fact, only 37% of PAL patients always have the characteristic profile associated with APA (i.e., plasma aldosterone > 15 ng/dL, PRA < 0.5 ng/mL/hr, ARR >35).[508]
To minimize the risk that the ARR will result in an incorrect diagnosis, several additional steps should be employed before proceeding with the ARR as a screening test for primary aldosteronism[442]:
|
1. |
The patient should be seated when blood samples are obtained. |
|||||||
|
2. |
Hypokalemia should be corrected with oral potassium supplementation because potassium depletion attenuates aldosterone secretion and leads to a false-negative ARR. |
|||||||
|
3. |
Plasma (or serum) aldosterone concentration (PAC) greater than 15 ng/dL: Although there is no clearly defined level, a plasma aldosterone level less than 15 ng/dL is unlikely to occur in patients with PAL (especially those with APA). However, a false-positive ARR can occur at very low PRA levels encountered in patients with low renin essential hypertension (e.g., PRA 0.1 ng/mL/hr, PAC 6 ng/dL, ARR 60).[426] |
|||||||
|
4. |
Antihypertensive medications:
|
|||||||
|
5. |
Captopril test: ACE inhibitors and ARBs stimulate renin secretion and should be discontinued 2 weeks before testing to reduce the likelihood of potentially false-negative ARR, particularly in patients with idiopathic hyperaldosteronism or an Ang II-R adenoma. However, several investigators have reported that acute administration of a single dose of captopril 25 to 50 mg 1 to 2 hours before measurement of plasma renin and aldosterone levels enhances the accuracy for diagnosing patients with primary aldosteronism and have recommended its use for screening. [519] [520] [521] [522] If antihypertensive medication is required, verapamil and α1-adrenergic receptor blockers do not significantly influence renin or aldosterone secretion and, thus, are less likely to confound the ARR. |
|||||||
|
6. |
If ARR screening test is positive (>25–50), then a salt-loading suppression test is indicated (see later). |
Problems with the ARR as a Screening Test for PAL.
The ARR has gained broad acceptance and is now widely used to screen patients with primary aldosteronism. However, several methodologic inconsistencies have limited the interpretation of the ARR results.[485] As discussed previously, the elevated ARR is predominantly an indicator of the low PRA level and is especially vulnerable to variability in this assay that can occur from antihypertensive medication use and volume depletion.[486] Several centers that have reported ARR for the diagnosis of PAL do not utilize Na suppression protocols.[485] Moreover, only limited data exist regarding the sensitivity and specificity of ARR. In one study of patients in whom the adrenal status was clearly defined, an ARR of 32 or higher had a specificity of 61%.[513] Some investigators do not require an absolutely elevated plasma aldosterone level for the interpretation of an elevated ARR.[438]
Critics of ARR for PAL screening raise other issues, including the risks of potentially unnecessary invasive testing and treatment (e.g., adrenal vein sampling [AVS]; adrenalectomy; see later). Moreover, bilateral adrenal hyperplasia predominates in patients with PAL detected by an elevated ARR. This diagnostic variant is not surgically remediable and requires treatment with antihypertensive medication, preferably a selective mineralocorticoid receptor antagonist (i.e., spironolactone or eplerenone). Hence, critics question the necessity of these elaborate maneuvers, when treatment with a mineralocorticoid receptor antagonist is the most likely outcome. The true sensitivity and specificity, cost efficacy, and safety can best be defined by properly designed clinical studies. Moreover, any safe screening test that can facilitate the stratification of patients with essential hypertension into more clearly defined pathophysiologic subgroups and can improve treatment efficacy is desirable.
Postural Stimulation Test.
Stimulation of renin and aldosterone secretion occurs in normal individuals during upright posture.[73] In subsets of PAL associated with autonomous aldosterone production (including Ang II-U adenoma, PAH), however, postural stimulation of aldosterone does not occur. [449] [455] [457] The postural stimulation test is conducted by drawing plasma cortisol and aldosterone levels at 8:00 am with the patient supine after an overnight recumbency and again while upright after 2 to 4 hours of ambulation. In subsets with highly autonomous aldosterone production, plasma aldosterone levels decrease during this test, reflecting the diurnal fall in ACTH. Normally, ACTH is a relatively minor stimulus for aldosterone production, but this effect is accentuated in Ang II-U adenoma and PAH because renin-angiotensin levels are highly suppressed.[514] A false-negative response, which might occur during a stress-related increase in ACTH, can be detected if plasma cortisol levels rise during upright posture. By contrast, in patients with idiopathic hyperaldosteronism or Ang II-R adenoma, renin and Ang II levels increase slightly during upright posture and aldosterone production increases owing to the increased sensitivity of the zona glomerulosa to Ang II.[449] In GRA, aldosterone production falls during the test because of the ACTH dependency of aldosterone biosynthesis. This response may, thus, lead to an inaccurate diagnosis of aldosterone-producing adenoma.
Na Loading.
Na-loading maneuvers are useful for identifying patients with PAL. [435] [451] [454] [494] [525] Accordingly, during volume expansion in normal individuals or in patients with primary hypertension, PRA levels decrease, and consequently, aldosterone secretion falls. In PAL, renin secretion is suppressed before salt loading, and therefore, additional volume expansion does not decrease aldosterone levels to the same extent as in normal subjects or patients with primary hypertension. Several salt-loading protocols have been validated for diagnostic screening[426]:
|
1. |
Oral Na loading for 3 to 5 days with 200 mEq/day or more (5 g Na/day). This may be accomplished by instructing the patient to eat a high-salt diet or to supplement the diet with NaCl tablets (1 g NaCl tablet = 17 mEq Na). On the last day of the high-salt diet, a 24-hour urine is collected to measure Na, K, and aldosterone. The test is positive if the aldosterone level is greater than 14 mg with a concomitant Na content greater than 200 mEq. Because Na-loading can cause kaliuresis and exacerbate hypokalemia, potassium chloride supplementation is required. |
|
|
2. |
Intravenous saline loading: Plasma aldosterone is measured after the infusion of 2 L 0.9% NaCl over 4 hours. PAL is ruled out if the plasma aldosterone level is less than 5 ng/dL and is confirmed if the level exceeds 10 ng/dL. Although a plasma aldosterone level in the 5- to 10-ng/dL range after Na loading is considered equivocal by some investigators, many consider a level greater than 5 ng/dL diagnostic of PAL.[426] |
|
|
Although this maneuver is useful for identifying patients with PAL, it does not adequately discriminate patients with an APA from those with nonadenomatous adrenal hyperplasia. By contrast, measurement of morning levels of plasma cortisol, aldosterone, and 18-hydroxycorticosterone after intravenous saline loading (1.25–2.0 L over 90-120 min) reportedly can distinguish these diagnostic subsets: In APA, the ratio of aldosterone to cortisol is greater than 2.2 or 18-hydroxycorticosterone to cortisol is greater than 3, whereas for patients with idiopathic hyperaldosteronism, the ratios are lower.[515] On a normal Na intake, a supine morning 18-hydroxycorticosterone level plasma greater than 50 ng/dL is characteristic of PAL, and a level 100 ng/dL or greater is diagnostic of aldosteronoma. [493] [526] |
||
|
3. |
Fludrocortisone suppression test: Plasma aldosterone and cortisol levels are measured in an upright position at 10:00 am after 4 days of administration of fludrocortisone (0.1 mg every 6 hours) and Na chloride supplementation (30 mEq thrice daily) with a corresponding 24-hour urine Na excretion rate of 3 mEq/kg/day. This test is diagnostic of PAL if, on day 4, the plasma aldosterone level exceeds 5 ng/dL, provided the concurrent PRA level is less than 1 ng/mL/hr, the serum potassium level is normal, and the plasma cortisol level at 10:00 am is no higher than it was at 7:00 am. [435] [447] |
Cortisol Metabolites.
C-18-Methyloxygenated metabolites of cortisol, 18-hydroxycortisol and 18-oxocortisol, are increased in PAL when it is caused by adenoma but not by nonadenomatous adrenal hyperplasia. [450] [471] This steroid pattern appears to reflect the loss of normal functional zonation of the adrenal gland (see earlier).
Lateralizing Tests
Adrenal Vein Sampling.
The diagnostic tests reviewed previously provide the biochemical evidence necessary to confirm the diagnosis of PAL. Although the results of these tests may identify surgically remediable variants, they do not locate the tumor and, thus, fail to guide surgical treatment. Adrenal CT and MRI scanning lack sufficient sensitivity and specificity to identify adrenal tumors less than 1.5 cm diameter and thus cannot reliably distinguish APA from bilateral adrenal hyperplasia. [448] [452] Thus, false-negative scan results can occur when a small APA is not identified because of limited spatial resolution or when an APA is misdiagnosed because of the concomitant benign unilateral or bilateral adrenal nodularity that occurs normally with aging.
The ability to measure plasma aldosterone concen-tration (PAC) from selectively catheterized adrenal veins has added an important dimension to the localization of APAs. [448] [449] [452] [502] [527] [528] Adrenal veins are catheterized by the percutaneous femoral approach, and blood is obtained from both adrenal veins and the inferior vena cava (IVC) below the level of the renal veins. Aldosterone and cortisol levels are measured from both adrenal veins and the IVC. To minimize stress-induced fluctuations in cortisol and aldosterone, continuous infusion of cosyntropin (50 mg/hr) is recommended, beginning 30 minutes before the catheterization and continuing throughout the procedure. Adrenal vein catheterization is considered to be technically successful if the adrenal vein cortisol level is significantly higher than that obtained from the IVC. The specific adrenal-to-IVC ratio cutoff value of 2 or greater for the cortisol concentration identifies a successful adrenal vein cannulation, although ratios ranging from 1.1 to 5 have been reported. [448] [452] [527] [528]
Recent studies have evaluated several criteria for lateralization of aldosterone secretion by AVS in which these levels are normalized for the corresponding adrenal venous cortisol concentrations, including[443]:
|
1. |
Lateralized ratio: Defined as the aldosterone-to-cortisol ratio of the dominant adrenal vein divided by the aldosterone-to-cortisol ratio of the nondominant adrenal vein. The patient with a lateralized ratio exceeding 5, together with a peripheral venous aldosterone level greater than 15 ng/dL, reportedly has about 180-times the odds of having an APA than patients having peripheral venous aldosterone level less than 15 ng/dL and a lateralized ratio less than 5.[518] Others have reported a lateralized ratio of greater than 4 to have a positive predictive index of 89%[443] and a sensitivity of 96% for the diagnosis of APA.[439] In a large series in which cosyntropin stimulation was not employed during AVS, and a very low ratio of cortisol adrenal-to-IVC was used to confirm successful adrenal vein catheterization, a lateralized ratio greater than 2 reportedly had a sensitivity of 80% for identifying APA.[517] |
|
|
2. |
Contralateral ratio: Defined as aldosterone-to-cortisol ratio of the nondominant adrenal vein divided by the aldosterone-to-cortisol ratio in the matching antecubital vein or IVC. When this value is less than 1, it indicates suppression of aldosterone secretion by the uninvolved adrenal gland and has been reported to have a high positive predictive value in patients with APA. It has been proposed that a contralateral ratio less than 1 is diagnostic of APA and is, thus, an important consideration when the vein from the affected adrenal gland (i.e., with the adenoma) is not successfully sampled. However, there is considerable disagreement regarding the importance of this value in separating the diagnosis of APA from bilateral adrenal hyperplasia. [448] [452] [529] |
|
|
3. |
Ipsilateral ratio (aldosterone-to-cortisol ratio in the dominant adrenal vein divided by the aldosterone-to-cortisol ratio in the matching antecubital vein or IVC). This value does not value in distinguishing the diagnosis of APA from bilateral adrenal hyperplasia.[443] |
Technical problems that are encountered during AVS include (1) difficulty in catheterizing the short right adrenal vein, (2) trauma, including adrenal hemorrhage that can result in acute adrenal insufficiency, (3) the dilution of blood by blood from nonadrenal sources, and (4) the episodic changes in aldosterone secretion coincident with changes in cortisol.[445] Most of these problems can be controlled by careful catheter localization, simultaneous plasma cortisol measurements to document appropriate catheter placement, and collection of blood during ACTH administration.
Radionuclide Scintigraphy.
[6b-131I] Iodomethyl-19-norcholesterol (NP-59) scintigraphy has the potential to correlate anatomy and function of APA. However, this test is limited by poor tracer uptake by tumors less than 1.5 cm in diameter and by the exposure to and disposal of a radioactive isotope.[439] This test is not routinely used at most centers for the diagnostic evaluation of primary aldosteronism.
The sensitivity and specificity of adrenal imaging techniques may differ substantially among medical centers, depending on the local resources and expertise. It is important to recognize that incidental, nonfunctioning adrenal masses are relatively common: They are found in 0.6% of all CT scans of the abdomen, and 2% to 9% of adults have grossly visible adenomas at autopsy. Conversely, a subset of patients with surgically curable PAL have radiographically normal adrenal glands. [448] [449] [530] Therefore, to minimize confusion during diagnostic evaluation, radiographic imaging procedures should be withheld until after biochemical confirmation of PAL has been accomplished.[520]
Diagnostic Strategy
The results of diagnostic screening of patients with this syndrome are often ambiguous, especially when the serum potassium level is in the normal range. Relatively simple tests that can improve the diagnostic accuracy include (1) 24-hour urinary aldosterone excretion rate 14 mg or greater and a PRA less than 1.0 ng/mL/hr, after Na loading for at least 3 days (urinary Na content > 200 mEq/day), (2) ARR greater than 50; with a concurrent serum aldosterone greater than 15 ng/dL, (3) failure to increase PRA after Na restriction, furosemide-induced diuresis,[445] and (4) supine plasma 18-hydroxycorticosterone levels above 50 ng/dL or ratio of plasma 18-hydroxycorticosterone to cortisol greater than 3 after saline infusion. Measurements of aldosterone should be performed only after potassium supplementation because aldosterone secretion is attenuated by the potassium deficit and, thus, may obfuscate the diagnosis. The presence of hypokalemia and renal potassium wasting (24-hr urine K >40 mEq), together with the characteristics described previously, confirms the diagnosis of primary aldosteronism.
The sensitivity and specificity of each of these diagnostic maneuvers can be adversely influenced by concurrent use of antihypertensive medications. For example, β-adrenoceptor antagonists markedly decrease PRA in primary hypertension and may alter the interpretation of these tests. [358] [531] Hypokalemia when caused by thiazide diuretics may be difficult to distinguish from PAL, although the PRA level is often elevated during diuretic use in patients with essential hypertension.[73] ACE inhibitors and calcium channel antagonists reportedly reduce aldosterone biosynthesis and improve hypokalemia in some patients with PAL [502] [532] (see later). Therefore, antihypertensive medications should be discontinued for at least 2 weeks before diagnostic evaluation and potassium supplements provided to hypokalemic patients. Spironolactone should be discontinued for at least 1 month before these biochemical assessments because it has a long duration of action.
Figure 42-13 is a diagnostic algorithm that can be useful for directing treatment when biochemical screening tests are indicative of PAL. Hypertensive patients with a low PRA level (<0.65 ng/mL/hr) warrant measurement of plasma aldosterone level, particularly if their BP is difficult to control. Those patients with an ARR greater than 25 to 50 should undergo either an oral or an intravenous Na-loading protocol followed by a repeat measurement of either plasma or 24-hour urine aldosterone level. Failure to suppress aldosterone by Na loading is diagnostic of primary aldosteronism. To exclude GRA, screening for the chimeric gene is indicated, particularly if there is a personal history or family history of early-onset hypertension, stroke, or aortic dissection. If negative, AVS is warranted. Adrenal imaging, preferably by CT scan, does not reliably exclude or confirm the diagnosis of APA, but it is reasonable at this point as it can assist the interventional radiologist in identifying anatomic landmarks. A positive lateralized ratio or, perhaps less reliably, a positive contralateral ratio is suggestive of a surgically remediable lesion regardless of the radiographic appearance of the adrenal gland. In those patients with nondiagnostic or unsuccessful AVS results, a positive postural stimulation test, and elevated levels of serum 18-hydroxycorticosterone and 24-hour urine 18-hydroxycortisol are strongly suggestive of a surgically remediable diagnostic subtype. In that case, we often treat the patient medically with a mineralocorticoid receptor antagonist (e.g., spironolactone, eplerenone) for 6 to 12 months and then repeat AVS after withdrawal of this medication for 4 to 6 weeks. Adrenalectomy should be preceded by several weeks of adequate control of hypertension and correction of hypokalemia and other metabolic abnormalities (see later).
|
|
|
|
|
|
|
FIGURE 42-13 Algorithm for diagnostic testing in patients with suspected primary aldosteronism. A/C ratio, aldosterone to cortisol ratio; DOC, deoxycorticosterone; GRA, glucocorticoid remediable aldosteronism; 18-OHB, plasma 18-hydroxycorticosterone; 18-OHF, 24-hour urine 18-hydroxycortisol; PRA, plasma renin activity. (From Vaughan E, Blumenfeld J: The adrenals. In Wein AJ, Kavoussi LR, Novick AC, et al (eds): Campbell-Walsh Urology, vol. 4. Philadelphia, WB Saunders, 2006, pp. 1819–1867.) |
|
If the patient fails to lateralize aldosterone secretion during AVS, has a negative postural stimulation test, and normal levels of 18-hydroxycorticosterone and 18-hydroxycortisol, adrenalectomy is not indicated, and the patient should be treated with a mineralocorticoid receptor antagonist. When a discrete adrenal tumor appears to be present in this situation, unilateral adrenalectomy may be considered, particularly in relatively young patients (<40 yr old[439]). However, the risk of persistent hypertension in this situation is not well established but is probably relatively high.
Treatment
Idiopathic Hyperaldosteronism (Bilateral Adrenal Hyperplasia).
The cornerstone of medical therapy in PAL caused by idiopathic hyperaldosteronism is a mineralocorticoid receptor antagonist (i.e., spironolactone, eplerenone). The efficacy of this drug class relates to the reduction in plasma volume in disorders associated with aldosterone excess. Although a favorable BP response to spironolactone has been associated with improved chances of surgical cure, it does not reliably predict outcome.[523] Side effects of spironolactone include painful gynecomastia, erectile dysfunction, decreased libido, and menstrual irregularities that are caused by nonspecific binding to cellular receptors for progesterone and dihydrotestosterone. In a study of 182 patients with essential hypertension treated with spironolactone, daily doses of 75 to 100 mg lowered BP as effectively as 150 to 300 mg/day. Overall, gynecomastia developed in 13% of patients and its occurrence was dose-related—6.9% of patients taking 50 mg/day were symptomatic compared with 52% of those taking a dose of 150 mg/day or more.[524]
Eplerenone is a steroid-based competitive and highly selective mineralocorticoid receptor antagonist that was recently approved for use in patients with primary hypertension. This drug has 0.1% of the binding affinity to androgen receptors and less than 1% of the binding affinity to progesterone receptors compared with spironolactone.[427] Although eplerenone is reported to be effective, with a side effect profile similar to that of placebo in patients with primary hypertension,[427] there are no reported studies comparing it with spironolactone in patients with primary aldosteronism.
Amiloride can also effectively lower BP and correct hypokalemia in patients with gynecomastia or other side effects associated with spironolactone.[525] The dihydropyridine calcium channel antagonists can acutely decrease BP and aldosterone secretion in patients with this syndrome. [502] [532] Other studies of longer duration, however, have failed to demonstrate these beneficial effects when nifedipine was used as monotherapy. [536] [537] ACE inhibitors have been reported to successfully treat some patients with hyperplasia in whom aldosterone production is not completely autonomous from Ang II stimulation.[492] Phentolamine does not acutely reduce BP; therefore, a role for α-adrenergic receptor blockade has not been established.[528] Nevertheless, long-term treatment with prazosin is effective in low-renin essential hypertension, suggesting that α-adrenergic receptor antagonists may have an ancillary role in the treatment of PAL.[529]
Subsets of patients with PAL who demonstrate autonomous aldosterone production should be managed with excision of the adrenal gland containing the adenoma or, in the case of nonadenomatous adrenal hyperplasia, the gland from which aldosterone secretion is predominant. This rationale is based on the observation that both the metabolic abnormalities and the hypertension are alleviated by unilateral adrenalectomy in a vast majority of these patients.[448] By contrast, patients with idiopathic hyperaldosteronism usually do not have significant improvement in hypertension after unilateral or bilateral adrenalectomy.
Aldosterone-Producing Adenoma.
Laparoscopic unilateral adrenalectomy is now the standard of care for patients with an APA. Although more than 90% of patients will have their BP controlled postoperatively, antihypertensive medication is required in 40% to 70%.[436] [449] Factors that have been associated with persistent hypertension after unilateral adrenalectomy include age greater than 50 years, duration of hypertension, increased serum creatinine, one first-degree relative with hypertension, and preoperative use of more than two antihypertensive medications. [436] [449] Preoperative renin system activity was found to be an important predictor of BP outcome.[440] Cured patients had significantly lower pretreatment PRA levels than those who were not cured. Furthermore, in cured patients, there was also a correlation between the preoperative urinary aldosterone excretion and the relative decrease in diastolic BP following adrenalectomy (r = 0.59). In that study, all patients in whom lateralization of aldosterone secretion occurred had hypertension cured or improved by adrenalectomy.
Hypertension in Chronic Kidney Disease: Volume-Vasoconstriction Analysis
Pathophysiology of Hypertension in Chronic Kidney Disease
Substantial evidence provided in this chapter illustrates that primary hypertension is not a single entity, but rather an array of heterogeneous disorders in which patients can be stratified according to distinct pathophysiologic mechanisms. As discussed earlier, our understanding of the complex interactions of fluid balance and vasoconstrictor mechanisms (e.g., RAS) in primary hypertension was derived from the analysis of secondary forms of hypertension, such as primary aldosteronism and unilateral renovascular disease. This paradigm can be extended to the spectrum of hypertensive mechanisms operating in CKD. As ESRD is the extreme expression of CKD, mechanisms of hypertension can often be studied more precisely in this setting than in the the intermediate stages of CKD and, then, applied to patients with less severe kidney failure. Some of these mechanisms are as follows:
Extracellular Volume Expansion
Studies from several dialysis centers in the 1960s to the present time have demonstrated that, in the majority of patients on maintenance hemodialysis, hypertension is due to extracellular fluid expansion. The primary evidence supporting this conclusion is that BP can be controlled by adjustments of ultratrafiltration during dialysis and by restriction of dietary Na intake.[530] This is underscored by the fact that, in 1960, the life of the first dialysis patient was saved when his malignant hypertension was successfully treated using aggressive ultrafiltration.
The impact of normal volume homeostasis on hypertension control and survival in dialysis patients has been illustrated by reports from the Tassin unit. [541] [542] Although 90% of patients in that unit start dialysis on one or more antihypertensive medication, within a few months after starting dialysis, the MAP is 98 mm Hg and fewer than 5% of the patients require medication. This remarkably effective control of BP is accomplished by establishing each patient's dry weight, defined as the weight at which BP remains normal both before and after each dialysis treatment without antihypertensive medication use. Key interventions that facilitate this endpoint are dietary Na restriction (to 3-4 g/day) and the relatively low ultrafiltration rate; the latter is enabled by the long dialysis time and low interdialytic weight gain (1.6 kg). The initial mean weight loss (2 kg) leads to a rapid decrease in BP.[531] Thereafter, BP continues to decrease more slowly as appetite improves and both lean and fat body mass increase, a phenonmenon referred to as the lag phase [540] [542] [543] ( Fig. 42-14 ). Similar improvements in BP and discontinuation of antihypertensive drug treatment, with transient decreases in dry weight, have been observed in nocturnal home hemodialysis programs.[534] BP control by the Tassin unit is achieved independently of the duration and dose (Kt/V urea) of hemodialysis, at least partly because postdialysis extracellular fluid volume is adequate, as determined by several methods including bioimpedance, ultrasound measurement of IVC diameter, and on-line monitoring of the change in blood volume. Compared with short dialysis (e.g., 3–4 hours per treatment), dry weight is easier to achieve with more prolonged hemodialysis because the ultrafiltration rate is lower, blood volume changes are smaller, and intradialysis symptoms are less frequent.[535]
|
|
|
|
|
|
|
FIGURE 42-14 Effect of prolonged hemodialysis on BP control. Before induction into 8-hour thrice-weekly hemodialysis treatment, 89% of patients were taking antihypertensive drugs. During 8-hour thrice-weekly treatment with progressive ultrafiltration and low Na diet, dry weight was obtained and BP control improved. Only 5% of patients required antihypertensive drug treatment after 3 months on this prolonged hemodialysis protocol. Postdialysis weight gradually increased after the 3rd month because of improved nutrition. |
|
Despite the substantial change to a less favorable case-mix index, BP control and survival rates reported by the Tassin group using longer duration hemodialysis have not changed significantly since 1968. In that cohort, the predialysis MAP is the most powerful predictor of mortality. Therefore, one reasonable conclusion is that the higher prevalence of BP control in the Tassin population contributes significantly to the two to three times lower mortality rate in the Tassin unit than in the U.S. dialysis population.[531]
During ultrafiltration, plasma volume falls and the initial compensation is a fluid shift from the extravascular to the intravascular space.[536] This transfer of fluid is mediated predominantly by interstitial hydrostatic pressure. The rate at which this plasma refilling occurs is related to the state of hydration, reflecting the increase in tissue compliance during excessive hydration.[537] Accordingly, in the grossly volume-overloaded state, tissue hydrostatic pressure remains high and promotes the transfer of fluid from interstitium to plasma. The plasma refilling rate can be remarkable high, ranging from 300 mL/hr to 2 L/hr without a measurable reduction in plasma volume.[536] At lesser states of hydration, tissue compliance is low, so that ultrafiltration reduces tissue compliance and the plasma refilling rate is insufficient to maintain plasma volume, leading to hypotension and reduced tissue perfusion.
This important relationship between volume homeostasis and BP control in the dialysis population is reinforced by the resurgence of hypertension in the 1980s as dialysis time was shortened. [541] [548] Moreover, reducing the time of each dialysis treatment has increased the risk that intradialytic hypotension will occur.[531] Intradialytic hypotension prevents dry weight from being established because it is treated by saline infusion, increased dialysate Na concentration, and further reduction in dialysis time. Na administration stimulates thirst, thereby increasing intradialytic weight gain and BP.[539] As BP increases, antihypertensive drug treatment is intensified, further impairing the compensatory responses necessary to prevent intradialytic hypotension. Thus, short dialysis time is a significant factor contributing to both hypertension and dialysis-related hypotension, both of which have been associated with increased risk of increased morbidity and mortality in ESRD patients. [111] [112]
Other factors can cause hypotension during ultrafiltration by adversely influencing the balance between ultrafiltration and plasma refilling.[540] Among these are concurrent antihypertensive drug treatment, impaired cardiac output caused by systolic and/or diastolic dysfunction, and abnormal regulation of peripheral arterial and venous resistance due to autonomic dysfunction. [551] [552]
In patients undergoing PD, Na balance has a direct impact on BP and cardiovascular risk.[543] Systolic and diastolic BPs are inversely related to both Na and fluid removal. Hospitalization rates due to cardiovascular and other causes are significantly higher in patients with hypertension and with a total Na removal that was below the median value. Moreover, when stratifying patients in quartiles based upon the amount of daily Na removal or fluid removal, the 3-year survival rates were worse at lower levels of Na and fluid removal, and these variables were each independent predictors of mortality. These findings support the role for Na-volume overload in the pathogenesis of hypertension in a significant proportion of patients with ESRD.
Volume overload is a common feature during PD treatment, described in approximately one fourth of patients. [554] [555] After conversion from PD to hemodialysis, significant decreases in body weight and BP occur within 3 months.[545] Volume overload has been attributed to loss of residual renal function, ultrafiltration membrane failure, and poor compliance. [553] [554] [555]
Excessive Renin-Angiotensin System Activity
A considerable body of data has demonstrated a strong relationship between higher levels of BP and faster kidney disease progression.[546] Several mechanisms have been implicated in the pathogenesis of glomerular and tubulointersitial fibrosis, including deleterious effects of high intraglomerular pressure and inflammatory responses to proteinuria. One pathophysiologic mechanism that is common to the progression of CKD and CVD is increased activity of the RAAS.[547] Ang II increases intraglomerular pressure and glomerular permselectivity to proteins and, with aldosterone, stimulates the activity of growth factors and other processes that cause fibrosis. [558] [559] The importance of excessive renin system activation in the pathogenesis of CKD is highlighted by the particular efficacy of ACE inhibitors and ARBs in slowing the progression of CKD in both diabetics and nondiabetics[546] (see later and Chapters 36 and 54 ).
As discussed earlier, in normotensive individuals, BP homeostasis is maintained by the dual control of Na-volume-mediated mechanisms when body Na is replete and, conversely, by vasoconstrictor-mediated events (i.e., renin-angiotensin) under conditions of Na depletion. In primary hypertension and in the secondary forms of hypertension discussed previously, BP is elevated when there is either sustained, excessive body volume or vasoconstrictor activity or when the relationship between these regulatory mechanisms is abnormal. In the vast majority of dialysis patients, hypertension can be controlled by maintaining dry weight via dietary Na restriction and by ultrafiltration, indicating the predominance of Na-volume-related mechanisms in its pathogenesis. [541] [560]
However, for some dialysis patients, hypertension is refractory to maneuvers directed at volume homeostasis. Elegant studies in the 1960s and 1970s identified excessive renin system activation as the mechanism of persistent hypertension in those patients. [561] [562] Vertes and colleagues[552] found that hypertension could be controlled without medication in 87.5% of hypertensive dialysis patients (mean BP decreasing from 180/110 to 140/86) by maintaining their dry weight (defined as the absence of edema and below which hypotension occurred) over a period of 2 weeks to 8 months. By contrast, in the remaining 12.5%, BP remained elevated despite reaching dry weight (mean BP decreasing from 208/124 to 190/120). Those with refractory hypertension despite volume control had significantly higher predialysis renin levels and were designated as having renin-dependent hypertension. The pathophysiologic relevance of excessive renin system activity was illustrated in that study when BP in the renin-dependent hypertensives was controlled (132/74 without antihypertensive medication) after bilateral nephrectomy, which eliminates conversion from prorenin to renin and renders PRA undetectable. [561] [563]
As in patients with normal BP, highly significant, inverse correlations exist between exchangeable Na (NaE) and PRA (r = -0.72) and Ang II (r = 0.71) in dialysis patients.[552b] These relationships are shifted in hypertensive dialysis patients, so that Ang II levels are higher than in normoten-sive dialysis patients at any level of NaE. Therefore, in CKD, as in primary hypertension, elevated BP is a consequence of an abnormal Na-renin product. Moreover, the reciprocal interactions between Na-volume and renin are dynamic, so that PRA levels are stimulated significantly during ultrafiltration. [561] [565] As in primary hypertension, this reactive renin increase in the dialysis population is an important cause of refractory hypertension.[554] With the advent of antihypertensive drugs that block the renin system (ACE inhibitors, ARBs, β-blockers, central α2-receptor blockers), refractory hypertension caused by renin in the dialysis patient can now be treated effectively treated without bilateral nephrectomy.
The relationship between renin and Na has also been identified in ESRD patients treated with PD. Approximately 70% of PD patients had hypertension refractory to treat-ment with antihypertensive medication.[550] After discontinuation of these agents, volume control by dietary Na restriction alone or in combination with additional ultrafiltration normalized BP in 85% of PD patients. Of those with persistent hypertension, BP was controlled with ACE inhibitors either by monotherapy or in combination with volume control. The findings indicate that, regardless of the dialysis modality, Na-volume overload is the predominant mechanism causing hypertension in ESRD and that excessive renin system activity accounts for the small percentage of patients (≈15%) who are refractory to volume control. However, with PD, volume control may be impaired as ultrafiltration becomes less efficient owing to changes in the peritoneal membrane.[550]
Excessive renin system activation is important in the pathogenesis of hypertension in autosomal dominant polycystic kidney disease (ADPKD), in which mean renin levels exceed those of primary hypertension. [567] [568] Moreover, the prevalence of BP control improved from 38% to 64% in ADPKD during the 15-year period after the introduction and increasing use of ACE inhibitors, despite the persistent rate of hypertension diagnosis (≈65%) and antihypertensive drug treatment (≈75%).[557]
Sympathetic Nervous System Activation
CKD is characterized by increased SNS activity. Plasma catecholamine levels have been found to be significantly elevated in CKD patients,[558] but these studies were limited because the plasma NE level is the net result of neuronal release and reuptake, metabolism, and clearance and is, thus, inadequate for quantifying SNS activity.[559]
This limitation has been overcome with the use of microneurographic techniques for direct sympathetic nerve recording, whereby muscle sympathetic nerve activity (MSNA) is measured by direct intraneural recording with a tungsten microelectrode in a peripheral nerve, usually the peroneal or radial nerve. MSNA represents the postganglionic sympathetic activity to the skeletal muscle circulation.[558] Using this technique, CKD was shown to be accompanied by reversible SNS activation.[560] MSNA was 2.5-fold higher in dialysis patients than in healthy controls with normal renal function. The additional observation that MSNA was similar in the control subjects and another group of hemodialysis subjects who had undergone bilateral nephrectomy supports a role for the kidney in the afferent limb that stimulates central sympathetic outflow. By contrast, baroreceptor function does not appear to be significantly impaired in ESRD, and therefore, SNS hyperactivity in CKD cannot be attributed to it. [573] [574]
Subsequent studies have elucidated the mechanisms relating SNS, BP, and renal function in patients with CKD. Ang II stimulates the SNS by augmenting MSNA (central effect) and by enhancing NE release by binding to the Ang II receptor at presynaptic neurons (peripheral effect).[558] Several lines of evidence support the causal relationship between increased MSNA and excessive renin system activation in the pathogenesis of hypertension in CKD. A study of ADPKD patients found that MSNA was significantly higher in hypertensive than in normotensive subjects regardless of GFR.[563] By contrast, MSNA was similar in normotensive ADPKD patients and healthy matched controls. In all ADPKD patients evaluated, MSNA was directly related to MAP, and both age and PRA were predictive for MSNA. This suggests that the increased MSNA is a consequence of the renal structural changes rather than the impairment in renal function.
MSNA is inversely related to extracellular fluid volume in both healthy control subjects and patients with a variety of CKDs.[564] This dynamic relationship between changes in volume and MSNA in CKD parallels that of the controls, but is shifted to a significantly higher level of MSNA. This inverse relationship is strikingly similar to that observed for volume and PRA. In addition, interruption of the renin system with either an ACE inhibitor or an ARB significantly lowers BP and MSNA in CKD. [574] [576] These two drug classes are equally effective, reinforcing the conclusion that renin system activation is directly involved in the SNS and BP responses. This is in sharp contrast with amlodipine, a dihydropyridine calcium channel blocker that lowers BP but stimulates MSNA. Furthermore, addition of monoxidine, a high-affinity agonist of the imidazoline receptor located in the rostral ventrolateral medulla of the brainstem, to eprosartan resulted in a significant further reduction in both BP and MSNA.[565]
Asymmetrical Dimethylarginine
NO has sympathoinhibitory and vagotonic effects that attenuate cardiovascular end-organ responses to sympathetic stimulation.[566] Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of NOS that has been identified in patients with ESRD. [579] [580] ADMA may contribute to dialysis-associated hypertension because it accumulates in the plasma of hemodialysis patients in a concentration high enough to inhibit NO synthesis in experimental models, although this view is controversial.[569] An ADMA infusion in guinea pigs increased systolic BP by 15%, and an ADMA bolus caused a dose-dependent increase in MAP up to 53 mm Hg.[568] In an uncontrolled study of healthy individuals, brachial artery infusion of ADMA caused a decrease in forearm blood flow by 28%. Moreover, the infusion of either ADMA or L-NAME caused a significant increase in BP, renal vascular resistance, and Na retention, with a corresponding decrease in renal plasma flow and cardiac output.[570]
The renal effects of ADMA may be of clinical relevance because, in Na-sensitive hypertensive patients, Na loading increases plasma concentrations of ADMA in association with suppression of the plasma concentration NO.[571]These results support the findings in salt-sensitive Dahl rats that high Na intake increases ADMA production, blunts NO synthesis, and increases BP.[571] The high prevalence of Na-sensitive hypertension in CKD patients, together with the elevated level of ADMA and reduced NO production, has led to the hypothesis that ADMA may limit Na excretion by the failing kidney and thereby participate in the pathogenesis of hypertension. [579] [584]
NO has a protective role for the cardiovascular system because it enhances arterial compliance and reduces peripheral vascular resistance, inhibits proliferation of vascular smooth muscle cells, and decreases platelet aggregability and adhesion of monocytes to the endothelium.[567] By blocking NO generation, ADMA initiates and promotes processes involved in atherogenesis, plaque progression, and rupture.[573] ADMA levels were higher in hemodialysis patients with CVD than in those without these complications.[574] Moreover, a prospective study of hemodialysis patients showed that, overall, adjusted risk of death and fatal and nonfatal cardiovascular events was progressively higher in those with ADMA levels at or above the median.[575] In the evaluation of surrogate markers of CVD, ADMA has been associated with carotid intima-media thickness, LV mass index, and impaired systolic function. [588] [589] There was an especially strong relationship between the ADMA level and the type of LV remodeling, with significantly higher ADMA levels in concentric LVH compared with eccentric LVH. Furthermore, in patients with initially normal intima-media thickness, ADMA and CRP were interacting factors in the progression of carotid intimal lesions, suggesting a link between ADMA and inflammation.[577]
Although ADMA has a low molecular weight and should be cleared significantly by hemodialysis, the dialysance of ADMA is markedly lower than expected because of significant protein binding.[578] There are conflicting data regarding the comparative effects of peritoneal and hemodialysis on plasma ADMA levels. [579] [581] Several pharmacologic interventions have been shown to decrease plasma ADMA levels, including treatment with an ACE inhibitor, ARB, estrogen, or rosiglitazone. [579] [581] However, the clinical significance of these responses has not been established.
Aortic Stiffness
Although hypertension is a significant cardiovascular risk factor in the general population, several large epidemiologic studies have not demonstrated an association between hypertension and cardiovascular risk in dialysis populations. [111] [591] [592] These negative findings have been attributed to limitations imposed by the standard, brachial BP measurements employed in those studies.[581] In normal individuals, pulse pressure increases from the central (thoracic aorta, carotid artery) to the peripheral blood vessels, reflecting the increase in arterial stiffness as vessel radius decreases. Large vessel disease develops rapidly in uremic patients and is responsible for the high incidence of ischemic heart disease, LVH, HF, sudden death, and stroke.[582] When conduit arteries become stiffer, as in patients with hypertension and/or ESRD, PWV increases and the reflected waves return more rapidly to the thoracic aorta. This leads to an augmented systolic BP and decreased diastolic BP in the thoracic aorta relative to the peripheral arteries (e.g., brachial). [595] [596] Consequently, pulse pressure rises significantly more in the aorta than in the brachial and other peripheral blood vessels.[28]
In ESRD patients, the central pulse pressure level and the disappearance of peripheral amplification of the pulse pressure were strong independent predictors of cardiovascular and all-cause mortality.[581] By contrast, brachial BP, including pulse pressure, had no predictive value for mortality in that study. These observations support the previous finding in ESRD patients that increased aortic stiffness, determined by measurement of aortic PWV, is a strong independent predictor of all-cause and mainly cardiovascular mortality.[582] Based upon these findings, it is plausible that the lack of association between hypertension and cardiovascular risk in other epidemiologic studies of ESRD may be due to the use of peripheral rather than central BP measurements. [111] [346] [591] [592]
Hypertension and the Renal Transplant Recipient
Several factors can contribute significantly to the etiology of hypertension in the renal allograft recipient; among them are immunosuppressive therapy, excessive renin secretion from native kidneys, acute rejection and chronic allograft nephropathy, transplant renal artery stenosis, and donor hypertension.
Immunosupressive Therapy
Precalcineurin Inhibitor Era.
Prior to the advent of cyclosporine, when azathioprine and glucocorticoids were the primary immunosupressive agents used, hypertension occurred in 40% to 50% of kidney transplant patients.[585] Several lines of evidence supported the predominant role of the renin system in its pathogenesis, including the higher PRA, the lack of BP reduction during dietary Na restriction, and the significant decrease in BP and corresponding increase in renal plasma flow during treatment with an ACE inhibitor and after native nephrectomy (thereafter PRA is undetectable). [598] [599] Sampling of venous effluent from the native and allograft kidneys indicated that the native kidneys were the source of excessive renin production in hypertensive patients treated with azathioprine.[588]
Calcineurin Inhibitors.
With the advent of calcineurin inhibition as immunosuppressive treatment, the prevalence of post-transplant hypertension increased significantly to between 50% to 70% of renal transplant patients. However, the pathophysiology of post-transplant hypertension during calcineurin inhibitor treatment differs from that with azathioprine. One notable difference is the predominant Na sensitivity of hypertension during calcinuerin blockade.[589] In contrast to hypertension encountered during the pre-cyclosporine era, the renin system during calcineurin inhibition tends to be suppressed and does not usually respond to treatment with an ACE inhibitor, [602] [603] although there are reports of favorable responses to anti-renin system drugs.[592] However, in animal models of calcineurin inhibitor hypertension, the RAS is activated, therefore, interpretation of this experimental data in a clinical context is questionable.[593]
Several lines of evidence indicate that calcineurin inhibitors cause Na retention and hypertension by stimulating SNS activity. During cyclosporine infusion in rat models, both renal afferent and efferent sympathetic nerve activity increased significantly. [606] [607] This was associated with 50% reductions in urine flow and both absolute and fractional excretion of Na. By contrast, Na excretion increased during cyclosporine infusion in denervated kidneys.[594]Renal afferent nerve discharge and BP were also significantly increased during infusion with tacrolimus, another potent calcineurin inhibitor, but were unaffected by rapamycin, a structural analog of tacrolimus that has no effect on calcineurin.[595] These findings indicate that calcineurin inhibition mediates SNS activation and Na retention associated with this immunosuppressive drug class.
MSNA in renal transplant recipients, after bilateral nephrectomy, was not significantly different from that in healthy control subjects. Therefore, native, diseased kidneys appear to contribute significantly to the increased MSNA observed in renal transplant recipients. Furthermore, MSNA does not appear to differ in patients treated with cyclosporine, tacrolimus, or calcineurin-independent immunosuppressants.[596]
Synapsins, a family of synaptic vesicle phosphoproteins that are essential for normal regulation of neurotransmitter release at synapses, have been implicated in the pathogenesis of cyclosporine stimulation of the SNS. In a mouse model, cyclosporine raises BP by stimulating renal sensory nerve endings that contain synapsin-positive microvesicles.[597] By contrast, knockout mice lacking synapsins I and II are not stimulated by cyclosporine, but respond fully to a control stimulus (capsaicin). Moreover, the reflex activation of efferent sympathetic nerve activity and the increase in BP by cyclosporine seen in the wild-type mice are greatly attenuated in synapsin-deficient mice.
Experimental animal, human histologic, and clinical studies indicate that cyclosporine increases renal vascular resistance, predominantly by stimulating afferent arteriolar vasoconstriction that can lead to arteriopathy. [610] [611] [612] [613] [614] A single oral dose of cyclosporine 3.5 mg/kg is followed by a 50% reduction in GFR and renal plasma flow within 2 to 4 hours after the maximum blood concentration is reached in renal transplant patients, most likely reflecting an acute increase in afferent arteriolar tone.[601] In a rat model, cyclospornine treatment caused greater than 40% reductions in both single-nephron GFR and glomerular plasma flow together with increased afferent arteriolar resistance and decreased glomerular capillary pressure.[599] This vasoconstrictor effect was significantly attenuated by the infusion of an antiendothelin serum or a specific ETA receptor antagonist, [611] [612] implicating endothelin in the pathophysiology of cyclosporine-mediated renal vasoconstriction. Furthermore, acute cyclosporine administration caused a significant, concurrent rise in urinary endothelin levels in concert with renal vasoconstriction.
There is abundant evidence that hypertension and renal vasoconstriction caused by calcineurin inhibitors can be attenuated by treatment with calcium channel antagonists. [613] [615] [616] [617] [618] Moreover, concurrent treatment with cyclosporine and a calcium channel blocker has been shown to significantly ameliorate cyclosporine nephrotoxicity. [615] [617] [619] [620] It has been proposed that these benefits may reflect attenuation of the endothelin-stimulated increase in vascular smooth muscle calcium concentration that occurs during calcineurin inhibitor-induced vasoconstriction.[601] However, the role of endothelin in the calcium channel blocker response is not clearly established, as L-type calcium channels, which are blocked by these drugs, have been reported to play a minor role in the renal vascular response to endothelin.[609]
Compared with cyclosporine, tacrolimus has been associated with improved renal allograft outcomes and reduced prevalence of hypertension. [622] [623] [624] [625] In the phase III U.S. Multicenter trial comparing cyclosporine- and tacrolimus-based immunosuppression in kidney transplantation, tacrolimus therapy was also associated with a significantly reduced requirement for medications to control hypertension (81% vs. 93%) during 5-year follow-up.[612]In a crossover design study in which transplant patients with stable renal function received consecutive 4-week courses of cyclosporine, tacrolimus, and then resumed cyclospornine, BP decreased significantly during tacrolimus treatment and increased during the second cyclosporine treatment phase.[614] In that study, mean nighttime BP also decreased significantly during tacrolimus compared with cyclosporine treatment. The higher BP levels during cyclosporine immunosuppression, together with its adverse effects on cholesterol levels, have raised the possibility that tacrolimus may be associated with a more favorable cardiovascular risk profile. [623] [624] [626] [627] [628]
Sirolimus.
The adverse effect of calcineurin inhibition on BP and its role in the development and progression of chronic allograft nephropathy have led to the development of non-nephrotoxic immunosuppressive agents with alternative mechanisms of action.[617] Sirolimus is an immunosuppressive agent that inhibits the mammalian target of rapamycin, which plays an important role in cell cycling. Although it is structurally homologous to tacrolimus and shares its binding protein, sirolimus does not inhibit calcineurin.[618] Sirolimus does not exacerbate the hypertensive response to corticosteroids and cyclosporine. Renal transplant patients randomized to cyclosporine withdrawal and sirolimus had significantly lower BP, required fewer antihypertensive medications, and had a higher GFR and a better graft survival rate after 48-month follow-up than those treated with cyclosporine and sirolimus. [631] [632] [633] These findings suggest that sirolimus may avoid the nephrotoxic and adverse BP effects of calcineurin inhibitor-based immunosuppression regimens.
Corticosteroids.
Since the 1960s, corticosteroids have been an integral part of immunosuppressive therapy after renal transplantation. A systematic review of the literature for steroid-related side effect data in adult renal trans-plant for the years 1985 through 1997 found that, at the end of the first post-transplantation year, approximately 15% of patients had developed steroid-related hypertension.[622] The hypertension prevalence dropped to 11% at 10 years post-transplantation because of patient mortality. In that analysis, steroid-induced hypertension and its complications were the most expensive side effect, followed by post-transplantation diabetes, avascular necrosis of the hip, cataracts, and peripheral bone fractures.[622]
The availability of new, potent, and more selective immunosuppressive drugs has enabled the early withdrawal of corticosteroids after renal transplantation without an appreciable increased risk for acute rejection. [635] [636] [637] [638]Moreover, corticosteroid-free immunosuppression with calcineurin inhibitor-based regimens have resulted in significant reductions in BP and lesser antihypertensive medication re-quirements, although the BP benefit is not uniformly sustained. [637] [638]
Transplant Renal Artery Stenosis
Transplant renal artery stenosis (TRAS) is a relatively frequent cause of hypertension and allograft dysfunction (see Chapters 43 and 65 ). It reportedly occurs in as many as 24% of renal transplants, whereas hemodynamically significant stenosis probably is found in approximately 5% these cases. [605] [639] Common clinical signs include hypertension, which may be of recent onset or refractory to treatment, and progressive allograft dysfunction. [282] [640] [641] It may occur at any time after renal transplantation and is often associated with impaired allograft function. The clinical heterogeneity of this disorder is underscored by the report that onset of acute renal failure without hypertension occurred in a subset of patients with stenosis of the iliac segment proximal to the transplant renal artery.[630] Bruits may be audible but are of limited diagnostic value because they occur relatively commonly after uncomplicated renal transplantation owing to turbulence in the iliac or femoral arteries.[631] Moreover, TRAS can be present in the absence of a bruit.[632]
TRAS may occur (1) at the anastomosis, (2) as a focal stenosis either proximal or distal to the anastomosis, or (3) as diffuse, multiple stenosis.[631] Factors that may contribute to the development of TRAS include atheromatous involvement and trauma to the donor or recipient vessels during procurement or transplantation.[632] Hemodynamic mechanisms have been identified, including turbulence related to end-to-side anastomosis and kinking of the transplanted renal artery. However, kinks in the transplanted renal artery that are visually impressive, but are not associated with a significant reduction in the peak systolic pressure beyond the stenosis, may not progress or compromise renal allograft function or BP control.[633]
Stenosis of the iliac artery proximal to the transplanted renal artery occurs in approximately 1.5% of TRAS.[630] Proximal TRAS presents within the 1st week after transplantation with anuria and delayed graft function, but not with significant elevation in BP. Alternatively, proximal TRAS may also present later in the post-transplant period with signs of obstructive nephropathy, including worsening hypertension and acute renal failure. Symptoms of progressive peripheral vascular disease (e.g., claudication) may also be apparent. Although iliac artery stenosis has been an uncommon cause of hypertension and allograft failure, its prevalence is expected to rise with the increasing use of extended donor criteria.
TRAS has been associated with viral infection,[634] raising the possibility of an inflammatory or immunologic mechanism.[635] A relationship between cytomegalovirus (CMV) disease and TRAS was established in a case-controlled study of patients with clinical and serologic evidence for CMV disease occurring between the time of transplantation and the diagnosis of TRAS. The pathophysiologic significance of CMV infection in TRAS is supported by studies that suggest a role for CMV in the pathogenesis of cardiac allograft vasculopathy. [648] [649] It is also possible that CMV infection is a marker for another process that has a more direct role in the pathogenesis of atherosclerotic renal complications.[638]
TRAS is the clinical expression of one-kidney one-clip Goldblatt hypertension.[414] Accordingly, the pathophysiology of hypertension in this disorder reflects an impaired pressure natriuresis relationship. In TRAS, during volume expansion, the BP elevation is volume-dependent owing to excessive Na intake and/or reduced GFR. PRA levels are suppressed by increased renal perfusion pressure of the juxtaglomerular baroreceptor and high levels of chloride delivery to the MD. In this case, BP is not responsive to volume depletion by dietary Na restriction or diuretic therapy because these maneuvers stimulate renin secretion. Thus, TRAS encompasses two forms of hypertension: (1) Na-volume dependent with suppressed PRA levels when Na-volume is expanded and (2) renin-dependent with unsuppressed PRA when Na-volume is depleted. During the latter, glomerular filtration pressure and GFR are also Ang II dependent, and are thus vulnerable to acute renal failure when the renin system is interrupted by treatment with an ACE inhibitor and, presumably, an ARB.[593]
Diagnostic Tests.
Doppler renal ultrasonography (DUS) is a noninvasive method that has a high sensitivity and specificity in the evaluation of native renal artery stenosis. [651] [652] In patients with TRAS, there appears to be an incremental role of congruent clinical and DUS findings—a high clinical suspicion together with a high-probability DUS finding provides a high yield of correctable TRAS.[629] The main limitation of the DUS method is operator dependence.
DUS has been useful for the diagnosis of iliac artery stenosis proximal to the transplant renal artery (see earlier). DUS criteria for diagnosing this lesion include (1) pulsatility index (PI) less than 1.0, where PI = (Vmax - Vmin)/Vmin (where Vmax = peak systolic velocity measured within the interlobular arteries, Vmin = end-diastolic velocity measured within the interlobular arteries), (2) decrease in PI compared with previous measurements, (3) pulsus parvus et tardus, (4) no transplant renal artery stenosis, (5) Vmax within the iliac artery proximal to the graft greater than 200 cm/sec, and (6) monophasic flow profile within the iliac artery distal from the transplant artery.[630] Visualization of the stenosis proximal to the transplant artery may not be feasible with DUS in 25% of cases because of the depth of the common iliac and of the iliac artery or an inadequate angle of the Doppler beam.[630]
Several other imaging modalities are available for evaluating TRAS (see Renovascular Hypertension, Chapters 43 and 65 ). Spiral CT, which enables three-dimensional visualization of the renal vasculature, requires iodinated radiocontrast material and, therefore, includes the risk of contrast nephropathy. Magnetic resonance angiography (MRA) has a high resolution for evaluating native and transplant renal arteries. [653] [654] This technique avoids operator dependence that limits DUS. MRA utilizes gadolinium, which has been associated with nephrotoxicity in patients with preexisting moderate to severe CKD, [655] [656] [657] although to a lesser extent than iodinated contrast agents. [655] [656] [657] Of potentially greater concern is the recently described association of gadolinium with nephrogenic systemic fibrosis.[645a] The utilization of MRA is limited by its higher cost and lesser availability than DUS.
Digital intra-arterial contrast angiography is the “gold standard” for identifying TRAS and for quantifying the hemodynamic significance of the stenosis.[646] However, the risks of this invasive method include bleeding, atheroembolism, traumatic arteriovenous fistulas, aneurysms, and contrast nephropathy, and thus, it should not be employed as a screening test.
In summary, the signs of TRAS are common in almost all patients at some point after renal transplantation. These include delayed graft function, hypertension that is difficult to control with increasing doses of antihypertensive medication, progressive renal failure in either the presence or the absence of drug treatment that interrupts the renin system, and claudication or other signs and symptoms of peripheral vascular disease. Under these circumstances, a screening test for TRAS is indicated. DUS has a high sensitivity and specificity and is not associated with adverse effects. However, it is operator dependent and may not be useful in the patient with an iliac artery stenosis. MRA is otherwise the screening method of choice. If either of these tests is indicative of TRAS, or if the screening test results are equivocal, but there is a high clinical suspicion, then additional evaluation with digital intraarterial contrast angiography is indicated.
Percutaneous transluminal renal angioplasty (PTRA) is the first-line treatment for TRAS. [640] [647] [659] [660] [661] Generally, PTRA is most effective for lesions that are short, linear, and distal from the anastomosis.[632] The initial technical success rate is over 80%, with clinical improvement of BP control over 75% and stabilization of renal function in over 80% of patients.[646] Restenosis rates after PTRA range from 10% to 33%.[646] However, higher technical success rates and clinical improvement (BP, renal function) have been reported when endovascular stents were used. [640] [662] Indications for stent placement that have been suggested include residual stenosis after PTRA of greater than 30%, creation of a flow-limiting flap, or a pressure gradient greater than 10 mm Hg after PTRA.[646]
Surgical revascularization of TRAS is indicated when PTRA is unsuccessful or stenoses are inaccessible. Surgical techniques include resection and revision of the anastomosis, renal artery patch angioplasty, renal artery bypass with either recipient saphenous vein or ipsilateral hypogastric artery, and ABO-compatible, preserved, cadaveric iliac artery grafts.[632] Technical limitations to these surgical procedures are dense scar tissue around the allograft and adherence of the renal vein and ureter to the renal artery. Surgical revascularization is associated with a significant risk of graft loss (≤15%–20%), ureteral injury (14%), reoperation (13%), and mortality (5%).[650] Success rates have ranged from 66% to 100%, with clinical success rates exceeding 90%. [644] [663]
In summary, the treatment modalities available for TRAS include angiographic methods (i.e., PTRA and endovascular stenting) or surgical revascularization. [639] [663] Although the efficacy and adverse effects associated with each of these methods have been reported, these studies are limited because they are from single centers, are retrospective, are uncontrolled, include relatively small sample sizes, and have relatively short follow-up periods. Therefore, broad recommendations based upon these data should be viewed cautiously. However, PTRA/stent appears to be the initial treatment of choice for patients with TRAS. Surgical revascularization appears to be preferable for lesions at the anastomosis or for recurrent stenoses following PTRA/stent. As with native renal artery stenosis, more definitive recommendations await a prospective, multicenter, randomized clinical trial of PTRA/stent and surgical revascularization in patients with TRAS.
Donor-Related Blood Pressure and Nephron Number
The concept that the genetic background of the donor kidney has a major impact on long-term BP in the recipients is supported by the finding that transplantation of a kidney from a genetically hypertensive rat causes hypertension in the recipient. [664] [665] In these studies, and in patients with primary hypertension undergoing kidney transplantation, BP traveled with the kidney in both directions, so that renal allografts from genetically hypertensive donors increased BP in genetically normotensive recipients, whereas renal grafts from genetically normotensive donors lowered BP in genetically hypertensive recipients.[652] Transmission of the hypertensive trait occurs even when the BP of the donor is controlled by antihypertensive medication or when prehypertensive donors were used and, thus, is apparently not due to hypertensive nephrosclerosis or other end-organ changes in the donor.[652]
One consideration regarding the mechanism of the genetic transmission of BP from the donor to the recipient relates to the nephron supply provided by the renal allograft. Inadequate renal functional reserve, nephron number, and/or vascular surface of the donor kidney relative to the recipient demand may promote nonimmunologically mediated progressive injury to transplanted kidney, including glomerulosclerosis and tubulointerstitial fibrosis that are central to the pathogenesis of hypertension and loss of the allograft.[653] In a study in which nephron number was estimated in renal allograft patients by using renal MRI and allograft biopsy, the total number of transplanted glomeruli was a major determinant of renal allograft function.[654] However, BP levels of the donor and the recipient were not reported in that study.
TWO FORMS OF VASOCONSTRICTION IN PRIMARY HYPERTENSION
The evidence presented thus far illustrates the dynamic reciprocity of two forms of vasoconstriction mediated by Na and by renin-angiotensin. These mechanisms are essential to maintain normal BP homeostasis, and when these mechanisms are impaired, hypertension occurs. This relationship is clearly evident in the secondary forms of hypertension described previously, especially malignant hypertension (renin-dependent) and in the disorders of mineralocorticoid excess (Na-volume dependent).
The spectral patterns of vasoconstriction demonstrated in the more extreme forms of hypertension described previously also operate in primary hypertension. When renin profiling is performed and indexed in patients with primary hypertension, about 20% are found to have high renin values and about 30% to have low renin values, with the remaining half distributed between these extremes [349] [668] (see Fig. 42-11 ). These findings support the concept that the lower range of renin values marks the presence of Na-volume-related vasoconstriction and that, as one proceeds to the high end of the renin spectrum, the vasoconstriction becomes increasingly renin-mediated. This concept is supported by the observed heterogeneity in BP responses to specifically targeted antihypertensive drugs ( Table 42-3 ). For example, diuretic agents, calcium channel antagonists, and α-adrenergic receptor blockers are especially effective in the low-renin range and become less effective in high-renin patients. [539] [669] [670] [671]
TABLE 42-3 -- Antihypertensive Drug Efficacy is Predicted by Pretreatment Plasma Renin Activity Level
|
Antihypertensive Drug Class |
Pretreatment PRA < 0.65 |
Pretreatment PRA ≥ 0.65 |
|
Angiotensin II receptor blocker |
+ |
++++ |
|
Angiotensin converting enzyme inhibitor |
+ |
++++ |
|
β-Adrenergic receptor blocker |
+ |
++++ |
|
Central α2-receptor agonist |
+ |
++++ |
|
Diuretic |
++++ |
+ |
|
Calcium channel blocker |
++++ |
+ |
|
α1-Adrenergic receptor blocker |
++++ |
+ |
Adapted from Laragh JH: Issues and goals in the selection of first-line drug therapy for hypertension. Hypertension 13(suppl 1):103, 1989.
|
PRA, plasma rennin activity. |
Drugs that interrupt the RAS (e.g., ACE inhibitors, Ang II receptor blockers, β-blockers, and presumably, renin inhibitors [ Table 42-3 , Fig. 42-15 ]; see later) are most effective in the high-renin forms of hypertension and least effective in the low-renin forms. [358] [672] [673] [674] [675] Moreover, the increase in RAAS activity that occurs in response to diuretic-induced Na-volume depletion, can blunt the antihypertensive efficacy of diuretics and is an important cause of diuretic resistance ( Fig. 42-16 ). The relevance of this mechanism is supported by the synergistic antihypertensive response that occurs when an anti-renin system drug is added to diuretic treatment in a patient resistant to diuretic monotherapy.[171] The heterogeneity in pathophysiology in essential hypertension can, thus, be correlated with pharmacologic responsiveness. [32] [73] [349] [676]
|
|
|
|
|
|
|
FIGURE 42-15 The acute effects (at 90 minutes) of intravenous and oral converting enzyme inhibitors on diastolic blood pressure. With both drugs, the percentage fall in BP is closely related to the pretreatment levels of PRA in quietly seated, untreated hypertensive patients. The left panel illustrates the effects of the intravenous administration of the nonapeptide isolated from snake venom, teprotide (SQ 20881), to 89 patients; data are replotted from Case DB, Atlas SA, Laragh JH, et al: Clinical experience with blockade of the renin-angiotensin-aldosterone system by an oral converting-enzyme inhibitor (SQ 14,225, captopril) in hypertensive patients. Prog Cardiovasc Dis 21:195–206, 1978. The right panel shows changes in seated diastolic BP in 166 patients 90 minutes after a single oral dose of 25 mg captopril. The data reveal remarkable and extremely similar correlations between the height of the pretreatment plasma renin values and the degree of induced fall in BP. Note that patients with plasma renin values below 1.0 ng/mL/hr usually exhibited no change in pressure. The data in both panels also provide strong indirect evidence that a plasma renin value closely reflects the active role of renin in supporting arterial pressure in hypertensive individuals. PRA values are expressed as nanograms angiotensin I formed per milliliter per hour. Multiply the values in this figure by 0.65 to conform to the National Bureau of Standards angiotensin I reference standard now adopted by our laboratory and commercial laboratories. |
|
|
|
|
|
|
|
|
FIGURE 42-16 Relation of BP response and renin system reactivity during antihypertensive treatment with a thiazide-type diuretic. Fifty patients with essential hypertension were treated with chlorthalidone 100 mg daily for 6 weeks and characterized by their BP response (responders = fall in mean pressure ≤10% below pretreatment level; 25 responders, 25 nonresponders). In the responders, mean pretreatment plasma renin level was lower (2.1 vs. 3.3 ng/ml/hr; P < .025) and urine aldosterone was higher (11.6 vs. 8.3 mcg/24 hr; P < .05) than in nonresponders. During treatment with chlorthalidone, the mean increase in aldosterone was sevenfold higher in the BP nonresponders than in the responders, reflecting the greater rise in PRA. Changes in body weight, serum potassium, and creatinine were comparable in these groups. These findings suggest that activation of the renin-angiotensin-aldosterone system during diuretic treatment attenuated its antihypertensive efficacy. (From Weber MA, Drayer JI, Rev A, Laragh JH: Disparate patterns of aldosterone response during diuretic treatment of hypertension. Ann Intern Med 87:558–563, 1977.) |
|
EVALUATION AND TREATMENT OF THE INDIVIDUAL PATIENT
General Principles
The evaluation of a new patient with high BP embraces all the principles of good medical practice. It relies on a complete history and physical examination and the routine application of appropriately chosen laboratory tests. A thorough initial evaluation can avoid the prescription of needless or inappropriate drugs for the lifetime commitment that hypertension may often require, and at the start, it can reveal surgically curable hypertension or other important medical diseases.
For most hypertensive patients, the pretreatment evaluation is most efficiently accomplished in the office setting. Multiple visits have the advantage of defining the persistence or lability of the hypertensive process. In general, the milder or more labile the hypertension is, the longer the evaluation period will be before commitment to therapy. Except when hypertension is severe or complications are impending or present, treatment should be withheld throughout the evaluation. For patients already on ineffective therapy, cautious withdrawal of the drugs during the initial evaluation is worthwhile to determine whether the hypertension is persistent or even drug induced and, in the case of multiple-drug therapy, whether all or any of the agents are necessary. Hospitalization is reserved for those patients with severe hypertensive disease, those with impending or rapidly evolving target organ damage, and those for whom the outpatient data suggest the need for specialized diagnostic procedures.
For some patients receiving relatively simple and well-tolerated therapy, the clinician may decide that the program already in force is adequate and need not be disturbed. However, one should not hesitate to stop medications in those in whom the regimen appears unsatisfactory or unpalatable. We have observed repeatedly that when hypertension persists in patients receiving multiple-drug therapy, the discontinuation of medications gradually and serially does not usually lead to any further rise in BP. Surprisingly often, the BP may actually improve as the medical regimen is simplified. In the Veterans Administration study of severe hypertension (diastolic pressure >110 mm Hg), 15% of those patients in whom all drugs were stopped remained normotensive for the ensuing 18 months of observation.[23] Serial withdrawal of drugs in patients who are poorly controlled with multiple-drug therapy puts the physician in the best position for reevaluating the disease process and setting up new therapeutic strategies. Moreover, secondary forms of hypertension are more prevalent in patients with refractory hypertension. [500] [676]
Goals of the Initial Evaluation
The five major goals of the initial evaluation are to (1) establish whether the hypertension is sustained and might benefit from treatment, (2) define coexisting diseases, (3) characterize other risk factors, (4) identify the presence and extent of target organ damage, and (5) identify or exclude curable causes of the hypertension.
A rational method for selecting drugs for the individual hypertensive patient must be based on an individual pathophysiologic evaluation. The diagnostic workup, aside from the routine complete blood count and urinalysis, includes serum K+, glucose, blood urea nitrogen, and serum creatinine concentrations; microalbumin; an ECG and a baseline echocardiogram for full evaluation of LV mass; and the PRA, which is described in the next section.
The first goal of this process is to identify or exclude definable and curable causes for the hypertensive disorder. Doing so may spare many patients a lifetime of needless, costly, and intrusive drug therapy, for often a cure can be accomplished. Clinical clues that secondary hypertension is present include (1) new onset of hypertension in patients over age 60 years, especially with diastolic BP greater than 100 mm Hg, (2) BP that is not adequately reduced by a multidrug regimen, (3) the presence of diffuse atherosclerotic disease, and (4) hypokalemia while not treated with a diuretic.[664]
The remaining 90% or so of patients, for whom no definable cause for the hypertension can be found but whom the PRA level can stratify pathophysiologically, are candidates for long-term drug therapy. This statistic assumes, of course, that their hypertension is significant and sustained, is possibly causing target organ damage, and is not responsive to simple nonpharmacologic forms of therapy (weight reduction, exercise, low-salt diet, and alcohol and tobacco withdrawal). For these individuals, the baseline evaluation process informs the selection of the most effective treatment.
Medical History
Evaluation of the severity and time course of the hypertensive disorder is important to allow planning of the pace of the medical workup and treatment. Normally, the evaluation is accomplished in an unhurried manner during several visits spaced at weekly or biweekly intervals. The initial examination, however, should provide enough information to determine whether the process must be accelerated.
Accordingly, after learning of any current symptoms, one should record the duration of the hypertension, the circumstances of its onset, and the highest known readings. Was the BP elevation merely discovered on routine examination? Has loss of well-being, decline in general vigor, or weight loss occurred? Does the patient have symptoms suggestive of sleep apnea, such as somnolence at work or snoring? Which drugs has the patient tried, and what effect have they produced? Has the patient taken any agents that may raise BP, such as decongestants, oral contraceptives, diet pills, antidepressants, cocaine, or other illicit drugs, or increased their intake of alcohol?
The neurologic history may disclose headaches. Classically, headaches in hypertensive patients are said to be occipital and pulsatile, most prominent on awakening, and gradually lessening during the day. Possibly, this symptom is no more common in hypertensive patients than in normotensive people. Moreover, studies indicate that when headaches do occur in hypertensive patients, they are not well correlated with the degree of elevation of either office or 24-hour ABP. [678] [679]
Signs and symptoms of autonomic nervous system vasomotor instability seem more common among hypertensive patients. These signs include a tendency for flushing and the patient may report excessive sweating or even a lack of sweating. The symptoms are common side effects of some antihypertensive medications, particularly direct arterial vasodilators (e.g., minoxidil, hydralalzine).
Other neurologic symptoms include blurred vision, unsteadiness of gait, depression, insomnia, sluggishness, and in some patients, a decreased libido. Whereas some of these symptoms may be nonspecific, blurred vision may reflect vascular changes in the fundi. More advanced hypertensive disease may also be accompanied by more defined focal sensory or motor neurologic changes, occurring paroxysmally and associated with either transient ischemic attacks or more sustained attacks presaging the onset of hypertensive encephalopathy or stroke. To the extent that these symptoms are related to hypertension, they will improve during successful treatment.
The cardiovascular system may be symptom free in early or uncomplicated hypertensive disease. Early signs of dysfunction are expressed by palpitations signifying either tachycardia or a forceful heartbeat, by increased fatigability, or by shortness of breath on effort, which may reflect the increased cardiac work of hypertension or impending HF. Young patients with labile pressure or largely systolic hypertension may exhibit tachycardia and signs of an unstable or hyperdynamic circulation. This sort of vasomotor instability can occur in normotensive people. Conversely, it could at times reflect higher cardiac output and stroke volume, which are described in some patients with early hypertensive disease. Palpitations may also reflect an arrhythmia. Cardiac arrhythmias are more common in hypertensive than in normotensive individuals, especially in the presence of LVH. [680] [681] Because coronary artery disease and MI are more prevalent in hypertensive patients, a history of angina pectoris or documented MI may be elicited.
The renal history may reveal antecedent acute glomerulonephritis, proteinuria, hematuria, nocturia, polyuria, or recurrent urinary tract infections. Renal colic or renal trauma should be noted, and one should suspect that the hypertension has a renal basis whenever it can be established that urinary tract symptoms or proteinuria preceded the hypertension. An abrupt onset of hypertension with rapid progression, especially in young or elderly patients, should lead to a strong suspicion of renovascular hypertension due to either fibromuscular hyperplasia or atherosclerosis, respectively. This suspicion is reinforced by retinopathy or by cardiac or renal involvement, all of which are likely to be more prominent in renovascular (renin-dependent) hypertension. Renin-secreting tumors of the juxtaglomerular apparatus (i.e., hemangiopericytoma) and Wilms tumor represent rare diseases that are more common in childhood but also may be associated with abrupt and severe hypertension.[669] Polycystic kidney disease is commonly associated with hypertension that is Ang II dependent. [567] [569]
Polyuria or nocturia may indicate more severe renal hypertension or a metabolic abnormality such as hyperglycemia, hypokalemia or hypercalcemia. Inability to concentrate the urine, with polydipsia, polyuria, and nocturia, commonly occurs in patients with primary aldosteronism, malignant hypertension, or chronic renal disorders, including glomerulonephritis, tubulointerstital nephropathy (e.g., polycystic kidney disease), or obstructive uropathy. Muscle weakness may accompany hypokalemia or hypercalcemia.
Patients should be asked about their smoking, drinking, exercise, and dietary habits.[1] Obesity can be an important factor in producing or amplifying hypertension. Excessive regular consumption of alcohol can also induce or aggravate hypertension, and in some patients, cessation of the habit may correct the hypertensive process. [683] [684] Tobacco, because it is a known vasoconstrictor, is especially contraindicated in hypertensive subjects, even though no causal relationship between smoking and the development of essential hypertension has been defined. [685] [686] Physical exercise reduces BP in prehypertensive and hypertensive subjects, [687] [688] although these reductions tend to be small. An estimate should be made of the adjustment of the patient to his or her life situation and of any emotional or psychiatric factors that seem relevant.[676] The risk analysis is completed by the identification of any target organ damage and of any other coexisting diseases.
Physical Examination
Special Aspects.
The general appearance is unrevealing in most patients with hypertension. However, a florid face—with or without a tendency for rapid color changes, which would suggest vasomotor instability—may signify an underlying metabolic process, PHEO, a hyperdynamic circulation, hyperthyroidism, or alternatively, the anxiety or the vasomotor instability characteristic of some patients with essential hypertension. Chronic alcoholism may also produce some of these signs, and it can also cause hypertension characterized by SNS activation on withdrawal from alcohol use. A ruddy complexion with a bluish tinge characterizes some patients with essential hypertension and reactive polycythemia (Gaisböck syndrome). High-renin patients with primary hypertension may also present with a dusky appearance associated with vasoconstriction and a higher hematocrit.
Truncal obesity with moon facies, frontal baldness, atrophic extremities with abdominal striae, atrophy of the skin, and spontaneous ecchymoses suggests Cushing's syndrome.[412] Multiple neurofibromas or café-au-lait discoloration of the skin suggests a familial basis for an associated PHEO.[363] Also, mucosal neuromas may be associated with other components of the MEN syndrome with hypertension. ESRD may be expressed by a pale yellowish skin, periorbital and peripheral edema, and uremic breath.
Blood Pressure.
In the vast majority of hypertensive patients, elevated BP is the only abnormal finding. Hence, the way in which the BP is measured assumes great importance. Establishing a diagnosis of hypertension often requires more than one visit, because the pressure tends to fall with repeated measurement. Even after several visits, however, a fairly sizable group of patients show a persistently elevated pressure in the clinic, although they are normotensive at other times.[17] This phenomenon, often referred to as white coat hypertension, can be detected only by including measurements made outside the clinic (see earlier). These measurements can be obtained by having the patient measure their BP at home or by 24-hour ambulatory monitoring. A knowledge of the patient's BP in these circumstances can be of great value in deciding on the need for treatment and in evaluating its efficacy.
The patient should be seated quietly, a cuff size appropriate to the arm diameter should be chosen, and several measurements should be taken over a 10-minute period. The diastolic BP is significantly higher when the BP is measured on an examination table, thus, the back should be supported and both feet placed on the floor, preferably while the patient is seated in a chair when possible.[677] The middle of the cuff on the upper arm should be at the level of the right atrium (the midpoint of the sternum patient. The patient should not talk, or be spoken to, while the measurements are taken. BP should be measured in both arms during the initial visit to identify patients with aortic coarctation or stenosis of the upper extremity arteries.
Korotkoff phase I sound has been associated with systolic BP and phase V designated as the diastolic BP. However, the Korotkoff sound method tends to give values for systolic pressure that are lower than the true intra-arterial pressure and diastolic values that are higher.[678] Phase V sounds may not be reliably determined in certain situations (e.g., pregnancy, arteriovenous fistula). An auscultatory gap occurs when Korotkoff sounds are inaudible between systolic and diastolic pressures. This phenomenon is prevalent in elderly patients with wide pulse pressures and may be eliminated by having the patient elevate the arm over the head for 30 seconds before measuring the BP.[17] To minimize the risk of observer error, the cuff should be deflated at 2 to 3 mm Hg/sec and the values reported to the nearest 2 mm Hg.
The mercury sphygmomanometer is the gold standard for clinical BP measurement. However, these are being phased out in many hospitals and clinics because of concerns related to environmental hazards associated with mercury spills. BP monitors that employ the oscillometric method are now commonly used in home and 24-hour ambulatory BP monitors. This technique is based upon the observation that oscillations of pressure in a sphygmomanometer cuff are recorded during gradual deflation and the point of maximal oscillation corresponds to the mean intra-arterial pressure. Systolic and diastolic pressures are estimated indirectly according to some empirically derived algorithm. Oscillometric monitors are easy to use, relatively inexpensive, and widely accessible and, thus, are commonly used. However, their accuracy may be limited because the amplitude of the oscillations depends on several factors other than BP, most importantly the stiffness of the arteries. Therefore, BP can be underestimated in elderly patients with stiff arteries and wide pulse pressures.[17] Regardless of the device, the standard location of BP measurement is at the brachial artery. Systolic BP is augmented and diastolic BP is decreased at downstream sites. In addition, devices that measure BP at the wrist are more susceptible to the hydrostatic effects of hand position, whereas finger monitors tend to be inaccurate and are not recommended. All monitors should be validated prior to use by comparison with a device that is known to be accurate, with BP readings within 5 mm Hg.
It is essential that the correct cuff size is used, as undercuffing large arms is the most common error in measuring BP in the outpatient clinic.[679] The recommended cuff sizes are[17] (1) arm circumference 22 to 26 cm, “small adult” cuff size: 12 to 22 cm, (2) arm circumference 27 to 34 cm, “adult” cuff size: 16 to 30 cm, (3) arm circumference 35 to 44 cm, “large adult” cuff size: 16 to 36 cm, and (4) arm circumference 45 to 52 cm, “adult thigh” cuff size: 16 to 42 cm.
Fundus.
Ophthalmoscopic examination of the optic fundi is one of the most valuable clinical tools for assessing target organ damage, the severity and duration of the hypertension, and the urgency for applying treatment. Moreover, patients with retinopathy are more likely to have white matter lesions (WMLs) observed by MRI than those without retinopathy.[680] The 5-year cumulative incidence of clinical stroke was higher in persons with than without WMLs and in persons with than without retinopathy. Patients with both WMLs and retinopathy had a significantly higher 5-year cumulative incidence of stroke than those without either WMLs or retinopathy (20.0% vs. 1.4%). Thus, the presence of hypertensive retinopathy has important implications both for acute management and for prognosis.
Heart.
The mechanical effects on the heart of sustained increase in BP may be reflected in the physical findings. A forceful apical thrust is common even in early hypertensive disease and may be exaggerated in the so-called hyperdynamic state. In contrast, a sustained, heaving LV pulse indicates significant LVH due to pressure overload. Among the earliest physical signs of cardiac involvement is the fourth heart sound (S4). The “atrial gallop” is occasionally heard in normal patients; is usually audible before cardiac enlargement is detectable, and reflects reduced ventricular compliance leading to a more forceful atrial contraction. The S4 may correlate with the finding of P wave abnormalities on the ECG. The S3 gallop may occur in young subjects with rapid ventricular filling. In older patients, it may be a late manifestation of hypertensive heart disease and reflects the early diastolic compliance abnormality of LV failure.
In severe hypertension, an accentuated aortic second sound may be accompanied by an aortic insufficiency murmur. This soft diastolic murmur may be heard in the second right interspace and along the left sternal border. It suggests dilatation of the aortic root and may indicate the need for more urgent therapy. When associated with primary aortic regurgitation disease, hypertension in elderly patients is usually systolic, with a wider pulse pressure. Surgical replacement of the regurgitant aortic valve is usually followed by an increase in diastolic BP. Aortic stenosis in the elderly, usually from calcific valvular disease, is associated with a systolic murmur, a narrow pulse pressure, and a slow carotid upstroke. Diastolic hypertension is rare or mild in this situation.
The syndrome of a hyperkinetic or hyperdynamic circulation may occasionally be encountered in adolescents and young adults with or without hypertension. If present, the hypertension is labile, largely systolic, and accompanied by tachycardia at rest, a forceful apical thrust, and occasional pulsation in the carotid arteries.
A harsh systolic murmur over the precordium or midscapular area of the back suggests coarctation of the aorta. This finding should lead the physician to compare the BPs in the arms and legs and obtain an echocardiographic examination of the aortic valve, because bicuspid aortic valves commonly occur in association with coarctation of the aorta.
Vascular System.
Bruits and thrills, indicative of occlusive disease, are more prevalent in hypertensive patients with vascular disease and may occur throughout the arterial tree. Accordingly, the physician should examine the carotid arteries, abdominal aorta, renal arteries, and femoral arteries. A diastolic component to a bruit or a palpable thrill over a peripheral vessel usually suggests a higher-grade stenosis. Systolic bruits without diastolic components tend to be less significant and may have no pathogenic importance when they occur in the abdomen.
A systolic bruit over the carotid artery can be significant. Carotid auscultation should be performed in every patient. The stethoscope is placed over the external carotid in the supraclavicular region as close to the angle of the jaw as possible. Particularly when a precordial bruit is also heard, this approach may help distinguish a transmitted sound from an intrinsic sound.
Bruits can be unilateral or bilateral. They may be audible throughout the cardiac cycle or only during systole. Although bruits are likely to occur with equal frequency in normotensive and hypertensive subjects, they have far graver prognostic significance in the hypertensive person. Although the carotid bruit is a marker for subsequent CVD, it does not predict the location of the lesion. Indeed, patients with carotid bruits are more likely to have MI than stroke.
A systolic bruit over the femoral artery suggests atherosclerotic disease but does not necessarily imply occlusion. When pulses in the lower extremities are absent or dampened, coarctation of the aorta should be suspected in a young person, and occlusive aortic femoral disease should be suspected in an older one. The ankle-arm BP index (AAI = ratio of ankle to arm systolic BP) is a simple, noninvasive, and inexpensive screening test.[681] An AAI value of 0.9 or less has recently been found to be highly predictive of subsequent mortality in several populations, including hemodialysis patients. [694] [695]
Abdomen.
The aorta should be palpated carefully in all patients inasmuch as aortic dilatation or aneurysm is a highly treatable condition best identified in the initial physical examination. A systolic and diastolic bruit in the upper epigastrium or in one or both upper quadrants of the abdomen suggests renal artery stenosis and should encourage the physician to pursue this diagnosis if other criteria are compatible. A palpable enlargement of one or both kidneys can suggest polycystic renal disease, hydronephrosis, or a renal tumor. Rarely is a PHEO large enough to be palpable and palpation should not be attempted when a PHEO is suspected, as it may precipitate a crisis. Purple striae and central obesity are signs of hypercortisolism that should prompt a laboratory evaluation of Cushing's syndrome.
Neurologic Examination.
Gross neurologic deficits in sensory or motor function, mentation, or mood are not likely to be ignored. More subtle deficits suggesting transient cerebral ischemia or autonomic dysfunction may be overlooked and should be sought clinically, especially when the history is suggestive.
Initial Laboratory Evaluation
The initial laboratory evaluation should include complete blood count and hematocrit together with urinalysis, microalbumin, blood urea nitrogen, serum creatinine, serum uric acid, fasting blood glucose, and serum electrolyte measurements; and a lipid profile. If the serum K+ level is borderline or low (i.e., ≤3.6 mEq/L), the test should be repeated on two or three separate occasions. The serum K+ concentration serves as a baseline value for the subsequent response to thiazide diuretics and often provides the first laboratory clue to the presence of primary or secondary aldosterone excess. A hemoglobin level is especially relevant in patients with renal disease who are treated with erythropoietin (EPO). Although the hemoglobin level during EPO therapy is generally not closely related to BP, severe hypertension may be more likely to occur when the hemoglobin level rises too rapidly or to excessive levels.
With the current widespread use of automated laboratory testing, a variety of other relevant tests may be added at little or no extra cost. Serum Ca2+ and circulating thyroid hormone levels may point to parathyroid or thyroid disease, which often exist without clear-cut clinical evidence. Measurement of serum cholesterol, HDL, low-density lipoprotein (LDL) and triglyceride levels should be included for assessment of cardiovascular risk.
When PHEO is suspected, screening with plasma metanephrines is indicated (see earlier). When signs and symptoms are suggestive of Cushing's syndrome, it should be screened for by a 24-hour urinary free cortisol level. Urinary aldosterone level, when combined with measurements of urinary Na and K excretion, is extremely valuable for establishing the diagnosis of primary aldosteronism and other hypertensive situations associated with either low renin levels or hypokalemia (see earlier). A plasma aldosterone/renin ratio greater than 25 to 50 (ng/dL:ng/mL/hr) has been suggested as a simple screening test for this disorder. [449] [696] However, there is some concern that this test may be misleading in patients with low renin primary hypertension or when it is measured during antihypertensive treatment with agents that affect renin secretion (see earlier).
A chest x-ray examination may be useful as part of every initial workup, particularly in patients older than 50 years. It can reveal a coarctation or aneurysm of the aorta and although chest x-ray can be useful for identifying patients with LVH, echocardiography is more sensitive [113] [697] (see Echocardiography, later).
Electrocardiogram
A routine ECG to identify signs of LVH should be performed in all new patients with established high BP. ECG criteria for LVH include (1) Cornell criteria is the product of QRS duration and the Cornell voltage combination (RaVL + SV3, with 6 mm added in women), with a threshold value of 2440 mm × ms and (2) Sokolow-Lyon voltage (SV1 + RV5/6) greater than 38 mm.[179] Other manifestations of LVH include T wave abnormalities, expressed either by notching or by a biphasic form, particularly in the precordial leads. As LVH progresses, R wave voltage increases, and then a characteristic strain pattern involving ST segment depressions and T wave inversion occurs. In addition, approximately 30% of MI that are evident on ECG are asymptomatic and, thus, may not be elicited by the history.[93]
Echocardiography
Although ECG criteria are highly specific for detecting LVH, they lack sufficient sensitivity. Echocardiography is the most sensitive method for detecting LVH, although the prevalence varies widely based upon the population studied (see Left Ventricular Hypertrophy, earlier). This method is not recommended for routine use, particularly in low-risk patients, because of the relatively high cost. However, LVH has been detected in 20% of a group of untreated hypertensive subjects considered at low risk of cardiovascular complications.[685] In addition, subjects in whom LVH regressed during antihypertensive treatment were at lower risk of cardiovascular mortality and all-cause mortality than those with persistent LVH despite an equivalent level of BP control.[178] Therefore, the role of echocardiogram in the routine evaluation of the hypertension is evolving and is an important component in the evaluation of the hypertensive patient in our center.
Ambulatory and Home Blood Pressure Monitoring
ABP is a fully automated device for measuring BP over an extended period, usually for 24 hours. It has been used as a research tool, defining BP characteristics of patients, including those with WCH and masked hypertension, for which prognosis and treatment may be influenced by their detection (see Ambulatory Blood Pressure, earlier). Medicare has approved this test for reimbursement for the patient with suspected WCH. The initial cost of a monitor and related equipment is approximately $2500. The predo-minant expense is the long-term cost of antihypertensive medication. If ABP use successfully identifies patients who have WCH but otherwise have normal BP and, thus, may not require medication, then the cost-benefit ratio should be favorable.
Although BP readings are generally higher in the medical office setting, these measurements do not correlate as well as home readings to the presence of abnormal markers of cardiovascular risk (e.g., LVH). [18] [120] [223] [699] In both untreated and treated hypertensive individuals home BP monitoring appears to be useful in the detection of WCH, but it may not be appropriate as an alternative to the ABP method.[687] Home BP monitoring is used increasingly in the evaluation and treatment of patients with hypertension. Home BP monitors are relatively inexpensive and simple to use. Although they are generally accurate, the patient's technique and the precision and reproducibility of the measurements should be validated during an office visit by the clinician.
Identifying Curable Forms of Hypertension
Renovascular Disease
As pointed out earlier in this chapter and in Chapter 43 , curable and definable forms of hypertension should be identified before long-term drug therapy is contemplated. The baseline evaluation has much to offer in detecting the presence or absence of surgically curable forms of hypertension as renovascular hypertension, primary aldosteronism, coarctation of the aorta, PHEO, and Cushing's syndrome.
The PRA level, which is unsuppressed in renovascular disease and suppressed in primary aldosteronism, is a valuable initial screen (see earlier). It is no more expensive or complicated than other commonly performed blood tests (e.g., thyroid and cholesterol), and it is potentially far more relevant, not only because it can enable the absolute diagnosis of curable hypertensive disorders but also because it can be used for physiologic evaluation and treatment planning.
The renin-Na nomogram, developed by plotting PRA against the 24-hour urinary Na+ level, provides correction for the fact that renin, as a regulatory hormone, rises normally in response to a low-salt diet and declines in response to a high-salt diet (see Fig. 42-11 ). As with most laboratory tests, the PRA level is most powerful when its deviations from normal are great. Low or high values lead one to suspect, respectively, adrenocortical or curable renovascular disease. Indeed, the baseline PRA and serum K+ measurements are the essential tools for the exclusion or diagnosis of these types of hypertension. The test originally involved the collection of a 24-hour urine specimen for Na+measurement and a venous blood sample for renin measurement that is collected while the patient is seated quietly in the office. However, for expedience, the 24-hour urine collection is not required, unless marked salt depletion is suspected either because of dietary Na restriction or owing to concurrent illness or medication use.
The matter of excluding curable hypertension has a special meaning and urgency because the possibilities of cure of renovascular disease have multiplied dramatically with the widespread use of screening tests (e.g., captopril test[358]) and the availability of PTRA and renal artery stent placement (see later). At NewYork-Presbyterian Hospital, balloon dilatation has been successfully employed. Approximately two thirds of those patients with normal renal function were able to stop taking drugs completely or had improved BP with antihypertensive medications, with comparable responses in the elderly population.[688] If not for advanced testing protocols, a large proportion of these patients would be on a lifetime regimen of drugs and would be incorrectly diagnosed with primary hypertension.
Any untreated hypertensive patient with an ambulatory PRA level greater than 1.6 ng/mL/hr is a candidate for further evaluation for unilateral renal artery stenosis. A study of 52 consecutive patients showed no patient with proven unilateral renal disease whose renin level was less than that.[358] However, renin levels can be lower in azotemic patients with hemodynamically significant bilateral renal artery stenosis because of the impaired Na+ excretion and volume expansion. This is especially relevant considering the emerging evidence that 15% of the ESRD population may have ischemic nephropathy, due to stenosis of the main renal arteries, as the basis for their progressive azotemia. [702] [703] Proteinuria may occasionally be pronounced in such patients, particularly when one renal artery is totally occluded (see Chapter 43 ). Therefore, any patient with an abnormal serum creatinine value, regardless of the PRA level, may also be a candidate for further evaluation, especially if there is no other basis for CKD.
In patients with plasma renin values greater than 1.6 ng/mL/hr, with a normal serum creatinine concentration, the captopril test is informative in the evaluation of suspected unilateral renovascular hypertension. This test, performed in untreated patients, is based on its inhibition of Ang II formation, while stimulating a reactive increase in renin secretion from the ischemic kidney. Patients who are Na+ depleted, because of either a low-salt diet or a use of a diuretic, are ineligible for the test because the baseline PRA is high, and a false-positive test is more likely.[358] We measure a 24-hour urine Na to identify patients on a low-Na diet prior to the captopril test.
During the captopril test, the patient is seated quietly for 45 minutes and then a blood sample for baseline PRA is drawn. A single dose of 25 mg captopril is then given orally to the quietly seated patient. The patient remains seated and BP is measured at 10- to 15-minute intervals and a second blood sample for PRA is obtained 1 hour after the captopril dose. Patients with renovascular hypertension react to this blockade with an unusually vigorous rise in renin secretion from the ischemic kidney, whereas those hypertensive patients without renal artery obstruction show little or no plasma renin response. The 60-minute plasma renin response, rather than the BP response, is the discriminator for the diagnosis of renovascular hypertension. The following criteria are suggestive of the presence of unilateral renal artery stenosis: (1) stimulated PRA 7.8 ng/mL/hr or more by 60 minutes, (2) absolute increase in PRA of 6.5 ng/mL/hr or more, and (3) percent increase in PRA of 150% or more, or 400% or more if baseline PRA is 1.3 ng/mL/hr or less.[358] Although a substantial BP decline usually accompanies the marked rise in plasma renin level, this finding is not altogether a reliable indicator of renin dependency or of renovascular hypertension because other transient defenses of the BP level may operate acutely.[358]
A positive captopril test strongly suggests the possibility of renovascular disease. In a series comparing 56 patients with proven renovascular disease with 112 patients with primary hypertension, the captopril test was found to be both highly sensitive and specific for renin-dependent hypertension related to renal artery stenosis.[358] Furthermore, it is perhaps the best screening tests for unilateral renovascular disease because it is safe, inexpensive and easy to perform and avoids the problem of disposal of radiopharmaceutical agents. Although some false-positive results are inevitable, false-negative results are uncommon.
A positive captopril test result does not discriminate between unilateral and bilateral kidney disease, nor does it discriminate between a parenchymal and an arteriolar lesion. In patients with a positive captopril test, these questions can be definitively resolved by digital subtraction angiography and by renal vein renin sampling during captopril stimulation. In typical unilateral renovascular disease, renin is secreted from only one kidney; a simple arithmetic analysis of the concentration of renin in each renal vein can be used to identify the renin-secreting kidney and assess its degree of ischemia. At the same time, the peripheral blood level of renin reflects the secretion rate of renin from that kidney.[691]
Primary Aldosteronism (see earlier)
If hormonal evidence for primary aldosteronism is found, then physiologic studies to assess autonomy of aldosterone secretion should be performed. These include measurements of aldosterone during postural stimulation test and during dietary Na loading or acute infusion of saline. If these tests are positive, then adrenal vein sampling should be performed to determine whether aldosterone secretion lateralizes. For the following reasons, CT or other imaging studies should be done after measurements of hormone levels confirm the diagnosis of primary aldosteronism: (1) Nonfunctioning adenomas are commonly discovered by CT scan, (2) curable forms occur in patients without a distinct adenoma, even when the adrenal glands radiographically appear normal, and (3) a dominant adrenal nodule, in a diffusely hyperplastic gland, may appear to be a solitary adenoma.
Drug Therapy for Primary Hypertension (see Chapter 45 )
After performing the initial evaluation, in which the diagnosis of secondary forms of hypertension has been excluded, the clinician is then faced with the treatment of primary hypertension. A relatively small proportion of patients will have a significant response to nonpharmacologic interventions, such as dietary Na restriction, weight loss, reduction in alcohol intake, and increased exercise. [78] [80] [705] However, pharmacologic treatment will be required in the vast majority of patients with primary hypertension, even in those with initial improvement during nonpharmacologic intervention.
The drug treatment of the hypertensive patient is a complex decision-making process.[693] It is complicated by the facts that there are many pharmacologically distinct drug classes available and that hypertensive patients are not all alike mechanistically, so that individuals respond quite differently to the various types of antihypertensive drugs. The nine major categories of antihypertensive agents are diuretics, specific aldosterone receptor blockers, calcium channel blockers, α-blockers, β-blockers, ACE inhibitors, type 1 angiotensin receptor blockers, a newly approved renin inhibitor and centrally acting α-agonists (see Chapters 45 and 46 ). The problem of which drug to choose for a particular patient is complicated by the fact that many different products are available within each class, which are often claimed by their manufacturer to differ importantly from other products in the same class. Such marketing claims can be confusing to physicians and patients. These issues are compounded because the selection of drugs is increasingly limited by contractual agreements between the health insurance and the pharmaceutical industries.
The drug selection process is simplified when considering the basic determinants of BP including Na-volume and renin-angiotensin vasoconstriction. The PRA test, measured in the seated patients, reliably defines the presence and the degree of either the Na-volume or the renin-vasoconstrictor factor in untreated patients or in those receiving antihypertensive drugs. The renin test is, therefore, central to pathophysiologically based treatment. Thus, hypertensive patients are characterized by
|
• |
PRA levels less than 0.65 ng/mL/hr with predominantly Na-volume–mediated hypertension or |
|
|
• |
PRA levels 0.65 ng/ml/hr or greater with predominantly plasma renin-angiotensin–mediated vasoconstrictor hypertension. |
The antihypertensive drug classes are divided into two major categories
|
• |
Drugs that reduce BP because of primary or secondary actions to reduce body Na and volume content by enhancing renal Na excretion (V drugs). |
|
|
• |
Drugs that lower BP by reducing or blocking the activity of the RAS (R drugs). |
A basic principle guiding this approach is that, in the normotensive individual, a higher BP per se suppresses PRA levels. Thus, any hypertensive patient whose PRA is not suppressed (≤0.65 ng/mL/hr) has an inappropriate amount of renin in the blood and therefore has a form of hypertension that is, at least partly, renin dependent. By contrast, hypertensive patients that do have suppressed PRA levels (<0.65) have a primarily Na-volume-dependent hypertension.[693]
Because plasma renin-angiotensin is vasculotoxic for the hypertensive patient, contributing to the pathogenesis of MI, HF, stroke, and progressive renal failure, drugs that block the renin system (R drugs) should be the initial choice for treatment of those hypertensive patients who do not have suppressed PRA levels. The R drugs include ACE inhibitors, ARBs, β-adrenergic receptor blockers, renin inhibitor and central α2-receptor blocker.[693]
Those patients with PRA less than 0.65 ng/mL/hr are treated with an anti-Na-volume drug (V drug). The V drugs include diuretics, α-adrenergic receptor blockers, and calcium channel blockers.
Newly Diagnosed or Untreated Hypertensive Patient
The evaluation and treatment process comprises a series of patient visits ( Fig. 42-17 ). During visit 1, BP is measured and blood is collected to measure PRA. During visit 2, BP is measured again to confirm that the patient is truly hypertensive and the result of the PRA test is evaluated. If the PRA is 0.65 ng/mL/hr or greater, the patient is placed into the renin-vasoconstriction-dependent (R) hypertension category. If the PRA is less than 0.65 ng/mL/hr, the patient is placed in the. Volume-dependent (V) hypertension category
|
|
|
|
|
|
|
FIGURE 42-17 Diagnosis and treatment of hypertension in the previously untreated patient. The peripheral paths (gray/dotted lines) show the alternate decision trees to assess potentially curable forms of hypertension, including renovascular hypertension and primary aldosteronism (see text). (From Laragh J: Laragh's lessons in pathophysiology and clinical pearls for treating hypertension. Lesson XVI: How to choose the correct drug treatment for each hypertensive patient using a plasma renin-based method and the volume-vasoconstriction analysis. Am J Hypertens 14:491–503, 2001.) |
|
Renin-Dependent Hypertension.
A patient in the R category at visit 2 will be started on a low-dose R drug. During visit 3, the BP will be measured. If BP is not controlled, the dose of the R drug will be increased. During visit 4, if BP is still not controlled, a V drug will be added to the treatment regimen to reduce the Na-volume component to the BP. During visit 5, if BP not yet controlled, the V drug dosage will be increased and blood will be drawn to check the PRA level during treatment. During visit 6, if BP is not controlled, the PRA level from visit 5 will determine the change in the treatment regimen. If the PRA level was less than 0.65 at visit 5, the R drug will be discontinued at visit 6 and a second V drug added. If the PRA level was between 0.65 and 6.5 at visit 5, a second R drug will be added at visit 6 to more effectively block the RAS. If the PRA level was above 6.5, the V drug is discontinued to reduce the reactive rise in renin induced by most V drugs and a second R drug will be added.
Sodium-Volume-Dependent Hypertension.
A patient in the V category will start on a low-dose V drug. During visit 3, about 3 weeks later, the patient will have his or her BP tested again. If BP is not controlled, the dose of the V drug will be increased. During visit 4, if BP is still not controlled, an R drug will be added to the treatment regimen, based on the rationale that the patient has both a volume and a renin component to the hypertension. During visit 5, if BP is still not controlled, the R drug dosage will be increased and blood will be drawn to check PRA levels. At visit 6, if BP is still not controlled, the PRA level collected at visit 5 will be used to determine the change in the treatment regimen. If the PRA level remains below 0.65 ng/mL/hr, the R drug will be discontinued and a second V drug added. If the PRA level is between 0.65 and 6.5 ng/mL/hr, a second R drug will be added to block the effects of the reactive rise in plasma renin. If the PRA level is above 6.5, the V drug will be discontinued to eliminate its stimulatory effect on renin secretion and a second R drug will be added.
Patients with Persistent Hypertension Despite Drug Treatment
This section provides an approach toward antihypertensive drug selection for the patient who presents initially with persistent hypertension despite ongoing drug treatment ( Fig. 42-18 ).
|
|
|
|
|
|
|
FIGURE 42-18 Selection of antihypertensive medication in the unsuccessfully treated hypertension patients (see text). (From Laragh J: Laragh's lessons in pathophysiology and clinical pearls for treating hypertension. Lesson XVI: How to choose the correct drug treatment for each hypertensive patient using a plasma renin-based method and the volume-vasoconstriction analysis. Am J Hypertens 14:491–503, 2001.) |
|
Visit 1 involves measuring BP and drawing blood to test PRA levels. The appropriate action to take during visit 2 depends on the current treatment regimen and the PRA level.[693]
Patient on a V Drug with Persistent Hypertension.
If the PRA level is below 0.65 ng/mL/hr, the dose of the drug should be increased to a maximum level as long as the PRA remains below 0.65 ng/mL/hr. In such a patient, the Na-volume factor is still operative and contributing to the hypertensive state. Because a renin factor is unlikely to be present in any patient with a low renin level, a patient on any V drug who remains hypertensive with a PRA level less than 0.65 ng/mL/hr is unlikely to respond to any R drug. Therefore, if a full dose of a V drug has already been tested, and assuming good compliance, a V drug with a different mechanism of action should then be added (e.g., diuretic added to an α-blocker or calcium channel blocker).
If the PRA level of the V drug-treated patient is between 0.65 and 6.5 ng/mL/hr, an R drug is added to block both volume and vasoconstrictor factors. If the PRA level is above 6.5 ng/mL/hr, the V drug is discontinued and the patient is switched to an R drug to eliminate the confounding renin stimulatory effect of the V drug.
Patient on an R Drug with Persistent Hypertension.
If the PRA level is below 0.65 ng/mL/hr, then it should be changed to a V drug because the low renin level indicates that there is no apparent renin-mediated vasoconstriction. However, if the PRA level is between 0.65 and 6.5, the dose of the R drug should be maximized. A patient who is unsuccessfully treated with a full dose of any R drug should then have a V drug added as long as PRA is less than 6.5 ng/mL/hr. Finally, if PRA is above 6.5, a V drug is unlikely to be effective and a second R drug is added to more effectively block the renin system.
Although the four classes of R drugs all block the RAS, they have different sites of action and may be additive for increasing inhibition of the renin system. Thus, at the recommended maximal therapeutic doses, neither ACE inhibitors nor ARBs completely block the renin system, and a reactive rise in renin secretion may overcome or attenuate the effectiveness of these agents. β-Blockers suppress adrenergically mediated renin release and can enhance the antihypertensive efficacy of ACE inhibitors and ARBs. Renin inhibitors block the conversion of angiotensinogen to angiotensin I. Although PRA decreases to low levels, secretion of renin by the JG cell is stimulated, leading to marked elevation in the concentration of renin in blood during treatment with a renin inhibitor. It is not yet known whether this reactive rise in renin may attenuate the antihypertensive efficacy of renin inhibitor treatment.
Patient on Multiple Drugs with Persistent Hypertension.
A PRA test on the first visit is extremely helpful in the patient on multiple drugs because it can reveal which mechanism predominates. Thus, PRA values less than 0.65 clearly indicates that Na-volume excess is present. In this case, the R drug should be stopped and a second V drug added. Conversely, if the PRA is between 0.65 and 6.5, the antirenin limb of treatment needs to be strengthened by the addition of a second R drug. Above 6.5 ng/mL/hr, the V drug should be stopped because it may be inducing excessive renin secretion. A second R drug can be added, if necessary.
Our experience using such a protocol at New York-Presbyterian Hospital indicates that about 25% of hypertensive patients will be controlled after the third visit and that 90% or more will be adequately controlled after the sixth visit. Moreover, in patients referred to us on a multiple-drug regimen, we can usually reduce the number of medications.[663]
Other strategies are more widely used for the selection of antihypertensive drug treatment. These approaches vary but employ an empirical approach that may include in the decision process the patient's age, race, or presence of comorbid conditions (e.g., prostatism) that are unrelated to the pathophysiology of their hypertensive disease and that do not identify a specific marker of vasoconstriction. [1] [707] An interesting alternative approach has been reported in which there is crossover rotation of representatives from each of the main classes of antihypertensive drugs. Although only 39% of patients achieved the target BP (≤140/90 mm Hg) with their first drug, 73% ultimately reached this goal with monotherapy after rotation to another drug class.[32] Moreover, in that crossover study, there were significant correlations between the BP responses to drugs that block the renin system (ACE inhibitors and β-blockers; r = 0.5, P < .0001) and drugs that are active in low-renin hypertension (calcium channel blockers and diuretics; r = 0.6, P < .01), but not between the other four pairings of treatments. The marked variability in the efficacy of drug treatment in primary hypertension described in this study, together with the concordance of BP responses found in this study and by the renin-based approach to drug selection (see earlier), highlight the heterogeneity of pathogenesis and its relevance to heterogeneity in essential hypertension.
Patient Nonadherence to Medical Management
One important factor in the relatively low rate of BP control is inadequate patient adherence to medical management.[3] Several patient characteristics that have been associated with poor BP control include older age, multiple drug regimen, lack of knowledge by the patient regarding their target BP, and antihypertensive drug side effects.[695]
Strategies have been identified that can improve adherence to medication treatment regimens, particularly in the elderly. A detailed medical history should be elicited, including use of both prescription and over-the-counter medications, doses, schedules, and side effects. Attempts should be made to simplify the drug regimen by reducing the number of drugs and dosing schedule. Hypertensive patients required to take a pill twice daily are less adherent to the drug regimen than those requiring a single pill.[696] Patient reminders, such as pill boxes, and timing of treatment with other tasks (e.g., meals), may be useful, although these may be limited in elderly patients with impaired cognitive or other functional capacity. Educating patients to the risks of uncontrolled hypertension as well as to the complications of treatment will improve their understanding of their disease and is likely to improve treatment efficacy.[695] However, patient education has limited efficacy, as only about 50% of patients recall what they are told by their physicians.[697]
Medication cost is a major issue relating to treatment adherence. Those patients who have difficulty paying for their medications take fewer drugs or smaller doses than prescribed by their physicians.[698] Medication cost has also been reported as a predictor of BP control in an indigent inner-city population—patients with Medicaid coverage were significantly less likely than the uninsured to report cost as a barrier to purchasing antihypertensive medications and seeing a physician.[699]
Lifestyle Modification
JNC7 recommends lifestyle modification as initial therapy of newly diagnosed patients with hypertension and as adjunct treatment for those requiring antihypertensive medication.[1] In addition to increased exercise, most of these recommendations are nutrition-based, including (1) reduction in dietary Na to 100 mmol/day (2.4 g/day), (2) weight loss for overweight and obese patients, (3) moderation of alcohol intake (≤2 drinks/day for men and ≤1 drink/day for women), and (4) adoption of the DASH diet, which emphasizes fruits, vegetables, low-fat dairy products, and small amounts of red meats.
These lifestyle interventions have several limitations. Although some studies have shown that lifestyle changes can decrease BP and, in some cases, prevent the development of hypertension, long-term maintenance of BP control is difficult to achieve with behavioral approaches such as weight loss and dietary Na restriction. [556] [713] Furthermore, no study has yet shown an additive effect of combining lifestyle interventions on BP.[701] A study of individuals in which combined treatment with multiple “established” lifestyle interventions (exercise, weight loss, dietary Na restriction) for 6 months found that BP reduction was less than expected (systolic -3.7 mm Hg, diastolic -1.7 mm Hg).[702] In that study, addition of the DASH diet together with these “established” lifestyle interventions produced a further decrease in BP of only -0.6/-0.9 mm Hg (-1.7/-1.6 mm Hg in hypertensive individuals). Several factors were implicated in the failure of this study to show more meaningful reductions in BP: (1) Participants were not provided with prepared meals, unlike the original DASH diet that found more impressive reductions in BP,[77] (2) urine K content was lower in this study than the original DASH study, (3) the BP effects may have been masked by BP reduction in the control group, although this would not account for the lack of effect of adding the DASH diet to the intervention group.
Although the antihypertensive mechanisms of all lifestyle interventions have not been defined, it is very likely that they act through physiologic mechanisms comparable with antihypertensive medications. This has been best defined for dietary Na restriction (see earlier). Accordingly, a nonlinear dose-response relationship for lifestyle changes might be expected, so that increasing the dose or adding a second agent with the same mechanism of action (e.g., two diuretics) in a patient with persistently elevated BP would not be expected to substantially lower BP any further.[701] By contrast, substituting a different drug that has a different pharmacologic action (e.g., ACE inhibitor for a diuretic) or employing a different lifestyle modification with another mechanism of action may be more effective. However, it is not feasible to exploit this concept because very little is known about the antihypertensive mechanisms of lifestyle interventions.
The DASH diet has other limitations for use in patients with CKD.[546] Specifically, the DASH diet has a protein content (18% protein, 1.4 g/kg/day) that is higher than the recommended daily allowance for healthy adults (0.8 g/kg/day) and exceeds the National Kidney Foundation K/DOQI guidelines for CKD stage 3 (0.75 g/kg/day) and CKD stage 4 (0.6 g/kg/day). This diet is also higher in phosphorus (1.7 g/day) than the recommended daily allowance (700 mg/day) and higher than is recommended for those with stage 3 CKD (0.8–1.0 g/day, adjusted to protein intake). The DASH diet also contains a high K content (approximately 4500 mg/day; 110–115 mEq/day) and may lead to the development of hyperkalemia, especially in those patients concurrently treated with ACE inhibitors, Ang II receptor blockers, K-sparing diuretics, and potassium supplements. Therefore, the DASH diet should not be routinely recommended to patients with GFR less than 60 mL/min/1.73 m2.
Drug Therapy for Chronic Kidney Disease (see Chapters 36 and 54 )
The general goals of antihypertensive treatment in CKD patients are the same as those in the general population—to effectively lower BP, to reduce the risk of CVD and stroke, and to slow the progression of kidney failure. Although CKD patients have a high rate of CVD, relatively few patients have been included in controlled trials of CVD reduction.[702a] Based on studies of other high-risk groups (e.g., patients with diabetes, HF) that show benefits related to BP reduction below the target 140/90 mm Hg, the National Kidney Foundation K/DOQI Clinical Practice Guidelines recommend a goal BP less than 130/80 for patients with CKD.[546]
ACE inhibitors and Ang II receptor blockers have several potential advantages for the hypertensive diabetic and nondiabetic CKD patient.[546] These benefits are greater in those with higher levels of proteinuria. Several randomized controlled treatment trials have found that regimens including ACE inhibitor blockers are more effective at reducing kidney end points than those that do not include these agents, even though BP was comparable in the various treatment groups. Ang II receptor blockers have also been shown to slow the rate of progressive CKD in diabetic subjects. Although no large, long-term, randomized, controlled trials of Ang II receptor blocker-based treatment in nondiabetic subjects have been reported, short-term studies with surrogate end points suggest that the benefits of these agents are similar to those of ACE inhibitors. [717] [718] Moreover, ACE inhibitors, Ang II receptor blockers, and nondihydropyridine calcium channel antagonists appear to have a greater antiproteinuric effect than other agents.[546] By contrast, calcium channel blockers are less effective at slowing the rate of CKD progression in proteinuric subjects despite comparable reductions in the BP level.[705] Renin inhibitors have yet to be evaluated in this context.
Diuretics are often effective in hypertensive CKD patients because of the high prevalence of fluid retention.[546] ALLHAT subjects with stage 3 CKD treated with chlorthalidone showed comparable CVD risk and rate of decline in renal function when compared with the lisinopril and amlodipine treatment groups and with the overall ALLHAT study population.[144] However, the kidney failure event rate in ALLHAT was low (≈5%); therefore the statistical analysis was limited. As with the findings in the overall population reported by ALLHAT (see earlier), concerns have been raised regarding the CKD subgroup analysis in this study: (1) Diuretics were not provided as second-line therapy, (2) the risk of kidney failure was lower than that reported in other studies of CKD, (3) proteinuria was not measured in ALLHAT. Therefore, it it is not possible to determine whether the different outcomes in ALLHAT, particularly regarding the lack of a superior effects of ACE inhibitors, compared with other drug trials are due to the study design and type of patient enrolled or to real differences in the efficacy of antihypertensive treatment strategies employed in ALLHAT.[546]
Although there is strong evidence that medications that interrupt the renin system (i.e., ACE inhibitors, Ang II receptor blockers) slow the rate of progression in CKD patients, several important issues have not been addressed. Most notably, how can patients be identified who are most likely to respond to this treatment strategy? Heavy proteinuria identifies patients at greatest risk of progressive CKD and those who are also most likely to benefit from antirenin treatment. Despite this risk stratification, the proportion of patients in these trials for whom progression to the study end point (e.g., ESRD, doubling of serum creatinine) is prevented by treatment with these agents is relatively small, although both medically and statistically significant. One possible limitation in these parallel design studies is that multiple antihypertensive drugs were added when BP did not respond to the ACE inhibitor or Ang II receptor blocker—in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, dihydropyridine calcium channel antagonists were used in more than 60% of the losartan group. Addition of drugs with potentially adverse effects (e.g., dihydropyridine calcium channel antagonists) might attenuate the beneficial effect of the study drug.
An alternative approach to the study of antirenin drugs is to stratify patients according to the activity of the renin system, as outlined previously. Because ACE inhibitors and Ang II receptor blockers are most likely to have the greatest antihypertensive effect in those with an activated renin system, it is biologically plausible that other beneficial effects related to the interruption of the renin system (e.g., decreased intraglomerular pressure, decreased progression of renal failure) are predictable by measuring the baseline PRA level. By contrast, patients with suppressed renin system activity might be less likely to respond to this type of treatment. Of note, none of the large, randomized, controlled ACE inhibitor or Ang I receptor blocker treatment trials reported renin system hormone levels.
Limitations of Clinical Trials of Antihypertensive Drug Treatment
One major conclusion of the JNC7 report was “More than two-thirds of hypertensive individuals cannot be controlled on one drug and will require two or more antihypertensive agents selected from different drug classes.”[1] This conclusion has been challenged because of the limited design and interpretation of the randomized controlled treatment trials cited by JNC7.[706] These trials used a parallel design in which two or more groups of patients were each assigned to a different step 1 drug. If the BP goal was not achieved, then one or more drugs were added stepwise while the previous medication was continued. [88] [721] [722] [723] Substitution or discontinuation of ineffective drugs was not an option in those protocols. This experimental approach has also been criticized conceptually because it assumes that the same pathophysiologic mechanism causes hypertension in all patients and that a diuretic should, therefore, be a universally effective, first-line treatment for all. [724] [725] [726] This monolithic treatment strategy ignores the evidence, outlined throughout this chapter, that a spectrum of mechanisms contributes to the pathophysiology of hypertension and that patients can be stratified accordingly. Rather than a mechanistic approach toward effective antihypertensive drug selection, the JNC7 treatment algorithm instead stratifies patients according to whether they have comorbid conditions such as diabetes, renal insufficiency, or HF.
What is the evidence to support these JNC7 treatment guidelines and why is it inadequate to justify the JNC recommendations? ALLHAT is a representative case.[88] The largest parallel-design, antihypertensive drug study ever conducted, more than 40,000 patients were enrolled in ALLHAT and treated during a 5-year follow-up. The study population was at high risk for CVD and stroke because of older age, relatively high prevalence of African Americans, diabetic individuals, and preexisting CVD. Patients were randomized to receive a thiazide diuretic (chlorthalidone), calcium channel blocker (amlodipine), ACE inhibitor (lisinopril), or β-blocker (doxazosin). The doxazosin limb was discontinued because of a reportedly higher incidence of HF (see earlier). If a target BP less than 140/90 was not reached with up-titration of the step 1 drug, then a step 2 drug was added, and if necessary, a step 3 drug as well. The step 2 drugs (i.e., atenolol, clonidine, reserpine) used in ALLHAT are R-type drugs and, thus, are most effective as monotherapy in renin-dependent hypertension and are less effective in volume-type hypertension (see earlier). With this drug protocol, more than 60% of the patients required that a step 2 or step 3 drug be added by year 5 of the study.
Based on the results of studies described previously, one could reasonably predict that, in ALLHAT, when the step 1 R-type drug (lisinopril) was ineffective, then V-type hypertension was probably present.[706] In that case, addition of a step 2 drug (all of which were R-type drugs) would be unlikely to lower BP further. Thus, by limiting the treatment options in the lisinopril limb solely to R-type drugs, twice as many in the lisinopril group as in the chlorthalidone group required progression to step 3 treatment.[88] Conversely, patients in the V-type step 1 groups (i.e., chlorthalidone or amlodipine) with persistent hypertension probably had an R-type mechanism; therefore, addition of a step 2 R-type drug was likely to improve their BP without requiring progression to step 3 treatment. Based on the heterogeneity of the pathophysiology and pharmacology of hypertension reviewed in this chapter, one could reasonably conclude that the design of ALLHAT placed the lisinopril treatment group at a disadvantage in comparison with the chlorthalidone group.
Although the difference in mean systolic BP between the chlorthalidone and the lisinopril groups in ALLHAT was relatively small (2 mm Hg higher in the lisinopril group), its pathophysiologic significance is indicated by the 15% higher risk of stroke and 10% higher risk of cardiovascular complications in the lisinopril group.[88] Further analysis showed that these treatment group differences in BP and risk of CVD were disproportionately high in African American patients and that the increased risk of stroke occurred solely in that subgroup. Specifically, in African American patients, mean systolic BP was 4 mm Hg higher in the lisinopril group than in the chlorthalidone group. This finding was associated with a 40% higher risk of stroke and 19% higher risk of CVD—approximately twice that of the non-African American patients. African-American hypertensive patients are more likely than non-African American patients to have a low renin level, providing a pathophysiologic basis for incomplete BP responses to both the step 1 treatment with lisinopril and to the step 2 drugs.[138]
In summary, parallel design treatment trials, in which antihypertensive drugs are added empirically in stepwise fashion with no opportunity to discontinue an ineffective drug, will predictably lead to the conclusion that multiple drugs are required to control BP even when monotherapy may have been effective. This outcome underscores the pathophysiologic heterogeneity of hypertensive disorders. The JNC7 treatment guidelines, unlike those of some other organizations, are limited because they fail to incorporate these basic principles.[30]
RECAPITULATION AND SUMMARY
Hypertension afflicts 20% or more of the adult populations of the world, depending on the arbitrary cutoffs used to define hypertension and normotension. About 90% of hypertension is classified, after exclusion of the known and curable causes (usually kidney or adrenal disorders), as primary hypertension. Historically, adult BP levels of 140/90 mm Hg or above were widely used to define the presence of hypertension. This threshold has recently been lowered with the recognition that other genetic, biologic, and behavioral factors, including age, gender, cigarette use, hypercholesterolemia, diabetes, and more recently, elevated PRA level are associated with increased cardiovascular risk. [93] [138]
Pressure natriuresis, the increase in urinary excretion of Na and water that occurs when arterial pressure increases, is a predominant mechanism that normally allows the kidney to regulate BP homeostasis. The RAAS plays a key role in this feedback control system by direct effects on peripheral vascular resistant (Ang II) and volume regulation (Ang II and aldosterone). BP elevation occurs when this pressure natriuresis mechanism is disrupted, for example, by excess activation of the renin system, reduction in renal mass, or impaired regulation of renal blood flow.
Measurement of PRA provides a useful method for understanding the pathophysiology of hypertension in the individual patient. When plasma renin is not suppressed (PRA ≤ 0.65 ng/mL/hr), renin-angiotensin is likely to be important in the pathophysiology, and thus, BP will decrease when treated with drugs that interrupt the renin system (i.e., ARBs, ACE inhibitors, β-adrenergic receptor blocker). By contrast, when PRA is suppressed (PRA < 0.65 ng/mL/hr), then renin-angiotensin is less likely to be a major factor. In the latter case, hypertension is more likely to be Na-volume-dependent and is more responsive to a diuretic, calcium channel blocker, or α-adrenergic receptor blocker. This strategy is further supported by the observations that, in the hypertensive patient, an elevated PRA level confers increased risk of MI, and when LVH is present, angiotensin receptor blockade decreases the risk of stroke.
Clinical trials of diuretic-based stepped-care regimens, in which drugs are added sequentially until the BP is subdued, have established the feasibility and reasonable safety of long-term oral drug regimens. Significant protection has been shown for stroke but, unfortunately, less so for cardiac events (e.g., MI), the latter accounting for 80% or so of the added risk burden of being hypertensive. Despite the generally favorable outcomes demonstrated in randomized, controlled treatment trials, only about half of all patients in the general population have their BP controlled with current drug treatment strategies. Altogether, only about one third of all hypertensive patients in the United States, and even fewer in other industrialized societies worldwide, have their BP controlled. A serious limitation of the clinical trials to date is that their design and analyses have assumed that all primary hypertension is alike and is a single process amenable to a single-drug treatment recipe. Unfortunately, this is not the case. Extrapolation from the mechanisms causing secondary forms of hypertension indicates that primary hypertension is heterogeneous in its hormonal and biochemical patterns and in its prognosis. Thus, clinicians have long known that many patients live a normal life span without cardiac or cerebral sequelae, whereas others, sometimes with lesser elevations in BP, die prematurely of a cardiac event or stroke. Furthermore, practicing physicians are well aware of gross differences in individual responses to the major drug classes. Each of these drug types, when randomly selected as monotherapy, will correct hypertension in about 40% to 45% of patients; but for each drug class, different subpopulations will respond. Thus, about the same percentage of patients will respond to monotherapy with either a diuretic or an ARB. However, an individual patient's BP often does not respond to all drug classes. When both agents are given concurrently, their effects summate and the combination controls BP in 80% or so of patients. This has prompted the recommendation that initial therapy should include two-drug therapy rather than the goal of achieving for every patient rather the “best-fit” strategy of using the fewest number of drugs in the lowest amount and frequency. Accordingly, future large-scale clinical trials are not likely to improve understanding of hypertension and its treatments unless every patient is given a prototype of every drug class and then classified as a nonresponder or a responder to each prototype drug studied.
In summary, primary hypertension is a heterogenous disorder that is associated with various hormonal and biochemical abnormalities that have a direct bearing on the individual patient's responsiveness to targeted antihypertensive medications and on the patients risk of CVD, stroke, and renal failure.
References
1. Chobanian AV, Bakris GL, Black HR, et al: Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42:1206-1252.
2. Chobanian AV, Bakris GL, Black HR, et al: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA 2003; 289:2560-2572.
3. Burt VL, Whelton P, Roccella EJ, et al: Prevalence of hypertension in the U.S. population: Results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension 1995; 25:305-314.
4. Barondess J: The future of generalism. Ann Intern Med 1993; 119:153-260.
5. Hajjar I, Kotchen TA: Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988-2000. JAMA 2003; 290:199-206.
6. Wolf-Maier K, Cooper RS, Banegas JR, et al: Hypertension prevalence and blood pressure levels in 6 European countries, Canada, and the United States. JAMA 2003; 289:2363-2369.
7. Mancia G, Ambrosioni E, Rosei EA, et al: Blood pressure control and risk of stroke in untreated and treated hypertensive patients screened from clinical practice: Results of the ForLife study. J Hypertens 2005; 23:1575-1581.
8. Gu Q, Paulose-Ram R, Dillon C, Burt V: Antihypertensive medication use among US adults with hypertension. Circulation 2006; 113:213-221.
9. Siegel D, Lopez J: Trends in antihypertensive drug use in the United States: Do the JNC V recommendations affect prescribing?. JAMA 1997; 278:1745-1748.
10. Lenfant C: Reflections on hypertension control rates: A message from the director of the National Heart, Lung, and Blood Institute. Arch Intern Med 2002; 162:131-132.
11. Smith Jr SC: Evidence-based medicine: Making the grade: Miles to go before we sleep. Circulation 2006; 113:178-179.
12. Riva-Rocci S: Un nuovo sfigmomanometro. Gaz Med Torino 1896; 47:981.
13. Korotkov N: A contribution to the problem of methods for the determination of the blood pressure. Izv Imperatorskoi VoennoMeditsinskoy Akad 1905; 11:365.
14. Pickering G: High Blood Pressure, London, Churchill, 1968.
15. Port S, Demer L, Jennrich R, et al: Systolic blood pressure and mortality. Lancet 2000; 355:175-180.
16. Alderman M: Measures and meaning of blood pressure. Lancet 2000; 355:159.
17. Pickering TG, Hall JE, Appel LJ, et al: Recommendations for blood pressure measurement in humans and experimental animals: Part 1: Blood pressure measurement in humans: A statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Circulation 2005; 111:697-716.
18. Mancia G, Parati G: Ambulatory blood pressure monitoring and organ damage. Hypertension 2000; 36:894-900.
19. Bobrie G, Chatellier G, Genes N, et al: Cardiovascular prognosis of “masked hypertension” detected by blood pressure self-measurement in elderly treated hypertensive patients. JAMA 2004; 291:1342-1349.
20. Blood Pressure Study: Actuarial Society of America and Association of Life Insurance Medical Directors. New York, 1925.
21. Actuaries Society: Build and Blood Pressure Study. New York, 1959.
22. Lew E: Hypertension and longevity. In: Laragh JH, Brenner BM, ed. Hypertension: Pathophysiology, Diagnosis, and Management, Vol 1. New York: Raven Press; 1990:175-190.
23. Veterans Administration Cooperative Study Group : Effects of treatment on morbidity in hypertension. Veterans Administration Cooperative Study Group on Antihypertensive Agents. JAMA 1967; 202:1028-1034.
24. Veterans Administration Cooperative Study Group on Antihypertensive Agents : Effects of treatment on morbidity in hypertension. JAMA 1970; 213:1143-1152.
25. Kannel WB: Blood pressure as a cardiovascular risk factor: Prevention and treatment. JAMA 1996; 275:1571-1576.
26. Alderman MH: Blood pressure management: Individualized treatment based on absolute risk and the potential for benefit. Ann Intern Med 1993; 119:329-335.
27. Luc M, Bortel V, Struijker-Boudier H, Safar M: Pulse pressure, arterial stiffness, and drug treatment of hypertension. Hypertension 2001; 38:914-921.
28. Nichols WW: Clinical measurement of arterial stiffness obtained from noninvasive pressure waveforms. Am J Hypertens 2005; 18:3S-10S.
29. O'Rourke M: Mechanical principles in arterial disease. Hypertension 1995; 26:2-9.
30. European SoH: European Society of Hypertension—European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003; 21:1011-1053.
31. Materson BJ, Reda DJ, Cushman WC: Department of Veterans Affairs single-drug therapy of hypertension study. Revised figures and new data. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Am J Hypertens 1995; 8:189-192.
32. Dickerson JE, Hingorani AD, Ashby MJ, et al: Optimisation of antihypertensive treatment by crossover rotation of four major classes. Lancet 1999; 353:2008-2013.
33. Deary AJ, Schumann AL, Murfet H, et al: Double-blind, placebo-controlled crossover comparison of five classes of antihypertensive drugs. J Hypertens 2002; 20:771-777.
34. Lifton RP, Gharavi AG, Geller DS: Molecular mechanisms of human hypertension. Cell 2001; 104:545-556.
35. Luft FC: Geneticism of essential hypertension. Hypertension 2004; 43:1155-1159.
36. Samani NJ: Genome scans for hypertension and blood pressure regulation. Am J Hypertens 2003; 16:167-171.
37. Hubner N, Yagil C, Yagil Y: Novel integrative approaches to the identification of candidate genes in hypertension. Hypertension 2006; 47:1-5.
38. Thiel BA, Chakravarti A, Cooper RS, et al: A genome-wide linkage analysis investigating the determinants of blood pressure in whites and African Americans. Am J Hypertens 2003; 16:151-153.
39. Kardia SL, Rozek LS, Krushkal J, et al: Genome-wide linkage analyses for hypertension genes in two ethnically and geographically diverse populations. Am J Hypertens 2003; 16:154-157.
40. Rao DC, Province MA, Leppert MF, et al: A genome-wide affected sibpair linkage analysis of hypertension: The HyperGEN network. Am J Hypertens 2003; 16:148-150.
41. Ranade K, Hinds D, Hsiung CA, et al: A genome scan for hypertension susceptibility loci in populations of Chinese and Japanese origins. Am J Hypertens 2003; 16:158-162.
42. Wu X, Kan D, Province M, et al: An updated meta-analysis of genome scans for hypertension and blood pressure in the NHLBI Family Blood Pressure Program (FBPP). Am J Hypertens 2006; 19:122-127.
43. Koivukoski L, Fisher SA, Kanninen T, et al: Meta-analysis of genome-wide scans for hypertension and blood pressure in Caucasians shows evidence of susceptibility regions on chromosomes 2 and 3. Hum Mol Genet 2004; 13:2325-2332.
44. Lalouel JM: Large-scale search for genes predisposing to essential hypertension. Am J Hypertens 2003; 16:163-166.
45. Freimer N, Sabatti C: The human phenome project. Nat Genet 2003; 34:15-21.
46. Harrap SB, Tzourio C, Cambien F, et al: The ACE gene I/D polymorphism is not associated with the blood pressure and cardiovascular benefits of ACE inhibition. Hypertension 2003; 42:297-303.
47. Sethi AA, Nordestgaard BG, Gronholdt ML, et al: Angiotensinogen single nucleotide polymorphisms, elevated blood pressure, and risk of cardiovascular disease. Hypertension 2003; 41:1202-1211.
48. Sethi AA, Nordestgaard BG, Tybjaerg-Hansen A: Angiotensinogen gene polymorphism, plasma angiotensinogen, and risk of hypertension and ischemic heart disease: A meta-analysis. Arterioscler Thromb Vasc Biol 2003; 23:1269-1275.
49. Franklin SS, Khan SA, Wong ND, et al: Is pulse pressure useful in predicting risk for coronary heart Disease? The Framingham Heart Study. Circulation 1999; 100:354-360.
50. Domanski M, Mitchell G, Pfeffer M, et al: Pulse pressure and cardiovascular disease-related mortality: Follow-up study of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 2002; 287:2677-2683.
51. Lloyd-Jones DM, Evans JC, Levy D: Hypertension in adults across the age spectrum: Current outcomes and control in the community. JAMA 2005; 294:466-472.
52. Vasan RS, Beiser A, Seshadri S, et al: Residual lifetime risk for developing hypertension in middle-aged women and men: The Framingham Heart Study. JAMA 2002; 287:1003-1010.
53. Grundy SM, Brewer Jr HB, Cleeman JI, et al: Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004; 109:433-438.
54. Wilson PW, D'Agostino RB, Parise H, et al: Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation 2005; 112:3066-3072.
55. Tuttle KR: Cardiovascular implications of albuminuria. J Clin Hypertens (Greenwich) 2004; 6:13-17.
56. El-Atat FA, Stas SN, McFarlane SI, Sowers JR: The relationship between hyperinsulinemia, hypertension and progressive renal disease. J Am Soc Nephrol 2004; 15:2816-2827.
57. Fox CS, Larson MG, Leip EP, et al: Predictors of new-onset kidney disease in a community-based population. JAMA 2004; 291:844-850.
58. Scheen AJ: Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 1. A meta-analysis of randomised clinical trials. Diabetes Metab 2004; 30:487-496.
59. Leiter LA, Lewanczuk RZ: Of the renin-angiotensin system and reactive oxygen species Type 2 diabetes and angiotensin II inhibition. Am J Hypertens 2005; 18:121-128.
60. Flegal KM, Carroll MD, Ogden CL, Johnson CL: Prevalence and trends in obesity among US adults, 1999-2000. JAMA 2002; 288:1723-1727.
61. Halperin RO, Sesso HD, Ma J, et al: Dyslipidemia and the risk of incident hypertension in men. Hypertension 2006; 47:45-50.
62. Kenchaiah S, Evans JC, Levy D, et al: Obesity and the risk of heart failure. N Engl J Med 2002; 347:305-313.
63. Hertz RP, Unger AN, Cornell JA, Saunders E: Racial disparities in hypertension prevalence, awareness, and management. Arch Intern Med 2005; 165:2098-2104.
64. Mancia G, Sega R, Milesi C, et al: Blood-pressure control in the hypertensive population. Lancet 1997; 349:454-457.
65. Rizzo J: Economics of patient non-compliance—Looking at the real world. Cardiol Rev 1996; 13:21-26.
66. Berlowitz DR, Ash AS, Hickey EC, et al: Inadequate management of blood pressure in a hypertensive population. N Engl J Med 1998; 339:1957-1963.
67. Meneton P, Jeunemaitre X, de Wardener HE, MacGregor GA: Links between dietary salt intake, renal salt handling, blood pressure, and cardiovascular diseases. Physiol Rev 2005; 85:679-715.
68. Intersalt Cooperative Research Group : Intersalt: An international study of electrolyte excretion and blood pressure. Results for 24-hour urinary sodium and potassium excretion. Intersalt Cooperative Research Group. BMJ 1988; 297:319-328.
69. Laragh JH, Pecker MS: Dietary sodium and essential hypertension: Some myths, hopes, and truths. Ann Intern Med 1983; 98:735-743.
70. Alderman MH, Cohen H, Madhavan S: Dietary sodium intake and mortality: The National Health and Nutrition Examination Survey (NHANES I). Lancet 1998; 351:781-785.
71. Yamori Y, Liu L, Ikeda K, et al: Different associations of blood pressure with 24-hour urinary sodium excretion among pre- and post-menopausal women. WHO Cardiovascular Diseases and Alimentary Comparison (WHO-CARDIAC) Study. J Hypertens 2001; 19:535-538.
72. Poulter NR, Khaw KT, Mugambi M, et al: Migration-induced changes in blood pressure: A controlled longitudinal study. Clin Exp Pharmacol Physiol 1985; 12:211-216.
73. Laragh JH, Sealey JE: Renin-angiotensin-aldosterone system and the renal regulation of sodium, potassium, and blood pressure homeostasis. In: Windhager EE, ed. Handbook of Physiology, Renal Physiology, Vol II. New York: Oxford Press; 1992:1409-1541.
74. Chrysant SG, Weir MR, Weder AB, et al: There are no racial, age, sex, or weight differences in the effect of salt on blood pressure in salt-sensitive hypertensive patients. Arch Intern Med 1997; 157:2489-2494.
75. Kempner W: Treatment of hypertensive vascular disease with rice diet. Am J Med 1948; 4:545-577.
76. Hinderliter A, Sherwood A, Gullette EC, et al: Reduction of left ventricular hypertrophy after exercise and weight loss in overweight patients with mild hypertension. Arch Intern Med 2002; 162:1333-1339.
77. Appel LJ, Moore TJ, Obarzanek E, et al: A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med 1997; 336:1117-1124.
78. Sacks FM, Svetkey LP, Vollmer WM, et al: Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med 2001; 344:3-10.
79. Vollmer WM, Sacks FM, Ard J, et al: Effects of diet and sodium intake on blood pressure: Subgroup analysis of the DASH-sodium trial. Ann Intern Med 2001; 135:1019-1028.
80. Whelton PK, Appel LJ, Espeland MA, et al: Sodium reduction and weight loss in the treatment of hypertension in older persons: A randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). TONE Collaborative Research Group. JAMA 1998; 279:839-846.
81. Alderman MH, Madhavan S, Cohen H, et al: Low urinary sodium is associated with greater risk of myocardial infarction among treated hypertensive men [see comments]. Hypertension 1995; 25:1144-1152.
82. Mancia G: Role of outcome trials in providing information on antihypertensive treatment: Importance and limitations. Am J Hypertens 2006; 19:1-7.
83. Medical Research Council Working Party: MRC trial of treatment of mild hypertension: Principal results. Medical Research Council Working Party. Br Med J (Clin Res Ed) 1985; 291:97-104.
84. Siscovick DS, Raghunathan TE, Psaty BM, et al: Diuretic therapy for hypertension and the risk of primary cardiac arrest. N Engl J Med 1994; 330:1852-1857.
85. Lewis CE, Grandits A, Flack J, et al: Efficacy and tolerance of antihypertensive treatment in men and women with stage 1 diastolic hypertension. Results of the Treatment of Mild Hypertension Study. Arch Intern Med 1996; 156:377-385.
86. Franse LV, Pahor M, Di Bari M, et al: Hypokalemia associated with diuretic use and cardiovascular events in the Systolic Hypertension in the Elderly Program. Hypertension 2000; 35:1025-1030.
87. Dahlof B, Devereux RB, Kjeldsen SE, et al: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet 2002; 359:995-1003.
88. ALLHAT I: Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288:2981-2997.
89. Lewington S, Clarke R, Qizilbash N, et al: Age-specific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360:1903-1913.
90. Qureshi AI, Suri MF, Kirmani JF, et al: Is prehypertension a risk factor for cardiovascular diseases?. Stroke 2005; 36:1859-1863.
91. Lloyd-Jones DM, Leip EP, Larson MG, et al: Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation 2006; 113:791-798.
92. Madhavan S, Alderman MH: The potential effect of blood pressure reduction on cardiovascular disease. A cautionary note. Arch Intern Med 1981; 141:1583-1586.
93. Kannel WB, Wilson PWF: Hypertension, other risk factors, and the risk of cardiovascular disease. In: Laragh JH, Brenner BM, ed. Hypertension: Pathophysiology, Diagnosis and Management, Vol 1. New York: Raven Press; 1995:99-114.
94. Lloyd-Jones DM, Evans JC, Larson MG, et al: Cross-classification of JNC VI blood pressure stages and risk groups in the Framingham Heart Study. Arch Intern Med 1999; 159:2206-2212.
95. Lew E: High blood pressure, other risk factors and longevity: The insurance viewpoint. In: Laragh JH, ed. Hypertension Manual, New York: Yorke Medical Books; 1974.
96. Young T, Peppard P, Palta M, et al: Population-based study of sleep-disordered breathing as a risk factor for hypertension. Arch Intern Med 1997; 157:1746-1752.
97. Nieto FJ, Young TB, Lind BK, et al: Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA 2000; 283:1829-1836.
98. Peppard PE, Young T, Palta M, Skatrud J: Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000; 342:1378-1384.
99. Wolk R, Shamsuzzaman AS, Somers VK: Obesity, sleep apnea, and hypertension. Hypertension 2003; 42:1067-1074.
100. Gami AS, Howard DE, Olson EJ, Somers VK: Day-night pattern of sudden death in obstructive sleep apnea. N Engl J Med 2005; 352:1206-1214.
101. Somers VK: Sleep—A new cardiovascular frontier. N Engl J Med 2005; 353:2070-2073.
102. Franklin SS: Blood pressure and cardiovascular disease: What remains to be achieved?. J Hypertens 2000; 19:S3-S8.
103. Franklin SS, Larson MG, Khan SA, et al: Does the relation of blood pressure to coronary heart disease risk change with aging? The Framingham Heart Study. Circulation 2001; 103:1245-1249.
104. Mitchell GF, Moye LA, Braunwald E, et al: Sphygmomanometrically determined pulse pressure is a powerful independent predictor of recurrent events after myocardial infarction in patients with impaired left ventricular function. SAVE investigators. Survival and Ventricular Enlargement. Circulation 1997; 96:4254-4260.
105. Benetos A, Safar M, Rudnichi A, et al: Pulse pressure: A predictor of long-term cardiovascular mortality in a French male population. Hypertension 1997; 30:1410-1415.
106. Madhavan S, Ooi WL, Cohen H, Alderman MH: Relation of pulse pressure and blood pressure reduction to the incidence of myocardial infarction. Hypertension 1994; 23:395-401.
107. Staessen JA, Fagard R, Thijs L, et al: Randomized double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997; 350:757-764.
108. SHEP Cooperative Research Group : Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 1991; 265:3255-3264.
109. Hansson L: The J-shaped curve and how far blood pressure should be lowered. In: Laragh JH, Brenner BM, ed. Hypertension: Pathophysiology, Diagnosis and Management, Vol 1. New York: Raven Press; 1995:2765-2770.
110. Kannel WB, Wilson PW, Nam BH, et al: A likely explanation for the J-curve of blood pressure cardiovascular risk. Am J Cardiol 2004; 94:380-384.
111. Port FK, Hulbert-Shearon TE, Wolfe RA, et al: Predialysis blood pressure and mortality risk in a national sample of maintenance hemodialysis patients. Am J Kidney Dis 1999; 33:507-517.
112. Goldfarb-Rumyantzev AS, Baird BC, Leypoldt JK, Cheung AK: The association between BP and mortality in patients on chronic peritoneal dialysis. Nephrol Dial Transplant 2005; 20:1693-1701.
113. Devereux R, Roman M: Hypertensive caridac hypertrophy: Pathophysiology and clinical characteristics. In: Laragh JH, Brenner BM, ed. Hypertension: Pathophysiology, Diagnosis and Management, Vol 1. 2nd ed. New York: Raven Press; 1995:409-432.
114. Mosterd A, D'Agostino RB, Silbershatz H, et al: Trends in the prevalence of hypertension, antihypertensive therapy, and left ventricular hypertrophy from 1950 to 1989. N Engl J Med 1999; 340:1221-1227.
115. Mansoor GA, Massie BM: Left ventricular hypertrophy: A potent cardiovascular risk factor and its relationship to office and ambulatory blood pressure. Blood Press Monit 1999; 4(suppl 1):S19-S22.
116. Wiinberg N, Bang LE, Wachtell K, et al: 24-h Ambulatory blood pressure in patients with ECG-determined left ventricular hypertrophy: Left ventricular geometry and urinary albumin excretion—A LIFE substudy. J Hum Hypertens 2004; 18:391-396.
117. Schillaci G, Verdecchia P, Sacchi N, et al: Clinical relevance of office underestimation of usual blood pressure in treated hypertension. Am J Hypertens 2000; 13:523-528.
118. Mule G, Nardi E, Cottone S, et al: Relationships between ambulatory white coat effect and left ventricular mass in arterial hypertension. Am J Hypertens 2003; 16:498-501.
119. Palatini P, Penzo M, Canali C, et al: Interactive action of the white-coat effect and the blood pressure levels on cardiovascular complications in hypertension. Am J Med 1997; 103:208-216.
120. Pierdomenico SD, Lapenna D, Bucci A, et al: Cardiovascular and renal events in uncomplicated mild hypertensive patients with sustained and white coat hypertension. Am J Hypertens 2004; 17:876-881.
121. Koren MJ, Devereux RB, Casale PN, et al: Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991; 114:345-352.
121a. Bella JN: Indexation of left ventricular mass to identify blood pressure-related left ventricular hypertrophy. Am J Hypertens 2005; 18:1263-1265.
122. Kizer JR, Arnett DK, Bella JN, et al: Differences in left ventricular structure between black and white hypertensive adults: The Hypertension Genetic Epidemiology Network study. Hypertension 2004; 43:1182-1188.
123. Matsumura K, Fujii K, Oniki H, et al: Role of aldosterone in left ventricular hypertrophy in hypertension. Am J Hypertens 2006; 19:13-18.
124. Rossi GP: Cardiac consequences of aldosterone excess in human hypertension. Am J Hypertens 2006; 19:10-12.
125. Hinderliter AL, Blumenthal JA, Waugh R, et al: Ethnic differences in left ventricular structure: Relations to hemodynamics and diurnal blood pressure variation. Am J Hypertens 2004; 17:43-49.
126. Stewart AD, Millasseau SC, Dawes M, et al: Aldosterone and left ventricular hypertrophy in Afro-Caribbean subjects with low renin hypertension. Am J Hypertens 2006; 19:19-24.
127. Du Cailar G, Ribstein J, Daures JP, Mimran A: Sodium and left ventricular mass in untreated hypertensive and normotensive subjects. Am J Physiol 1992; 263:H177-H181.
128. Palmieri V, Wachtell K, Bella JN, et al: Usefulness of the assessment of the appropriateness of left ventricular mass to detect left ventricular systolic and diastolic abnormalities in absence of echocardiographic left ventricular hypertrophy: The LIFE study. J Hum Hypertens 2004; 18:423-430.
129. Levy D, Larson MG, Vasan RS, et al: The progression from hypertension to congestive heart failure. JAMA 1996; 275:1557-1562.
130. Haider AW, Larson MG, Franklin SS, Levy D: Systolic blood pressure, diastolic blood pressure, and pulse pressure as predictors of risk for congestive heart failure in the Framingham Heart Study. Ann Intern Med 2003; 138:10-16.
131. Moser M, Hebert PR: Prevention of disease progression, left ventricular hypertrophy and congestive heart failure in hypertension treatment trials. J Am Coll Cardiol 1996; 27:1214-1218.
132. Gavras H, Brown JJ, Lever AF, et al: Acute renal failure, tubular necrosis, and myocardial infarction induced in the rabbit by intravenous angiotensin II. Lancet 1971; 2:19-22.
133. Domanski MJ, Exner DV, Borkowf CB, et al: Effect of angiotensin converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction. A meta-analysis of randomized clinical trials. J Am Coll Cardiol 1999; 33:598-604.
134. Reiffel JA: Practical algorithms for pharmacologic management of the post myocardial infarction patient. Clin Cardiol 2005; 28:I28-I37.
134a. Schmeider RE, Hilgers KF, Schlaich MP, Schmidt BMW: Renin-angiotensin system and cardiovascular risk. Lancet 2007; 207:1208-1219.
135. Brunner HR, Laragh JH, Baer L, et al: Essential hypertension: Renin and aldosterone, heart attack and stroke. N Engl J Med 1972; 286:441-449.
136. Alderman MH, Madhavan S, Ooi WL, et al: Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension [see comments]. N Engl J Med 1991; 324:1098-1104.
137. Blumenfeld JD, Sealey JE, Alderman MH, et al: Plasma renin activity in the emergency department and its independent association with acute myocardial infarction. Am J Hypertens 2000; 13:855-863.
138. Alderman MH, Cohen HW, Sealey JE, Laragh JH: Plasma renin activity levels in hypertensive persons: Their wide range and lack of suppression in diabetic and in most elderly patients. Am J Hypertens 2004; 17:1-7.
139. Perry Jr HM, Davis BR, Price TR, et al: Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke: The Systolic Hypertension in the Elderly Program (SHEP). JAMA 2000; 284:465-471.
140. Phillips S, Whisnant J: Hypertension and stroke. In: Laragh JH, Brenner BM, ed. Hypertension: Pathophysiology, Diagnosis and Management, Vol 1. New York: Raven Press; 1995:465-478.
141. Hunsicker LG, Adler S, Caggiula A, et al: Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study. Kidney Int 1997; 51:1908-1919.
142. K/DOQI WG: K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease. Am J Kidney Dis 2004; 43:1-290.
143. Ridao N, Luno J, Garcia de Vinuesa S, et al: Prevalence of hypertension in renal disease. Nephrol Dial Transplant 2001; 16(suppl 1):70-73.
144. Rahman M, Pressel S, Davis BR, et al: Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: A report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 2005; 165:936-946.
145. Levey AS, Beto JA, Coronado BE, et al: Controlling the epidemic of cardiovascular disease in chronic renal disease: What do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney Dis 1998; 32:853-906.
146. Shlipak MG, Fried LF, Cushman M, et al: Cardiovascular mortality risk in chronic kidney disease: Comparison of traditional and novel risk factors. JAMA 2005; 293:1737-1745.
146a. Jones CA, Francis ME, Eberhardt MS, et al: Microalbuminuria in the US population: Third national health and nutrition examination survey. Am J Kidney Dis 2002; 39:445-459.
147. Rosa TT, Palatini P: Clinical value of microalbuminuria in hypertension. J Hypertens 2000; 18:645-654.
148. Karalliedde J, Viberti G: Microalbuminuria and cardiovascular risk. Am J Hypertens 2004; 17:986-993.
149. Wang W, Lee ET, Fabsitz RR, et al: A longitudinal study of hypertension risk factors and their relation to cardiovascular disease: The Strong Heart Study. Hypertension 2006; 47:403-409.
150. Romundstad S, Holmen J, Kvenild K, et al: Microalbuminuria and all-cause mortality in 2089 apparently healthy individuals: A 4.4-year follow-up study. The Nord-Trondelag Health Study (HUNT), Norway. Am J Kidney Dis 2003; 42:466-473.
151. Roest M, Banga JD, Janssen WM, et al: Excessive urinary albumin levels are associated with future cardiovascular mortality in postmenopausal women. Circulation 2001; 103:3057-3061.
152. Agrawal B, Berger A, Wolf K, Luft FC: Microalbuminuria screening by reagent strip predicts cardiovascular risk in hypertension. J Hypertens 1996; 14:223-228.
153. Yudkin JS, Forrest RD, Jackson CA: Microalbuminuria as predictor of vascular disease in non-diabetic subjects. Islington Diabetes Survey. Lancet 1988; 2:530-533.
154. Schmieder RE, Martus P, Klingbeil A: Reversal of left ventricular hypertrophy in essential hypertension. A meta-analysis of randomized double-blind studies. JAMA 1996; 275:1507-1513.
155. Wachtell K, Olsen MH, Dahlof B, et al: Microalbuminuria in hypertensive patients with electrocardiographic left ventricular hypertrophy: The LIFE study. J Hypertens 2002; 20:405-412.
156. Olsen MH, Wachtell K, Bella JN, et al: Albuminuria predicts cardiovascular events independently of left ventricular mass in hypertension: A LIFE substudy. J Hum Hypertens 2004; 18:453-459.
157. Crippa G: Microalbuminuria in essential hypertension. J Hum Hypertens 2002; 16(suppl 1):S74-S77.
158. USRDS Coordinating Center: United States Renal Data System 2003 Annual Data Report. Am J Kidney Dis 2003; 42:1-230.
159. Horl MP, Horl WH: Hemodialysis-associated hypertension: Pathophysiology and therapy. Am J Kidney Dis 2002; 39:227-244.
160. Kamata T, Hishida A, Takita T, et al: Morphologic abnormalities in the brain of chronically hemodialyzed patients without cerebrovascular disease. Am J Nephrol 2000; 20:27-31.
161. Opelz G, Wujciak T, Ritz E: Association of chronic kidney graft failure with recipient blood pressure. Collaborative Transplant Study. Kidney Int 1998; 53:217-222.
162. Tutone VK, Mark PB, Stewart GA, et al: Hypertension, antihypertensive agents and outcomes following renal transplantation. Clin Transplant 2005; 19:181-192.
163. Opelz G, Dohler B: Improved long-term outcomes after renal transplantation associated with blood pressure control. Am J Transplant 2005; 5:2725-2731.
164. Kasiske BL, Anjum S, Shah R, et al: Hypertension after kidney transplantation. Am J Kidney Dis 2004; 43:1071-1081.
165. Mange K, Cizman B, Joffe M, Feldman H: Arterial hypertension and renal allograft survival. JAMA 2000; 283:633-638.
166. Perera G: Hypertesnive vascular disease. J Chron Dis 1955; 1:33.
167. Smith WM: Treatment of mild hypertension: Results of a ten-year intervention trial. Circ Res 1977; 40:I98-I105.
168. Hypertension Detection and Follow-Up Program Cooperative Group : I. Redcution of mortality in persons with high blood pressure, including hypertension. II Mortality by race, sex, and age. JAMA 1979; 242:2562.
169. Kaplan N: Kaplan's Clinical Hypertension, Philadelphia, Lippincott Williams & Wilkins, 2002.
170. Psaty BM, Smith NL, Siscovick DS, et al: Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis. JAMA 1997; 277:739-745.
171. Weber MA, Drayer JI, Rev A, Laragh JH: Disparate patterns of aldosterone response during diuretic treatment of hypertension. Ann Intern Med 1977; 87:558-563.
172. Staessen JA, Gasowski J, Wang JG, et al: Risks of untreated and treated isolated systolic hypertension in the elderly: Meta-analysis of outcome trials. Lancet 2000; 355:865-872.
173. Verdecchia P, Reboldi G, Angeli F, et al: Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke prevention. Hypertension 2005; 46:386-392.
174. Roman MJ, Alderman MH, Pickering TG, et al: Differential effects of angiotensin converting enzyme inhibition and diuretic therapy on reductions in ambulatory blood pressure, left ventricular mass, and vascular hypertrophy. Am J Hypertens 1998; 11:387-396.
175. Collins R, Peto R, MacMahon S, et al: Blood pressure, stroke, and coronary heart disease. Part 2, Short-term reductions in blood pressure: Overview of randomised drug trials in their epidemiological context [see comments]. Lancet 1990; 335:827-838.
176. Mathew J, Sleight P, Lonn E, et al: Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril. Circulation 2001; 104:1615-1621.
177. Devereux RB, Wachtell K, Gerdts E, et al: Prognostic significance of left ventricular mass change during treatment of hypertension. JAMA 2004; 292:2350-2356.
178. Devereux RB, Dahlof B, Gerdts E, et al: Regression of hypertensive left ventri-cular hypertrophy by losartan compared with atenolol: The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial. Circulation 2004; 110:1456-1462.
179. Okin PM, Devereux RB, Jern S, et al: Regression of electrocardiographic left ventricular hypertrophy during antihypertensive treatment and the prediction of major cardiovascular events. JAMA 2004; 292:2343-2349.
180. McQueen MJ, Lonn E, Gerstein HC, et al: The HOPE (Heart Outcomes Prevention Evaluation) Study and its consequences. Scand J Clin Lab Invest Suppl 2005; 240:143-156.
181. Garg R, Yusuf S: Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995; 273:1450-1456.
182. Pitt B, Segal R, Martinez FA, et al: Randomized trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet 1997; 349:747-752.
183. Cohn JN, Tognoni G: A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345:1667-1675.
184. Pitt B, Remme W, Zannad F, et al: Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348:1309-1321.
185. Pitt B, Zannad F, Remme W, et al: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341:709-717.
185a. Foody JM, Farrell MA, Krumholz HM: Beta-blocker therapy in heart failure: scientific review. JAMA 2002; 287:883-889.
186. Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L: Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circulation 1990; 82:1730-1736.
187. ALLHAT Collaborative Research Group: ALLHAT: Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack trial (ALLHAT). JAMA 2000; 283:1967-1975.
188. Liebson P, Grandits G, Dianzumba S, et al: Comparison of five antihypertensive monotherapies and placebo for change in left ventricular mass in patients receiving nutrtional-hygienic therapy in the Treatment of Mild Hypertension Study (TOMHS). Circulation 1995; 91:698-706.
189. Cohn J, Archibald D, Zieche S, et al: Effect of vasodilator therapy on mortality in congestive heart failure: Results of a Veteran's Administration Cooperative Study. N Engl J Med 1986; 314:1547-1552.
190. Kostis J, Davis B, Cutler J, et al: Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA 1997; 278:212-216.
191. Wallace J, Levy LL: Blood pressure after stroke. JAMA 1981; 246:2177-2180.
192. Okumura K, Ohya Y, Maehara A, et al: Effects of blood pressure levels on case fatality after acute stroke. J Hypertens 2005; 23:1217-1223.
193. Leonardi-Bee J, Bath PM, Phillips SJ, Sandercock PA: Blood pressure and clinical outcomes in the International Stroke Trial. Stroke 2002; 33:1315-1320.
194. Voko V, Bots M, Hofman A, et al: J-Shaped relation between blood pressure and stroke in treated hypertension. Hypertension 1999; 34:1181-1185.
195. Strandgaard S: Autoregulation of cerebral blood flow in hypertensive patients. The modifying influence of prolonged antihypertensive treatment on the tolerance to acute, drug-induced hypotension. Circulation 1976; 53:720-727.
196. Calhoun D, Oparil S: Treatment of hypertensive crisis. N Engl J Med 1990; 323:1177-1183.
197. Powers W: Acute hypertenion after stroke: The scientific basis for treatment decisions. Neurology 1993; 43:461-467.
198. Bath PM: How to manage blood pressure in acute stroke. J Hypertens 2005; 23:1135-1136.
199. Willmot M, Leonardi-Bee J, Bath PM: High blood pressure in acute stroke and subsequent outcome: A systematic review. Hypertension 2004; 43:18-24.
200. Brott N, Lu M, Kothari R, et al: Hypertension and its treatment in the NINDS rt-PA stroke trial. Stroke 1998; 29:1504-1509.
201. Blumenfeld JD, Laragh JH: Management of hypertensive crises: The scientific basis for treatment decisions. Am J Hypertens 2001; 14:1154-1167.
202. Lindenauer PK, Mathew MC, Ntuli TS, et al: Use of antihypertensive agents in the management of patients with acute ischemic stroke. Neurology 2004; 63:318-323.
203. Grossman E, Messerli FH, Grodzicki T, Kowey P: Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies? [see comments]. JAMA 1996; 276:1328-1331.
204. Feigin V, Rinkel G, Algra A, et al: Calcium antagonists in patients with aneursymal subarachnoid hemorrhage: A systematic review. Neurology 1998; 50:876-883.
205. Radhakrishnan D, Menon D: Haemodynamic effects of intravenous nimodipine following aneurysmal subarachnois hemorrhage: Implications for monitoring. Anesthesia 1997; 52:489-500.
206. Porchet F, Chiolero R, de Tribolet N: Hypotensive effect of nimodipine during treatment for aneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien) 1995; 137:62-69.
207. Hayashi M, Kobayashi H, Kawano H, et al: Treatment of systemic hypertension and intracranial hypertension in cases of brain hemorrhage. Stroke 1988; 19:314-321.
208. Haley EJ, Kassell N, Torner J: A randomized controlled trial of high-dose intravenous nicardipine in aneurysmal subarachnoid hemorrhage: A report of the Cooperative Aneurysm Study. J Neurosurg 1993; 78:537-547.
209. Pickering TG: Extending the reach of ambulatory blood pressure monitoring: Masked and resistant hypertension. Am J Hypertens 2005; 18:1385-1387.
210. Perloff D, Sokolow M, Cowan R: The prognostic value of ambulatory blood pressures. JAMA 1983; 249:2792-2798.
211. Staessen JA, Thijs L, Fagard R, et al: Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension. Systolic Hypertension in Europe Trial Investigators. JAMA 1999; 282:539-546.
212. Ohkubo T, Imai Y, Tsuji I, et al: Prediction of mortality by ambulatory blood pressure monitoring versus screening blood pressure measurements: A pilot study in Ohasama. J Hypertens 1997; 15:357-364.
213. Clement DL, De Buyzere ML, De Bacquer DA, et al: Prognostic value of ambulatory blood-pressure recordings in patients with treated hypertension. N Engl J Med 2003; 348:2407-2415.
214. Redon J, Campos C, Narciso ML, et al: Prognostic value of ambulatory blood pressure monitoring in refractory hypertension: A prospective study. Hypertension 1998; 31:712-718.
215. Verdecchia P, Porcellati C, Schillaci G, et al: Ambulatory blood pressure. An independent predictor of prognosis in essential hypertension. Hypertension 1994; 24:793-801.
216. Ohkubo T, Imai Y, Tsuji I, et al: Relation between nocturnal decline in blood pressure and mortality. The Ohasama Study. Am J Hypertens 1997; 10:1201-1207.
217. Fagard RH, Staessen JA, Thijs L, et al: Response to antihypertensive therapy in older patients with sustained and nonsustained systolic hypertension. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Circulation 2000; 102:1139-1144.
218. Celis H, Staessen JA, Thijs L, et al: Cardiovascular risk in white-coat and sustained hypertensive patients. Blood Press 2002; 11:352-356.
219. Pierdomenico SD, Lapenna D, Bucci A, et al: Cardiovascular outcome in treated hypertensive patients with responder, masked, false resistant, and true resistant hypertension. Am J Hypertens 2005; 18:1422-1428.
220. Liu JE, Roman MJ, Pini R, et al: Cardiac and arterial target organ damage in adults with elevated ambulatory and normal office blood pressure. Ann Intern Med 1999; 131:564-572.
221. Sega R, Trocino G, Lanzarotti A, et al: Alterations of cardiac structure in patients with isolated office, ambulatory, or home hypertension: Data from the general population (Pressione Arteriose Monitorate E Loro Associazioni [PAMELA] Study). Circulation 2001; 104:1385-1392.
222. Bjorklund K, Lind L, Zethelius B, et al: Isolated ambulatory hypertension predicts cardiovascular morbidity in elderly men. Circulation 2003; 107:1297-1302.
223. Guyton A, Hall J, Coleman T, et al: The dominant role of the kidneys in long-term arterial pressure regulation in normal and hypertensive states. In: Laragh JH, Brenner BM, ed. Hypertension: Pathophysiology, Diagnosis, and Management, Vol 2. New York: Raven Press; 1995:1311-1326.
224. Hall JE: The kidney, hypertension, and obesity. Hypertension 2003; 41:625-633.
225. Sealey JE, Laragh JH: The renin-angiotensin-aldosterone system for the normal regulation of blood pressure and sodium and potassium homeostasis. In: Laragh JH, Brenner BM, ed. Hypertension: Pathophysiology, Diagnosis, and Management, Vol 2. New York: Raven Press; 1995:1763-1797.
226. Cowley Jr AW, Roman RJ: The role of the kidney in hypertension. JAMA 1996; 275:1581-1589.
227. Evans RG, Majid DS, Eppel GA: Mechanisms mediating pressure natriuresis: What we know and what we need to find out. Clin Exp Pharmacol Physiol 2005; 32:400-409.
228. McDonough AA, Leong PK, Yang LE: Mechanisms of pressure natriuresis: How blood pressure regulates renal sodium transport. Ann N Y Acad Sci 2003; 986:669-677.
229. Granger JP, Alexander BT, Llinas M: Mechanisms of pressure natriuresis. Curr Hypertens Rep 2002; 4:152-159.
230. Garcia-Estan J, Roman RJ: Role of renal interstitial hydrostatic pressure in the pressure diuresis response. Am J Physiol 1989; 256:F63-F70.
231. Roman RJ, Cowley Jr AW, Garcia-Estan J, Lombard JH: Pressure-diuresis in volume-expanded rats. Cortical and medullary hemodynamics. Hypertension 1988; 12:168-176.
232. Sadowski J, Dobrowolski L: The renal medullary interstitium: Focus on osmotic hypertonicity. Clin Exp Pharmacol Physiol 2003; 30:119-126.
233. DiBona GF: Functionally specific renal sympathetic nerve fibers: Role in cardiovascular regulation. Am J Hypertens 2001; 14:163S-170S.
234. DiBona GF: Neural control of the kidney: Functionally specific renal sympathetic nerve fibers. Am J Physiol Regul Integr Comp Physiol 2000; 279:R1517-R1524.
235. Thames MD, DiBona GF: Renal nerves modulate the secretion of renin mediated by nonneural mechanisms. Circ Res 1979; 44:645-652.
236. Osborn JL, Thames MD, DiBona GF: Renal nerves modulate renin secretion during autoregulation. Proc Soc Exp Biol Med 1982; 169:432-437.
237. Osborn J, DiBona G, Thames M: Beta-1 receptor mediation of renin secretion elicited by low-frequency renal nerve stimulation. J Pharm Exp Ther 1981; 216:265-269.
238. DiBona GF: Peripheral and central interactions between the renin-angiotensin system and the renal sympathetic nerves in control of renal function. Ann N Y Acad Sci 2001; 940:395-406.
239. Schweda F, Kurtz A: Cellular mechanism of renin release. Acta Physiol Scand 2004; 181:383-390.
240. Kim SM, Mizel D, Huang YG, et al: Adenosine as a mediator of macula densa-dependent inhibition of renin secretion. Am J Physiol Renal Physiol 2006; 290:F1016-F1023.
241. Schweda F, Segerer F, Castrop H, et al: Blood pressure-dependent inhibition of renin secretion requires A1 adenosine receptors. Hypertension 2005; 46:780-786.
242. Paliege A, Mizel D, Medina C, et al: Inhibition of nNOS expression in the macula densa by COX-2-derived prostaglandin E(2). Am J Physiol Renal Physiol 2004; 287:F152-F159.
243. Schnermann J: Cyclooxygenase-2 and macula densa control of renin secretion. Nephrol Dial Transplant 2001; 16:1735-1738.
244. Nguyen G: The (pro)renin receptor: pathophysiological roles in cardiovascular and renal pathology. Curr Opin Nephrol Hypertens 2007; 16:129-133.
244a. Lenz T, Sealey JE, Maack T, et al: Half-life, hemodynamic, renal, and hormonal effects of prorenin in cynomolgus monkeys. Am J Physiol 1991; 260:R804-R810.
244b. von Lutterotti N, Catanzaro DF, Sealey JE, Laragh JH: Renin is not synthesized by cardiac and extrarenal vascular tissues. A review of experimental evidence [see comments]. Circulation 1994; 89:458-470.
244c. Nguyen G, Delarue F, Burckle C, et al: Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 2002; 109:1417-1427.
244d. Danser A, Batenburg W, van Esch J: Prorenin and the (pro)renin receptor—an update. Nephrol Dial Transplant 2007; 22:1288-1292.
244e. Ichihara A, Kaneshiro Y, Takemitsu T, et al: Nonproteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension. Hypertension 2006; 47:894-900.
245. Kim S, Iwao H: Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 2000; 52:11-34.
246. Zhou MS, Schulman IH, Raij L: Nitric oxide, angiotensin II, and hypertension. Semin Nephrol 2004; 24:366-378.
247. Touyz RM, Schiffrin EL: Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells. Pharmacol Rev 2000; 52:639-672.
248. Kwon TH, Nielsen J, Kim YH, et al: Regulation of sodium transporters in the thick ascending limb of rat kidney: response to angiotensin II. Am J Physiol Renal Physiol 2003; 285:F152-F165.
249. Liu F-Y, Cogan M: Angiotensin II stimulation of hydrogen ion secretion in the rat early proximal tubule. Modes of action, mechanisms, and kinetics. J Clin Invest 1988; 82:601.
250. Leong PK, Devillez A, Sandberg MB, et al: Effects of ACE inhibition on proximal tubule sodium transport. Am J Physiol Renal Physiol 2006; 290:F854-F863.
251. Romero DG, Plonczynski M, Vergara GR, et al: Angiotensin II early regulated genes in H295R human adrenocortical cells. Physiol Genomics 2004; 19:106-116.
252. Holland OB, Carr B, Brasier AR: Aldosterone synthase gene regulation by angiotensin. Endocr Res 1995; 21:455-462.
253. Laragh JH: The renin system and new understanding of the complications of hypertension and their treatment. Arzneimittelforschung 1993; 43:247-254.
254. Ghose RP, Hall PM, Bravo EL: Medical management of aldosterone-producing adenomas. Ann Intern Med 1999; 131:105-108.
255. Morganti A, Lopez-Ovejero JA, Pickering TG, Laragh JH: Role of the sympathetic nervous system in mediating the renin response to head-up tilt. Their possible synergism in defending blood pressure against postural changes during sodium deprivation. Am J Cardiol 1979; 43:600-604.
256. Goodfriend TL, Elliott ME, Catt KJ: Angiotensin receptors and their antagonists. N Engl J Med 1996; 334:1649-1654.
257. Moore AF, Heiderstadt NT, Huang E, et al: Selective inhibition of the renal angiotensin type 2 receptor increases blood pressure in conscious rats. Hypertension 2001; 37:1285-1291.
258. Carey RM, Wang ZQ, Siragy HM: Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function. Hypertension 2000; 35:155-163.
259. Carey RM: Update on the role of the AT2 receptor. Curr Opin Nephrol Hypertens 2005; 14:67-71.
260. Roman RJ: P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev 2002; 82:131-185.
261. Zhang YB, Magyar CE, Holstein-Rathlou NH, McDonough AA: The cytochrome P-450 inhibitor cobalt chloride prevents inhibition of renal Na,K-ATPase and redistribution of apical NHE-3 during acute hypertension. J Am Soc Nephrol 1998; 9:531-537.
262. Dos Santos EA, Dahly-Vernon AJ, Hoagland KM, Roman RJ: Inhibition of the formation of EETs and 20-HETE with 1-aminobenzotriazole attenuates pressure natriuresis. Am J Physiol Regul Integr Comp Physiol 2004; 287:R58-R68.
263. Ortiz P, Stoos BA, Hong NJ, et al: High-salt diet increases sensitivity to NO and eNOS expression but not NO production in THALs. Hypertension 2003; 41:682-687.
264. Sanchez S, Martin MJ, Ortiz P, et al: Role of prostaglandins and nitric oxide in gastric damage induced by metamizol in rats. Inflamm Res 2002; 51:385-392.
265. Cowley Jr AW, Mori T, Mattson D, Zou AP: Role of renal NO production in the regulation of medullary blood flow. Am J Physiol Regul Integr Comp Physiol 2003; 284:R1355-R1369.
266. Wu F, Park F, Cowley Jr AW, Mattson DL: Quantification of nitric oxide synthase activity in microdissected segments of the rat kidney. Am J Physiol 1999; 276:F874-F881.
267. Mattson DL: Importance of the renal medullary circulation in the control of sodium excretion and blood pressure. Am J Physiol Regul Integr Comp Physiol 2003; 284:R13-R27.
268. Szentivanyi Jr M, Maeda CY, Cowley Jr AW: Local renal medullary L-NAME infusion enhances the effect of long-term angiotensin II treatment. Hypertension 1999; 33:440-445.
269. Jin XH, McGrath HE, Gildea JJ, et al: Renal interstitial guanosine cyclic 3′,5′-monophosphate mediates pressure-natriuresis via protein kinase G. Hypertension 2004; 43:1133-1139.
270. Wilcox CS: Oxidative stress and nitric oxide deficiency in the kidney: A critical link to hypertension?. Am J Physiol Regul Integr Comp Physiol 2005; 289:R913-R935.
271. Bright R: Reports of Medical Cases. Selected with a View of Illustrating the Symptoms and Cure of Diseases by a Reference to Morbid Anatomy. London, Longman, Rees, 1827.
272. Tigerstedt R, Bergman P: Niere und kresilauf. Scand Arch Physiol 1898; 8:223.
273. Goldblatt H, Lynch R, Hanzai R: Studies on experimental: Production of persistent elevation of systolic blood pessure by means of renal ischemia. J Exp Med 1934; 59:347.
274. Laragh J, Angers M, Kelley W, Lieberman S: Hypotensive agents and pressor substances: The effect of norepinephrine, angiotensin II, and others on the secretory rate of aldosterone in man. JAMA 1960; 174:234.
275. Ames R, Borkowski A, Sicinski A, Laragh J: Prolonged infusions of angiotensin II and norepinephrine and blood pressure, electrolyte balance, aldosterone, and cortisol secretion in normal man and in cirrhosis with ascites. J Clin Invest 1965; 44:1171.
276. Laragh JH, Ulick S, Januszewicz V, et al: Electrolyte metabolism and aldosterone secretion in benign and malignant hypertension. Ann Intern Med 1960; 53:259-272.
277. Cowley Jr AW, Guyton AC: Baroreceptor reflex effects on transient and steady-state hemodynamics of salt-loading hypertension in dogs. Circ Res 1975; 36:536-546.
278. Guidi E, Menghetti D, Milani S, et al: Hypertension may be transplanted with the kidney in humans: A long-term historical prospective follow-up of recipients grafted with kidneys coming from donors with or without hypertension in their families. J Am Soc Nephrol 1996; 7:1131-1138.
279. Chabanel A, Chien S: Blood viscosity as a factor in human hypertension. In: Laragh JH, Brenner BM, ed. Hypertension: Pathophysiology, Diagnosis, and Management, Vol 1. New York: Raven Press; 1995:365-376.
280. Sommers S, Relman A, Smithwick R: Histologic studies of kidney biopsy specimens from patients with hypertension. Am J Pathol 1958; 34:685.
281. Sommers S, McLaughlin R, McAuley R: Pathology of diastolic hypertension as a generalized vascular disease. J Cardiol 1962; 9:653.
282. Sommers S: Hypertension and kidney disease. Prog Cardiovasc Dis 1965; 8:210.
283. Bradley S: Physiology of essential hypertension. Am J Med 1948; 4:398.
284. Hollenberg NK, Adams DF, Solomon H, et al: Renal vascular tone in essential and secondary hypertension: Hemodynamic and angiographic responses to vasodilators. Medicine (Baltimore) 1975; 54:29-44.
285. Bradley S, Bradley G, Tyson C: Renal function in renal diseases. Am J Med 1950; 9:766.
286. Nickel J, Lawrence P, Leifer E, Bradley S: Renal function, electrolyte excretion and body fluids in patientswith chronic renal insufficiency before and after sodium depletion. J Clin Invest 1953; 32:68.
287. Mulvaney M: Structural changes in the resistance vessels in human hypertension. In: Laragh JH, Brenner BM, ed. Hypertension: Pathophysiology, Diagnosis, and Management, Vol 1. New York: Raven Press; 1995:503-513.
288. Schiffrin EL, Touyz RM: From bedside to bench to bedside: Role of renin-angiotensin-aldosterone system in remodeling of resistance arteries in hypertension. Am J Physiol Heart Circ Physiol 2004; 287:H435-H446.
289. Bakker EN, van der Meulen ET, van den Berg BM, et al: Inward remodeling follows chronic vasoconstriction in isolated resistance arteries. J Vasc Res 2002; 39:12-20.
290. Intengan HD, Schiffrin EL: Vascular remodeling in hypertension: Roles of apoptosis, inflammation, and fibrosis. Hypertension 2001; 38:581-587.
291. Loirand G, Rolli-Derkinderen M, Pacaud P: RhoA and resistance artery remodeling. Am J Physiol Heart Circ Physiol 2005; 288:H1051-H1056.
292. Suematsu M, Suzuki H, Delano FA, Schmid-Schonbein GW: The inflammatory aspect of the microcirculation in hypertension: Oxidative stress, leukocytes/endothelial interaction, apoptosis. Microcirculation 2002; 9:259-276.
293. Schiffrin EL: Peroxisome proliferator-activated receptors and cardiovascular remodeling. Am J Physiol Heart Circ Physiol 2005; 288:H1037-H1043.
294. Benkirane K, Amiri F, Diep QN, et al: PPAR-gamma inhibits ANG II-induced cell growth via SHIP2 and 4E-BP1. Am J Physiol Heart Circ Physiol 2006; 290:H390-H397.
295. Sealey JE, Blumenfeld JD, Bell GM, et al: On the renal basis for essential hyperten-sion: Nephron heterogeneity with discordant renin secretion and sodium excretion causing a hypertensive vasoconstriction-volume relationship. J Hypertens 1988; 6:763-777.
296. Norrelund H, Christensen KL, Samani NJ, et al: Early narrowed afferent arteriole is a contributor to the development of hypertension. Hypertension 1994; 24:301-308.
297. Mulvany MJ: Effects of angiotensin converting enzyme inhibition on vascular remodelling of resistance vessels in hypertensive patients. J Hypertens Suppl 1996; 14:S21-S24.
298. Tracy RE: The heterogeneity of vascular findings in the kidneys of patients with benign essential hypertension. Nephrol Dial Transplant 1999; 14:1634-1639.
299. Mitchell KD, Navar LG: Enhanced tubuloglomerular feedback during peritubular infusions of angiotensins I and II. Am J Physiol 1988; 255:F383-F390.
300. Skott O, Briggs JP: Direct demonstration of macula densa-mediated renin secretion. Science 1987; 237:1618-1620.
301. Luft F, Grim C, Willis L, et al: Natriuretic response to saline infusion in normotensive and hypertensive man: The role of renin suppression in exaggerated natriuresis. Circulation 1977; 55:779-784.
302. Olsen ME, Hall JE, Montani JP, et al: Mechanisms of angiotensin II natriuresis and antinatriuresis. Am J Physiol 1985; 249:F299-F307.
303. Olsen ME, Hall JE, Montaini JP, Guyton AC: Angiotensin II natriuresis and anti-natriuresis: Role of renal artery pressure in anaesthetized dogs. J Hypertens Suppl 1984; 2:S347-S350.
304. Cowley Jr AW, Mattson DL, Lu S, Roman RJ: The renal medulla and hypertension. Hypertension 1995; 25:663-673.
305. Kone BC: Nitric oxide synthesis in the kidney: Isoforms, biosynthesis, and functions in health. Semin Nephrol 2004; 24:299-315.
306. Miyata N, Cowley Jr AW: Renal intramedullary infusion of L-arginine prevents reduction of medullary blood flow and hypertension in Dahl salt-sensitive rats. Hypertension 1999; 33:446-450.
307. Haynes WG, Noon JP, Walker BR, Webb DJ: Inhibition of nitric oxide synthesis increases blood pressure in healthy humans. J Hypertens 1993; 11:1375-1380.
308. Madrid MI, Garcia-Salom M, Tornel J, et al: Interactions between nitric oxide and angiotensin II on renal cortical and papillary blood flow. Hypertension 1997; 30:1175-1182.
309. Szentivanyi Jr M, Park F, Maeda CY, Cowley Jr AW: Nitric oxide in the renal medulla protects from vasopressin-induced hypertension. Hypertension 2000; 35:740-745.
310. Kohan DE: The renal medullary endothelin system in control of sodium and water excretion and systemic blood pressure. Curr Opin Nephrol Hypertens 2006; 15:34-40.
311. Ahn D, Ge Y, Stricklett PK, et al: Collecting duct-specific knockout of endothelin-1 causes hypertension and sodium retention. J Clin Invest 2004; 114:504-511.
312. Ge Y, Stricklett PK, Hughes AK, et al: Collecting duct-specific knockout of the endothelin A receptor alters renal vasopressin responsiveness, but not sodium excretion or blood pressure. Am J Physiol Renal Physiol 2005; 289:F692-F698.
313. Girchev R, Backer A, Markova P, Kramer HJ: Impaired response of the denervated kidney to endothelin receptor blockade in normotensive and spontaneously hypertensive rats. Kidney Int 2004; 65:982-989.
314. Folkow B: Psychosocial and central nervous influences in primary hypertension. Circulation 1987; 76:I10-I19.
315. Henry JP, Liu J, Meehan W: Psychosocial stress and experimental hypertension. In: Laragh JH, Brenner BM, ed. Hypertension: Pathophysiology, Diagnsosis, and Management, Vol 1. New York: Raven Press; 1995:905-922.
316. Nathan M, Reis D: Chronic labile hypertension produced by lesions of the nucleus tractus solitarius in the cat. Circ Res 1977; 40:72.
317. Carey RM, Dacey RG, Jane JA, et al: Production of sustained hypertension by lesions in the nucleus tractus solitarii of the American foxhound. Hypertension 1979; 1:246-254.
318. Johnson RJ, Gordon KL, Suga S, et al: Renal injury and salt-sensitive hypertension after exposure to catecholamines. Hypertension 1999; 34:151-159.
319. Johnson RJ, Herrera-Acosta J, Schreiner GF, Rodriguez-Iturbe B: Subtle acquired renal injury as a mechanism of salt-sensitive hypertension. N Engl J Med 2002; 346:913-923.
320. Esler M, Rumantir M, Kaye D, Lambert G: The sympathetic neurobiology of essential hypertension: Disparate influences of obesity, stress, and noradrenaline transporter dysfunction?. Am J Hypertens 2001; 14:139S-146S.
321. Oparil S, Chen Y-F, Berecek K: The role of the central nervous system in hypertension. In: Laragh JH, Brenner BM, ed. Hypertension: Pathophysiology, Diagnosis, and Treatment, Vol 1. New York: Raven Press; 1995:713-740.
322. Pickering TG, Harshfield GA, Kleinert HD, et al: Blood pressure during normal daily activities, sleep, and exercise. Comparison of values in normal and hypertensive subjects. JAMA 1982; 247:992-996.
323. Rozanski A, Blumenthal JA, Kaplan J: Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation 1999; 99:2192-2217.
324. Davy KP, Hall JE: Obesity and hypertension: Two epidemics or one?. Am J Physiol Regul Integr Comp Physiol 2004; 286:R803-R813.
325. Pausova Z: From big fat cells to high blood pressure: A pathway to obesity-associated hypertension. Curr Opin Nephrol Hypertens 2006; 15:173-178.
326. Huggett RJ, Burns J, Mackintosh AF, Mary DA: Sympathetic neural activation in nondiabetic metabolic syndrome and its further augmentation by hypertension. Hypertension 2004; 44:847-852.
327. Marsh AJ, Fontes MA, Killinger S, et al: Cardiovascular responses evoked by leptin acting on neurons in the ventromedial and dorsomedial hypothalamus. Hypertension 2003; 42:488-493.
328. Rahmouni K, Correia ML, Haynes WG, Mark AL: Obesity-associated hypertension: New insights into mechanisms. Hypertension 2005; 45:9-14.
329. Robles RG, Villa E, Santirso R, et al: Effects of captopril on sympathetic activity, lipid and carbohydrate metabolism in a model of obesity-induced hypertension in dogs. Am J Hypertens 1993; 6:1009-1015.
330. Masuzaki H, Yamamoto H, Kenyon CJ, et al: Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice. J Clin Invest 2003; 112:83-90.
331. O'Rourke MF, Kelly RP: Wave reflection in the systemic circulation and its implications in ventricular function. J Hypertens 1993; 11:327-337.
332. O'Rourke MF, Adji A: An updated clinical primer on large artery mechanics: Implications of pulse waveform analysis and arterial tonometry. Curr Opin Cardiol 2005; 20:275-281.
333. Cohn JN, Quyyumi AA, Hollenberg NK, Jamerson KA: Surrogate markers for cardiovascular disease: Functional markers. Circulation 2004; 109:IV31-VI46.
334. O'Rourke MF, Safar ME: Letter regarding article by Devereux et al, “Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial.”. Circulation 2005; 111:e377.
335. de Luca N, Asmar RG, London GM, et al: Selective reduction of cardiac mass and central blood pressure on low-dose combination perindopril/indapamide in hypertensive subjects. J Hypertens 2004; 22:1623-1630.
336. Hirata K, Vlachopoulos C, Adji A, O'Rourke MF: Benefits from angiotensin-converting enzyme inhibitor “beyond blood pressure lowering”: Beyond blood pressure or beyond the brachial artery?. J Hypertens 2005; 23:551-556.
337. Williams B, Lacy PS, Thom SM, et al: Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: Principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 2006; 113:1213-1225.
338. Ledingham JG, Bull MB, Laragh JH: The meaning of aldosteronism in hypertensive disease. Circ Res 1967; 21(suppl 2):177+.
339. Laragh J, Sealey JE, Sommers S: Patterns of adrenal secretion and urinary excretion of aldosterone and plasma renin actvity in normal and hypertensive subjects. Circ Res 1966; 18:158.
340. Laragh JH, Sealey JE: Relevance of the plasma renin hormonal control system that regulates blood pressure and sodium balance for correctly treating hypertension and for evaluating ALLHAT. Am J Hypertens 2003; 16:407-415.
341. Pickering TG, Herman L, Devereux RB, et al: Recurrent pulmonary oedema in hypertension due to bilateral renal artery stenosis: Treatment by angioplasty or surgical revascularisation. Lancet 1988; 2:551-552.
342. Volhard E, Fahr T: Die Brightsche Nierenkrankheit Klinik: Pathologie und Atlas, Berlin, Springer, 1914.
343. Laragh J: The role of aldosterone in man: Evidence for regulation of electrolyte balance and arterial pressure by a renal-adrenal system which may be involved in malignant hypertension. JAMA 1960; 174:293.
344. Laragh J, Ulick S, Januszewicz V: Aldosterone secretion and primary and malignant hypertension. J Clin Invest 1960; 39:1091.
345. Vaughan C, Dealnty N: Hypertensive emergencies. Lancet 2000; 356:411-417.
346. Masson G, Kashii C, Matsunaga M, Page I: Hypertensive vascular disease induced by heterologous renin. Circ Res 1966; 18:219.
347. Laragh JH, Baer L, Brunner HR, et al: Renin, angiotensin and aldosterone system in pathogenesis and management of hypertensive vascular disease. Am J Med 1972; 52:633-652.
348. Laragh J: The meaning of plasma renin measurements: Renin and sodium volume-medicated (low renin) forms of vascocontriction in experimental and human hypertension and in the oedematous states of nephrosis and heart failure. J Hypertens 1984; 2:141.
349. Buhler FR, Laragh JH, Baer L, et al: Propranolol inhibition of renin secretion. A specific approach to diagnosis and treatment of renin-dependent hypertensive diseases. N Engl J Med 1972; 287:1209-1214.
350. Case DB, Atlas SA, Laragh JH, et al: Clinical experience with blockade of the renin-angiotensin-aldosterone system by an oral converting-enzyme inhibitor (SQ 14,225, captopril) in hypertensive patients. Prog Cardiovasc Dis 1978; 21:195-206.
351. Laragh JH, Case DB, Atlas SA, Sealey JE: Captopril compared with other antirenin system agents in hypertensive patients: Its triphasic effects on blood pressure and its use to identify and treat the renin factor. Hypertension 1980; 2:586-593.
352. Lopez-Ovejero JA, Saal SD, D'Angelo WA, et al: Reversal of vascular and renal crises of scleroderma by oral angiotensin-converting-enzyme blockade. N Engl J Med 1979; 300:1417-1419.
353. Laragh JH: The classification and treatment of essential hypertension using the renin-sodium index for vasoconstriction-volume analysis. Johns Hopkins Med J 1975; 137:184-194.
354. Pickering T, Blumenfeld J: Renovascular hypertension. In: Brenner BM, Rector FC, ed. The Kidney, Vol 2. Philadelphia: WB Saunders; 1999:2007-2034.
355. Cervenka L, Horacek V, Vaneckova I, et al: Essential role of AT1A receptor in the development of 2K1C hypertension. Hypertension 2002; 40:735-741.
356. Braam B, Navar LG, Mitchell KD: Modulation of tubuloglomerular feedback by angiotensin II type 1 receptors during the development of Goldblatt hypertension. Hypertension 1995; 25:1232-1237.
357. Garovic V, Textor SC: Renovascular hypertension: Current concepts. Semin Nephrol 2005; 25:261-271.
358. Muller FB, Sealey JE, Case DB, et al: The captopril test for identifying renovascular disease in hypertensive patients. Am J Med 1986; 80:633-644.
359. Pickering TG, Sos TA, Vaughan Jr ED, et al: Predictive value and changes of renin secretion in hypertensive patients with unilateral renovascular disease undergoing successful renal angioplasty. Am J Med 1984; 76:398-404.
360. Pickering TG, Sos TA, James GD, et al: Comparison of renal vein renin activity in hypertensive patients with stenosis of one or both renal arteries. J Hypertens Suppl 1985; 3(suppl 3):S291-S293.
361. Sealey JE, Buhler FR, Laragh JH, Vaughan Jr ED: The physiology of renin secretion in essential hypertension. Estimation of renin secretion rate and renal plasma flow from peripheral and renal vein renin levels. Am J Med 1973; 55:391-401.
362. Garovic VD, Textor SC: Renovascular hypertension and ischemic nephropathy. Circulation 2005; 112:1362-1374.
363. Lenders JW, Eisenhofer G, Mannelli M, Pacak K: Phaeochromocytoma. Lancet 2005; 366:665-675.
364. Plouin PF, Chatellier G, Rougeot MA, et al: Plasma renin activity in phaeochromocytoma: Effects of beta-blockade and converting enzyme inhibition. J Hypertens 1988; 6:579-585.
365. Bravo EL, Tagle R: Pheochromocytoma: State-of-the-art and future prospects. Endocr Rev 2003; 24:539-553.
366. Lo CY, Lam KY, Wat MS, Lam KS: Adrenal pheochromocytoma remains a frequently overlooked diagnosis. Am J Surg 2000; 179:212-215.
367. McNeil AR, Blok BH, Koelmeyer TD, et al: Phaeochromocytomas discovered during coronial autopsies in Sydney, Melbourne and Auckland. Aust N Z J Med 2000; 30:648-652.
368. Sutton MG, Sheps SG, Lie JT: Prevalence of clinically unsuspected pheochromocytoma. Review of a 50-year autopsy series. Mayo Clin Proc 1981; 56:354-360.
369. Anderson Jr GH, Blakeman N, Streeten DH: The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients. J Hypertens 1994; 12:609-615.
370. Omura M, Saito J, Yamaguchi K, et al: Prospective study on the prevalence of secondary hypertension among hypertensive patients visiting a general outpatient clinic in Japan. Hypertens Res 2004; 27:193-202.
371. Plouin PF, Degoulet P, Tugaye A, et al: [Screening for phaeochromocytoma: In which hypertensive patients? A semiological study of 2585 patients, including 11 with phaeochromocytoma (author's transl)]. Nouv Presse Med 1981; 10:869-872.
372. La Batide-Alanore A, Chatellier G, Plouin PF: Diabetes as a marker of pheochromocytoma in hypertensive patients. J Hypertens 2003; 21:1703-1707.
373. Otsuka F, Miyoshi T, Murakami K, et al: An extra-adrenal abdominal pheochromocytoma causing ectopic ACTH syndrome. Am J Hypertens 2005; 18:1364-1368.
374. Kizer JR, Koniaris LS, Edelman JD, St John Sutton MG: Pheochromocytoma crisis, cardiomyopathy, and hemodynamic collapse. Chest 2000; 118:1221-1223.
375. Newell K, Prinz RA, Braithwaite S, Brooks M: Pheochromocytoma crisis. Am J Hypertens 1988; 1:189S-191S.
376. Mansmann G, Lau J, Balk E, et al: The clinically inapparent adrenal mass: Update in diagnosis and management. Endocr Rev 2004; 25:309-340.
377. Baguet JP, Hammer L, Mazzuco TL, et al: Circumstances of discovery of phaeochromocytoma: A retrospective study of 41 consecutive patients. Eur J Endocrinol 2004; 150:681-686.
378. Streeten DH, Anderson Jr GH: Mechanisms of orthostatic hypotension and tachycardia in patients with pheochromocytoma. Am J Hypertens 1996; 9:760-769.
379. Munakata M, Aihara A, Imai Y, et al: Altered sympathetic and vagal modulations of the cardiovascular system in patients with pheochromocytoma: Their relations to orthostatic hypotension. Am J Hypertens 1999; 12:572-580.
380. Bergland BE: Pheochromocytoma presenting as shock. Am J Emerg Med 1989; 7:44-48.
381. Grouzmann E, Werffeli-George P, Fathi M, et al: Angiotensin-II mediates norepinephrine and neuropeptide-Y secretion in a human pheochromocytoma. J Clin Endocrinol Metab 1994; 79:1852-1856.
382. Bravo EL: Pheochromocytoma: New concepts and future trends. Kidney Int 1991; 40:544-556.
383. Kamari Y, Sharabi Y, Leiba A, et al: Peripartum hypertension from pheochromocytoma: A rare and challenging entity. Am J Hypertens 2005; 18:1306-1312.
384. Ahlawat SK, Jain S, Kumari S, et al: Pheochromocytoma associated with pregnancy: Case report and review of the literature. Obstet Gynecol Surv 1999; 54:728-737.
385. Maher ER, Eng C: The pressure rises: Update on the genetics of phaeochromocytoma. Hum Mol Genet 2002; 11:2347-2354.
386. Neumann HP, Bausch B, McWhinney SR, et al: Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 2002; 346:1459-1466.
387. Eisenhofer G, Kopin IJ, Goldstein DS: Catecholamine metabolism: A contemporary view with implications for physiology and medicine. Pharmacol Rev 2004; 56:331-349.
388. Eisenhofer G, Huysmans F, Pacak K, et al: Plasma metanephrines in renal failure. Kidney Int 2005; 67:668-677.
389. Raber W, Raffesberg W, Bischof M, et al: Diagnostic efficacy of unconjugated plasma metanephrines for the detection of pheochromocytoma. Arch Intern Med 2000; 160:2957-2963.
390. Eisenhofer G, Keiser H, Friberg P, et al: Plasma metanephrines are markers of pheochromocytoma produced by catechol-O-methyltransferase within tumors. J Clin Endocrinol Metab 1998; 83:2175-2185.
391. Kudva YC, Sawka AM, Young Jr WF: Clinical review 164: The laboratory diagnosis of adrenal pheochromocytoma: The Mayo Clinic experience. J Clin Endocrinol Metab 2003; 88:4533-4539.
392. Sawka AM, Jaeschke R, Singh RJ, Young Jr WF: A comparison of biochemical tests for pheochromocytoma: Measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab 2003; 88:553-558.
393. Witteles RM, Kaplan EL, Roizen MF: Sensitivity of diagnostic and localization tests for pheochromocytoma in clinical practice. Arch Intern Med 2000; 160:2521-2524.
394. Bravo EL: Evolving concepts in the pathophysiology, diagnosis, and treatment of pheochromocytoma. Endocr Rev 1994; 15:356-368.
395. Eisenhofer G, Goldstein DS, Walther MM, et al: Biochemical diagnosis of pheochromocytoma: How to distinguish true- from false-positive test results. J Clin Endocrinol Metab 2003; 88:2656-2666.
396. Cook FJ, Chandler DW, Snyder DK: Effect of buspirone on urinary catecholamine assays. N Engl J Med 1995; 332:401.
397. Whalen RK, Althausen AF, Daniels GH: Extra-adrenal pheochromocytoma. J Urol 1992; 147:1-10.
398. Motta-Ramirez GA, Remer EM, Herts BR, et al: Comparison of CT findings in symptomatic and incidentally discovered pheochromocytomas. AJR Am J Roentgenol 2005; 185:684-688.
399. Pacak K, Linehan WM, Eisenhofer G, et al: Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med 2001; 134:315-329.
400. Ilias I, Yu J, Carrasquillo JA, et al: Superiority of 6-[18F]-fluorodopamine positron emission tomography versus [131I]-metaiodobenzylguanidine scintigraphy in the localization of metastatic pheochromocytoma. J Clin Endocrinol Metab 2003; 88:4083-4087.
401. Ilias I, Pacak K: Anatomical and functional imaging of metastatic pheochromocytoma. Ann N Y Acad Sci 2004; 1018:495-504.
402. Blumenfeld J, Cohen N, Anwar M, et al: Hypertension and a tumor of the glomus jugulare region. Evidence for epinephrine biosynthesis [see comments]. Am J Hypertens 1993; 6:382-387.
403. Kocak S, Aydintug S, Canakci N: Alpha blockade in preoperative preparation of patients with pheochromocytomas. Int Surg 2002; 87:191-194.
404. Engelman K, Horwitz D, Jequier E, Sjoerdsma A: Biochemical and pharmacologic effects of alpha-methyltyrosine in man. J Clin Invest 1968; 47:577-594.
405. Engelman K, Jequier E, Udenfriend S, Sjoerdsma A: Metabolism of alpha-methyltyrosine in man: Relationship to its potency as an inhibitor of catecholamine biosynthesis. J Clin Invest 1968; 47:568-576.
406. Steinsapir J, Carr AA, Prisant LM, Bransome Jr ED: Metyrosine and pheochromocytoma. Arch Intern Med 1997; 157:901-906.
407. Perry RR, Keiser HR, Norton JA, et al: Surgical management of pheochromocytoma with the use of metyrosine. Ann Surg 1990; 212:621-628.
408. Imperato-McGinley J, Gautier T, Ehlers K, et al: Reversibility of catecholamine-induced dilated cardiomyopathy in a child with a pheochromocytoma. N Engl J Med 1987; 316:793-797.
409. Hauptman JB, Modlinger RS, Ertel NH: Pheochromocytoma resistant to alpha-adrenergic blockade. Arch Intern Med 1983; 143:2321-2323.
410. Ulchaker JC, Goldfarb DA, Bravo EL, Novick AC: Successful outcomes in pheochromocytoma surgery in the modern era. J Urol 1999; 161:764-767.
411. Lebuffe G, Dosseh ED, Tek G, et al: The effect of calcium channel blockers on outcome following the surgical treatment of phaeochromocytomas and paragangliomas. Anaesthesia 2005; 60:439-444.
412. Vaughan E, Blumenfeld J: The adrenals. In: Wein AJ, Kavoussi LR, Novick AC, et al ed. Campbell-Walsh Urology, vol 4. Philadelphia: WB Saunders; 2006:1819-1867.
413. Tobian L, Coffee K, McCrea P: Contrasting exchangeable sodium in rats with different types of Goldblatt hypertension. Am J Physiol 1969; 217:458-460.
414. Gavras H, Brunner HB, Vaughan ED, Laragh JH: Angiotensin-sodium interaction in blood pressure maintenance of renal hypertensive and normotensive rats. Science 1973; 180:1369-1371.
415. Baer L, Sommers SC, Krakoff LR, et al: Pseudo-primary aldosteronism. An entity distinct from true primary aldosteronism. Circ Res 1970; 27:203-220.
416. Brunner HR, Kirshman JD, Sealey JE, Laragh JH: Hypertension of renal origin: Evidence for two different mechanisms. Science 1971; 174:1344-1346.
417. Hricik DE, Browning PJ, Kapelman R, et al: Captopril-induced functional renal insufficiency in patients with bilateral renal-artery stenoses or renal-artery stenosis in a solitary kidney. N Engl J Med 1983; 308:373.
418. Erne P, Bolli P, Bertel O, et al: Factors influencing the hypotensive effects of calcium antagonists. Hypertension 1983; 5:II97-II102.
419. Resnick LM, Laragh JH, Sealey JE, Alderman MH: Divalent cations in essential hypertension. Relations between serum ionized calcium, magnesium, and plasma renin activity. N Engl J Med 1983; 309:888-891.
420. Resnick L: The cellular ionic basis of hypertension and allied clinical conditions. Prog Cardiovasc Dis 1999; 42:1-22.
421. Resnick LM, Nicholson JP, Laragh JH: Alterations in calcium metabolism mediate dietary salt sensitivity in essential hypertension. Trans Assoc Am Physicians 1985; 98:313-321.
422. Iwamoto T, Kita S, Katsuragi T: Salt-sensitive hypertension, Na+/Ca2+ exchanger, and vascular smooth muscle. Trends Cardiovasc Med 2005; 15:273-277.
423. Nicholson JP, Resnick LM, Laragh JH: The antihypertensive effect of verapamil at extremes of dietary sodium intake. Ann Intern Med 1987; 107:329-334.
424. Wilcox CS, Welch WJ, Murad F, et al: Nitric oxide synthase in macula densa regulates glomerular capillary pressure. Proc Natl Acad Sci U S A 1992; 89:11993-11997.
425. Tolins JP, Shultz PJ: Endogenous nitric oxide synthesis determines sensitivity to the pressor effect of salt. Kidney Int 1994; 46:230-236.
426. Mulatero P, Dluhy RG, Giacchetti G, et al: Diagnosis of primary aldosteronism: From screening to subtype differentiation. Trends Endocrinol Metab 2005; 16:114-119.
427. Young Jr WF: Minireview: Primary aldosteronism—Changing concepts in diagnosis and treatment. Endocrinology 2003; 144:2208-2213.
428. New MI, Geller DS, Fallo F, Wilson WS: Monogenic low renin hypertension. Trends Endocrinol Metab 2005; 16:92-97.
429. O'Neil RG: Aldosterone regulation of sodium and potassium transport in the cortical collecting duct. Semin Nephrol 1990; 10:365-374.
430. Kahle KT, Wilson AC, Lifton RP: Regulation of diverse ion transport pathways by WNK4 kinase: A novel molecular switch. Trends Endocrin Metab 2005; 16:98-103.
431. Rossier BC: Negative regulators of sodium transport in the kidney: Key factors in understanding salt-sensitive hypertension?. J Clin Invest 2003; 111:947-950.
432. Verrey F, Loffing J, Zecevic M, et al: SGK1: aldosterone-induced relay of Na+ transport regulation in distal kidney nephron cells. Cell Physiol Biochem 2003; 13:21-28.
433. Knepper MA, Kim GH, Masilamani S: Renal tubule sodium transporter abundance profiling in rat kidney: Response to aldosterone and variations in NaCl intake. Ann N Y Acad Sci 2003; 986:562-569.
434. Knowlton AI, Laragh JH: Electrolyte changes in renal cortex, inner medulla and papilla in renal artery clamp hypertension. Proc Soc Exp Biol Med 1970; 133:1048-1054.
435. Hall JE, Granger JP, Smith Jr MJ, Premen AJ: Role of renal hemodynamics and arterial pressure in aldosterone “escape.”. Hypertension 1984; 6:I183-I192.
436. de Bold AJ, Ma KK, Zhang Y, et al: The physiological and pathophysiological modulation of the endocrine function of the heart. Can J Physiol Pharmacol 2001; 79:705-714.
437. Meneton P, Loffing J, Warnock DG: Sodium and potassium handling by the aldosterone-sensitive distal nephron: The pivotal role of the distal and connecting tubule. Am J Physiol Renal Physiol 2004; 287:F593-F601.
438. Stowasser M, Gordon RD, Gunasekera TG, et al: High rate of detection of primary aldosteronism, including surgically treatable forms, after “non-selective” screening of hypertensive patients. J Hypertens 2003; 21:2149-2157.
439. Young WF, Stanson AW, Thompson GB, et al: Role for adrenal venous sampling in primary aldosteronism. Surgery 2004; 136:1227-1235.
440. Blumenfeld JD, Sealey JE, Schlussel Y, et al: Diagnosis and treatment of primary hyperaldosteronism [see comments]. Ann Intern Med 1994; 121:877-885.
441. Ulick S, Blumenfeld J, Atlas S, et al: The unique steroidogenesis of the aldosteronoma in the differential diagnosis of primary aldosteronism. J Clin Endocrinol Metab 1992; 76:873-878.
442. Stowasser M, Gordon RD: Primary aldosteronism—Careful investigation is essential and rewarding. Mol Cell Endocrinol 2004; 217:33-39.
443. Espiner EA, Ross DG, Yandle TG, et al: Predicting surgically remedial primary aldosteronism: Role of adrenal scanning, posture testing, and adrenal vein sampling. J Clin Endocrinol Metab 2003; 88:3637-3644.
444. Komlosi P, Fintha A, Bell PD: Current mechanisms of macula densa cell signalling. Acta Physiol Scand 2004; 181:463-469.
445. Weinberger MH, Grim CE, Hollifield JW, et al: Primary aldosteronism: Diagnosis, localization, and treatment. Ann Intern Med 1979; 90:386-395.
446. Ganguly A, Dowdy AJ, Luetscher JA, Melada GA: Anomalous postural response of plasma aldosterone concentration in patients with aldosterone-producing adrenal adenoma. J Clin Endocrinol Metab 1973; 36:401-404.
447. Ganguly A: Primary aldosteronism. N Engl J Med 1998; 339:1828-1834.
448. Fontes R, Kater C, Biglieri E, Irony I: Reassessment of the predictive value of the postural stimulation test in primary aldosteronsim. Am J Hypertens 1991; 4:786-791.
449. Tunny TJ, Gordon RD, Klemm SA, Cohn D: Histological and biochemical distinctiveness of atypical aldosterone-producing adenomas responsive to upright posture and angiotensin. Clin Endocrinol (Oxf) 1991; 34:363-369.
449a. Imai T, Seo H, Murata Y, et al: Dexamethasone-nonsuppressible cortisol in two cases with aldosterone-producing adenoma. J Clin Endocrinol Metab 1991; 72:575-581.
450. Banks WA, Kastin AJ, Biglieri EG, Ruiz AE: Primary adrenal hyperplasia: A new subset of primary hyperaldosteronism. J Clin Endocrinol Metab 1984; 58:783-785.
451. Irony I, Kater CE, Biglieri EG, Shackleton CH: Correctable subsets of primary aldosteronism. Primary adrenal hyperplasia and renin responsive adenoma. Am J Hypertens 1990; 3:576-582.
452. Arteaga E, Biglieri EG, Kater CE, et al: Aldosterone-producing adrenocortical carcinoma. Preoperative recognition and course in three cases. Ann Intern Med 1984; 101:316-321.
453. Isles CG, MacDougall IC, Lever AF, Fraser R: Hypermineralocorticoidism due to adrenal carcinoma: Plasma corticosteroids and their response to ACTH and angiotensin II. Clin Endocrinol (Oxf) 1987; 26:239-251.
454. Kendrick ML, Curlee K, Lloyd R, et al: Aldosterone-secreting adrenocortical carcinomas are associated with unique operative risks and outcomes. Surgery 2002; 132:1008-1011.discussion 1012
455. Sutherland DJ, Ruse JL, Laidlaw JC: Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Can Med Assoc J 1966; 95:1109-1119.
456. Lifton RP, Dluhy RG, Powers M, et al: A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992; 355:262-265.
457. McMahon GT, Dluhy RG: Glucocorticoid-remediable aldosteronism. Cardiol Rev 2004; 12:44-48.
458. Mulatero P, Morello F, Veglio F: Genetics of primary aldosteronism. J Hypertens 2004; 22:663-670.
459. Rich GM, Ulick S, Cook S, et al: Glucocorticoid-remediable aldosteronism in a large kindred: Clinical spectrum and diagnosis using a characteristic biochemical phenotype. Ann Intern Med 1992; 116:813-820.
460. Litchfield WR, Coolidge C, Silva P, et al: Impaired potassium-stimulated aldosterone production: A possible explanation for normokalemic glucocorticoid-remediable aldosteronism [see comments]. J Clin Endocrinol Metab 1997; 82:1507-1510.
461. Ulick S, Chan C: Physiologic insights from the search for unknown steroids in low renin essential hypertension. In: Mantero F, Takeda R, Scoggins B, ed. The Adrenal and Hypertension: From Cloning to Clinic, New York: Raven Press; 1989:313-322.
462. White PC: Steroid 11 beta-hydroxylase deficiency and related disorders. Endocrinol Metab Clin North Am 2001; 30:61-79.vi
463. White PC: Disorders of aldosterone biosynthesis and action. N Engl J Med 1994; 331:250-258.
464. Dluhy RG, Lifton RP: Glucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab 1999; 84:4341-4344.
465. Pilon C, Mulatero P, Barzon L, et al: Mutations in CYP11B1 gene converting 11beta-hydroxylase into an aldosterone-producing enzyme are not present in aldosterone-producing adenomas. J Clin Endocrinol Metab 1999; 84:4228-4231.
466. Stowasser M, Gunasekera TG, Gordon RD: Familial varieties of primary aldosteronism. Clin Exp Pharmacol Physiol 2001; 28:1087-1090.
467. Gordon RD, Laragh JH, Funder JW: Low renin hypertensive states: Perspectives, unsolved problems, future research. Trends Endocrinol Metab 2005; 16:108-113.
468. Ulick S, Levine LS, Gunczler P, et al: A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol. J Clin Endocrinol Metab 1979; 49:757-764.
469. Quinkler M, Stewart PM: Hypertension and the cortisol-cortisone shuttle. J Clin Endocrinol Metab 2003; 88:2384-2392.
470. Arriza JL, Weinberger C, Cerelli G, et al: Cloning of human mineralocorticoid receptor complementary DNA: Structural and functional kinship with the glucocorticoid receptor. Science 1987; 237:268-275.
471. Ulick S, Wang JZ, Blumenfeld JD, Pickering TG: Cortisol inactivation overload: A mechanism of mineralocorticoid hypertension in the ectopic adrenocorticotropin syndrome [see comments]. J Clin Endocrinol Metab 1992; 74:963-967.
472. Stewart PM: Mineralocorticoid hypertension. Lancet 1999; 353:1341-1347.
473. Farese Jr RV, Biglieri EG, Shackleton CH, et al: Licorice-induced hypermineralocorticoidism. N Engl J Med 1991; 325:1223-1227.
474. Stewart PM, Wallace AM, Valentino R, et al: Mineralocorticoid activity of liquorice: 11-Beta-hydroxysteroid dehydrogenase deficiency comes of age. Lancet 1987; 2:821-824.
475. Edwards CR, Stewart PM, Burt D, et al: Localisation of 11 beta-hydroxysteroid dehydrogenase—Tissue specific protector of the mineralocorticoid receptor. Lancet 1988; 2:986-989.
476. Quaschning T, Ruschitzka F, Shaw S, Luscher TF: Aldosterone receptor antagonism normalizes vascular function in liquorice-induced hypertension. Hypertension 2001; 37:801-805.
477. Liddle G, Coppage W: A familial renal disorder simulating primary aldosteronism but with negligible aldosterone secretion. Trans Assoc Am Physicians 1963; 76:199-213.
478. O'Shaughnessy KM, Karet FE: Salt handling and hypertension. J Clin Invest 2004; 113:1075-1081.
479. Shimkets RA, Warnock DG, Bositis CM, et al: Liddle's syndrome: Heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell 1994; 79:407-414.
480. Warnock DG: Liddle syndrome: An autosomal dominant form of human hypertension. Kidney Int 1998; 53:18-24.
481. Schild L, Canessa CM, Shimkets RA, et al: A mutation in the epithelial sodium channel causing Liddle disease increases channel activity in the Xenopus laevis oocyte expression system. Proc Natl Acad Sci U S A 1995; 92:5699-5703.
482. Geller DS, Farhi A, Pinkerton N, et al: Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science 2000; 289:119-123.
483. Bravo EL, Tarazi RC, Dustan HP, et al: The changing clinical spectrum of primary aldosteronism. Am J Med 1983; 74:641-651.
484. Mulatero P, Stowasser M, Loh KC, et al: Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab 2004; 89:1045-1050.
485. Kaplan NM: The current epidemic of primary aldosteronism: Causes and consequences. J Hypertens 2004; 22:863-869.
486. Padfield PL: Primary aldosteronism, a common entity? The myth persists. J Hum Hypertens 2002; 16:159-162.
487. Ferriss JB, Beevers DG, Brown JJ, et al: Clinical, biochemical and pathological features of low-renin (“primary”) hyperaldosteronism. Am Heart J 1978; 95:375-388.
488. Nakada T, Furuta H, Katayama T, et al: The effect of adrenal surgery on plasma atrial natriuretic factor and sodium escape phenomenon in patients with primary aldosteronism. J Urol 1989; 142:13-18.
489. Ferriss JB, Beevers DG, Brown JJ, et al: Low-renin (“primary”) hyperaldosteronism. Differential diagnosis and distinction of sub-groups within the syndrome. Am Heart J 1978; 95:641-658.
490. Mosso L, Carvajal C, Gonzalez A, et al: Primary aldosteronism and hypertensive disease. Hypertension 2003; 42:161-165.
491. Conn JW: The evolution of primary aldosteronism: 1954-1967. Harvey Lect 1966; 62:257-291.
492. Melby J: Primary aldosteronism. Kidney Int 1984; 26:769-778.
493. Takeda R, Matsubara T, Miyamori I, et al: Vascular complications in patients with aldosterone producing adenoma in Japan: Comparative study with essential hypertension. The Research Committee of Disorders of Adrenal Hormones in Japan. J Endocrinol Invest 1995; 18:370-373.
494. Suzuki T, Abe H, Nagata S, et al: Left ventricular structural characteristics in unilateral renovascular hypertension and primary aldosteronism. Am J Cardiol 1988; 62:1224-1227.
495. Rossi GP, Cesari M, Pessina AC: Left ventricular changes in primary aldosteronism. Am J Hypertens 2003; 16:96-98.
496. Rossi GP, Di Bello V, Ganzaroli C, et al: Excess aldosterone is associated with alterations of myocardial texture in primary aldosteronism. Hypertension 2002; 40:23-27.
497. Rossi GP, Sacchetto A, Pavan E, et al: Remodeling of the left ventricle in primary aldosteronism due to Conn's adenoma. Circulation 1997; 95:1471-1478.
498. Rossi GP, Sacchetto A, Visentin P, et al: Changes in left ventricular anatomy and function in hypertension and primary aldosteronism. Hypertension 1996; 27:1039-1045.
499. Porodko M, Auer J, Eber B: Conn's syndrome and atrial fibrillation. Lancet 2001; 357:1293-1294.
500. Rossi GP: Aldosterone as a cardiovascular risk factor. Trends Endocrin Metab 2005; 16:104-107.
501. Milliez P, Girerd X, Plouin PF, et al: Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 2005; 45:1243-1248.
502. Conn JW: Plasma renin activity in primary aldosteronism. Importance in differential diagnosis and in research of essential hypertension. JAMA 1964; 190:222-225.
503. Streeten DH, Anderson Jr GH, Wagner S: Effect of age on response of secondary hypertension to specific treatment. Am J Hypertens 1990; 3:360-365.
504. Oelkers W, Diederich S, Bahr V: Primary hyperaldosteronism without suppressed renin due to secondary hypertensive kidney damage. J Clin Endocrinol Metab 2000; 85:3266-3270.
505. Sealey JE, Gordon RD, Mantero F: Plasma renin and aldosterone measurements in low renin hypertensive states. Trends Endocrinol Metab 2005; 16:86-91.
506. Hiramatsu K, Yamada T, Yukimura Y, et al: A screening test to identify aldosterone-producing adenoma by measuring plasma renin activity. Results in hypertensive patients. Arch Intern Med 1981; 141:1589-1593.
507. Auchus RJ: Aldo is back: Recent advances and unresolved controversies in hyperaldosteronism. Curr Opin Nephrol Hypertens 2003; 12:153-158.
508. Tanabe A, Naruse M, Takagi S, et al: Variability in the renin/aldosterone profile under random and standardized sampling conditions in primary aldosteronism. J Clin Endocrinol Metab 2003; 88:2489-2494.
509. Castro OL, Yu X, Kem DC: Diagnostic value of the post-captopril test in primary aldosteronism. Hypertension 2002; 39:935-938.
510. Racine MC, Douville P, Lebel M: Functional tests for primary aldosteronism: Value of captopril suppression. Curr Hypertens Rep 2002; 4:245-249.
511. Rossi E, Regolisti G, Negro A, et al: High prevalence of primary aldosteronism using postcaptopril plasma aldosterone to renin ratio as a screening test among Italian hypertensives. Am J Hypertens 2002; 15:896-902.
512. Agharazii M, Douville P, Grose JH, Lebel M: Captopril suppression versus salt loading in confirming primary aldosteronism. Hypertension 2001; 37:1440-1443.
513. Hirohara D, Nomura K, Okamoto T, et al: Performance of the basal aldosterone to renin ratio and of the renin stimulation test by furosemide and upright posture in screening for aldosterone-producing adenoma in low renin hypertensives. J Clin Endocrinol Metab 2001; 86:4292-4298.
514. Schambelan M, Brust NL, Chang BC, et al: Circadian rhythm and effect of posture on plasma aldosterone concentration in primary aldosteronism. J Clin Endocrinol Metab 1976; 43:115-131.
515. Arteaga E, Klein R, Biglieri EG: Use of the saline infusion test to diagnose the cause of primary aldosteronism. Am J Med 1985; 79:722-728.
516. Biglieri EG, Schambelan M: The significance of elevated levels of plasma 18-hydroxycorticosterone in patients with primary aldosteronism. J Clin Endocrinol Metab 1979; 49:87-91.
517. Rossi GP, Sacchetto A, Chiesura-Corona M, et al: Identification of the etiology of primary aldosteronism with adrenal vein sampling in patients with equivocal computed tomography and magnetic resonance findings: Results in 104 consecutive cases. J Clin Endocrinol Metab 2001; 86:1083-1090.
518. Phillips JL, Walther MM, Pezzullo JC, et al: Predictive value of preoperative tests in discriminating bilateral adrenal hyperplasia from an aldosterone-producing adrenal adenoma. J Clin Endocrinol Metab 2000; 85:4526-4533.
519. Doppman JL, Gill Jr JR, Miller DL, et al: Distinction between hyperaldosteronism due to bilateral hyperplasia and unilateral aldosteronoma: Reliability of CT. Radiology 1992; 184:677-682.
520. Radin DR, Manoogian C, Nadler JL: Diagnosis of primary hyperaldosteronism: Importance of correlating CT findings with endocrinologic studies. AJR Am J Roentgenol 1992; 158:553-557.
521. Blumenfeld JD, Sealey JE, Mann SJ, et al: Beta-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensin-aldosterone system in normotensive and hypertensive subjects. Am J Hypertens 1999; 12:451-459.
522. Nadler JL, Hsueh W, Horton R: Therapeutic effect of calcium channel blockade in primary aldosteronism. J Clin Endocrinol Metab 1985; 60:896-899.
523. Celen O, O'Brien M, Melby J, Beazeley R: Factors influencing outcome of surgery for primary aldosteronism. Arch Surg 1996; 131:646-650.
524. de Gasparo M, Whitebread SE, Preiswerk G, et al: Antialdosterones: Incidence and prevention of sexual side effects. J Steroid Biochem 1989; 32:223-227.
525. Griffing GT, Cole AG, Aurecchia SA, et al: Amiloride in primary hyperaldosteronism. Clin Pharmacol Ther 1982; 31:56-61.
526. Bravo EL, Fouad FM, Tarazi RC: Calcium channel blockade with nifedipine in primary aldosteronism. Hypertension 1986; 11:91-94.
527. Bursztyn M, Grossman E, Rosenthal T: The absence of long-term therapeutic effect of calcium channel blockade in the primary aldosteronism of adrenal adenomas. Am J Hypertens 1988; 1:88S-90S.
528. Bravo E, Tarazi R, Dustan H, Fouad F: The sympathetic nervous system and hypertension in primary aldosteronism. Hypertension 1985; 7:90-96.
529. Bolli P, Awann F, Buhler FR: Acute hypotensive response to post-synaptic alpha-blockade with prazosin in low and normal renin hypertension. J Cardiovasc Pharmacol 1980; 2:S399-S405.
530. Charra B, Bergstrom J, Scribner BH: Blood pressure control in dialysis patients: Importance of the lag phenomenon. Am J Kidney Dis 1998; 32:720-724.
531. Laurent G, Charra B: The results of an 8 h thrice weekly haemodialysis schedule. Nephrol Dial Transplant 1998; 13(suppl 6):125-131.
532. Saad E, Charra B, Raj DS: Hypertension control with daily dialysis. Semin Dial 2004; 17:295-298.
533. Chazot C, Charra B, Vo Van C, et al: The Janus-faced aspect of “dry weight.”. Nephrol Dial Transplant 1999; 14:121-124.
534. Chan CT, Harvey PJ, Picton P, et al: Short-term blood pressure, noradrenergic, and vascular effects of nocturnal home hemodialysis. Hypertension 2003; 42:925-931.
535. Katzarski KS, Charra B, Luik AJ, et al: Fluid state and blood pressure control in patients treated with long and short haemodialysis. Nephrol Dial Transplant 1999; 14:369-375.
536. Koomans HA, Geers AB, Mees EJ: Plasma volume recovery after ultrafiltration in patients with chronic renal failure. Kidney Int 1984; 26:848-854.
537. Guyton AC: Interstitial fluid pressure. II. Pressure-volume curves of interstitial space. Circ Res 1965; 16:452-460.
538. Cheigh J, Milite C, Sullivan J, et al: Hypertension is not adequately controlled in hemodialysis patients. Am J Kidney Dis 1992; 5:453-459.
539. Rahman M, Dixit A, Donley V, et al: Factors associated with inadequate blood pressure control in hypertensive hemodialysis patients. Am J Kidney Dis 1999; 33:498-506.
540. Chaignon M, Chen WT, Tarazi RC, et al: Effect of hemodialysis on blood volume distribution and cardiac output. Hypertension 1981; 3:327-332.
541. Daugirdas JT: Pathophysiology of dialysis hypotension: An update. Am J Kidney Dis 2001; 38:S11-S17.
542. Sherman RA: Intradialytic hypotension: An overview of recent, unresolved and overlooked issues. Semin Dial 2002; 15:141-143.
543. Ates K, Nergizoglu G, Keven K, et al: Effect of fluid and sodium removal on mortality in peritoneal dialysis patients. Kidney Int 2001; 60:767-776.
544. Tzamaloukas AH, Saddler MC, Murata GH, et al: Symptomatic fluid retention in patients on continuous peritoneal dialysis. J Am Soc Nephrol 1995; 6:198-206.
545. Rottembourg J: Residual renal function and recovery of renal function in patients treated by CAPD. Kidney Int Suppl 1993; 40:S106-S110.
546. National Kidney Foundation: K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease. Am J Kidney Dis 2004; 43:S1-S290.
547. Abdi R, Brenner BM: Impact of renin angiotensin system blockade on renal function in health and disease: An end or a beginning?. Semin Nephrol 2004; 24:141-146.
548. Schiffrin EL: Effects of aldosterone on the vasculature. Hypertension 2006; 47:312-318.
549. August P, Suthanthiran M: Transforming growth factor beta and progression of renal disease. Kidney Int Suppl 2003; 87:S99-S104.
550. Gunal AI, Duman S, Ozkahya M, et al: Strict volume control normalizes hypertension in peritoneal dialysis patients. Am J Kidney Dis 2001; 37:588-593.
551. Schalekamp MA, Schalekamp-Kuyken MP, de Moor-Fruytier M, et al: Interrelationships between blood pressure, renin, renin substrate and blood volume in terminal renal failure. Clin Sci Mol Med 1973; 45:417-428.
552. Vertes V, Cangiano JL, Berman LB, Gould A: Hypertension in end-stage renal disease. N Engl J Med 1969; 280:978-981.
552a. Sealey JE, White RP, Laragh JH, Rubin AL: Plasma prorenin and renin in anephric patients. Circ Res 1977; 41:17-21.
552b. Davies DL, Beevers DG, Briggs JD, et al: Abnormal relation between exchangeable sodium and the renin-angiotensin system in malignant hypertension and in hypertension with chronic kidney failure. Lancet 1973; 1:683-686.
553. Davies DL, Beevers DG, Briggs JD, et al: Abnormal relation between exchangeable sodium and the renin-angiotensin system in malignant hypertension and in hypertension with chronic renal failure. Lancet 1973; 1:683-686.
554. Vaughan Jr ED, Carey RM, Ayers CR, Peach MJ: Hemodialysis-resistant hypertension: Control with an orally active inhibitor of angiotensin-converting enzyme. J Clin Endocrinol Metab 1979; 48:869-871.
555. Chapman A, Johnson A, Gabow P, Schrier R: The renin-angiotensin-aldosterone system and autosomal dominanat polycystic kidney disease. N Engl J Med 1990; 323:1091-1096.
556. Chapman A, Schrier R: Pathogenesis of hypertension in autosomal dominant polycystic kidney disease. Semin Neprhol 1991; 11:653-660.
557. Ecder T, Edelstein C, Fick-Brosnahan G, et al: Progress in blood pressure control in autosomal dominant polycystic kidney disease. Am J Kidney Dis 2000; 36:266-271.
558. Neumann J, Ligtenberg G, Klein II, et al: Sympathetic hyperactivity in chronic kidney disease: Pathogenesis, clinical relevance, and treatment. Kidney Int 2004; 65:1568-1576.
559. In: Kopin I, ed. The Sympathetic Nervous System and Hypertension, New York: Springer-Verlag; 1981:283-289.
560. Converse Jr RL, Jacobsen TN, Toto RD, et al: Sympathetic overactivity in patients with chronic renal failure. N Engl J Med 1992; 327:1912-1918.
561. Converse Jr RL, Jacobsen TN, Jost CM, et al: Paradoxical withdrawal of reflex vasoconstriction as a cause of hemodialysis-induced hypotension. J Clin Invest 1992; 90:1657-1665.
562. Ligtenberg G, Blankestijn P, Oey P, et al: Reduction of sympathetic hyperactivity by enalapril in patients with chronic renal failure. N Engl J Med 1999; 340:1321-1328.
563. Klein IH, Ligtenberg G, Oey PL, et al: Sympathetic activity is increased in polycystic kidney disease and is associated with hypertension. J Am Soc Nephrol 2001; 12:2427-2433.
564. Klein IH, Ligtenberg G, Neumann J, et al: Sympathetic nerve activity is inappropriately increased in chronic renal disease. J Am Soc Nephrol 2003; 14:3239-3244.
565. Neumann J, Ligtenberg G, Oey L, et al: Moxonidine normalizes sympathetic hyperactivity in patients with eprosartan-treated chronic renal failure. J Am Soc Nephrol 2004; 15:2902-2907.
566. Chowdhary S, Townend JN: Role of nitric oxide in the regulation of cardiovascular autonomic control. Clin Sci (Lond) 1999; 97:5-17.
567. Kielstein JT, Zoccali C: Asymmetric dimethylarginine: A cardiovascular risk factor and a uremic toxin coming of age?. Am J Kidney Dis 2005; 46:186-202.
568. Vallance P, Leone A, Calver A, et al: Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 1992; 339:572-575.
569. Anderstam B, Katzarski K, Bergstrom J: Serum levels of NG, NG-dimethyl-l-arginine, a potential endogenous nitric oxide inhibitor in dialysis patients. J Am Soc Nephrol 1997; 8:1437-1442.
570. Kielstein JT, Impraim B, Simmel S, et al: Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans. Circulation 2004; 109:172-177.
571. Fujiwara N, Osanai T, Kamada T, et al: Study on the relationship between plasma nitrite and nitrate level and salt sensitivity in human hypertension: Modulation of nitric oxide synthesis by salt intake. Circulation 2000; 101:856-861.
572. Schmidt RJ, Baylis C: Total nitric oxide production is low in patients with chronic renal disease. Kidney Int 2000; 58:1261-1266.
573. Cooke J: Asymmetrical dimethylarginine: The Über marker?. Circulation 2004; 109:1813-1819.
574. Kielstein JT, Boger RH, Bode-Boger SM, et al: Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: Relationship to treatment method and atherosclerotic disease. J Am Soc Nephrol 1999; 10:594-600.
575. Zoccali C, Bode-Boger S, Mallamaci F, et al: Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: A prospective study. Lancet 2001; 358:2113-2117.
576. Zoccali C, Mallamaci F, Maas R, et al: Left ventricular hypertrophy, cardiac remodeling and asymmetric dimethylarginine (ADMA) in hemodialysis patients. Kidney Int 2002; 62:339-345.
577. Zoccali C, Benedetto FA, Maas R, et al: Asymmetric dimethylarginine, C-reactive protein, and carotid intima-media thickness in end-stage renal disease. J Am Soc Nephrol 2002; 13:490-496.
578. Kielstein JT, Boger RH, Bode-Boger SM, et al: Low dialysance of asymmetric dimethylarginine (ADMA)—In vivo and in vitro evidence of significant protein binding. Clin Nephrol 2004; 62:295-300.
579. Zager PG, Nikolic J, Brown RH, et al: U-Curve association of blood pressure and mortality in hemodialysis patients. Kidney Int 1998; 54:561-569.
580. Leypoldt JK, Cheung AK, Delmez JA, et al: Relationship between volume status and blood pressure during chronic hemodialysis. Kidney Int 2002; 61:266-275.
581. Safar ME, Blacher J, Pannier B, et al: Central pulse pressure and mortality in end-stage renal disease. Hypertension 2002; 39:735-738.
582. Blacher J, Guerin AP, Pannier B, et al: Impact of aortic stiffness on survival in end-stage renal disease. Circulation 1999; 99:2434-2439.
583. London GM: Role of arterial wall properties in the pathogenesis of systolic hypertension. Am J Hypertens 2005; 18:19S-22S.
584. London GM, Guerin AP, Pannier B, et al: Large artery structure and function in hypertension and end-stage renal disease. J Hypertens 1998; 16:1931-1938.
585. First M, Neylan J, Rocher L, Tejani A: Hypertension after renal transplantation. J Am Soc Nephrol 1994; 4:S30-S36.
586. Curtis JJ, Luke RG, Diethelm AG, et al: Benefits of removal of native kidneys in hypertension after renal transplantation. Lancet 1985; 2:739-742.
587. Curtis JJ, Luke RG, Jones P, et al: Hypertension after successful renal transplantation. Am J Med 1985; 79:193-200.
588. Linas SL, Miller PD, McDonald KM, et al: Role of the renin-angiotensin system in post-transplantation hypertension in patients with multiple kidneys. N Engl J Med 1978; 298:1440-1444.
589. Curtis JJ: Hypertension in cyclosporine-treated renal transplant recipients is sodium dependent. Am J Med 1988; 85:134-138.
590. Bantle J, Nath KA, Sutherlan DER, et al: Effects of cyclosporine on the renin-angiotensin-aldosterone system and potassium excretion in renal transplant recipients. Arch Intern Med 1985; 145:505-508.
591. van der Schaaf MR, Hene RJ, Floor M, et al: Hypertension after renal transplantation. Calcium channel or converting enzyme blockade?. Hypertension 1995; 25:77-81.
592. Inigo P, Campistol JM, Lario S, et al: Effects of losartan and amlodipine on intrarenal hemodynamics and TGF-beta(1) plasma levels in a crossover trial in renal transplant recipients. J Am Soc Nephrol 2001; 12:822-827.
593. Luke RG, Curtis JJ: Biology and treatment of transplant hypertension. In: Laragh JH, Brenner BM, ed. Hypertension: Pathophysiology, Diagnosis and Management, Vol 2. New York: Raven Press; 1995:2471-2483.
594. Moss N, Powell S, Falk R: Intravenous cyclosporine activates afferent and efferent renal nerves and causes sodium retention in innervated kidneys in rats. Proc Natl Acad Sci U S A 1985; 82:8222-8226.
595. Zhang W, Victor RG: Calcineurin inhibitors cause renal afferent activation in rats: A novel mechanism of cyclosporine-induced hypertension. Am J Hypertens 2000; 13:999-1004.
596. Hausberg M, Kosch M, Harmelink P, et al: Sympathetic nerve activity in end-stage renal disease. Circulation 2002; 106:1974-1979.
597. Zhang W, Li JL, Hosaka M, et al: Cyclosporine A-induced hypertension involves synapsin in renal sensory nerve endings. Proc Natl Acad Sci U S A 2000; 97:9765-9770.
598. Perico N, Ruggenenti P, Gaspari F, et al: Daily renal hypoperfusion induced by cyclosporine in patients with renal transplantation. Transplantation 1992; 54:56-60.
599. Kon V, Sugiura M, Inagami T, et al: Role of endothelin in cyclosporine-induced glomerular dysfunction. Kidney Int 1990; 37:1487-1491.
600. Lanese D, Conger J: Effects of endothelin receptor antagonist on cyclosporine-induced vasoconstriction in isolated rat renal arterioles. J Clin Invest 1993; 91:2144-2149.
601. Ruggenenti P, Perico N, Mosconi L, et al: Calcium channel blockers protect transplant patients from cyclosporine-induced daily renal hypoperfusion. Kidney Int 1993; 43:706-711.
602. Myers BD, Newton L: Cyclosporine-induced chronic nephropathy: An obliterative microvascular renal injury. J Am Soc Nephrol 1991; 2:S45-S52.
603. van den Dorpel MA, Zietse R, Ijzermans JN, Weimar W: Prophylactic isradipine treatment after kidney transplantation: A prospective double-blind placebo-controlled randomized trial. Transpl Int 1994; 7(suppl 1):S270-S274.
604. van den Dorpel MA, Zietse R, Ijzermans JN, et al: Effect of isradipine on cyclosporin A-related hypertension. Blood Press Suppl 1994; 1:50-53.
605. Madsen JK, Sorensen SS, Hansen HE, Pedersen EB: The effect of felodipine on renal function and blood pressure in cyclosporin-treated renal transplant recipients during the first three months after transplantation. Nephrol Dial Transplant 1998; 13:2327-2334.
606. Madsen JK, Zachariae H, Pedersen EB: Effects of the calcium antagonist felodipine on renal haemodynamics, tubular sodium handling, and blood pressure in cyclosporin-treated dermatological patients. Nephrol Dial Transplant 1997; 12:480-484.
607. Suthanthiran M, Haschemeyer RH, Riggio RR, et al: Excellent outcome with a calcium channel blocker-supplemented immunosuppressive regimen in cadaveric renal transplantation. A potential strategy to avoid antibody induction protocols. Transplantation 1993; 55:1008-1013.
608. Rodicio JL, Morales JM, Ruilope LM: Lipophilic dihydropyridines provide renal protection from cyclosporin toxicity. J Hypertens Suppl 1993; 11:S21-S25.
609. Pollock DM, Jenkins JM, Cook AK, et al: L-Type calcium channels in the renal microcirculatory response to endothelin. Am J Physiol Renal Physiol 2005; 288:F771-F777.
610. Morales JM: Influence of the new immunosuppressive combinations on arterial hypertension after renal transplantation. Kidney Int Suppl 2002; 82:81-87.
611. Margreiter R: Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: A randomised multicentre study. Lancet 2002; 359:741-746.
612. Vincenti F, Jensik SC, Filo RS, et al: A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: Evidence for improved allograft survival at five years. Transplantation 2002; 73:775-782.
613. Kramer BK, Zulke C, Kammerl MC, et al: Cardiovascular risk factors and estimated risk for CAD in a randomized trial comparing calcineurin inhibitors in renal transplantation. Am J Transplant 2003; 3:982-987.
614. Ligtenberg G, Hene RJ, Blankestijn PJ, Koomans HA: Cardiovascular risk factors in renal transplant patients: Cyclosporin A versus tacrolimus. J Am Soc Nephrol 2001; 12:368-373.
615. First MR: Tacrolimus based immunosuppression. J Nephrol 2004; 17(suppl 8):S25-S31.
616. Jardine AG: Assessing the relative risk of cardiovascular disease among renal transplant patients receiving tacrolimus or cyclosporine. Transpl Int 2005; 18:379-384.
617. Chapman JR, O'Connell PJ, Nankivell BJ: Chronic renal allograft dysfunction. J Am Soc Nephrol 2005; 16:3015-3026.
618. Kahan BD: Sirolimus-based immunosuppression: Present state of the art. J Nephrol 2004; 17(suppl 8):S32-S39.
619. Oberbauer R, Segoloni G, Campistol JM, et al: Early cyclosporine withdrawal from a sirolimus-based regimen results in better renal allograft survival and renal function at 48 months after transplantation. Transpl Int 2005; 18:22-28.
620. Morales JM: Cardiovascular risk profile in patients treated with sirolimus after renal transplantation. Kidney Int Suppl 2005; 23:S69-S73.
621. Morales JM, Campistol JM, Kreis H, et al: Sirolimus-based therapy with or without cyclosporine: Long-term follow-up in renal transplant patients. Transplant Proc 2005; 37:693-696.
622. Veenstra DL, Best JH, Hornberger J, et al: Incidence and long-term cost of steroid-related side effects after renal transplantation. Am J Kidney Dis 1999; 33:829-839.
623. Woodle ES, Vincenti F, Lorber MI, et al: A multicenter pilot study of early (4-day) steroid cessation in renal transplant recipients under simulect, tacrolimus and sirolimus. Am J Transplant 2005; 5:157-166.
624. Rostaing L, Cantarovich D, Mourad G, et al: Corticosteroid-free immunosuppression with tacrolimus, mycophenolate mofetil, and daclizumab induction in renal transplantation. Transplantation 2005; 79:807-814.
625. ter Meulen CG, van Riemsdijk I, Hene RJ, et al: Steroid-withdrawal at 3 days after renal transplantation with anti-IL-2 receptor alpha therapy: A prospective, randomized, multicenter study. Am J Transplant 2004; 4:803-810.
626. Vanrenterghem Y, Lebranchu Y, Hene R, et al: Double-blind comparison of two corticosteroid regimens plus mycophenolate mofetil and cyclosporine for prevention of acute renal allograft rejection. Transplantation 2000; 70:1352-1359.
627. Bruno S, Remuzzi G, Ruggenenti P: Transplant renal artery stenosis. J Am Soc Nephrol 2004; 15:134-141.
628. Beecroft JR, Rajan DK, Clark TW, et al: Transplant renal artery stenosis: Outcome after percutaneous intervention. J Vasc Interv Radiol 2004; 15:1407-1413.
629. Goel MC, LaPerna L, Whitelaw S, et al: Current management of transplant renal artery stenosis: Clinical utility of duplex Doppler ultrasonography. Urology 2005; 66:59-64.
630. Voiculescu A, Hollenbeck M, Plum J, et al: Iliac artery stenosis proximal to a kidney transplant: Clinical findings, duplex-sonographic criteria, treatment, and outcome. Transplantation 2003; 76:332-339.
631. Fervenza FC, Lafayette RA, Alfrey EJ, Petersen J: Renal artery stenosis in kidney transplants. Am J Kidney Dis 1998; 31:142-148.
632. Shames BD, Odorico JS, D'Alessandro AM, et al: Surgical repair of transplant renal artery stenosis with preserved cadaveric iliac artery grafts. Ann Surg 2003; 237:116-122.
633. Chua GC, Snowden S, Patel U: Kinks of the transplant renal artery without accompanying intraarterial pressure gradient do not require correction: Five-year outcome study. Cardiovasc Intervent Radiol 2004; 27:643-650.
634. Pouria S, State OI, Wong W, Hendry BM: CMV infection is associated with transplant renal artery stenosis. QJM 1998; 91:185-189.
635. Wong W, Fynn SP, Higgins RM, et al: Transplant renal artery stenosis in 77 patients—Does it have an immunological cause?. Transplantation 1996; 61:215-219.
636. Fateh-Moghadam S, Bocksch W, Wessely R, et al: Cytomegalovirus infection status predicts progression of heart-transplant vasculopathy. Transplantation 2003; 76:1470-1474.
637. Valentine H: The role of viruses in cardiac allograft vasculopathy. Am J Transplant 2004; 4:169-177.
638. Ducloux D, Deschamps M, Yannaraki M, et al: Relevance of toll-like receptor-4 polymorphisms in renal transplantation. Kidney Int 2005; 67:2454-2461.
639. Riehl J, Schmitt H, Bongartz D, et al: Renal artery stenosis: Evaluation with colour duplex ultrasonography. Nephrol Dial Transplant 1997; 12:1608-1614.
640. Radermacher J, Chavan A, Schaffer J, et al: Detection of significant renal artery stenosis with color Doppler sonography: Combining extrarenal and intrarenal approaches to minimize technical failure. Clin Nephrol 2000; 53:333-343.
641. Zhang H, Prince MR: Renal MR angiography. Magn Reson Imaging Clin N Am 2004; 12:487-503.vi
642. Rusinek H, Kaur M, Lee VS: Renal magnetic resonance imaging. Curr Opin Nephrol Hypertens 2004; 13:667-673.
643. Bokhari SW, Wen YH, Winters RJ: Gadolinium-based percutaneous coronary intervention in a patient with renal insufficiency. Catheter Cardiovasc Interv 2003; 58:358-361.
644. Sam 2nd AD, Morasch MD, Collins J, et al: Safety of gadolinium contrast angiography in patients with chronic renal insufficiency. J Vasc Surg 2003; 38:313-318.
645. Erley CM, Bader BD, Berger ED, et al: Gadolinium-based contrast media compared with iodinated media for digital subtraction angiography in azotaemic patients. Nephrol Dial Transplant 2004; 19:2526-2531.
645a. Perazella MA, Rodby RA: Gadolinium use in patients with kidney disease. Semin Dial 2007; 20:179-185.
646. Spinosa DJ, Isaacs RB, Matsumoto AH, et al: Angiographic evaluation and treatment of transplant renal artery stenosis. Curr Opin Urol 2001; 11:197-205.
647. Greenstein SM, Verstandig A, McLean GK, et al: Percutaneous transluminal angioplasty. The procedure of choice in the hypertensive renal allograft recipient with renal artery stenosis. Transplantation 1987; 43:29-32.
648. Sankari BR, Geisinger M, Zelch M, et al: Post-transplant renal artery stenosis: Impact of therapy on long-term kidney function and blood pressure control. J Urol 1996; 155:1860-1864.
649. Salvadori M, Di Maria L, Rosati A, et al: Efficacy and safety of Palmaz stent implantation in the treatment of renal artery stenosis in renal transplantation. Transplant Proc 2005; 37:1047-1048.
650. Fervenza F, Lafayette R, Alfrey E, Peterson J: Renal artery stenosis in kidney transplants. Am J Kidney Dis 1998; 31:142-148.
651. Guidi E, Menghetti D, Milani S, et al: Hypertension may be transplanted with the kidney in human: A long-term historical prospective follow-up of recipients grafted with kidneys coming from donors with or without hypertension in their families. J Am Soc Nephrol 1996; 7:1131-1138.
652. Rettig R, Grisk O: The kidney as a determinant of genetic hypertension: Evidence from renal transplantation studies. Hypertension 2005; 46:463-468.
653. Brenner B: In renal transplantation, one size may not fit all. J Am Soc Nephrol 1992; 3:162-169.
654. Fulladosa X, Moreso F, Narvaez JA, et al: Estimation of total glomerular number in stable renal transplants. J Am Soc Nephrol 2003; 14:2662-2668.
655. Laragh JH: Renin system understanding for analysis and treatment of hypertensive patients: A means to quantify the vasoconstrictor elements, diagnose curable renal and adrenal causes, assess risk of cadiovascular morbidity, and find the best fit drug. In: Laragh JH, Brenner BM, ed. Hypertension: Pathophysiology, Diagnosis, and Management, Vol 2. New York: Raven Press; 1995:1813-1836.
656. Laragh JH: The renin system in high blood pressure, from disbelief to reality: Converting-enzyme blockade for analysis and treatment. Prog Cardiovasc Dis 1978; 21:159-166.
657. Resnick LM, Nicholson JP, Laragh JH: Calcium, the renin-aldosterone system, and the hypotensive response to nifedipine. Hypertension 1987; 10:254-258.
658. Vaughan Jr ED, Laragh JH, Gavras I, et al: Volume factor in low and normal renin essential hypertension. Treatment with either spironolactone or chlorthalidone. Am J Cardiol 1973; 32:523-532.
659. Case DB, Wallace JM, Keim HJ, et al: Estimating renin participation in hypertension: Superiority of converting enzyme inhibitor over saralasin. Am J Med 1976; 61:790-796.
660. Case DB, Atlas SA, Laragh JH, et al: Use of first-dose response or plasma renin activity to predict the long-term effect of captopril: Identification of triphasic pattern of blood pressure response. J Cardiovasc Pharmacol 1980; 2:246-339.
661. Gavras H, Brunner HR, Laragh JH, et al: An angiotensin converting-enzyme inhibitor to identify and treat vasoconstrictor and volume factors in hypertensive patients. N Engl J Med 1974; 291:817-821.
662. Case DB, Wallace JM, Keim HJ, et al: Possible role of renin in hypertension as suggested by renin-sodium profiling and inhibition of converting enzyme. N Engl J Med 1977; 296:641-646.
663. Blumenfeld JD, Laragh JH: Renin system analysis: A rational method for the diagnosis and treatment of the individual patient with hypertension. Am J Hypertens 1998; 11:894-896.
664. Anderson G, Blakeman N, Streeten D: Prediction of renovascular hypertension. Am J Hypertens 1988; 1:301-304.
665. Bulpitt CJ, Dollery CT, Carne S: Change in symptoms of hypertensive patients after referral to hospital clinic. Br Heart J 1976; 38:121-128.
666. Muiesan ML, Padovani A, Salvetti M, et al: Headache: Prevalence and relationship with office or ambulatory blood pressure in a general population sample (the Vobarno Study). Blood Press 2006; 15:14-19.
667. Messerli FH, Ventura HO, Elizardi DJ, et al: Hypertension and sudden death. Increased ventricular ectopic activity in left ventricular hypertrophy. Am J Med 1984; 77:18-22.
668. McLenachan JM, Henderson E, Morris KI, Dargie HJ: Ventricular arrhythmias in patients with hypertensive left ventricular hypertrophy. N Engl J Med 1987; 317:787-792.
669. Corvol P, Pinet E, Plouin P: Primary reninism. In: Laragh JH, Brenner BM, ed. Hypertension: Pathophysiology, Diagnosis, and Management, Vol 2. New York: Raven Press; 1995:2069-2080.
670. Bulpitt CJ: How many alcoholic drinks might benefit an older person with hypertension?. J Hypertens 2005; 23:1947-1951.
671. Tobe SW, Soberman H, Kiss A, et al: The effect of alcohol and gender on ambulatory blood pressure: Results from the Baseline Double Exposure study. Am J Hypertens 2006; 19:136-139.
672. Groppelli A, Giorgi DM, Omboni S, et al: Persistent blood pressure increase induced by heavy smoking. J Hypertens 1992; 10:495-499.
673. Lemogoum D, Van Bortel L, Leeman M, et al: Ethnic differences in arterial stiffness and wave reflections after cigarette smoking. J Hypertens 2006; 24:683-689.
674. Kokkinos P, Pittaras A, Manolis A, et al: Exercise capacity and 24-h blood pressure in prehypertensive men and women. Am J Hypertens 2006; 19:251-258.
675. Ishikawa-Takata K, Ohta T, Tanaka H: How much exercise is required to reduce blood pressure in essential hypertensives? A dose-response study. Am J Hypertens 2003; 16:629-633.
676. Tobe SW, Kiss A, Szalai JP, et al: Impact of job and marital strain on ambulatory blood pressure results from the double exposure study. Am J Hypertens 2005; 18:1046-1051.
677. Cushman WC, Cooper KM, Horne RA, Meydrech EF: Effect of back support and stethoscope head on seated blood pressure determinations. Am J Hypertens 1990; 3:240-241.
678. Hunyor SN, Flynn JM, Cochineas C: Comparison of performance of various sphygmomanometers with intra-arterial blood-pressure readings. BMJ 1978; 2:159-162.
679. Marks LA, Groch A: Optimizing cuff width for noninvasive measurement of blood pressure. Blood Press Monit 2000; 5:153-158.
680. Wong TY, Klein R, Sharrett AR, et al: Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA 2002; 288:67-74.
681. Hankey GJ, Norman PE, Eikelboom JW: Medical treatment of peripheral arterial disease. JAMA 2006; 295:547-553.
682. Fishbane S, Youn S, Flaster E, et al: Ankle-arm blood pressure index as a predictor of mortality in hemodialysis patients. Am J Kidney Dis 1996; 27:668-672.
683. Hamlet SM, Tunny TJ, Woodland E, Gordon RD: Is aldosterone/renin ratio useful to screen a hypertensive population for primary aldosteronism?. Clin Exp Pharmacol Physiol 1985; 12:249-252.
684. Rayner BL, Goodman H, Opie LH: The chest radiograph. A useful investigation in the evaluation of hypertensive patients. Am J Hypertens 2004; 17:507-510.
685. Suarez C, Villar J, Martel N, et al: Should we perform an echocardiogram in hypertensive patients classified as having low and medium risk?. Int J Cardiol 2006; 106:41-46.
686. Verdecchia P, Schillaci G, Reboldi G, et al: Different prognostic impact of 24-hour mean blood pressure and pulse pressure on stroke and coronary artery disease in essential hypertension. Circulation 2001; 103:2579-2584.
687. Stergiou GS, Efstathiou SP, Argyraki CK, et al: White coat effect in treated versus untreated hypertensive individuals: A case-control study using ambulatory and home blood pressure monitoring. Am J Hypertens 2004; 17:124-128.
688. Bloch MJ, Trost DA, Whitmer J, et al: Ostial renal artery stent placement in patients 75 years of age or older. Am J Hypertens 2001; 14:983-988.
689. Scoble JE, Maher ER, Hamilton G, et al: Atherosclerotic renovascular disease causing renal impairment—A case for treatment. Clin Nephrol 1989; 31:119-122.
690. Mailloux LU, Napolitano B, Bellucci AG, et al: Renal vascular disease causing end-stage renal disease, incidence, clinical correlates and outcomes: A 20-year clinical experience. Am J Kidney Dis 1994; 24:662-669.
691. Vaughan Jr ED, Buhler FR, Laragh JH, et al: Renovascular hypertension: Renin measurements to indicate hypersecretion and contralateral suppression, estimate renal plasma flow, and score for surgical curability. Am J Med 1973; 55:402-414.
692. Freis ED: Improving treatment effectiveness in hypertension. Arch Intern Med 1999; 159:2517-2521.
693. Laragh J: Laragh's lessons in pathophysiology and clinical pearls for treating hypertension. Lesson XVI: How to choose the correct drug treatment for each hypertensive patient using a plasma renin-based method and the volume-vasoconstriction analysis. Am J Hypertens 2001; 14:491-503.
694. Preston RA, Materson BJ, Reda DJ, et al: Age-race subgroup compared with renin profile as predictors of blood pressure response to antihypertensive therapy. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. JAMA 1998; 280:1168-1172.
695. Knight EL, Bohn RL, Wang PS, et al: Predictors of uncontrolled hypertension in ambulatory patients. Hypertension 2001; 38:809-814.
696. Savage DD, Devereux RB, Laragh JH: Hypertrophic cardiomyopathy. Letter. N Engl J Med 1979; 301:442.
697. Schillinger D, Piette J, Grumbach K, et al: Closing the loop: Physician communication with diabetic patients who have low health literacy. Arch Intern Med 2003; 163:83-90.
698. Mitchell J, Mathews HF, Hunt LM, et al: Mismanaging prescription medications among rural elders: The effects of socioeconomic status, health status, and medication profile indicators. Gerontologist 2001; 41:348-356.
699. Ahluwalia JS, McNagny SE, Rask KJ: Correlates of controlled hypertension in indigent, inner-city hypertensive patients. J Gen Intern Med 1997; 12:7-14.
700. Midgley JP, Matthew AG, Greenwood CM, Logan AG: Effect of reduced dietary sodium on blood pressure: A meta-analysis of randomized controlled trials. JAMA 1996; 275:1590-1597.
701. Pickering TG: Lifestyle modification and blood pressure control: Is the glass half full or half empty?. JAMA 2003; 289:2131-2132.
702. Appel LJ, Champagne CM, Harsha DW, et al: Effects of comprehensive lifestyle modification on blood pressure control: Main results of the PREMIER clinical trial. JAMA 2003; 289:2083-2093.
702a. Himmelfarb J: Chronic kidney disease and the public health: Gaps in evidence from intervention trials. JAMA 2007; 297:2630-2639.
703. Laverman GD, Navis G, Henning RH, et al: Dual renin-angiotensin system blockade at optimal doses for proteinuria. Kidney Int 2002; 62:1020-1025.
704. Nielsen S, Dollerup J, Nielsen B, et al: Losartan reduces albuminuria in patients with essential hypertension. An enalapril controlled 3 months study. Nephrol Dial Transplant 1997; 12(suppl 2):19-23.
705. Agodoa LY, Appel L, Bakris GL, et al: Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: A randomized controlled trial. JAMA 2001; 285:2719-2728.
706. Blumenfeld J: JNC-7 versus renin-based strategies for optimal antihypertensive drug treatment. Another look at the evidence. Am J Hypertens 2004; 17:1002-1004.
707. Dahlof B, Lindholm LH, Hansson L, et al: Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991; 338:1281-1285.
708. Black HR, Elliott WJ, Grandits G, et al: Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA 2003; 289:2073-2082.
709. Hansson L, Zanchetti A, Carruthers SG, et al: Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998; 351:1755-1762.
710. Alderman MH: ALLHAT and beyond. Am J Hypertens 2003; 16:512-514.
711. Laragh J, Sealey J: Relevance of the plasma renin hormonal control system that regulates blood pressure and sodium balance correctly treating hypertension and evaluating ALLHAT. Am J Hypertens 2003; 16:407-415.
712. Messerli FH: ALLHAT, or the soft science of the secondary end point. Ann Intern Med 2003; 139:777-780.
