Brenner and Rector's The Kidney, 8th ed.

CHAPTER 48. Cardiovascular Aspects of Chronic Kidney Disease

Lawrence P. McMahon Patrick S. Parfrey

Introduction and Background, 1697

Cardiovascular Disease, 1697

Cardiovascular Disease and Stage of Chronic Kidney Disease, 1697

Pathology and Pathophysiology, 1699

Cardiac Disease, 1699

Vascular Disease, 1706

Epidemiology and Cardiac Risk Factors, 1707

Overview, 1707

Chronic Kidney Disease as an Independent Cardiac Risk Factor, 1708

Traditional Risk Factors, 1709

Management, 1712

Diagnosis, 1712

Treatment, 1715

Multiple Risk Factor Intervention, 1721

Summary, 1721

INTRODUCTION AND BACKGROUND

Cardiovascular Disease

Cardiovascular disease is the main cause of death for patients with chronic kidney disease (CKD). In a 5% sample of the United States Medicare population in 1998 and 1999, Foley and colleagues found that CKD (defined by clinical events) was associated with a substantially increased incidence of congestive heart failure and of atherosclerotic vascular disease events, in both diabetics and nondiabetics.[1] In dialysis patients, the cardiac death rate is reported as being between 104 and 157 per 1000 patient years, with heart disease accounting for 40% to 45% of all deaths worldwide, with similar proportions evident in transplant patients. [1] [2] [3] [4] Compared to the general population the annual cardiovascular death rate in dialysis patients is higher for all age groups, though particularly for the young whose mortality is up to 100 times greater than the general population ( Fig. 48-1 ).[5] Indices of morbidity are also high. The probability of having a myocardial infarction or angina requiring hospitalization in hemodialysis patients is 10% per year,[6] and such patients have a 5-year mortality of up to 90%. There is a similar probability of developing pulmonary edema, requiring hospitalization or additional ultrafiltration. Evidence of disease however may present well before the onset of dialysis[7] with approximately 35% of patients demonstrating clinical manifestations of heart failure by the time they require dialysis. [8] [9]

FIGURE 48-1 Annual cardiovascular disease mortality for patients undergoing dialysis, by age, gender, and race, compared with the general population (GP). ESRD, end-stage renal disease. (From Foley RN, Parfrey PS, Sarnak M: The clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 32 (suppl):S112–S115, 1998, with permission.)

Most clinical consequences of cardiac disease result from cardiomyopathy or ischemic heart disease. Cardiomyopathy may present as an enlarged, dilated left ventricle (LV) with or without systolic dysfunction, or as a hypertrophic ventricle with normal left ventricular volume and diastolic dysfunction.[10] Myocardial ischemia may also be present ( Fig. 48-2 ). Although symptoms of ischemic heart disease are most often attributable to the presence of critical coronary artery disease (defined as the presence of critical narrowing of the large coronary vessels due to atherosclerotic plaques), they may also result from non-atherosclerotic disease, associated with small vessel disease and LV hypertrophy. Myocardial infarction and angina can result from decreased perfusion of the myocardium from either cause. It has also become evident that the structure of large arteries can be altered not only by atherogenesis, but also by arteriosclerosis.[11] Intramural vascular remodeling occurs as a consequence of sustained hemodynamic overload causing conduit vessel dilatation and hypertrophy. The consequent increase in vessel stiffness and decreased compliance has been shown to contribute adversely to LV structure and function, and are strongly associated with an increased risk of mortality.[12]

FIGURE 48-2 Cause of cardiac death in patients with chronic kidney disease. LV, left ventricular.

The relative contribution of each of these disorders to cardiac dysfunction in CKD varies from patient to patient. However, in each patient there is a persistent and complex interplay of destructive vascular events and myocyte dysfunction, which if unrecognized, ultimately results in cardiac failure and death (see Fig. 48-2 ). Ischemic symptoms result from coronary artery disease or non-atherosclerotic ischemic disease. Arteriosclerosis contributes directly to ischemic symptoms, LV hypertrophy, and systolic dysfunction by increasing cardiac workload. Coronary artery disease predisposes to diastolic dysfunction and to systolic failure. Left ventricular hypertrophy is nearly always present in dilated cardiomyopathy, but also causes diastolic dysfunction with or without normal systolic function.

Cardiac disease can also result from the development of valvular heart disease. Most valvular lesions observed in patients with CKD are acquired and develop from dystrophic calcifications of the valvular annulus and leaflets, particularly the aortic and mitral valves. Such calcification is now known to be present far more frequently than previously recognized with a prevalence of up to 55% and 39% for the aortic and mitral valves respectively. [13] [14]Once considered benign, aortic valve sclerosis is now also associated with an increased cardiovascular mortality in the general community.[15] In CKD, it is part of the spectrum of valvular disease and may sometimes evolve rapidly to hemodynamically significant stenosis.

Cardiovascular Disease and Stage of Chronic Kidney Disease

Presentation with cardiovascular disease is influenced by the duration, severity, and type of renal disease. Left ventricular hypertrophy is already evident in 40% of patients with moderate renal insufficiency[16] and as high as 75% of those commencing dialysis.[7] Both forms (concentric and eccentric) are associated with an increased mortality risk in dialysis patients and associated risk factors, including hypertension, diabetes, tobacco use, and anemia predispose to the much more rapid development of symptomatic cardiomyopathy.[17] Such patients display a higher incidence of cardiovascular abnormalities at an earlier stage of CKD and a younger age, often becoming symptomatic or exhibiting significant morbidity well before reaching end-stage kidney function.

By the time of starting dialysis only a minority of patients has a normal echocardiogram and some (15% in one study) even display systolic dysfunction.[7] The characteristic changes in LV geometry subsequently are a progressive increase over time in both LV volume and LV mass, particularly during the first years,[17] and possibly more so in patients on peritoneal dialysis. [18] [19] As a result the geometry of the heart changes from concentric LV hypertrophy with normal LV volume to eccentric LV hypertrophy with dilatation, the end stage of this resulting in severe LV dilatation with systolic dysfunction (see Fig. 48-3B ). Eventually, LV growth and a decrease in myocardial contractility each contribute to the development of elevated LV pressures for a given volume, thus predisposing to symptomatic heart failure.[20]

FIGURE 48-3 A, Morphology of ventricular myocytes in cardiac hypertrophy and failure. Concentric left ventricular hypertrophy (LVH) occurs in response to LV pressure overload, and eccentric LV hypertrophy in response to LV volume overload. Sarcomeric disorganization and apoptosis are additional characteristics of hypertrophic cardiomyopathies. (From Hunter JJ, Chien KR: Signaling pathways for cardiac hypertrophy and failure. N Engl J Med 341:1276, 1999, with permission.) B, Patterns of LV growth. An increase in LV mass index beyond gender-specific limits (i.e., f, female; m, male) is, by definition, LV hypertrophy (right panels). An increase in relative LV wall thickness (diastolic LV posterior wall and septal thickness divided by LV end-diastolic diameter) beyond a ratio of 0.45 is called concentric remodeling or hypertrophy (upper panels). An increase in LV mass despite normal relative wall thickness is called eccentric LV hypertrophy. The arrows indicate the most frequent pathophysiologic mechanisms. (From Schunkert H, Hense HW: A heart price to pay for anaemia. Nephrol Dial Transplant 16:445–448, 2001, with permission.)

Transplant patients historically have been selected as suitable candidates from the dialysis population by being relatively free from significant symptomatic cardiac disease. Although mortality rates are lower than for dialysis patients they are still substantially higher than in the community, and cardiovascular disease remains the predominant cause of death.[3] There is evidence that systolic dysfunction, LV dilatation, and concentric hypertrophy improve after renal transplantation[21] and that further regression continues following the first year if hypertension is controlled.[22] Nonetheless transplant patients remain subject to a wide variety of harmful influences after transplantation, particularly diabetes, hypertension, and dyslipidemia. In addition, the vascular changes induced by past renal disease are not nullified after transplantation, which is complicated further by the inexorable deterioration in renal function over time in most transplant patients.

The now well-established staging of CKD by the Kidney Disease Outcomes Quality initiative (K/DOQI) working party[23] is a clear and simple guide in assessing renal dysfunction. Although the staging of dialysis and transplant patients is clear, many studies have historically not addressed the level of renal dysfunction in pre-dialysis patients with precision. The influence of cardiovascular disease in patients with CKD is manifest early and increases as renal function declines, but the evidence for the stage at which this occurs is not well defined. It is for this reason that the current chapter approaches studies under the more simplistic categories of pre-dialysis, dialysis, and transplantation.

PATHOLOGY AND PATHOPHYSIOLOGY

Cardiac Disease

Left Ventricular Hypertrophy

Pathophysiology

Left ventricular (LV) hypertrophy is an adaptive process occurring in response to a long-term increase in myocardial work caused by LV pressure or volume overload, and results from the interaction between mechanical stimuli, locally generated growth factors, and vasoactive substances. The work performed by the heart in each cardiac cycle (stroke work) is the product of LV pressure and stroke volume. The heart rate multiplied by stroke work is the total work per minute performed by the heart. As stroke work increases, myocardial energy expenditure and oxygen consumption increase proportionately. According to the law of Laplace, left ventricular tensile wall stress (s) relates directly to the intraventricular pressure (P) generated, as well as the internal radius (r) of the ventricular cavity. It is inversely proportional to the ventricular wall thickness (q) so that s = Pr/2q. Thus the wall tension at any given pressure increases with the radius, and vice versa. Physiologically, following a sustained increase in pressure and cavity volume (or both) there is a reactionary increase in wall thickness that reduces the systolic tension (and hence oxygen consumption), which must be developed by each myocyte. It is this wall remodeling that results in LV hypertrophy. Biomechanical stress (such as that exerted by pressure and volume overload) has been found to be a powerful inducer of LV growth through the expression of embryonic and proto oncogenes encoding growth factors and growth factor receptors. [24] [25] Intriguingly, it also appears a common biochemical pathway is responsible for the development of both compensatory hypertrophy and apoptosis.[26]

The initial effects of LV hypertrophy are beneficial. As indicated earlier, the energy-sparing effects of a stable parietal tensile stress permits the generation of higher intraventricular pressures without a large increase in wall stress. Such changes can be observed physiologically; for instance, cardiac hypertrophy is a normal response during late pregnancy, after prolonged training in athletes and with normal growth from infancy to adulthood. In each of these cases, an appropriate relationship is maintained between the r/q ratio and systolic pressure generated, so that the intrinsic performance of the myocardium is not altered. Initially hypertrophic responses to chronic pressure and/or volume overload are also adaptive. Modifications in the heart structure result in an increased work capacity while keeping the parietal tensile stress stable, thus sparing energy.[27]

Eventually however LV hypertrophy becomes maladaptive with a sustained imbalance between energy expenditure and production, resulting in a chronic energy deficit and myocyte death. [25] [28] The pathogenesis of a reduced energy deficit is complex and appears related to a number of factors including diminished myocardial capillary density,[29] decreased coronary reserve with reduced subendocardial perfusion,[30] and increased stiffness of the aorta and major conduit arteries.[31] Within the myocardium, over-stretching of papillary muscles is coupled with oxidant stress, apoptosis, architectural rearrangement of myocytes, and impairment in force development of the myocardium.[32] There is evidence recently also that abnormal expression of proto oncogenes promotes the development of, particularly, fibroblasts with an increase in extracellular collagen matrix and hence the development of myocardial fibrosis. [25] [33] Consequences of these alterations are electrophysiological abnormalities and maintenance of systolic efficiency at the expense of impaired diastolic filling. Arrhythmias are caused partly by conduction aberrations secondary to fibrosis and by prolongation of the action potential from a slower reuptake of calcium by the sarcoplasmic reticulum. The latter, together with fibrotic change and increased LV wall stiffness, contribute substantially to abnormal diastolic function. Eventually, in conditions of chronic and sustained overload, the deleterious effects of hypertrophy, increased LV chamber pressure and fibrosis dominate, leading to the development of cardiomyopathy and LV failure.[25]

Clinico-Pathological Features

At autopsy, the hearts of dialysis patients are frequently enlarged with grossly thickened walls and often a markedly dilated LV cavity. Light microscopic examination of the myocardium reveals hypertrophy of the myocytes and hyperplasia of the non-myocytic components.[34] The coronary arteries are also enlarged and thickened with evidence of atheromatous plaques and intramural calcification. These features represent the end-stage of injurious and persistent forces evident throughout the period of CKD.

The pathophysiological process underlying dilated cardiomyopathy in hemodialysis has been explored by a Japanese group who performed endomyocardial biopsies in 40 hemodialysis patients with dilated cardiomyopathy, and compared them with biopsies in 50 non-dialysis patients with idiopathic dilated cardiomyopathy.[14] Although the degree of myocyte disarray was similar in both groups, those on hemodialysis had a substantially greater mean myocyte diameter across the nucleus, consistent with the dilated phase of LV hypertrophy.

The myocardial changes relate primarily to an attempt by the contracting myocytes to respond and adapt to the excessive pressure and volume loads resulting in hypertrophy ( Fig. 48-3A ). Because myocytes are unable to replicate, they hypertrophy by producing more sarcomeres, which are deposited within the myocyte either in parallel in concentric hypertrophy, or in series in eccentric hypertrophy.[26]

The principal factors comprising pressure and volume overload in patients with CKD are known collectively as hemodynamic risk factors. Pressure overload results from a sustained increase in LV afterload, as occurs in hypertension, arteriosclerosis, and aortic stenosis. Volume overload results from increased extracellular volume, anemia, and arteriovenous fistulas. Factors are rarely discrete however and one will often contribute to the effects of the other. An increase in extracellular volume, for instance, will result not only in an increased volume load on the LV but will also exacerbate underlying hypertension and contribute to reduced arterial compliance, each with subsequent effects on LV morphology ( Fig. 48-3B ).

Concentric hypertrophy is considered an adaptive mechanism to chronic LV pressure overload. The parallel addition of new sarcomeres produces an increase in myocyte thickness. The increased LV mass is associated with increased thickness of both the interventricular septum and the LV free (or “posterior”) wall. The volume of the ventricle remains normal so that, relative to the LV end-diastolic diameter, wall thickness is increased. Eccentric hypertrophy is an adaptive mechanism to states of chronic volume overload in which LV end-diastolic pressure tends to normalize at the expense of increased end-diastolic volume. Left ventricular volume overload induces addition of new sarcomeres mainly in series and myocytes grow longer. The increased LV mass is associated with an increased LV volume and some increase in LV posterior wall thickness (PWT); although the LV end-diastolic diameter to PWT ratio is lower than in concentric hypertrophy. Asymmetric hypertrophy is a variant of concentric hypertrophy whereby the septal wall is disproportionately thickened in relation to the posterior LV wall. This can result from an increased afterload, which exposes the septum to greater stress than the free wall or from stimulation of the sympathetic nervous system. [36] [37]

In addition to the dominant influence of pressure and volume overload, humoral factors may also contribute to alterations in LV morphology and hence LV hypertrophy. A number of these have now been defined (e.g., cardiac natriuretic peptides, troponin, homocysteine, asymmetric dimethyl arginine, endothelin) but whether they are markers of hypertrophy or significant factors in the pathogenic process now remains to be demonstrated. [38] [39] [40] [41]Raised sympathetic activity and catecholamine levels may also contribute either directly or indirectly to the pathologic process. A high sympathetic activity for instance is associated with sleep apnea and nocturnal hypoxia, which are in turn associated with cardiovascular complications in dialysis patients. [42] [43]

Thus, patients with CKD are exposed to variable but sustained conditions of volume and pressure overload, which in the setting of humoral and sympathetic imbalance, result in a combination of both concentric and eccentric hypertrophy, though the primary pattern of hypertrophy usually develops in accordance with the predominant initial mechanical stress. [7] [16] Initially, the hypertrophy is a balanced response to reduce the individual work of each muscle fiber, regulate cardiac efficiency, and improve the LV working capacity. However, with time the degree of hypertrophy relative to the volume of the left ventricle may prove inadequate[44] predisposing to the development of sustained energy deficit and cell death. Such cell death, in the presence of LV hypertrophy and continuing pressure and volume overload, may ultimately be catastrophic leading to further LV dilatation and, eventually, systolic dysfunction. In the final stages of cardiomyopathy, hypoperfusion results: the maximally hypertrophied myocardium expends most of its energy of contraction in developing pre-ejection wall tension and is unable to maintain cardiac output ( Fig. 48-4 ).

FIGURE 48-4 Cause of cardiac failure in chronic kidney disease and relationships between hemodynamic and other risk factors.

Interstitial Fibrosis

The interstitium constitutes 25% of the normal myocardium and it retains this proportion in even the largest hearts, through a proliferation of the cellular, vascular, and connective tissue elements normally present.[34] The causes of myocardial fibrosis relate to proliferation of fibroblasts within the interstitium, and in CKD there are numerous pathways permitting a disproportionate degree of fibrosis within, particularly, the left ventricle—often in a perivascular distribution.

Interstitial myocardial fibrosis is a prominent finding in CKD[45] and has been demonstrated at autopsy in patients with uremia. From these and animal studies it appears that uremia is an important factor related to intermyocardiocytic fibrosis, independent of hypertension, diabetes mellitus, anemia, heart weight, and dialysis. Clinical studies have shown also that the extent of myocardial fibrosis in dialysis patients is more marked than in patients with diabetes mellitus or essential hypertension with similar LV mass.[46] This is seen particularly in LV hypertrophy, more so in pressure than in volume overload, and is exacerbated by many factors, including male gender, senescence, ischemia, and effects of hormones such as catecholamines, angiotensin II, aldosterone, and transforming growth factors.[47] An additional humoral factor contributing to myocardial fibrosis appears to be hyperparathyroidism. Recent studies have demonstrated that parathyroid hormone is a permissive factor in the genesis of cardiac interstitial fibrosis. The extensive intramyocardial fibrosis in dialysis patients with elevated parathyroid hormone could account for attenuation of the hypertrophic response to pressure overload and the development of high-stress cardiomyopathy and cardiac failure.

Irrespective of the inducing factor(s), because the cardiac myocytes remain normal in number, the proliferation of fibroblasts and increase in collagen matrix result in a marked imbalance in the myocyte to fibroblast ratio. An abnormal alignment of myocytes subsequently occurs, which may lead to abnormal interdigitation in systole, and limitation of slippage during diastole.[48] The predominant clinical effects appear to relate to diastolic dysfunction and an increase in arrhythmias. Impaired diastolic function may occur when fibrotic change induces a slower re-uptake of calcium by the sarcoplasmic reticulum resulting in a delayed relaxation phase of the cardiac cycle. Concurrent prolongation of the action potential causes a delay in depolarization, which in turn contributes to re-entry tachycardias and severe arrhythmias, an effect that is augmented by fibrosis-induced conduction aberrations and cardiac hypertrophy per se. [49] [50]

Cardiac Failure

Functional Abnormalities

Assessment of LV functional abnormalities in patients with CKD is often difficult ( Table 48-1 ). Absence of symptoms does not imply intact functional reserve regardless of the stage of disease. Dialysis patients in particular are also prone to variations in fluid loading and humoral homeostasis during dialysis which may both augment and reduce the capacity to detect underlying abnormalities in systolic and diastolic function. [51] [52] [53] [54] Additional difficulties in differentiating abnormalities in LV function relate to assessing the common and often concurrent phenomena of pre-existing heart disease and effects of prolonged hemodynamic overload. Primary myocardial dysfunction and pure volume overload can each present with acute pulmonary edema. Similar difficulties can be encountered when trying to distinguish clinically between systolic and diastolic dysfunction. In reality, as has been outlined for other conditions, multiple pathologies are frequently present simultaneously, although usually it is one particular condition that predominates in a clinical context.


TABLE 48-1 -- Number of Patients with Comorbid Cardiac Conditions among Incident Dialysis Patients in the United States and Canada

Comorbid Condition

U.S., 1996–1997 (N = 2443)[*]

Canada, 1994–1995 (N = 822)[†]

Canada, 1983–1991 (N = 432)[‡]

Cardiac failure

36

35

31

Myocardial infarction

16

18

12

Angina

N/A

21

19

Peripheral vascular disease

20

17

8

Insulin-dependent diabetes

33

21

15

LV hypertrophy

N/A

N/A

74

LV dilatation

N/A

N/A

36

LV systolic dysfunction

N/A

N/A

15

Data from Foley RN, Parfrey PS, Harnett JD, et al: Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney Int 47:186–192, 1995.

LV, left ventricle; N/A, not available.

*

United States Renal Data System special study, DMMS wave 2, retrospective chart extraction. U.S. Renal Data System: Patient characteristics at the start of ESRD: Data from the HCFA Medical Evidence Form. Am J Kidney Dis 34(suppl 1):S63–S73, 1999, with permission.

†

Eleven centers, prospective evaluation by physician on starting dialysis. Data from Barrett BJ, Parfrey PS, Morgan J, et al: Prediction of early death in end-stage renal disease patients starting dialysis. Am J Kidney Dis 29:214–222, 1997.

‡

Three centers, retrospective evaluation of patients, who survived 6 months on dialysis and entered prospective echocardiographic study.

Diastolic Dysfunction

Hemodialysis patients with LV hypertrophy often have some impairment in diastolic function ( Fig. 48-5 ). The degree of disturbance is probably more than that observed in those with hypertensive heart disease, but milder than that observed in those with hypertrophic cardiomyopathy. [45] [46] [55] The abnormal ventricular filling in uremia results from increased LV stiffness caused by intramyocardial fibrosis and associated delayed relaxation. By virtue of an increase in LV stiffness, small changes in volume result in large changes in LV pressure, thus predisposing to symptomatic pulmonary edema.[8] The reverse is also true and is often the presenting feature of diastolic dysfunction: volume depletion results in a large fall in LV pressure with symptomatic hypotension and hemodynamic instability.[56]

FIGURE 48-5 Compliance characteristics of left ventricular (LV) hypertrophy during diastolic filling. Normal myocardial compliance is defined by the curve on the right, which shows the relationship between LV end-diastolic volume and LV end-diastolic pressure. With (uremic) LV hypertrophy, myocardial compliance is decreased, and the pressure-volume relationship is shifted to the left, operating within a narrow range while maintaining similar resting end-diastolic pressures. Consequently, an increase in plasma volume leads to cardiac failure, and a decrease leads to hypotension. (From Palmer BF, Henrich WL: The effect of dialysis on left ventricular contractility. In Parfrey PS, Harnet JD (eds): Cardiac Dysfunction in Chronic Uremia. Boston, Kluwer Academic, 1992, with permission.)

Systolic Dysfunction

Resting systolic function is usually normal or even increased in patients with advanced renal disease in the absence of antecedent cardiac disease.[57] However, decreased systolic function may be observed in pre dialysis patients with cardiac disease or in patients with prolonged and marked hemodynamic overload. Approximately 15% of patients have systolic dysfunction by the time of starting dialysis.[7] Diminished myocardial contractility may also be a result of overload cardiomyopathy where the myocardium relies upon Starling forces to maintain a normal output. This manifestation of cardiomyopathy has a substantially worse prognosis than either concentric LV hypertrophy or LV dilatation with normal systolic function.[21] In dialysis patients, systolic dysfunction is strongly associated with the presence of ischemic heart disease or sustained biomechanical stress (or both). It can however also be a reversible manifestation of severe uremia, improving when the uremic environment is removed. Uremic serum has been found to reduce the force of contraction of cultured myocytes in a concentration-dependent manner.[58] Renal transplantation has also been shown to normalize systolic function in dialysis patients with systolic dysfunction and subsequently to reduce but not normalize LV mass index, [59] [60] although such improvement has not yet been shown to confer a survival benefit.[61]

Symptomatic Cardiac Failure

Left ventricular failure is a clinical condition that can be defined as the inability of the heart to maintain sufficient output to meet metabolic demands at rest, or to maintain such demands only at the expense of a sufficiently raised venous pressure to result in pulmonary edema. When left untreated, myocardial hypertrophy can be viewed as an early milestone in the clinical course of cardiac failure. In a Canadian cohort study 275 patients had serial echocardiograms, the first on starting dialysis and then after 1 year of dialysis therapy.[20] An increase in LV mass index was an independent risk factor for the development of subsequent heart failure (hazard ratio 1.3 per each 20 g/m2 increase), as was a reduction in fractional shortening (hazard ratio 1.43 per 5% decrease). There is some evidence that attention to hemodynamic risk factors may reduce LV hypertrophy, and possibly mortality. [62] [63] Such effects may have important clinical consequences: patients with diabetes for instance have been found to have a reduced hospitalization rate for congestive cardiac failure after successful renal transplantation.[64]

The pathophysiologic consequences of systolic dysfunction include an increase in both the end diastolic fiber length and end diastolic volume (i.e., through the Frank-Starling mechanism), increased sympathetic activity, enhanced secretion of regulatory hormones (such as angiotensin II, arginine vasopressin, vasoactive endothelial hormones, and brain and atrial natriuretic peptide), and the presence of ouabain-like substances, which through impairment of Na+K+ATPase, result in enhanced contractility although at the expense of impaired relaxation. [65] [66] In a circuit already coping with an elevated LV volume and pressure this can easily result, as previously seen, in a raised pulmonary capillary pressure. The clinical presentation then is one of symptomatic heart failure, with dyspnea and pulmonary venous congestion, ultimately resulting in acute pulmonary edema. This end-stage clinical manifestation of cardiac disease may result from systolic failure, usually caused by dilated cardiomyopathy or ischemia (or both), or from diastolic dysfunction in association with LV hypertrophy.

Ischemic Heart Disease

Atheromatous Coronary Artery Disease

In humans, basal myocardial perfusion is constant regardless of the severity of coronary artery stenosis. During conditions requiring increased flow, a progressive relative decrease in perfusion occurs after the degree of stenosis is 40% or more, and can not increase above basal conditions when the stenosis is 80% or greater.[67] Thus, stenosis progressively exhausts the coronary vasodilator reserve (defined as the ratio of maximal to basal coronary perfusion).

Coronary artery disease, characterized by critical stenoses of the major coronary arteries, is highly prevalent in the CKD population, both because of the demographic characteristics of the patient population and their underlying disease states, such as hypertension and diabetes mellitus. Estimates of prevalence by the time the patient reaches the need for dialysis vary from 15% [7] [8] to 73%.[68] The wide range in prevalence most likely relates to whether the patient presents symptomatically or the condition is detected on screening, often for transplantation. It is estimated that over 50% of patients, particularly diabetics, may have asymptomatic disease. [69] [70]

It appears that the uremic milieu or the prevailing comorbidities (or both) provide the hemodynamic, humoral, and metabolic abnormalities that favor vascular wall damage ( Fig. 48-6 ). Arterial hypertension causes increased tensile stress, and shear stress alterations occur at internal vessel orifices and bifurcations. Both types result in endothelial cell activation.[70] Changes in tensile and shear stress activate stretch- and flow-sensitive cationic channels producing secretions of vasoactive and growth-regulating factors. Subsequent effects include alterations in cytokine migration, cellular apoptosis, and extracellular matrix synthesis. There is evidence of chronic in vivo endothelial activation and injury in uremia. [71] [72]

FIGURE 48-6 Cause of ischemic heart disease in dialysis patients. LV, left ventricular.

In addition to endothelial injury and activation however, the vascular pathology of chronic uremia includes autocrine and endocrine sequelae from a diverse range of seemingly unrelated circumstances. These include (1) a propensity for atherogenic lipid profiles and dyslipidemia[73]; (2) a complex derangement of platelet function that increases bleeding time but is associated with high levels of prothrombotic factors[74]; (3) an increased oxidant stress because of increased production of reactive oxygen species and diminished antioxidant levels (thus increasing oxidative modification of lipids and enhancing atherogenesis)[75]; (4) hyperhomocysteinemia, which may have toxic effects on the endothelium and favor vascular thrombosis [76] [77]; (5) disturbances of glucose metabolism, which may be atherogenic through numerous metabolic anomalies and through hyperglycemia-induced irreversible modification of extracellular molecules, such as advanced glycation end products[70]; and (6) dysregulation in the balance between proinflammatory cytokines and their inhibitors, which may contribute to a chronic immuno-inflammatory disorder,[77] [79] with cytokine activation mediated in turn through the production of increased oxidant stress and acute phase reactants. [80] [81]

Recently, two factors have received particular attention for their contribution to the development of atheroma in CKD: inflammation and vascular wall calcification.

Evidence from experimental and clinical studies has shown that inflammation in general, and C-reactive protein (CRP) specifically, may contribute directly to the pathogenesis of atherosclerosis and its complications both in the general community and in patients with CKD. CRP has been shown to bind to damaged cells promoting activation of the complement system[82]; it displays calcium-dependent in vitro binding and aggregation of LDL and VLDL,[83] and is a potent stimulator of tissue factor by monocytes.[84] Epidemiological studies support its pathogenetic role as a cardiovascular risk factor in the general community, [85] [86] [87] which may be amenable to intervention by agents such as aspirin[86] and pravastatin.[88] In CKD, the source of the (sometimes marked) elevation in CRP is uncertain. Potential sources include back filtration of endotoxin during dialysis,[89] type of vascular access type,[90]unrecognized infection, or bio-incompatibility of peritoneal dialysate.[91] C-reactive protein levels have been shown to have a powerful predictive capacity for mortality in both hemodialysis and peritoneal dialysis patients,[92] and to be an independent predictor of the number of atherosclerotic plaques and intima-media thickness in carotid arteries of hemodialysis[93] and predialysis patients,[94] respectively.

The deposition of calcium in vessel walls in patients with CKD has also received much attention in recent years. In one study, coronary atherosclerotic plaque morphology was distinguished most readily by composition rather than by size or number. Calcium deposition in such plaques was extreme.[95] Additional differences compared to non-uremic controls in this post-mortem study included increased media thickness and a reduced lumen area. Such findings are entirely consistent with current clinical assessments of patients with CKD, in relation to both coronary and larger peripheral vessels. [96] [97] [98] Markers of coronary and carotid calcification included longer duration of dialysis, hyperparathyroidism, estimates of calcium and phosphate load, CRP levels, elevated homocysteine levels, and age—although manifest calcification is already evident in such adults from the age of 20. [97] [98] Importantly, lesions progressed with time and persisted after transplantation. Although coronary artery calcification is predictive of subsequent coronary events in the general population, its clinical significance in patients with CKD is not known. It is possible that the more generalized arterial calcification observed in dialysis patients is not predictive of atherosclerotic coronary events, but is a marker for arteriosclerosis, diminished vascular compliance, and a risk factor for LV hypertrophy. London and colleagues have recently examined the differences between intimal and medial aortic calcification.[99] Intimal calcification is associated with older age, and a history or high risk of atherosclerosis, and medial calcification with younger age, lower risk of atherosclerosis, longer duration of hemodialysis, and serum calcium-phosphate abnormalities. Medial calcification implies arteriosclerosis with noncompliance of the large conduit vessels.

The etiology of such changes in vessel walls almost certainly relates to the positive calcium and phosphate balance to which CKD patients are exposed, through both increased intake and inadequate excretion. Calcium-containing phosphate buffers, together with hyperparathyroidism, vitamin D use, and a “closed” skeleton unable to buffer increased levels of raised calcium and phosphate, all undoubtedly contribute to vessel calcification. There is evidence now also to suggest that raised plasma phosphate can alter the phenotype of smooth muscle cells from contractile to secretory, acting as one of a series of triggers permitting new bone formation in vessel walls.[100] Whether the newer calcium- and aluminium-free phosphate binders result in less vessel calcification is yet to be shown.

Coronary arterial calcification (CAC) measured by electron beam computerized tomography is associated with coronary plaque burden in the general population. In the Dallas Heart Study,[101] the prevalence of high CAC scores (>400) was 1.4% in non-diabetic non-CKD residents and 3.5% in non-diabetic with CKD residents. However, in diabetic patients without CKD the prevalence was 4.7%, compared with 55.7% in diabetic patients with CKD.[101]The Framingham Offspring study of 319 subjects suggested a modest relationship between CAC scores and GFR in patients free of CVD.[102] Whether CAC in ESRD is diagnostic of atherosclerotic disease is unclear as two small cross-sectional studies showed contrasting results. [103] [104]

Non-Atheromatous Coronary Disease

About 25% of dialysis patients with ischemic symptoms do not have critical coronary artery disease.[105] A significant percentage of pre-dialysis and transplant patients are similarly affected. It is likely that these symptoms result from microvascular disease and the underlying cardiomyopathy, in which a reduction in coronary vasodilator reserve, and altered myocardial oxygen delivery and use, predispose to ischemic symptoms (see Fig. 48-6 ). In dialysis patients, the presence of LV hypertrophy predisposes to non-atherosclerotic ischemic disease. LV hypertrophy is primarily a response to increased tensile stress requiring an overall increase in myocardial energy. As the demand for oxygen increases the coronary vasculature dilates above baseline. A further increase in myocardial oxygen requirement may not be met with an adequate increase in coronary flow, especially if there are pathologic changes in the large coronary arteries or in the small coronary vessels.

Numerous other mechanisms may exacerbate non-occlusive ischemia. Small-vessel smooth muscle cell hypertrophy and endothelial cell abnormalities have been described in uremia and LV hypertrophy. [106] [107] Myocyte-capillary mismatch has been reported in human uremic myocardium, which exposes the myocytes to the risk of hypoxia through a relatively reduced capillary density.[108] In addition, canine studies have demonstrated that chronic aortic stiffening can reduce cardiac transmural perfusion and aggravate subendocardial ischemia by reducing subendocardial blood flow despite an increase in mean coronary flow.[109] Finally, susceptibility to myocardial ischemia may be increased as a result of dysregulation of high energy phosphate compounds during ischemia. A reduced phospho-creatinine-adenosine triphosphate ratio under hypoxic stress has been observed in the myocardium of uremic animals, possibly related to hyperparathyroidism.[110]

Dialysis Hypotension

The pathophysiology of this clinical manifestation is multifactorial and not fully understood. It may occur in the presence of systolic failure, diastolic dysfunction, or ischemic disease. In the letter, it is usually associated with chest pain, whether atherosclerotic or nonatherosclerotic in origin. In dilated cardiomyopathy, hypotension during dialysis will only occur in patients who are unable to increase resting cardiac output in response to plasma volume depletion. Such patients usually have severe systolic failure, as the dialysis procedure actually improves myocardial performance in most patients with depressed LV function.[111] In one study, the predominant cause of dialysis-induced hypotension was found to be impaired myocardial reserve rather than ischemia. Those patients who were “hypotension-prone” demonstrated a reduced increment in cardiac index (L.min-1.m-2) on dobutamine-atropine stress echocardiography compared to those who were “hypotension-resistant”, indicative of a markedly reduced myocardial reserve.[112]

Left ventricular hypertrophy may also be a contributing factor to dialysis hypotension. Because of diminished LV compliance, the relationship between LV end-diastolic pressure and volume is exaggerated (see Fig. 48-5 ). As a result, during dialysis, relative hypovolemia may result in a disproportionately large decrease in LV end diastolic pressure, which in turn leads to a decreased stroke volume and hypotension, if a compensatory increase in peripheral resistance does not occur. A high prevalence of LV hypertrophy among dialysis patients prone to dialysis hypotension has been reported.[113]

Arrhythmias

In patients without renal failure, left ventricular hypertrophy and coronary heart disease appear to be associated with an increased risk of arrhythmias. As outlined earlier, these cardiac diseases are among the most prevalent in patients with CKD. In addition, serum electrolyte levels that can affect cardiac conduction including potassium, calcium, magnesium, and hydrogen are often abnormal or undergo rapid fluctuations during hemodialysis.

Hence, arrhythmias and sudden death are of particular concern in dialysis patients. In cross-sectional studies, the prevalence of arrhythmias is high: between 68% and 88% for atrial arrhythmias, 56% to 76% for ventricular arrhythmias, and premature ventricular complexes were found in 14% to 21%. [114] [115] Older age, pre-existing heart disease, left ventricular hypertrophy, and Digoxin therapy were associated with a higher prevalence and greater severity of cardiac arrhythmias. However, because of the considerable variation in the frequency and severity of arrhythmias during and after dialysis, the clinical significance in a given patient is unclear.

Coronary artery disease has been associated with a higher frequency of arrhythmias in some,[116] but not all studies on hemodialysis.[114] Neither has the association between coronary disease, left ventricular hypertrophy, and fatal arrhythmia (sudden death) been clarified. There are also conflicting data about the effect of dialysis, and various dialysis compositions and dialysis protocols on the occurrence of rhythm disturbances. Some studies show a higher incidence of premature ventricular contractions during dialysis or in the immediate postdialysis period, [114] [115] whereas in others no differences could be observed. Most atrial arrhythmias are of low clinical significance. However sustained, rate-related (fast or slow) impairment of LV filling can certainly produce hemodynamic consequences.

The majority of the premature ventricular contractions are unifocal and number less than 30 per hour; however, high-grade ventricular arrhythmias like multiple premature ventricular contractions, ventricular couplets, and ventricular tachycardia were found in 27% of 92 patients with 24-hour Holter monitoring.[117] The finding of high-grade ventricular arrhythmias in the presence of coronary artery disease has been associated with an increased risk of cardiac mortality and sudden death.[118] Whereas the dialysis method, membrane, and buffer used do not seem to have a direct effect on the incidence of arrhythmias, dialysis-associated hypotension seems to be an important factor in precipitating high-grade ventricular arrhythmias, irrespective of the type of dialysis.[119]

Arrhythmias in peritoneal dialysis patients appear different from hemodialysis patients. Holter monitor recordings of 21 such patients revealed a high frequency of atrial or ventricular premature beats (or both).[120] There were no differences in the type or frequency of the extrasystoles between the day on which dialysis was administered or deliberately withheld. It seems that, in contrast to hemodialysis, peritoneal dialysis by itself is not responsible for provoking or aggravating arrhythmias. The arrhythmias are more a reflection of the patient's age, underlying ischemic heart disease, or an association with left ventricular hypertrophy. [121] [122]

A recent study, in which 27 peritoneal dialysis patients were compared with 27 hemodialysis patients, revealed that severe cardiac arrhythmias occurred in only 4% of the former and in 33% of the latter group.[123] Patients in both groups were matched for age, sex, duration of treatment, and etiology of chronic renal failure. The lower frequency of left ventricular hypertrophy, the maintenance of a relatively stable blood pressure, the absence of sudden hypotensive events, and the significantly lower incidence of hyperkalemia in patients on peritoneal dialysis may explain the lower incidence of severe arrhythmias in these patients.

The use of Digoxin in hemodialysis patients has also raised concern regarding precipitation of arrhythmias, especially in the immediate postdialysis period, when both hypokalemia and relative hypercalcemia may occur.[116]However, a crossover study of 55 patients “on-and-off” Digoxin found no associated increase in the incidence of arrhythmias.[124]

Valvular Disease

Most valvular lesions observed in patients with CKD are acquired and develop from dystrophic calcification of the valvular annulus and leaflets, particularly the aortic and mitral valves.[125]

The prevalence of aortic valve calcification in dialysis patients is up to 55%, similar to that in the elderly general population, although it occurs 10 to 20 years earlier. [14] [125] [126] Aortic valve orifice stenosis in CKD evolves from valve sclerosis, which itself is now recognized generally to be associated with an increased cardiovascular mortality.[15] In dialysis patients the prevalence of aortic stenosis is 3% to 13%.[97] It may sometimes evolve rapidly (within 6 months) to hemodynamically significant stenosis, with a worsening of LV hypertrophy and rapidly evolving symptomatology. Age, duration of dialysis, a raised phosphate level, and an elevated calcium phosphate product appear to be the most important risk factors for the development of aortic stenosis. [125] [128]

Mitral valve calcification is not as common as aortic valve disease in CKD and may have a different pathophysiology. In one study evaluated by echocardiography mitral annulus calcification was present in 45% of 92 hemodialysis patients (compared to 10% of age and gender-matched controls).[125] Other studies have found a prevalence of 39% and 18% in hemodialysis and peritoneal dialysis patients (respectively), 16% in pre-dialysis patients, and 10% in the general population. [13] [129] Age and calcium phosphate product have been correlated with valve calcification although, in one study of 135 peritoneal dialysis patients with low parathyroid hormone levels, a constant involvement of the posterior cusp, together with left atrial enlargement, was observed.[129] Valve calcification has also been associated with rhythm and cardiac conduction defects, valvular insufficiency, and peripheral vascular calcification. Although most studies have identified abnormalities in calcium phosphate metabolism as the predominant underlying risk factor, additional factors include specific involvement of the posterior cusp, left atrial dilatation, duration of dialysis, and duration of pre-dialysis systolic hypertension. Factors associated with a decreased survival include severity of calcification, mitral regurgitation, and reduced left ventricular function. [13] [125] [126] [129]

Vascular Disease

Large Vessel Disease

Arteriosclerosis

Increased cardiovascular morbidity and mortality have been correlated, either directly or indirectly, with various estimates of elevated left ventricular afterload in patients with CKD. [130] [131] [132] [133] [134] Postulated etiological factors include increased arterial wall stiffness, raised sympathetic tone mediated by elevated noradrenaline levels, primary hormonal aberrations associated with CKD, seasonal changes, and autonomic dysregulation. [42] [53] [54] [130] [134] [135]

Some of these factors have only recently been identified. Many, however, are related to two established components of LV afterload: hypertension and reduced arterial wall compliance, for which some studies exist. Before examining these however, it is important first to recognize the pathophysiological similarities and differences by which they are characterized.

Hypertension has usually been attributed to a reduction in the caliber or number of muscular arteries (150 to 400 mm diameter) resulting in an increase in peripheral resistance. This approach however does not acknowledge that blood pressure fluctuates during the cardiac cycle and that systolic and diastolic levels represent only the limits of this fluctuation. Fourier analysis of the blood pressure curve can determine both its steady state (mean blood pressure) and oscillatory (fluctuation about the mean) components. The former is determined exclusively by cardiac output and peripheral resistance (pressure and flow considered constant over time). The oscillatory component is determined by the pattern of LV ejection, the visco-elastic properties of large conduit arteries, and the intensity and timing of arterial wave reflection.[136] A faster pulse wave velocity (PWV) is primarily associated with arterial stiffness which, in CKD, is an acceleration of the normal aging process with vessel dilatation and a diffuse, non-occlusive medial and intimal wall hypertrophy (arteriosclerosis). It has been correlated with shortened stature, male gender, smoking, blood pressure, diabetes, volume overload, humoral imbalance, and age. [137] [138] [139]

The clinical characteristics of hypertension therefore will depend on the predominant abnormality. Increased peripheral resistance is characterized principally by an increased diastolic and mean blood pressure, whereas increased arterial stiffness and early wave reflections are indicated by an increased systolic and widened pulse-pressure. Because the peripheral resistance of most dialysis patients is within the normal range, it is likely that effects from an accelerated PWV contribute more significantly to cardiovascular morbidity than an elevation in mean blood pressure. Increased systolic blood pressure and pulse pressure are observed in dialysis patients and, unlike blood pressure levels, are closely correlated with LV hypertrophy. [139] [140] [141]

Atheroma

The pathology and pathogenesis of atheromatous disease in larger peripheral vessels is also addressed in the earlier section on Atheromatous Ischemic Heart Disease. Atherosclerotic plaques are primarily intimal, focal, and patchy, inducing occlusive lesions and compensatory focal enlargement of arterial diameters. Mechanical and humoral factors predispose to atheroma, which has a predilection for such sites as bifurcations, bending, or where there is pronounced arterial tapering. Turbulence or low-average shear stress characterizes these sites during the cardiac cycle. Atheroma is uncommon in sites where laminar shear stress is high, such as at flow dividers, the inner sites of arteries downstream from dividers, or on the outer wall of an arterial bend. [142] [143]

Small Vessel Disease

Hypertension

The pathophysiology of hypertension in CKD has been covered extensively in other sections of this book. Several mechanisms are involved in the development of hypertension, each probably of varying significance at different stages of disease. At an early stage of CKD, the link between the kidney and hypertension is not clear. As dysfunction progresses, salt and water retention produce an increase in extracellular volume, which together with an increase in perip-heral resistance results in hypertension. Factors responsible for the latter include enhanced sympathetic activity, activation of the renin-angiotensin system, and endothelial cell dysfunction.

Various functional abnormalities have been found in recent years within the endothelial cell in hypertensive patients with CKD. Reduced nitric oxide production, increased levels of endothelin-1, and increased oxygen free-radical activity all support the notion of a primary endothelial role in hypertension in these patients. [144] [145] [146] Additional potential influences include renal vasculopathy, which has been found to correlate with the presence of hypertension in CKD, a permissive role of hyperparathyroidism for a hypertensive effect of intracellular calcium, and low initial nephron number in association with reduced birthweight. [147] [148]

Diabetes

The pathophysiology of diabetic vascular disease is complex and is also covered in other sections of this book. Through a combination of sustained chronic hyperglycemia, dyslipidemia, and insulin resistance, adverse and pro-atherogenic metabolic events including increase oxidative stress, protein kinase C activation and an increased activation of the receptor for advanced glycation end product (RAGE) are engendered. Four important destructive and interactive mechanisms result. These include (1) impaired endothelial cell function, mainly through an imbalance in vasoactive hormonal and paracrine factors,[149] (2) vasoconstriction and smooth muscle hypertrophy,[150] (3) increased production of inflammatory cytokines and cellular adhesion molecules,[151] and (4) a prothrombotic milieu through calcium-dependent platelet activation and increased expression of pro-coagulant clotting factors including tissue factor and plasmin activator inhibitor 1.[152] Subsequent profound effects on vessel morphology and function result, which in renal disease, are further complicated and exacerbated by increased exposure to traditional and uremic risk factors.

EPIDEMIOLOGY AND CARDIAC RISK FACTORS

Overview

In an era where diabetes and hypertension are the predominant causes of CKD, it is not surprising that there is an associated high incidence of cardiovascular disease ( Table 48-2 ). It is possible that CKD is also an independent risk factor for cardiovascular disease. Cardiovascular events occur more frequently than renal events in CKD and more patients die than reach dialysis. [1] [153] (For further discussion, see later section on Uremia as an Independent Cardiac Risk Factor.)


TABLE 48-2 -- Potentially Modifiable Cardiovascular Risk Factors in Chronic Kidney Disease, Identified by Cohort Studies

Predialysis LVH

Renal Transplant

Dialysis

Death

LVH

CHF

IHD

LVH

CHF

IHD

Anemia

+

+

+

-

+

+

-

+

Hypertension

+

+

+

+

+

+

+

-

Hyperlipidemia

-

-

-

+

-

-

-

-

Smoking

-

-

-

+

-

+

+

+

Hypoalbuminemia

-

-

-

+

-

+

-

+

C-reactive protein

-

-

-

-

-

-

-

+

Homocysteine

-

-

-

-

-

-

-

+

Divalent ion abnormalities

-

-

-

-

-

-

-

+

CHF, congestive heart failure; IHD, ischemic heart disease; LVH, left ventricular hypertrophy.

The predominant burden of ill health in CKD however occurs during the period of dialysis. The survival of dialysis patients is worse than that of patients with colon or prostate cancer, resulting predominantly from an excessively high cardiovascular mortality rate. Figure 48-1 shows the annual percent cardiovascular mortality by gender, race, and diabetic status in hemodialysis, peritoneal dialysis, and renal transplant patients, compared to the general population. In the past, the mortality rate for hemodialysis patients has been 35 times higher than the general population; however, this may have improved in the past decade. [5] [154] [155] Overall annual adjusted death rates in patients waiting for renal transplant and for transplant recipients decreased from 1989 to 1996: the relative risk decreasing by 23% in the former group and by 30% in the latter.[155] Slope analysis of the cause-specific mortality rates for cardiovascular disease and for infection showed nearly equivalent, linear, decreases for both groups. These favorable trends probably represent equal advances in transplantation, dialysis, and general medical care.

Various, likely interrelated, pathological and disease states contribute to the high mortality in CKD. Figure 48-7A shows the survival of patients starting dialysis by echocardiographic diagnosis. Those with systolic dysfunction had significantly worse survival than those with a normal echocardiogram through all time frames, whereas those with concentric LV hypertrophy and LV dilatation had significantly worse late survival, beginning 2 years after starting dialysis.[21] Confirmation that LV mass was a strong and independent predictor for survival and cardiovascular events in dialysis patients was confirmed recently, as was the prognostic impact of the different types of hypertrophy.[53] Aortic stiffness has also been found to be an independent predictor of all-cause and cardiovascular mortality in French and Japanese dialysis patients. [141] [156] Congestive heart failure has been consistently shown to be a strong independent risk factor for death in CKD ( Fig. 48-7B ), whereas in one study ischemic heart disease was not when assessed independent of age, diabetes, and the presence of cardiac failure.[157] In diabetics however, both heart failure and ischemic heart disease are independent predictors of death.[158]

FIGURE 48-7 A, Survival of patients starting dialysis, comparing those with normal echocardiogram, concentric left ventricular (LV) hypertrophy, LV dilatation, and systolic dysfunction at baseline. (From Parfrey PS, Foley RN, Harnett JD, et al: Outcome and risk factors for left ventricular disorders in chronic uremia. Nephrol Dial Transplant 11:1280, 1996, with permission.) B, Survival of patients starting dialysis, comparing those with and without cardiac failure at baseline. (From Foley RN, Parfrey PS, Harnett JD, et al: Clinical and echocardiographic cardiovascular disease in patients starting dialysis therapy: Prevalence, associations, and prognosis. Kidney Int 47:189, 1995, with permission.)

Other cardiovascular events in CKD are associated with a high mortality. One- and 5-year mortality after acute myocardial infarction in dialysis patients was 59% and 90% respectively by 5 years, which may reflect the catastrophic effect of impaired coronary perfusion in overload cardiomyopathy.[159] In Japan, mortality after stroke in dialysis patients was 47% at 1 month and 64% at 1 year.[160] Survival after interventions for vascular disease in dialysis patients is similar. Median survival was 1.72 years after lower limb revascularization in dialysis patients as opposed to 5.17 years after the same procedure in control subjects.[161]

Chronic Kidney Disease as an Independent Cardiac Risk Factor

In high-risk populations, proteinuria and decreased GFR are independent cardiovascular risk factors. [162] [163] [164] [165] [166] [167] However, in low-risk community populations, less consistent results are evident. For example, decreased GFR is a risk factor for CVD in Atherosclerosis Risk in Communities (ARIC) and NHANES II, but not in the Framingham and NHANES I studies. [168] [169] [170] [171] [172] In the Cardiovascular Health Study, the 3-year probability of cardiovascular events increased as the GFR declined below 70 ml/min ( Fig. 48-8 ).[173] However, the probability decreased substantially after adjustment for traditional risk factors. Furthermore, in ARIC, high serum creatinine was associated with an increased risk of coronary events and of stroke among middle-aged individuals with anemia, whereas no increased risk was found in individuals with high serum creatinine in the absence of anaemia.[171] [172] Whether anemia is a marker for more severe renal failure or is itself an independent cardiovascular risk factor is not clear.

FIGURE 48-8 Three-year probability of cardiovascular events before and after adjustment for traditional risk factors by glomerular filtration rate in the Cardiovascular Health Study. GFR, Glomerular filtration rate. (From Manjunath G, Tighiouart H, Coresh J, et al: Level of kidney function as a risk factor for cardiovascular outcomes in the elderly. Kidney Int 63:1121–1129, 2003.)

After starting dialysis therapy atheromatous event rates are much higher than before dialysis. The incidence of de novo coronary events, stroke, and peripheral vascular disease of hemodialysis patients, after 2.2 years follow-up from start of dialysis in the United States, were 10.2%, 2.2%, and 14% respectively.[161] Certainly, the uremic state is cardiomyopathic. This is supported by numerous studies: high incidence of heart failure in CKD,[1] a high prevalence of cardiac failure on starting dialysis,[8] a higher rate of de novo symptomatic heart failure in renal transplant recipients than in the general population,[175] and a high incidence of de novo cardiac failure in hemodialysis patients (13.6% over 2.2 years mean follow-up in United States[174] and 17% over 3.4 years follow-up in Canada.[157]

The reason why proteinuria and decreased GFR are cardiovascular risk factors is not evident. It may be because these factors are associated with (1) a higher prevalence of traditional risk factors, (2) a more severe burden of traditional risk factors causing end-organ damage, (3) concomitant generalized endothelial dysfunction, coagulation/fibrinolytic abnormalities, inflammation, or other non-traditional risk factors. In CKD, pro-atherogenic tendencies are balanced at least to some extent by an anti-atherogenic effect. The adipocyte protein, adiponectin for example, seems to play a protective role in experimental models of vascular injury. In one study of 227 hemodialysis patients, plasma adiponectin levels were 2.5 times higher than in normal subjects and inversely predictive of cardiovascular outcome.[42] Adiponectin was also inversely related to several metabolic risk factors, including insulin levels, triglyceride levels, and von Willebrand factor levels, and directly related to HDL cholesterol levels in a manner to suggest it was protective to the cardiovascular system.

In summary, the cardiovascular risk associated with CKD compared to the general population should take account of (1) different CVD risk relationships at different degrees of renal impairment, (2) an independent contribution to outcome events by associated cardiomyopathic disease, and (3) uremia-related atherogenic risk factors not addressed in the Framingham risk equation. It appears from Figure 48-8 that the greatest hazard for CVD in CKD is explained by the traditional risk factors.

Traditional Risk Factors

There has been a paucity of large prospective cohort studies on cardiovascular outcomes conducted in the CKD population in which incident patients are enrolled at the same phase of CKD, free of clinical CVD, with an interval between the measurement of risk factors and de novo cardiovascular events, with power to adjust for multiple factors, and adjustment made for traditional risk factors, interventions, and confounders. Nevertheless, age, hypertension, diabetes, dyslipidemia, smoking, and obesity have been validated as traditional risk factors for CVD in patients with CKD. A complicating aspect of interpreting the impact of certain traditional risk factors in CKD, such as hypertension and diabetes, is that they accelerate the progression of renal disease, thus perhaps multiplying their effect in this population. This may be one explanation for the high prevalence of cardiovascular disease in CKD. It may also be that some cardiovascular events have a different pathogenesis, or that non-traditional risk factors are important. The Choices for Healthy Outcomes In Caring for ESRD (CHOICE) study has also demonstrated that many atherosclerotic risk factors are more prevalent in incident patients with ESRD.[176]

Hypertension

Hypertension is often prominent in CKD regardless of the stage. As such, it is an independent risk factor for LV hypertrophy, cardiac failure, and symptomatic ischemic heart disease. [21] [22] [157] [175] [177]

Pre-Dialysis

About 70% to 80% of patients with CKD have hypertension, the prevalence increasing as GFR declines. The level of systolic blood pressure is correlated with GFR and proteinuria, and hypertension is more common in glomerular than tubulo-interstitial disease. Although over 70% of patients are treated with antihypertensive agents, less than half achieve levels below 140/90. [23] [178] [179] [180]

Dialysis

Up to 80% of patients starting hemodialysis and 50% starting peritoneal dialysis are hypertensive. It is frequently inadequately treated: the 1996 Core Indicators project reported that 53% of prevalent adult hemodialysis patients had pre-dialysis systolic blood pressures in excess of 150 mm Hg, and 17% had predialysis diastolic blood pressures of 90 mm Hg or more. The comparable rates in peritoneal dialysis patients were 29% and 18%, respectively.[171] More than 70% exceed the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VI criteria).[182] Independent predictors of higher blood pressure levels include higher interdialytic weight gains, noncompliance with the prescribed dialysis regimen, and younger age. [182] [183] [184] [185]

Despite strong evidence that high blood pressure is an independent risk factor for cardiac events in CKD, low blood pressure is associated with a higher risk of death in multiple studies of dialysis patients.[186] The counterintuitive relationship of lower blood pressure and mortality in dialysis patients is probably the result of (1) blood pressure falling after the development of symptomatic heart disease, (2) a high proportion of patients with symptomatic cardiac disease on starting dialysis, and (3) methods of data analysis. [187] [188] When data are analyzed with systolic or diastolic blood pressure as separate models, the inverse relationship between blood pressure and mortality is usually seen. When both systolic and diastolic blood pressure are considered together, systolic or increased pulse pressure predict cardiovascular events, whereas diastolic blood pressure has an inverse relationship.[188]

Transplantation

Hypertension is also common in transplant patients, with an estimated prevalence of 50% to 90%. Apart from effects of vascular modelling during the period of dialysis, numerous concurrent factors post-transplantation such as obesity, raised extracellular volume, medications, and renal dysfunction may all contribute to hypertension in this group. The vasoconstrictive effects of calcineurin inhibitors in particular augment hypertension after transplantation.[189]

Dyslipidemia

Similar to hypertension, the prevalence of dyslipidemia in patients with CKD is high. In early stages of disease, the prevalence varies according to renal function and the degree of proteinuria. [178] [190] As GFR falls, triglyceride levels increase and HDL-cholesterol falls. As proteinuria increases, total cholesterol, LDL-cholesterol, and triglycerides all increase, whereas HDL-cholesterol decreases. Approximately 50% of hemodialysis patients and 70% of peritoneal dialysis patients demonstrate dyslipidemia.[190] Hemodialysis patients characteristically demonstrate alterations from the general population only in triglyceride (elevated) and HDL-cholesterol (reduced) levels. In peritoneal dialysis and transplant patients, levels of total and LDL-cholesterol, and triglycerides are usually higher than in the general population. In transplant patients, this may be partly immunosuppression-related, with tacrolimus permitting a more favorable profile than cyclosporine, and sirolimus producing significant increases in both cholesterol and triglyceride levels.[191]

Monitoring and management of dyslipidemia are often inadequate. Only 8% to 18% of non-diabetic patients take lipid-lowering drugs prior to dialysis and 4% to 10% of dialysis patients use HMG-CoA reductase inhibitors (statins). Fewer than 40% of transplant patients and 60% of dialysis patients have their lipids measured during the course of a year. [178] [191] [192]

Few longitudinal studies have examined the relationship between lipid abnormalities and cardiac outcomes in CKD, although dyslipidemia has been linked to progression of renal disease. In pre-dialysis patients, low HDL-cholesterol levels have also been identified as an independent risk factor for cardiovascular events, and significant associations have been found between various lipid abnormalities and cardiovascular events in transplant patients.[193] [194] Studies in dialysis patients have found a ‘U’-shaped relationship either with cardiovascular events or with overall mortality: one 10-year prospective cohort study in 1167 Japanese hemodialysis patients demonstrated that patients with a serum cholesterol between 200 and 220 mg/dL had the best outcome.[195] It is likely however that confounding factors such as concurrent malnutrition or inflammation (or both) explain these findings. [196] [197] With respect to dyslipidemia, a prospective study of 833 incident dialysis patients found an inverse association of total cholesterol with mortality.[196] However, this was only evident in the presence of systemic inflammation (HR = 0.89; 95% CI 0.84–0.95) whereas the trend was reversed in the absence of inflammation (HR 1.32; 95% CI 1.07–1.63). Measures of systemic inflammation included pre-defined serum levels of C-reactive protein, albumin, and IL-6. It was concluded that the expected adverse effect of hyperlipidemia was confounded by the presence of inflammation; a non-traditional uremia-related risk factor. The same study has reported that small apolipoprotein (a) size and high lipoprotein (a) levels predict atherosclerotic CVD, but the association of cardiovascular events with small isoforms is stronger than the association with high concentrations.[198]

Tobacco Use

Approximately 25% of pre-dialysis patients and 50% of dialysis and transplant patients do or have smoked. This is now clearly linked to the progression of kidney disease, the development of cardiovascular disease, and mortality. At the start of dialysis therapy smoking has been independently associated with de novo heart failure, peripheral vascular disease, and death.[174] In renal transplant recipients the risk of cardiovascular disease, cerebrovascular disease, and death are increased with smoking. [194] [197] [199] [200]

Diabetes

The presence of diabetes in patients with moderate to severe CKD predicts cardiovascular deterioration in patients with and without cardiovascular disease at baseline.[201] Diabetic patients are more prone to coronary artery disease, impaired LV function with normal coronary arteries and LV hypertrophy. [202] [203] An increase in LV mass appears related to the level of blood pressure. A comparison of the pathologic spectrum of hypertensive, diabetic, and mixed heart disease showed that the last group had a significantly higher heart weight and a higher total fibrosis score than either of the other two.[204]

In one study of a cohort of dialysis patients who survived at least 6 months after the initiation of dialysis, 15% had insulin-dependent diabetes and 12% non insulin-dependent diabetes. On starting dialysis therapy the prevalence of clinical manifestations of cardiac disease was significantly higher in patients with diabetes compared with patients without diabetes. Only 11% of diabetic patients had normal echocardiographic dimensions compared with 25% of nondiabetic patients, predominantly because of the prevalence of severe LV hypertrophy (34% versus 18%).[158] Among this group of incident diabetic dialysis patients, older age, LV hypertrophy, a history of smoking, ischemic heart disease, cardiac failure, and hypoalbuminemia were independently associated with mortality. The excessive cardiac morbidity and mortality of diabetic patients compared with nondiabetic patients seemed to be mediated via ischemic disease rather than progression of cardiomyopathy.

Echocardiographic determination of LV size and function may be a good predictor of survival. In another study, diabetic dialysis patients with abnormal LV wall motion and abnormal LV internal diameter had the lowest mean survival (8 months), a mortality rate not matched by any subgroup defined by coronary anatomy, ventricular function, or clinical manifestation.[205]

Diabetes has also been found to be an independent risk factor for ischemic heart disease and for cardiac failure in renal transplant recipients. [22] [178] [194]

Left Ventricular Hypertrophy

Left ventricular hypertrophy is a condition that has been exceptionally common in CKD, identified in up to 75% of patients starting dialysis in one study from the mid 1990s.[7] It appears to regress in a substantial proportion of patients after transplantation despite maintenance of blood pressure at similar levels prior to grafting.[59] This implies that some factor(s) other than hypertension, possibly fluid overload, maintain(s) LV hypertrophy. In dialysis patients LV hypertrophy is a strong predictor for the subsequent development of heart failure and of ischemic heart disease.[21] In transplant recipients, the presence of LV hypertrophy during the first year is also an independent predictor for the development of death and subsequent cardiac failure.[206]

Other Traditional Risk Factors

Other risk factors for cardiovascular disease are well defined in the general population (see Fig. 48-6 ); however, there is either insufficient data in CKD groups (physical activity and menopause) or they are not amenable to change (such as age and sex).

Uremia-Related Risk Factors

These risk factors can be classified into hemodynamic and metabolic, some of which are peculiar to the uremic state and some magnified. Hemodynamic factors include anemia, increased extracellular volume, and arteriovenous fistulae. Recent studies have identified numerous met-abolic factors, including hypoalbuminemia, inflammation, hyperhomocysteinemia, oxidative stress, abnormal divalent ion metabolism (calcium and phosphate), dyslipidemia (elevated apolipoprotein-B), high serum fibrinogen concentrations, and others. [207] [208]

Non-Traditional Risk Factors

The ARIC study of population samples from four U.S. communities identified 807 individuals with an estimated GFR of 15 to 59 ml/min from a total of 17,888 residents. Traditional risk factors predictive of coronary heart disease included age, male sex, smoking, hypertension, diabetes, and hypercholesterolaemia.[207] In addition, non-traditional risk factors included increased waist circumference, elevated apolipoprotein B levels, anemia, hypoalbuminemia, and hyperfibrinogenemia.[207]

A prospective study from France of 344 prevalent renal transplant recipients[208] found that not only classic cardiovascular risk factors were associated with an increased incidence of atherosclerotic events, but also some non-traditional risk factors such as a high serum homocysteine and high C-reactive protein level were significant independent predictors.

Hemodynamic Risk Factors

Anemia

In moderate to severe CKD, prior to dialysis (GFR < 50 mL/min), anemia is associated with LV growth.[16] In dialysis patients, worsening anemia is associated with progressive LV dilatation and hypertrophy, and with the development of de novo heart failure. [17] [157] In renal transplant recipients anemia is an independent risk factor for the development of electrocardiographically diagnosed LV hypertrophy and of symptomatic heart failure. [22] [175] [206] In patients with CKD, moderate to severe anemia been found to be a risk factor for stroke and or coronary events. [171] [172]

Increased Extracellular Volume

At all stages of CKD, sodium and water overload may cause plasma volume expansion, LV dilatation, and LV hypertrophy. This is particularly so in dialysis patients. Greater interdialytic weight gain is independently associated with higher blood pressure in hemodialysis patients, and the latter is a risk factor for cardiac events.[209] Left ventricular hypertrophy is possibly more severe in long-term peritoneal dialysis patients, a finding associated with pronounced volume expansion, hypertension, and hypoalbuminemia.[19] In 125 incident peritoneal dialysis patients, lower total sodium and fluid removal rates, in addition to higher blood pressure, comorbidity, lower serum creatinine levels, and higher residual renal function were independent factors affecting survival.[210]

Arteriovenous Fistulae

Blood flow in arteriovenous fistulae and grafts predisposes to LV volume overload. In one study, 20 renal transplant recipients with a mean fistula flow of 1790 ± 648 ml/min were assessed.[211] Three to four months after fistula closure LV end diastolic diameter decreased from 51.5 to 49.3 min (P < 0.01) and LV mass index fell from 135 to 120 g/m2 (P < 0.01). Recently these findings were confirmed in another similar study.[212]

Arteriosclerosis

Increased pulse pressure and systolic blood pressure are closely correlated with LV hypertrophy. [139] [141] Raised pulse pressure, increased carotid wall thickness, and elevated PWV have all been associated with an increased mortality. [130] [131] [132] This is addressed more fully in the earlier section on Pathology and Pathophysiology.

Mode of Dialysis Therapy

Although Canadian and Italian cohorts on dialysis programs in the eighties and early nineties found higher risks for death in peritoneal dialysis compared to hemodialysis patients, more recent comparative studies from the same groups found no difference in mortality. [213] [214] [215] The hemodialysis state constitutes a condition of hemodynamic overload and metabolic perturbation lethal in its impact on the heart. However, the Lombardy study reported that the risk of de novo cardiovascular disease did not differ by treatment modality.[213]

Dialysis provides inadequate treatment of the uremic state, yet the target quantity required to limit the contribution of “uremic toxins” to cardiac dysfunction is unknown. The recent failure of the HEMO study to demonstrate a difference in mortality according to the prescribed dose of dialysis suggests that the partial removal of fluid and uremic toxins, at least within the range used, is insufficient to significantly affect the underlying high mortality rate.[216] Whether further improvements in dialysis technology, such as daily or nocturnal dialysis, will diminish the uremic component of cardiac disease is unclear and awaits longer term studies.

Renal transplantation is the best model of what happens to the heart when uremia is treated properly. Although hypertension usually persists, as does the fistula and sometimes hypervolemia, anemia is usually corrected as is the metabolic perturbation. Improvements in concentric LV hypertrophy and LV dilatation are seen, but the most striking observation is the improvement in systolic dysfunction.[59] It is not known which adverse risk factors characteristic of the uremic state have been corrected to produce this improvement in LV contractility. In a virtually complete national U.S. survey of diabetic dialysis patients there was a significant decrease in the risk of hospitalization for cardiac failure after renal transplantation compared to patients on the renal transplant waiting list, even accounting for selection bias.[64]

Metabolic Risk Factors

Hypoalbuminemia

Hypoalbuminemia has been shown repeatedly to be a potent predictor of outcome in dialysis patients. Hypoalbuminemia is associated with LV dilatation and predisposes to both de novo cardiac failure and ischemic heart disease.[217] It is more characteristic of peritoneal dialysis than of hemodialysis patients, and in patients treated with each modality disease may result from different mechanisms. It is in fact likely that the path to death is different in hemodialysis patients, as a higher proportion develops cardiac failure, which predisposes to earlier death. In renal transplant recipients, hypoalbuminemia is an independent risk factor for the development of both de novo cardiac failure and ischemic heart disease, a similar observation to that made in dialysis patients. [17] [175]

Inflammation

C-Reactive protein (CRP) is an acute phase reactant and a marker for inflammation. It has also become recognized as an important link in the development of atheroma in CKD. In one study, hemodialysis patients in the highest CRP quartile had a five-fold increased relative risk of cardiovascular death compared with those in the lowest.[218] The association between CRP and cardiovascular death in dialysis patients has also been corroborated by other studies.[219] [220] There is no doubt, from these studies, that inflammation is a strong cardiovascular risk factor; however, some caution in their interpretation is suggested. Each was conducted in prevalent, rather than incident, dialysis patients thus with an unavoidable survivor bias; and some at least may have been compromised by inadequate power to adjust for all risk factors and/or by the inclusion of patients who already have symptomatic cardiovascular disease.

Hyperhomocysteinemia

The pathogenesis of atheroma formation by homocysteine remains obscure, although endothelial cell injury, oxidative stress, and a hypercoagulable state each may play some role. [221] [222] [223] Elevated levels of homocysteine are a risk factor for cardiovascular disease in the general population and appear to be associated with further risk in patients with chronic renal disease. [224] [225] Most hemodialysis patients have grossly elevated plasma homocysteine levels, but the absolute level is dependent on nutritional status, protein intake, and serum albumin.[226] Lower homocysteine levels in patients with cardiovascular disease appear to be related to the higher prevalence of malnutrition and hypoalbuminemia in affected patients.[226] Prospective studies have also demonstrated that hyperhomocysteinemia is an adverse prognostic factor for cardiovascular disease outcomes in dialysis patients. [227] [228]

Oxidative Stress

Oxidative stress is said to occur when there is an imbalance between formation of reactive oxygen species (ROS) and antioxidant defense mechanisms. Generation of ROS (e.g., hydrogen peroxide, H2O2; free radicals such as superoxide, O2-, and hydroxyl radical, OH-) are continuously formed in vivo and play an important role in host defense against tumor cells and pathogens. [229] [230] A number of enzymatic and non-enzymatic defense mechanisms have evolved to “detoxify” ROS. The predominant non-enzymatic agents include vitamin E, vitamin C, selenium, and zinc. Superoxide dismutase and glutathione peroxidase are the main antioxidant enzymes. Enhanced oxidative stress may be identified by an increase in the products of lipid peroxidation (e.g., malondialdehyde), a decrease in substances that enhance oxidative resistance (e.g., plasmalogen), or a decrease in reducing substances (e.g., glutathione). It is thought that oxidative stress is important in the formation of atheroma because lipid peroxidation products in particular are consistently found in atheromatous streaks and sclerotic lesions.[231]

In CKD, markers of oxidative stress are increased and thus may be an important trigger in the complex chain of events leading to atherosclerosis. [231] [232] In one study, serum malondialdehyde was significantly higher in hemodialysis patients with cardiovascular disease than those without.[233] Dialysis may also further contribute to oxidative stress through removal of antioxidants or stimulation of ROS through the use of incompatible dialysis components.

Abnormal Divalent Ion Metabolism

Persistently elevated calcium and phosphate concentrations are increasingly recognized to be associated with increased cardiovascular mortality. In patients with CKD, data from the Veterans' Affairs Consumer Health Information and Performance Sets (CHIPS) of 6730 patients with CKD revealed that a serum phosphate level more than 3.5 mg/dl was associated with mortality, independent of other risk factors and of estimated GFR.[234] However, this mortality risk may not necessarily be a direct toxic effect of phosphate, but may reflect confounding by the possibility that increased serum phosphate levels may be a marker for more severe CKD.[235] A database analysis of 40,538 prevalent hemodialysis patients from the USRDS also demonstrated that high serum phosphate, serum calcium, and serum parathyroid hormone concentrations were associated with increased all-cause and cardiovascular mortality.[236] This study included only survivors of dialysis, thus limiting the conclusions that can be made. However, the CHOICE study, which enrolled incident hemodialysis patients, confirmed the adverse impact of divalent ion abnormalities.[237]

Increased prevalence and extent of coronary artery calcification, particularly in young dialysis patients, has been significantly associated with higher serum phosphate, calcium—phosphate product, and calcium intake.[131] Whether this calcification represents specific changes within atherosclerotic plaques or a stage associated with arteriosclerosis is not clear. The presence of vascular calcification in hemodialysis patients was associated in one study with increased stiffness of large capacity, elastic type arteries such as the aorta and common carotid artery. The extent of arterial calcifications increased with the use of calcium-based phosphate binders.[96]

An attractive but unproven hypothesis is that disturbed divalent ion metabolism promotes vascular calcification, which produces noncompliant large vessels. This in turn predisposes to LV hypertrophy, cardiac failure, and subsequent death.

Prothrombotic Factors

Decreased platelet aggregation and increased bleeding time occur in patients with chronic renal disease, especially chronic renal insufficiency and hemodialysis patients.[74] Elevated levels of fibrinogen and other procoagulant factors are also observed in CKD and hyperfibrinogenemia has been linked to increased coronary events.[207] In the general population the percentage reduction of cardiac disease by aspirin in patients with prior myocardial infarct, stroke, transient ischemic attacks, unstable angina, coronary bypass graft surgery, coronary angioplasty, atrial fibrillation, valvular heart disease, and peripheral vascular disease is approximately 25%.[238] It is unknown whether this risk is similarly diminished in patients with CKD.

Other Potential Risk Factors

There is some evidence that circulating levels of apoptotic molecules (soluble Fas and soluble Fas ligand) may play an important clinical role in atherogenesis. [239] [240] Epidemiological studies are now required to define this relationship better.

Carnitine insufficiency also has been associated with atherogenic risk although elucidation through appropriate clinical longitudinal studies is currently lacking. Some patients may benefit from administration of carnitine, possibly through an improvement in erythrocyte sodium/potassium ATPase activity and prolonged red cell lifespan.[241] It is an expensive compound however and further preliminary trials would appear wise before larger interventional studies are considered.

Summary

Current epidemiologic evidence supports the importance of the traditional cardiovascular risk factors in predisposing to the excessive cardiovascular event rate in chronic uremia. In addition, the hemodynamic and metabolic perturbations characteristic of uremia likely exacerbate both cardiac and vascular disease and further augment the mortality risk in these patients.

MANAGEMENT

Diagnosis

Substantial developments in diagnostic techniques for the appraisal of cardiovascular disease have occurred in the past decade. These diagnostic tools can often be applied across the spectrum of CKD, can be used to investigate both ischemic and cardiomyopathic disease, and are limited by the same clinical considerations, both renal and cardiovascular. In a practical context, it is of course assumed that careful clinical appraisal will always precede further investigation.

Cardiac Disease

Electrocardiography

The increasing prevalence of LV hypertrophy as renal function worsens predisposes to abnormalities in resting and exercise ECG in patients with CKD. In dialysis patients, minor incremental changes in the PR and QRS intervals together with non-specific ST-T wave changes are frequently seen in the resting ECG. Changes may be more manifest during dialysis due to the substantial intra- and extra-cellular electrolyte shifts, and a concurrent reduction in extracellular fluid levels has been found to alter the QRS amplitude.[242] In episodes of acute coronary ischemia, however (unstable angina and myocardial infarction) classical ECG changes occur.

Ambulatory ECG recordings have identified asymptomatic ST-T wave changes particularly during and after dialysis.[243] Whether this relates to underlying coronary ischemia or electrolyte shifts has not been determined. Exercise-related ECG changes should be interpreted with caution. Resting abnormalities, a restricted maximal pulse rate (autonomic neuropathy) and limited exercise capacity in patients with CKD may mask or, alternatively, erroneously predict underlying ischemia.

Biochemical Markers of Ischemia

Serial estimates of standard myocardial enzyme levels (creatine phosphokinase and lactate dehydrogenase), when elevated, reliably diagnose acute myocardial infarction in CKD, although single estimates have poor specificity.[244]

Recently, attention has focused on the role of troponin levels in acute ischemia. The troponin complex regulates the contraction of striated muscle and consists of three subunits: troponin C, which binds to calcium ions; troponin I, which binds to actin and inhibits actin-myosin interac-tions; and troponin T, which binds to tropomyosin, thereby attaching the troponin complex to the thin filament. The presence of either troponin T or I in the serum can be used to assess acute ischemia. Although each is present in both skeletal and cardiac muscle, they are encoded on different genes and retain immunologic specificity. They are considered more sensitive estimates of myocardial infarction than cardiac enzymes, and have been shown to predict short-term cardiac mortality. [245] [246] In CKD, despite concerns regarding impaired troponin clearance as renal function worsened, third-generation cardiac troponin T assays were found to be an independent predictor of death in 7033 patients within 30 days across the whole spectrum of renal dysfunction.[247]

Echocardiography

Two-dimensional and M mode echocardiography provide a noninvasive assessment of left ventricular structure and function, together with imaging of valves and pericardium. Systolic dysfunction, diagnosed by low fractional shortening or ejection fraction can be determined, as can LV geometry and LV hypertrophy. The degree of hypertrophy can be identified by increased LV wall thickness or by calculating LV mass index according to various formulae. Systolic failure is measured more accurately using nuclear scintigraphy as is the detection of regional wall abnormalities.

Although estimates of LV mass using echocardiography are highly reproducible between observers, its measurement varies over the course of a hemodialysis session by as much as 25 g/m2.[248] This occurs because LV internal diastolic diameter decreases as a result of fluid removal during the procedure. A concurrent decrease in LV wall thickness is not observed. Consequently the LV mass index measured predialysis is higher than the post dialysis measurement, although the actual LV mass has not changed. Therefore where possible, imaging should be carried out when the patient has achieved their “base weight”: the weight below which hypotension or symptoms such as muscle cramps occur.

Diastolic LV function can be assessed noninvasively using pulsed Doppler analysis of flow across the mitral valve during diastole. Normally, as the mitral valve opens, ventricular relaxation occurs, with a rapid increase in flow leading to an E (“early”) peak, followed by a later increase, the A (“atrial”) peak, which reflects atrial contraction. Assuming normal atrial function, the increased stiffness of the hypertrophic LV leads to a smaller E peak, and a larger A peak, expressed conveniently as a decreased E/A ratio.

Dobutamine stress echocardiography is achieving recognition as a screening tool for ischemic heart disease in patients with CKD. It can also be used in patients with valvular disease or impaired systolic function to assess underlying systolic reserve. In the general population, the overall sensitivity and specificity for the detection of coronary artery disease has been reported as 80% and 84% respectively, with improved sensitivity as the number of affected vessels increases.[249] In one study, sensitivity was comparable to exercise-related scintigraphic scanning in patients with known coronary artery disease, although it maybe reduced in women and in the elderly. [249] [250] In CKD, it has some inherent advantages over scintigraphy, particularly for those patients unable to exercise significantly. For dialysis patients, negative predictive values in excess of 95% have been reported with reasonable patient numbers and follow-up times.[251]

Nuclear Scintigraphic Scanning

Nuclear scintigraphy can be used both for assessment of myocardial systolic function and for ischemia. The former method examines ejection fraction of the left and/or right ventricles and relies upon gated analysis techniques. Care must be taken with regards to associated valve regurgitation, which when present, can substantially confound functional estimates. If valve function is intact, accurate estimates of systolic function at rest and with exercise can be achieved.

The predominant role for nuclear scanning techniques, however, is in the assessment of myocardial ischemia, both as a screening tool in the work-up for transplantation and in cases of diagnostic uncertainty. Exercise-based studies as well as the use of dipyridamole to enhance vasodilatation are commonly used, together with one or other of 99mTc-labelled thallium, methoxyisobutylisonitrile (MIBI), or metaiodobenzylguanidine (MIBG). Inherent problems with scintigraphy must be taken into consideration. Blood pressure may be too high or too low to permit safe administration of a vasodilatory agent; high endogenous circulating levels of adenosine may blunt the efficacy of dipyridamole; coronary flow reserve may be reduced due to LV hypertrophy and small vessel disease; and symmetrical coronary disease and/or a blunted tachycardic response due to autonomic neuropathy can mask significant pathology. [251] [252]

Recent studies have shown a varying response to and reliability of scanning. One study of 80 patients reported a significantly increased mortality in those with, compared to those without, reversible ischemia. Fixed as opposed to reversible defects were predictive of future cardiac deaths but at a later period.[252] Dahan and colleagues found a positive and negative predictive value of 47% and 91% respectively for coronary events using comparative thallium scanning and coronary angiography in a study of 60 asymptomatic hemodialysis patients over 2.8 years.[253] Other studies have shown a poor sensitivity and positive predictive value for mortality over time.[254] It is likely that both on-site expertise and the recognized testing limitations in patients with CKD influence the utility of nuclear scanning and therefore dictate the interpretation and screening strategy for a particular center.

Electron-Beam Ultrafast Computed Tomography-Derived Coronary Artery Calcification

Electron-beam ultrafast computed tomography (EBCT)-derived coronary artery calcification is a relatively new technique that relies upon the principle that coronary artery calcification is a reliable surrogate for significant coronary atherosclerosis.[255] This is far from certain in patients with CKD. As has been discussed, widespread and severe vessel wall calcification is common in uremia. Nonetheless, evidence is accumulating that an increased calcium content per se is a poor prognostic sign. [14] [156] [256] It is noteworthy that EBCT has been used recently to demonstrate a reduction in coronary artery calcification after treatment with the non-calcium containing medication sevelamer although subsequent effects on cardiovascular events or mortality are not known.[257] The role of EBCT in evaluating risk or disease in transplant patients is also unknown.

Coronary Angiography

The diagnosis of large vessel coronary artery disease can be problematic in patients with CKD for several reasons. Patients are frequently asymptomatic, have a relatively high prevalence of nonatherosclerotic ischemia, and many who are at highest risk are unable to exercise sufficiently to facilitate non-invasive diagnosis. Despite newer diagnostic tools becoming available, the sensitivity and specificity of most are limited and the gold standard for diagnosis of coronary artery disease remains coronary angiography.[258]

In patients not on dialysis, there is some risk of contrast nephropathy[259] and in all patients with CKD there is a risk of cholesterol embolization with angiography. Additional concerns relating to cost, access, and demand limit the availability of angiography so that the procedure in these patients should be reserved for those patients with unstable angina/myocardial infarction on maximal therapy in whom coronary revascularization is a viable therapeutic modality.

Screening of patients to determine suitability for transplantation is another issue. Recently, some effort has been directed to establishing guidelines to determine patients most at risk and, hence, potential benefit from coronary catheterization. In one study, it was found that over 60% of angiograms in 89 patients being assessed for transplantation could have been avoided by restricting angiography to diabetics and those patients with a history or symptoms of ischemic heart disease, without changing their place on the transplant list.[260] Most units now have a strategy (often a cascade algorithm) to determine those patients requiring more intensive cardiac work-up in this context, usually stratified into diabetics and non-diabetics. The American Society of Transplant Physicians advocates screening all but those at lowest risk for ischemic heart disease, which acknowledges the high prevalence of asymptomatic coronary artery disease in the dialysis population. [68] [258]

Vascular Disease

Peripheral vascular disease carries a high burden of disease in all dialysis units, which with the increasing rate of diabetes as a cause of kidney failure, is likely to further increase. Several techniques are now available for the evaluation of peripheral blood vessels and blood flow, including duplex ultrasonography and color-flow imaging, the ankle-brachial index test, venous plethysmography and brachial artery reactivity, magnetic resonance imaging and angiography, intravascular ultrasound, and digital imaging.

Duplex Ultrasonography and Doppler Color-Flow Imaging

Technical advances in ultrasonography have allowed reproducible measurements of blood vessels and blood flow in a wide variety of vessels.[261] The various vascular beds have typical waveforms, and alterations from normal indicate disease. General features of a diseased arterial segment include spectral broadening of the waveform signal, increased flow velocity at the site of vessel narrowing, and pre-stenotic waveform characteristics above a site of obstruction or poststenotic characteristics below it. Peak systolic velocity is the most reliable waveform measurement and the one least subject to interobserver variability.[262]

The assessment of large vessel pulse wave velocity (PWV) has become important in the assessment of risk factor analysis and is correlated closely with pulse pressure.[12] It requires the use of Doppler ultrasound to measure the arterial flow tracing transcutaneously at two different, accessible, arterial sites simultaneously (usually the carotid and femoral). From this, the aortic PWV can be calculated simply by the following formula: PWV = D/Δt, where D = the distance between the two recording sites and Δt = the difference in time. An increase in pulse wave velocity due to large vessel stiffening, as described earlier, is probably a predictor of mortality, which can be modified favorably by the use of angiotensin-converting enzyme (ACE) inhibitors in particular.

Ankle-Brachial Index Test

The most useful initial screening test for arterial disease of the lower extremities is the ankle-brachial index. It is determined by continuous-wave Doppler interrogation of blood pressure measurements in the ankle and arm. The index is determined by dividing ankle systolic blood pressure by arm systolic blood pressure. Measurements are usually taken at rest and after a standardized treadmill exercise. Completion of the protocol without pain virtually excludes the diagnosis of vascular claudication. A normal resting ankle-brachial index is 1 to 1.1. Progressive decrements indicate worsening, often multi level, arterial stenosis. A resting ankle pressure of less than 50 mm Hg or an ankle-brachial index of less than 0.26 indicates severe, limb-threatening arterial compromise.[263] The hallmark of arterial insufficiency, however, of the lower extremity is a decrease in the ankle-brachial index after exercise.

Potential problems of the ankle-brachial index test include changes in brachial pressure caused by upper extremity vascular disease and calcification of blood vessels. Diabetics often display an increased ankle-brachial index due to arteriosclerosis and medial wall calcification. In this case, a toe systolic-pressure index (compared to arm pressure) can be useful: normal values are greater than 0.6.

Plethysmography and Brachial Artery Reactivity

Recently, venous plethysmography and high-precision ultrasound have been used in dialysis patients to assess post-ischemic forearm blood flow and brachial and radial artery reactivity to heat-induced peripheral dilatation. By combining plethysmographic data, and assessment of intima-media thickness (IMT), PWV, and LV mass, it has been possible to show that dialysis patients have a reduced post-ischemic vasodilatory capacity that correlates with large vessel stiffening, IMT, markers of endothelial cell activation, and LV mass index. [264] [265] Initial suggestions are that endothelial dysfunction in these patients may be a factor influencing large vessel cardiovascular change. Large vessel compliance was improved by chronic ACE inhibition with perindopril, suggesting not only a possible causal link between endothelial cell activation and large vessel compliance but one amenable to treatment.

Magnetic Resonance Imaging and Angiography

Magnetic resonance imaging and angiography are becoming widely used techniques for evaluating blood vessels. Magnetic resonance techniques are especially useful in evaluating arterial dissection and characterizing vessel-wall morphology (including hematoma or thrombus). Some success has also been found in imaging renal and mesenteric vessels, which is an attractive option in patients in whom invasive investigation is relatively contraindicated, particularly those at high risk of cholesterol embolization or radiocontrast-induced nephropathy. Current limitations include the high cost of the study, patient dissatisfaction with the technique (especially the claustrophobia experienced during a scan), the need for ensuring the patient is free of metal subject to the powerful magnetic field produced during scanning, and difficulty with patient positioning. Decreased scan times and more open design of the newer machines have lessened patient-related problems.

Intravascular Ultrasound

Intravascular ultrasound is most widely used as an adjunct to peripheral vascular and coronary intervention and can characterize vessel and plaque morphology. Using high-frequency ultrasound transducers and imaging of the vessel lumen, this technique avoids some of the drawbacks of transcutaneous ultrasound such as shadowing artifact from vessel-wall calcification and acoustic impedance from inter-posed tissues. Computerized three-dimensional reconstruction techniques can be used to display a map or facsimile of the vessel lumen.

Digital Imaging

Digital-imaging technology is an important advance in non-invasive imaging of the vascular system. The ability to store information in digital format allows remote reading and serial comparisons of studies with the use of telemedicine.[266] Theoretically, the patient's entire imaging history could be stored in this format and could be easily transferred to different imaging stations, despite differences in viewing equipment or software. Such an application has important clinical and research applications.

Treatment

Cardiac Disease

Cardiomyopathy and Cardiac Failure

A reversible precipitating or aggravating factor is frequently found in patients with CKD presenting with cardiac failure. Arrhythmias, underlying myocardial ischemia, marked anemia, uncontrolled hypertension, and the use of drugs that may adversely affect cardiac performance (particularly those associated with negative inotropic activity or tachycardia) can all precipitate a clinical presentation of cardiac failure.

In patients with CKD also, the synergistic and destructive effects of an increase in extracellular volume frequently co-exist with cardiac failure, and in combination with myocardial dysfunction precipitate the need for initiation of dialysis. Dialysis patients with severe myocardial impairment may require ultrafiltration acutely, which is associated with less metabolic perturbation than acute dialysis. Careful assessment of target weight will subsequently be required and more formal cardiac evaluation, according to the clinical context, will be required. For reasons outlined earlier, echocardiograms are most accurate when performed at the patient's “base weight”, which may not be possible until several days after an acute admission. In diabetic dialysis patients, there is also some evidence that transplantation reduces the incidence of cardiac failure and associated hospitalization rate.[64] An approach to the management of LV disorders is shown in Figure 48-9 .

FIGURE 48-9 An approach to the treatment of left ventricular (LV) disorders and cardiac failure in patients with chronic kidney disease. RAS, renin-angiotensin system.

Pharmacotherapy

In a clinical setting, most patients with cardiac failure and CKD require numerous medications for appropriate control and treatment. Combination therapy is therefore the rule, and interactions between medications needs careful consideration, particularly with regards to dose reduction or frequency. Other issues, such as effects on co-morbid conditions (e.g., diabetes, peripheral vascular disease, glaucoma, chronic airflow obstruction), compliance, and potential interactions with other drugs (e.g., immunosuppression, anticoagulants, or statin therapy) can be important.

Loop diuretics are indispensable for achieving and maintaining euvolemia in all patients with cardiac failure, including those with CKD. Their effect will be attenuated in patients with advanced renal failure, but not as severely as thiazide diuretics, which usually become ineffective with a glomerular filtration rate (GFR) below 30 mL/min. The synergistic diuretic effect of loop diuretics and thiazides, however, persists even at relatively advanced stages of renal insufficiency and can be a useful therapeutic option. The effects of aldosterone antagonists are unpredictable in patients with CKD. They exert a weak diuretic action and perhaps their primary reason for consideration of use resides in their recently reported benefit in cardiac disease and/or reduction in proteinuria in patients with and without CKD. [267] [268] [269] [270] Hyperkalemia in particular can result when these drugs are combined with blockade of the renin-angiotensin system and/or β-receptor antagonists in the setting of CKD. Dose reduction or avoidance is advised in such circumstances.

Angiotensin-converting enzyme inhibitors have been clearly shown to improve symptoms, morbidity, and survival in non-uremic individuals with heart failure.[271] The benefit of ACE inhibition is applicable to those with diastolic and systolic dysfunction. ACE inhibitors should also be used to prevent cardiac failure in asymptomatic patients whose LV ejection fraction is less than 35% and in post-myocardial infarction patients with an ejection fraction of 40% or less. [272] [273] Although these drugs have not been as well studied in patients with CKD, it is reasonable to consider using them when there is no contraindication. It is unlikely the use of ACE inhibitors produces a reduction in GFR generally in CKD, given the beneficial effects on renal function preservation observed in diabetics by angiotensin receptor blockade (ARB). [274] [275] [276] Their effects in patients with a GFR less than 25 mL/min are unpredictable and, until better data are available, caution is advisable in this group as well as in patients with severe renovascular disease, acute renal dysfunction, and after transplantation. Hyperkalemia in moderately advanced CKD and renal artery stenosis in a transplanted kidney are additional concerns requiring monitoring after starting treatment. Apart from reno-protection in diabetics, there is less information available for ARB. They are probably as effective as ACE inhibitors for cardiac failure, but there is no evidence that the risk of serious side effects is any lower. The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial showed that in 1513 patients with type II diabetes and overt nephropathy, losartan decreased the risk of ESRD and prevented CHF.

β-receptor antagonists improve the prognosis of persons with asymptomatic systolic dysfunction, regardless of whether or not the patient has had a myocardial infarction.[278] Comparable mortality-based trials have not been conducted in the dialysis population, but improvement in LV dimensions and fractional shortening have been demonstrated.[279] Chronic activation of the adrenergic nervous system is recognized in hemodialysis patients. It contributes to the development of LV hypertrophy, ischemia, and myocyte damage, and exerts a maladaptive role in chronic heart failure.[280] In a meta-analysis of 22 trials in patients with mild to moderate heart failure the odds ratio for death was 0.65 with β-receptor antagonists, and the odds ratio for hospitalization with heart failure was 0.64.[281] In more severe heart failure, agents such as Carvedilol and Bisoprolol have also been proven effective.[282]An Italian RCT in 114 dialysis patients with dilated cardiomyopathy demonstrated that carvedilol reduced 2-year mortality rates (51.7% mortality in carvedilol group compared with 73.2% in the placebo group, p < 0.01). There were also fewer cardiovascular deaths and hospital admissions in the carvedilol group.[283] However, it is possible that the positive effects of the adrenergic system in supporting the failing circulation may be inappropriately blocked in some patients, exacerbating heart failure.[284] In recommending increased utilization of β-receptor antagonists in dialysis patients, one should remember that the contraindications to their use—reactive airways disease, sinus-node dysfunction, and cardiac conduction abnormalities—occur frequently in this group of patients. Furthermore, the dose of some drugs, such as Atenolol, often must be reduced according to the degree of renal impairment, and agents with intrinsic sympathomimetic activity appear to be detrimental in patients with cardiac failure and should not be used.

The use of Digoxin is controversial. It improves symptoms in non-renal subjects with heart failure, and clinical deterioration may occur when it is discontinued.[285] It has not however been found to reduce mortality and is associated with a variety of risks in patients with severe impairment of kidney function. These include a predisposition to toxicity because of impaired clearance as renal function declines, and an increased risk of arrhythmia in association with hypokalemia, which can occur particularly during or after dialysis. Based on these results, it is reasonable to consider its use for rate control in atrial fibrillation and in patients with substantial systolic dysfunction and/or symptoms despite the use of other agents, with or without atrial fibrillation. It should usually be avoided in subjects with diastolic dysfunction because the increased contractility can exacerbate diastolic function. Cautious use in this group to control rapid atrial fibrillation is reasonable, particularly if β-receptor antagonists are contraindicated. Other inotropic agents, with the possible exception of Dobutamine in intractable cases, are not currently recommended.

The management of diastolic dysfunction is less well defined. Attempts to eliminate the cause are generally the focus of therapy. This includes aggressive control of hypertension, management of anemia, and control of other factors responsible for the development of LV hypertrophy. Relatively contraindicated in systolic cardiac failure, the drugs of choice in diastolic failure are probably Verapamil or Diltiazem, which enhance LV diastolic relaxation, although evidence pertaining to their superiority is relatively limited.[286] Other agents to consider include long-acting nitrates, which may be advantageous in some patients, and β-receptor antagonists are useful for managing concurrent ischemia and tachycardia. Excessive diuresis and, as mentioned, Digoxin should be avoided because of a likely increase in hypercontractility or a worsening of the degree of CKD. Direct vasodilators, such as Prazosin, Hydralazine, or Minoxidil, are generally contraindicated in this setting.[287]

Ischemic Heart Disease

The treatment of both the acute (unstable angina and acute myocardial infarction) and the non-acute presentations of coronary artery disease (stable angina and cardiac failure) in patients with CKD is the same as in the general population.

Pharmacotherapy

Patients with CKD and stable angina who have not had an infarct should be treated with standard anti-anginal agents for relief of symptoms. For those who have had an infarct, β-receptor blockade should be prescribed if tolerated, as should an ACE inhibitor for patients with LV dysfunction. To date there have been no studies of aspirin for either the primary or secondary treatment of myocardial ischemia in the CKD or dialysis population. Although the benefit of aspirin in non-uremic patients is substantial, the risk of complications, mainly bleeding, probably increases as renal function declines and effects of uremia increase. This is also the finding of a recent meta-analysis of aspirin therapy comprising over 45,000 subjects in the general community.[288] Consequently, advocating widespread use of aspirin for the primary prevention of coronary artery disease cannot be recommended. The benefits likely outweigh the risks, however, for patients with acute presentations of ischemia or who are at high risk of the same. There are few studies regarding the efficacy of clopidogrel in CKD and further details regarding risk versus benefit are required before recommendations can be made.

Coronary Revascularization

Despite the relatively high incidence of asymptomatic ischemia in CKD, due presumably to autonomic disease associated with uremia or diabetes, there is no evidence to suggest that investigation and treatment of this group result in an improved mortality. For patients who have had an infarction, angiography is indicated when there are symptoms of myocardial ischemia at rest or after minimal exertion or if there is early, severe ischemia during a stress test. For other patients, coronary angiography should be limited to those with symptoms refractory to medical therapy. As in the general population, coronary arteriography should be reserved for patients in whom revascularization (angioplasty, stenting, or bypass grafting) would be undertaken if critical coronary artery disease were identified. This decision can be difficult, particularly in light of a recognized inability to predict lifespan in dialysis patients.[8] It should therefore be based on an assessment of the significance of the lesion, operative risk, and overall life expectancy made by cardiologist and nephrologist.

The initial success rate for coronary angioplasty for patients with CKD is in excess of 90% in most published series. The restenosis rate in the general population is roughly 30% at 1 year. The rate in uremic patients is unclear as studies have been difficult to compare, although early studies that performed repeat angiography in all patients demonstrated poor results, with over 80% re-stenosis in some series. One of the larger studies to assess clinical outcome in CKD patients analyzed a registry of over 5000 patients undergoing coronary angioplasty.[289] Initial success was similar in all groups, but 1-year mortality varied proportionately with renal function, with an increase in mortality from 18.3% in patients with a creatinine clearance less than 30 mL/min to 1.5% if more than 70 mL/min. Other reports have found similar results. [290] [291]

In hemodialysis patients, the in-hospital mortality for coronary artery bypass grafting (CABG) is 12.5%, or four times higher than in the general population. [292] [293] Hence, there is a consensus in favor of bypass surgery for left main or extensive three-vessel disease and in favor of angioplasty for single-vessel disease. In the remaining multivessel cases it appears that angioplasty with stents had similar clinical outcomes to CABG, but repeated revascularization was more frequent.[294] In view of the propensity for restenosis after angioplasty in dialysis patients, CABG is probably the revascularization procedure of choice, although angioplasty with stenting may be useful in single-vessel disease or multivessel disease with culprit lesions.[294] There are encouraging reports also of a substantial reduction in restenosis rate up to 6 months after stenting with the use of sirolimus-coated stents in high-risk patients.[295]

It is uncertain if transplant patients are at an increased risk of death from myocardial ischemia [170] [296] and there is little information as to the outcome of revascularization procedures. However, case reports and small series suggest that transplanted patients with near normal renal function have a peri-operative mortality rate and long-term survival rate close to that observed in the non-dialysis population. [297] [298] [299]

In summary, the evidence suggests that patients with CKD in general are at higher risk of complications and have poorer long-term outcomes, regardless of the revascularization procedure used. It is not meaningful to compare clinical trials of angioplasty and CABG due to the marked inherent selection bias. Coronary artery stenting does appear to confer a benefit however over angioplasty alone and immunosuppression-coated stents may have further advantages. Effectively, the decision for a particular procedure will rely upon the specific cardiac and overall clinical condition of the patient, together with available resources.

Arrhythmias and Valvular Disease

Specific and detailed management of cardiac arrhythmias is largely beyond the scope of this text. An awareness of the potential for and type of arrhythmia likely to be encountered is advocated and management should accord with general principles. Perhaps the most important practical consideration is to solicit cardiological advice and support in patients with resistant or troublesome arrhythmias or poor cardiac function (or both). The combination will frequently co-exist. Consideration of renal metabolism of drugs (such as Digoxin and β-receptor antagonists) in patients with impaired renal function is necessary, as is the disturbed homeostasis of mono- and di-valent ions in the CKD population. Hyperkalemia, hypocalcemia, hypomagnesemia, and hyponatremia can all potentially complicate the pathogenesis and management of cardiac arrhythmias.

In patients with CKD with mitral or aortic valve disease primary control of potentiating factors (listed earlier), frequent monitoring once valve aperture is encroached, and appraisal of the individual patient and associated co-morbidities once surgery is considered, would appear to be a reasonable approach to treatment.

Vascular Disease

Discussion of much of the extensive vascular disease that patients with CKD experience is beyond the scope of this chapter. Diabetic patients in particular are prone to macro- and micro-vascular disease in most arterial beds from a relatively early stage of renal impairment. A variety of risk factors prediposes to vascular disease in these beds, as occurs in the coronary arterial tree.

Carotid Artery Disease

Carotid ultrasonography has become a useful surrogate marker of large vessel vascular disease. It is the mainstay of diagnosis of symptomatic and asymptomatic carotid disease and is used to assess both atherosclerotic plaques and intima-media thickness (IMT). Unfortunately, interventional studies of carotid artery disease are limited. There are no reports of treatment and associated outcome of atheromatous plaque disease in CKD and evaluation of IMT is at best a surrogate end-point. No interventional studies attempting to reduce risk factor exposure have yet shown a clear benefit on IMT. [300] [301] Further prospective interventional studies hopefully will help clarify the significance and relevance of both carotid atheroma and IMT on morbidity and mortality in CKD.

Peripheral Vascular Disease

Peripheral vascular disease (PVD) is an extremely debilitat-ing and expensive co-morbid cardiovascular complication among patients with CKD. It is present more commonly in dialysis patients, presumably because of the concentration of atherogenic risk factors in this group, though it is seen also in pre-dialysis and transplant groups. Its prevalence in incident dialysis patients is estimated to be over 15%. In transplantation, amputation for PVD is the most common vascular complication after renal transplantation, occurring in 13% to 25% of allograft recipients within 5 years of transplantation.[302] Peripheral vascular disease is more common in diabetics, and other risk factors include age (in non-diabetics only), hypertension, dyslipidemia, smoking, and coronary artery disease. Blacks may be at lower risk for the development of PVD.[303]

In the United Kingdom and Sweden reductions in limb amputation by up to 80% have been described after treatment in specialized multidisciplinary clinics. [304] [305] The cost-benefit ratio for such clinics is considerable. Specific treatment includes prevention, conservative management, and amputation. General measures of primary foot care are inadequately reinforced in most cases. Smoking cessation is theoretically important although no studies to assess the benefits of cessation have been performed. Exercise is probably the best conservative measure available to improve claudication symptoms; however, it is of little benefit in advanced microvascular disease.

Medications are not frequently used in these patients. A randomized study of Pentoxifylline showed no benefit in walking distance compared to placebo in one study. Furthermore levels accumulate in moderate renal impairment. Cilostazol, a new cAMP phosphodiesterase inhibitor, has improved claudication distances in randomized trials, but has altered lipid binding in CKD and may not be safe.[306] The use of statins does not appear to be of benefit, and there is no evidence pertaining to aspirin or other agents.

Angioplasty is suitable in some patients although lesions are often multiple, diffuse, and involve small vessels. Recurrence of symptoms in non-CKD patients occurs early and there are no trials examining effects in patients with CKD. Intermittent claudication is the most common reason for bypass surgery (73% in one study)[307] and evidence for appropriate intervention in CKD is lacking. Nonetheless, in dialysis patients, conservative therapy (amputation or auto-amputation) has been advocated as a primary maneuver because of the high risk of primary failure of bypass surgery, symptom recurrence, and peri-operative mortality.[308]

A total of almost 36,000 amputations were performed in the United States Medicare Dialysis program between 1991 and 1994. The crude amputation rate for all patients on dialysis was 4.3/100 person years, compared to 13.8/100 person years for diabetic patients. The rate increased over the 3 years. Survival after amputation was appalling, with only 30% still alive after 2 years. The presence of gangrene, below-knee amputation (compared to above toe), and age over 55 years were associated with a higher risk of death after amputation. In another recent study Dossa and colleagues recorded a hospital mortality and 2-year survival rate of 7% and 79% in 375 predialysis patients, and 24% and 27% in 88 dialysis patients.[309] In each of these studies, the amputation rate in transplant patients was significantly lower than for dialysis patients. Particular risk factors for the transplant group included associated ischemic heart disease, undergoing dialysis before transplantation, and having an abnormal brachial-ankle index at the time of transplantation.[310]

Risk Factor Intervention

Traditional

Most individual cardiac risk factors are more prevalent in subjects with CKD (see Fig. 48-6 , Tables 48-2 and 48-3 [2] [3]). Furthermore, they are commonly clustered within the individual. Hence efforts to reduce cardiovascular risk, although dealt with separately here, often incorporate a multifaceted approach that addresses numerous risk factors simultaneously.


TABLE 48-3 -- Traditional and Nontraditional Risk Factors for Cardiovascular Disease in Chronic Kidney Disease, Identified by Cohort Studies and Randomized Controlled Trials to Test Interventions that Decrease Risk Factors

Risk Factor

Cohort

RCT

CKD

Dialysis

CKD

Dialysis

Smoking

+

+

NA

NA

Hypertension

+

+

+

ND

RAS blocked

+

+

+

ND

Lipid

+

+

+

-

Diabetes

+

-

ND

ND

Obesity

+

+

ND

NA

Fibrinogen

+

+

-

+

Anemia

+

+

-

-

Hypoalbuminia

+

+

ND

ND

Inflammation

+

+

ND

ND

Degree of kidney impairment

+

+

NA

-

Oxidant stress

-

?+

-

?+

Hyperphosphatemia

+

+

ND

ND

Homocysteine

+

+

ND

ND

CKD, chronic kidney disease; NA, not applicable; ND, not done; RAS, renin-angiotensin system; RCT, randomized controlled trial; +, positive; -, negative.

Hypertension

Pre-Dialysis

The use of ACE inhibitors or angiotensin receptor blockade (ARB) is considered the agent of first choice in most patients due to their documented benefit in delaying the progression of CKD in both diabetic and non-diabetic disease, particu-larly with associated proteinuria. [163] [272] [275] [311] [312] [313] [314] Ramipril has improved cardiovascular disease outcomes in patients with decreased GFR and at least one cardiovascular disease risk factor, in addition to either diabetes or manifest vascular disease.[163] Losarten has reduced hospitalization for heart failure in diabetics with overt nephropathy.[274] It appears that the beneficial impact of blockade of the renin-angiotensin system is more than can be accounted for by lowering of blood pressure.

Calcium channel blockers, particularly the dihydropyridines, have not compared well against ACE inhibitors and ARB in the reduction of proteinuria, delay in progression of renal function, or cardiovascular events. [275] [314] [315]The use of β-receptor antagonists, diuretics, and other vasodilators are dependent on the response to treatment and underlying co-morbidities. The more common of these have been covered in earlier sections on cardiac failure and ischemic heart disease.

Management of hypertension should generally aim for levels less than 130/85 mm Hg for individuals with parenchymal disease, 125/75 mm Hg if there is more than 1 g/day of proteinuria, and less than 130/80 mm Hg for those with diabetes and less than 1 g/day of proteinuria. [182] [316] [317] [318] In some patients, particularly diabetics with moderate to advanced renal dysfunction, blood pressure can be highly resistant to intervention, requiring extensive combination treatment.

Dialysis

The mainstay of therapy in dialysis patients is maintenance of normal extracellular fluid volume, with evidence to suggest a dialysis regimen with long, slow ultrafiltration is associated with normotension, regression of LV hypertrophy, and improved survival. [186] [319] A reasonable target blood pressure for antihypertensive treatment is a pre-dialysis blood pressure less than 140/90 mm Hg, unless the patient develops symptomatic hypotension or low blood pressure during or after dialysis. Patients with a blood pressure over 140/90 mm Hg after achievement of their base weight should have antihypertensive drugs prescribed.

Selection of antihypertensive agents is best guided by the presence of associated co-morbidities. In their absence, there are reports supporting ACE inhibitors, possibly through their effect on a reduction in pulse wave velocity and arterial stiffness. In two studies of hemodialysis patients, ACE inhibitors were associated with regression of LV hypertrophy. [320] [321] There are not, however, large randomized trials to support one agent over another. Hence, patients with reduced LV systolic function are likely to benefit from ACE inhibitors or ARB, and patients with relatively intact LV function post myocardial infarction should be treated with β-receptor antagonists. Practical difficulties in this patient group in particular include associated cerebro-vascular or coronary disease, advanced age, and cardiovascular instability in relation to ultrafiltration. In such situations, blood pressure will require individual targeting and some compromise on the optimal target will be necessary.

Transplantation

There are limited data on intervention in the transplant group. Calcium channel blockers are widely used because they are well tolerated and because of their effects in counter-acting calcineurin-mediated vasoconstriction. The use of ACE inhibitors or ARB is probably justified in most patients, although issues relating to hyperkalemia, anemia and uremia warrant consideration, particularly in the first 12 months post transplantation. [176] [322] The American Society of Transplantation recommends maintaining blood pressure below 140/90 mm Hg, lower if possible, in line with JNC VI for subjects with kidney disease.[323]

Dyslipidemia

In short-term studies, statins have been recognized as being safe and efficient in patients with CKD. [324] [325] [326] Results of longer-term studies with hard endpoints have also become available in the past few years. In a secondary analysis of three randomized controlled trials with pravastatin, a subset of patients (n = 4491) with a GFR between 30 and 60 mL/min had a reduction in the incidence of myocardial infarction, coronary death, or coronary revascularization.[327] This is consistent with the results from the Heart Protection Study (n = 20,536) in which Simvastatin reduced cardiovascular events by 39% in patients with serum creatinine more than 1.4 mg/dL (men), more than 1.2 mg/dL (women).[318] Even though the experience with the use of fibrates in CKD patients is limited, a subgroup analysis of the Veterans' Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) study showed that in 1046 men with GFR of 75 ml/min, gemfibrozil lowered the incidence of the primary composite outcome (coronary death or non-fatal infarction) compared to placebo.[329]

The Assessment of LEscol in Renal Transplantation (ALERT) study was a randomized, placebo-controlled trial in 2102 transplant recipients investigating the effect of fluvastatin on primary composite endpoints of cardiac death, non-fatal MI, or coronary intervention. Although the fluvastatin and placebo groups did not differ significantly for the primary outcome, a post hoc analysis using alternative outcomes suggested that fluvastatin reduced the incidence of cardiac death or definite myocardial infarction from 104 to 70 events.[330] However, the 4-D (Die Deutsche Diabetes Dialyse) study in diabetic dialysis patients found that 20 mg per day of atorvastatin failed to reduce the composite end point of cardiovascular death, nonfatal MI, or stroke in dialysis patients with type II diabetes.[331]

The weight of evidence currently therefore would appear to suggest that patients with CKD do benefit from statin and, possibly, fibrate therapy; that transplant patients may from statins; but that diabetic dialysis patients may not be advantaged by such treatment. Whether the anti-inflammatory effects of statin treatment in dialysis patients are beneficial remains to be determined. Failure to control LDL-cholesterol levels with statins is not uncommon; however, combination therapy in severe CKD is controversial because of the high risk of side effects. Elevated serum triglyceride or low HDL-cholesterol, in the absence of increased LDL-cholesterol should be managed by diet and increased physical activity, but drug therapy to reduce cardiac risk is not currently recommended.

Smoking

There are no studies demonstrating that cessation of smoking improves the outcome of CKD at any stage. Nevertheless, it is reasonable to extrapolate data from the general population that indicates smoking cessation reduces cardiovascular risk over time.[332] Nicotine or bupropion therapy should be considered to help cessation although the kidney metabolizes nicotine and the dosage may need to be reduced as GFR declines. Little information concerning bupropion is currently available.

Diabetes

Only limited data are available regarding potential benefits of tight glycemic control in pre-dialysis diabetic patients. In the dialysis group, monitoring has probably been inadequate with one report from the United States suggesting that fewer than half of those with diabetes have an annual HbA1C level and less than 10% have more than three estimates per year.[333] There is one report to suggest that tight glycemic control after transplantation may reduce the development of new diabetic changes in the transplanted kidney[334] and one also to suggest that transplantation in diabetics reduces the risk of hospitalization from cardiac failure.[64] All-cause mortality may also be reduced in type I diabetics with combined renal and pancreatic transplantation.[335]

In the absence of definitive evidence, the approach to treatment probably derives from data obtained from the general population, but patient specific information must be considered. Tight glycemic control would seem an appropriate aim in pre-dialysis patients unless hypoglycemic episodes are troublesome or unpredictable. There is less support for near-euglycemic levels in dialysis patients because of the inability to influence renal function and the propensity for hypoglycemia due to glucose diffusion during dialysis. In transplant patients, tight glucose control may be difficult because of the hyperglycemic tendency of immunosuppressive agents; and in both dialysis and transplant patients lack of awareness of hypoglycemia due to autonomic neuropathy and advanced vascular disease has the potential for serious adverse events. Thus an individual approach to therapy in such situations is advisable.

Other Traditional Risk Factors

There are little objective data regarding treatment of other risk factors in this population. Exercise in pre-dialysis patients has been shown to improve well-being and increase muscle strength.[336] Exercise may also favorably influence lipid profiles and blood pressure levels in dialysis patients. [337] [338] In the absence of contraindications it would seem reasonable to encourage a graded exercise program from as early a stage as possible in patients with CKD, although cardiovascular assessment should be considered in high-risk patients.

Uremia-Related Risk Factors (see Figs. 48-4 and 48-6 [4] [6], Tables 48-2 and 48-3 [2] [3])

Anemia

Although results from the Australian Multicenter Pre-dialysis Study were inconclusive on an intention-to-treat analysis, patients whose hemoglobin concentration fell below 100 g/dL over 2 years had a significant increase in LV mass compared to those who were maintained with Epoetin at near-physiological levels. No adverse effects were observed (see Figs. 48-4 and 48-6 [4] [6], Tables 48-2 and 48-3 [2] [3]).[339] The results of Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), a large trial in diabetic CKD patients with moderate to severe renal impairment, are awaited to further test whether higher hemoglobin levels have a beneficial impact on cardiovascular events.[340]

In hemodialysis patients in the short term, hemoglobin normalization improves the hyperkinetic heart, as shown by a decrease in LV diameter and systolic hyperfunction.[57] Recently, the hypothesis that anemia causes LV dilatation and hypertrophy, and subsequently death has been tested in hemodialysis patients by comparing patients randomly allocated to normalization of hemoglobin (using recombinant erythropoietin) or partial correction.[341] No difference in LV volume or mass was observed between the two targets over a 2-year follow-up in 596 incident dialysis patients free of symptomatic CVD. In a prior study of hemodialysis patients with severe LV dilatation no regression was observed over 12 months.[342] In hemodialysis patients with symptomatic heart disease, normalization of hemoglobin failed to improve mortality and was associated with an increased risk of vascular access loss.[343]

On current evidence, it would appear that there is little gain, and possibly some harm, in attempting to achieve physiological hemoglobin concentrations in patients with CKD. Currently, one can conclude that hemoglobin levels above conventional targets (10–11.5 g/l) do not have a beneficial impact on cardiac structure or cardiovascular events in hemodialysis patients, and may induce higher risk for vascular access clotting and other thrombotic events.[341] [343] In the pre-dialysis group, results from the TREAT study may help clarify these issues further. On occasion normalization of hemoglobin in selected patients on grounds of enhanced quality of life or functional capacity may be indicated.[341]

Left Ventricular Hypertrophy and Arteriosclerosis

London and colleagues[344] compared the effects of an ACE inhibitor (perindopril) with a CCB (nitrendipine) in a double-blinded, randomized trial involving 24 HD patients with LV hypertrophy over a period of 12 months. At baseline, each group displayed LV hypertrophy due predominantly to an increased LV end-diastolic diameter. Similar and significant changes were found in blood pressure, total peripheral resistance, aortic and arterial pulse wave velocities and arterial wave reflections. After treatment, there was a significant decrease in LV mass in the perindopril-treated group only. It was also found that LV mass reductions were related not to changes in LV wall thickness but rather to a reduction in LV end-diastolic diameter. A prior controlled clinical study[345] reported similar effects, with improved arterial distensibility and reduced wall thickness in response to long-term treatment with both a dihydropyridine CCB and ACE inhibitor but a reduction in LV mass only evident with use of an ACE inhibitor.

A similar cohort of patients was examined for the effects of blood pressure changes on 150 dialysis patients over a mean of 51 months.[12] Independent predictors of cardiovascular mortality included no reduction in pulse wave velocity (PWV) in response to a blood pressure decrease (RR 2.59, 95% CI 1.51–4.43), an increased LV mass (RR 1.11 per 10 g increase in LV mass index, 95% CI 1.03–1.19), age (RR 1.69, 95% CI 1.32–2.17), pre-existing cardiovascular disease, and importantly, lack of ACE inhibitor treatment (RR 0.19, 95% CI 0.14–0.43). These findings were consistent with earlier descriptive studies but for the first time suggested there might be a survival advantage in reducing PWV. Importantly, ACE inhibitors appeared also to have a favorable effect on survival in this patient group, which was independent of blood pressure change.

Inflammation

As has been discussed, the source of elevated CRP levels in patients with CKD is uncertain. Accordingly, attempts at reducing inflammation have been general rather than specific and sometimes unintentional. [85] [346] [347] [348]

Both aspirin and statins have been studied in respect to their effects on reducing inflammation in both patients with CKD and the general population. Aspirin has been shown to be of greatest benefit in patients with the highest CRP levels, and a recent meta-analysis of 14 randomized controlled trials in hemodialysis patients (n = 2632) suggested that antiplatelet therapy resulted in a 41% reduction in cardiovascular events.[349] A reduction in CRP with the use of statin therapy has now also been shown in hemodialysis patients.[348]

Hyperhomocysteinemia

A combination of high-dose folic acid, vitamin B12, and vitamin B6 lower homocysteine levels by 25%, which may restore normal levels in patients with CKD or in renal transplant recipients, but not in dialysis patients.[350]However, no trials have yet shown that lowering homocysteine levels improves cardiovascular outcome. [300] [301] [351] A recent randomized trial involving a small number (n = 510) of hemodialysis patients taking three different doses of folic acid also failed to showed any difference in the composite endpoints of mortality and cardiovascular events.[352]

Thus, screening for homocysteine levels cannot be advocated as part of a general management principle. Data do not support supplementation either with vitamin B6 or B12, nor elevated daily doses of folate above 5 mg per day. Administration of folinic acid may have a role from promising initial studies[353] but further results are awaited.

Oxidative Stress

Although evidence of increased oxidative stress in CKD exists, there are no longitudinal studies examining the impact of oxidative stress on subsequent de novo cardiac events. One small, randomized study suggests there may be some clinical advantage in the use of antioxidants. Vitamin E supplementation (800 IU daily) and, in nearly 50% of patients also vitamin C, were given to 196 hemodialysis patients with cardiovascular disease, resulting in a significant (54%) reduction in myocardial infarction compared to controls but no difference in mortality.[354] The event rate in this study was over three times that of the earlier Heart Outcomes Prevention Evaluation (HOPE) study, which had found no significant difference in the composite primary outcomes (myocardial infarction, stroke, or cardiovascular death) using lower doses of vitamin E in patients with moderate CKD (serum creatinine 1.4–2.3 mg/dL).[355] Finally, the antioxidant N-Acetylcysteine (600 mg twice daily) was compared to placebo in 134 hemodialysis patients, with a reduced incidence of composite ischemic events being found.[356]

At this stage, these dissonant results do not permit recommendations for the use of antioxidant therapy and further controlled trials are awaited.

Abnormal Divalent Ion Metabolism

Patients with CKD are in a substantive positive calcium balance from an early stage of disease. Attempts to minimize the calcium load in the context of PTH and phosphate control have a sound teleological and, possibly, empirical base. The appropriate use of vitamin D analogues and phosphate binders are currently recommended to achieve target levels of divalent ions and related compounds. For serum calcium this target is between 9.2 and 9.6 mg/dL, and for serum phosphate 2.5 and 5.5 mg/dL to achieve a calcium-phosphate product of less than 55 mg2/dL2. The optimum range for intact parathyroid hormone levels (PTH) is suggested to be between 100 and 200 pg/mL.[357]

In the context of advanced vascular calcification and its associated mortality in CKD, the use of agents that avoid calcium and aluminium is highly desirable. The relative benefits of Sevelamer Hydrochloride (a non-calcium, non-aluminum phosphate binder) has been compared to calcium carbonate in 114 hemodialysis patients. It showed that at 52 weeks patients treated with calcium carbonate had significant increases in coronary artery (34%, p < 0.01) and aortic (32%, p < 0.01) calcification compared to the sevelamer-treated patients.[342] Trials with calcimimetic agents, which reduce parathyroid hormone levels, are currently being performed. In view of the pathogenic role of PTH on intracellular calcium accumulation in myocytes and vascular smooth-muscle cells, calcium channel blockade is a rational therapeutic intervention to prevent cardiovascular disease. Preliminary animal evidence to suggest that deposition of intramural calcium in a rat model with CKD may be prevented with the use of a molecule related to transforming growth factor-β, bone mineral protein 7 (BMP 7), requires confirmation and assessment of relevance in human disease.[358]

Other

In one large meta-analysis of non-CKD patients examining primary prevention of coronary artery disease, the absolute benefit of aspirin was 0.15% reduction per year in myocardial infarction compared with an increased risk of 0.04% per year for major non-cerebral hemorrhage (non-cerebral bleeds causing death, transfusion, or surgery) and 0.18% per year for minor hemorrhage.[360]

Aspirin therapy probably worsens the platelet defect in CKD and increases the risk of bleeding. Despite these risks, in light of recent evidence, patients with overt cardiovascular disease should probably be prescribed low-dose aspirin to reduce the risk of subsequent cardiovascular events.[349] However, individual treatment decisions must be based on considerations of patients' individual risks, likely benefits, and preferences.

Multiple Risk Factor Intervention

It is likely that under-utilization of efficacious therapies occurs in patients with CKD and that optimal targets for treatment are not achieved. [361] [362] The excellent results achieved in the STENO study of diabetic patients receiving intensive therapy, and of heart failure patients treated in multidisciplinary clinics, suggest that a similar approach in patients with CKD could produce better outcomes than conventional health care delivery models.[363] The objective of enhancing appropriate utilization of interventions to slow progression of renal disease and to prevent cardiovascular disease requires a multifaceted, multidisciplinary approach, which may not be feasible with current primary care provider models.

SUMMARY

The burden of cardiovascular disease in patients with CKD is high. The mechanisms likely alter with the degree of renal impairment, the number of associated risk factors and, possibly, the cause of kidney failure.

Traditional risk factors are powerful predictors of cardiovascular disease and studies support interventions to lower blood pressure, stop smoking, block the renin-angiotensin system, lower lipids, and use anti-platelet agents.

Uremia-related risk factors, particularly inflammation, anemia, hypoalbuminemia, proteinuria, and divalent ion abnormalities, are increasingly associated with cardiovascular disease. However, interventional studies are largely of unproven benefit or have produced dissonant results. The role of oxidant stress, dyslipidemia, and other potential factors also require further study as does the question of whether as a group they are causative of, or simply markers for, disease.

Common sequelae of uremia include LV hypertrophy, dilated cardiomyopathy, coronary artery disease, and arteriosclerosis. These conditions occur frequently and predis-pose to various pre-terminal conditions including cardiac failure, myocardial infarction, arrhythmias, and dialysis hypotension.

Efforts to improve cardiovascular outcomes by single risk factor intervention have been largely unsuccessful. It is likely that early attention to the multiple risk factors evident in each patient, both traditional and uremia-related, will be more successful. The conclusion that there is little to gain, and there may be harm, by normalization of hemoglobin in CKD using erythropoietin has received further support from the resuls of two randomized controlled trials in predialysis patients, CHOIR and CREATE. [364] [365]

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