Gary R. Briefel
This chapter will focus on the role of the primary care provider in the identification, evaluation, and treatment of patients with chronic kidney disease (CKD). Until recently,
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the management of patients with CKD has been focused on the diagnosis and treatment of the underlying disease process, preventing progression of renal disease and on timely referral to a nephrologist for renal replacement therapies. Although these goals are still important, it has become evident that earlier detection of renal disease and preventing the associated comorbidities in the predialysis stage, particularly cardiovascular complications, are of equal importance. This is because a large percentage of patients with CKD die, primarily from cardiovascular complications, before requiring renal replacement therapies.
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TABLE 52.1 K/DOQI Definition of Chronic Kidney Disease |
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Despite the numbers of patients with CKD seen in primary practitioners’ offices, there is evidence that many patients are not getting optimal care. For example, too few patients at risk for kidney disease are screened for proteinuria or have measurements of kidney function. Of those found to have proteinuria, only a minority are treated appropriately (see Chapter 48). Erythropoietin (see Anemia) is underutilized and too many patients are severely anemic at the time they start dialysis. Similarly, patients are often referred late to nephrologists for preparation for renal replacement therapies. Consequently, there is insufficient time for dialysis access planning and not enough have permanent vascular access when dialysis is initiated.
The National Kidney Foundation has developed clinical practices guidelines (Kidney Disease Outcomes Quality Initiative [K/DOQI]) for the definition (Table 52.1), evaluation, and treatment of CKD and these guidelines are continuously being updated. They are available online athttp://www.kidney.org/professionals/kdoqi/guidelines.cfm. The K/DOQI guidelines have established five stages of chronic kidney disease that are associated with different levels of kidney function, complications, and intervention strategies to help clinicians in evaluation, planning, and treatment (Table 52.2).
The understanding of the reasons why CKD progress has increased, and the ability to modify the natural history has improved. Because the primary care provider often discovers patients with the early stages of kidney disease, it is important to be familiar with the initial phases of evaluation and management. It has also been recognized that the predialysis management of patients who develop end-stage renal disease (ESRD) has an impact on subsequent morbidity. Therefore, emphasis should be placed on early identification of patients with kidney disease and on improving coordination between the primary care provider and the nephrologist.
Epidemiology of Chronic Kidney Diseases
Chronic kidney diseases are conditions that can result in progressive loss of kidney function and of equal importance lead to complications associated with that decreased function. CKD, either presenting as a primary event or complicating another illness, is a common clinical problem. The impact of CKD extends well beyond the numbers who progress to ESRD since patients with that diagnosis often have a reduced quality of life, are more likely to be hospitalized, to have anemia, or to develop and die from cardiovascular disease than a comparable population
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of patients without CKD (1). Although precise estimates on the prevalence of chronic renal diseases are lacking, data derived from the Third National Health and Nutrition Examination Survey indicate that there are approximately 8.3 million individuals with a glomerular filtration rate (GFR) less than 60 mL/min/1.73m2 in the United States (2). The prevalence in selected subgroups is higher.
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TABLE 52.2 Chronic Kidney Disease (CKD): A Clinical Action Plan |
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FIGURE 52.1. The past, current, and projected incidence and prevalence of end-stage renal disease. (Modified from U.S. Renal Data System: USRDS 2000 annual data report.) |
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The epidemiology of patients who require renal replacement therapy (dialysis or renal transplantation) and enter the ESRD Program (the Medicare-funded program that provides coverage for virtually all patients in the United States who need dialysis) is well described. Data are collected and analyzed by the federally funded United States Renal Disease System (USRDS) (3). At the end of 2002, more than 320,000 patients were being treated for ESRD under the Medicare program in the United States with either dialysis or kidney transplantation. Since 1972, the year Medicare coverage was extended to patients with chronic renal failure who needed dialysis, the incidence of end-stage renal failure in patients who enter dialysis and transplant programs has increased from 71 per million per year to more than 330 per million per year in 2002. Almost 100,000 new patients entered the ESRD Program in 2002, and this figure has been increasing yearly by almost 5%. The incidence and prevalence of ESRD is projected to increase further over the next 10 years (Fig. 52.1) in concert with the aging of the population. Medicare expenditures for the ESRD Program have grown to 17.9 billion dollars and account for almost 7% of the entire Medicare budget (Fig. 52.2).
The number of patients with ESRD requiring dialysis has been noted to be 30% to 40% higher in men than in women and to peak between the ages of 65 and 74 years. The incidence of ESRD has also been estimated to be three to four times greater in nonwhites than in whites, because of either higher prevalence of hypertension or greater end organ sensitivity to the effect of hypertension in nonwhites. The reported distribution of dialysis patients entering the ESRD Program by primary renal diagnosis is diabetic nephropathy, 39.5%; hypertensive large vessel disease, 25.2%; glomerulonephritis, 9.1%; secondary glomerulonephritis/vasculitis, 2.2%; interstitial nephritis, 3.8%; cystic/hereditary/congenital kidney disease, 2.8%; neoplasms/tumors, 1.7%; miscellaneous/unknown, 15.7% (Table 52.3) (4). Patients with renal disease related to acquired immunodeficiency syndrome (AIDS) remain a
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small fraction of the total, with an incidence rate of 1.4 new patients per million population.
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FIGURE 52.2. Estimated Medicare costs for the End-Stage Renal Disease Program. (Modified from U.S. Renal Data System: USRDS 2000 annual data report.) |
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TABLE 52.3 Primary Renal Disease Demographics for Dialysis Patients Entering the End-Stage Renal Disease (ESRD) Program (1994–1998) |
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Classification
Kidney diseases are often classified according to whether they produce acute or chronic renal failure. They may be further subdivided into those with prerenal, renal, or postrenal components. Prerenal azotemia is caused by factors that produce a decrease in renal perfusion. Diminished perfusion may result from anatomic lesions such as might occur with renal artery stenosis, but more commonly it is related to decreased cardiac output (heart failure), vasodilation (septic shock), or volume depletion (vomiting, diarrhea, or excessive diuretic use). Prerenal azotemia caused by volume depletion, for example, may often be superimposed on existing chronic renal failure from other causes. Obstructing lesions that occur distal to the kidney parenchyma, involving the renal pelvis, ureters, bladder, or urethra, cause postrenal azotemia. Common examples of such lesions are prostatic enlargement, nephrolithiasis, and retroperitoneal cancers.
Most conditions that cause CKD directly involve the kidney parenchyma and are classified according to the anatomic region that is primarily affected (Table 52.4). Glomerular lesions can be caused by proliferation of endothelial or mesangial cells (e.g., postinfectious glomerulonephritis), thickening of the basement membrane (e.g., membranous glomerulopathy, diabetic nephropathy), glomerulosclerosis (e.g., focal sclerosis), or combinations of the three (e.g., membranoproliferative glomerulonephritis). Any of the diseases that cause glomerular lesions, if sustained, can lead to chronic glomerulonephritis. Clinically, glomerular diseases are often associated with hypertension, edema, renal insufficiency, hematuria, and proteinuria.
Diseases that affect primarily the tubulointerstitial areas of the kidney are characterized morphologically by interstitial inflammation, fibrosis, and tubular atrophy. In the past, these lesions were often equated with bacterial infections of the kidney (pyelonephritis), but today most are caused by toxins (e.g., analgesics, heavy metals), metabolic derangements (e.g., hyperuricemia, hypercalcemia), or immunologic disorders (e.g., methicillin-induced interstitial nephritis). The glomeruli are only secondarily involved in the tubulointerstitial diseases. Polycystic and medullary cystic kidney diseases are a subgroup of the tubulointerstitial nephropathies and are characterized histologically by the presence of a multitude of thin-walled cysts derived from tubular epithelium. Patients with interstitial forms of kidney disease are not usually hypertensive or edematous, and they often produce large volumes of urine with high sodium content. Typically, nonnephrotic-range proteinuria (i.e., less than 3.5 g/day), sterile pyuria, and hyperchloremic metabolic acidosis are present.
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TABLE 52.4 Classification of Diseases That May Result in CKD |
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Lesions of the renal vessels may be located in the main renal arteries (e.g., atherosclerosis, fibromuscular dysplasia), in medium-sized arteries or arterioles (e.g., polyarteritis nodosa, scleroderma, atheroembolic disease), or in the renal veins (e.g., renal vein thrombosis). Renal insufficiency is a result of reduction in blood flow to the glomeruli. Involvement of the renal vessels is often part of a systemic illness that also affects vessels in other areas
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of the body. The clinical features of the renal vasculitides are very similar to those of glomerulonephritis except that nephrotic-range proteinuria (by definition more than 3.5 g/day) is uncommon.
A number of renal diseases can variably affect one or more of the kidney's anatomic regions. For instance, renal involvement in multiple myeloma may take the form of a diffuse thickening of the glomerular basement membrane (light-chain nephropathy), or more often it causes a tubulointerstitial nephropathy. Systemic lupus erythematosus (SLE) is another example of a disease that can produce either glomerular or tubulointerstitial damage.
Renal diseases can be further subclassified according to whether they are congenital, part of a systemic disorder, primary to the kidney, or the result of injury. The congenital or hereditary diseases most often encountered are polycystic kidney disease and the Alport form of hereditary nephritis. Diabetes mellitus and hypertension are the most common systemic disorders producing chronic renal failure, and approximately 65% of the patients entering dialysis programs have one of these two diseases (Table 52.3). Immunologic injury to the kidney can be in the form of glomerular immune complex deposition, as in systemic lupus erythematosus, or antiglomerular basement membrane antibody disease, best exemplified by Goodpasture syndrome. Most immunologically mediated diseases affect predominantly the vessels or glomeruli, but they can also damage the tubulointerstitial areas, as is seen in drug-induced interstitial nephritis (e.g., due to methicillin). Drugs (e.g., aspirin) and toxins (e.g., heavy metals) most often produce damage to the interstitium. Metabolic disorders (e.g., diabetes mellitus [DM], oxalosis) can result in damage to any region of the kidney.
Pathophysiology of Chronic Kidney Disease
The course of many CKDs is characterized by the progressive loss of functioning nephrons. Once a certain level of renal impairment has been reached, further deterioration seems to be inevitable, even when the original insult is transient and other causes of additional damage have been excluded. One mechanism that has been postulated to explain the progressive nature of renal disease is related to the maladaptive response to injury (5). According to this hypothesis, after a reduction in nephron mass, angiotensin II mediated hemodynamic changes occur that lead to hyperperfusion of the remaining glomeruli. These changes are considered to be adaptive because they result in initially increased GFRs. However, experiments have shown that this state of glomerular hypertension, if sustained, can in itself be harmful (Fig. 52.3). Glomeruli of nephrons exposed to prolonged hyperperfusion begin to leak protein, become sclerotic, and eventually are destroyed. Angiotensin II may also damage the kidney
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through nonhemodynamic effects, such as the stimulation of inflammatory and fibrosing factors. Current theories also implicate toxicity from filtered proteins or lipids, perhaps mediated by release of cytokines or other inflammatory products, as an important mechanism of renal parenchymal damage. As more nephrons are lost, the stimulus for hyperperfusion of the residual nephrons is increased and the process becomes self-perpetuating. There is evidence that many diseases that produce limited kidney damage (e.g., patchy cortical necrosis, analgesic nephropathy, radiation nephritis) may progress to ESRD by this mechanism.
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FIGURE 52.3. Proposed sequence of events whereby a chronic reduction in kidney mass and the consequent increase in glomerular pressures and flows lead to progressive renal damage. QA, Blood flow; ΔP, transcapillary hydraulic pressure. (Redrawn from Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis, aging, renal ablation, and intrinsic renal disease. N Engl J Med 1982;307:652 .) |
The ability of the impaired kidney to maintain the concentrations of individual components of the body's fluids within normal limits is variable. The concentrations of substances that are simply filtered and neither secreted nor resorbed by the tubule, such as urea, begin to rise early in the course of renal impairment (GFR 50% of normal). In contrast, the serum concentration of phosphorus, which is under the influence of parathyroid hormone (PTH), is kept within the normal range until more than approximately 80% of renal function is lost. This is because in renal failure, increased PTH activity progressively reduces the amount of phosphorus resorbed by the tubule (normally 80% of filtered phosphorus is resorbed), in parallel with the reduction in renal mass. Once the GFR falls below approximately 20% of normal, this mechanism can no longer keep pace, and the serum phosphorus level begins to rise. Other solutes, such as sodium and potassium, are even better regulated, and their concentrations are maintained within the normal range until the GFR is less than 5% to 10% of normal.
Eventually the reserve capacity of the kidney is overwhelmed and a number of signs, symptoms, and metabolic abnormalities appear that are characteristic of uremia. Uremia is a complex syndrome that results from the failure of the kidney to fulfill its excretory, endocrine, and metabolic functions. In the patient with ESRD, virtually every organ system is affected to some degree. The mechanisms for only some of the abnormalities that appear in uremia are well understood. Efforts to explain the metabolic consequences of renal failure by the retention of toxic wastes are only partially satisfying. Not all manifestations of uremia can be attributed to the retention of metabolic waste products. Many well-described endocrine and metabolic derangements are of equal significance in the pathogenesis of uremia. A deficiency of certain hormones results when the failing kidney is no longer able to produce them in adequate quantities (e.g., erythropoietin, 1,25-dihydroxyvitamin D3). Other hormones normally degraded or metabolized by the kidney may be present in excess (e.g., PTH, insulin, prolactin). Alternatively, the damaged kidney may elaborate an excess of hormone (e.g., renin). Hormone levels or activity may also be altered as a consequence of abnormal protein binding (e.g., thyroid hormone), peripheral resistance (e.g., insulin, PTH), or loss of feedback control (e.g., luteinizing hormone).
Evaluation of Chronic Kidney Disease
Presentation
Kidney disease can most easily be recognized when it is associated with clearly defined clinical syndromes such as urinary tract obstruction or laboratory abnormalities such as proteinuria, hematuria, or an elevated serum creatinine level. The recognition of one of these abnormalities is helpful in focusing the ensuing diagnostic evaluation. Often, the presence of renal disease is discovered during the evaluation of a systemic disease of which renal dysfunction is only a part (e.g., DM, hypertension).
Because of the remarkable reserve and adaptive capabilities of the kidney, symptoms of uremia (see History and Physical Examination) do not appear until glomerular filtration is reduced to 10% to 15% of normal. Therefore, unless clearly overt signs of renal involvement are present (e.g., gross hematuria), many patients progress to advanced renal failure asymptomatically. In other patients, whose renal insufficiency is detected early in its course by routine blood tests, specific findings in the history and on the physical examination may also be absent. Special laboratory testing in these patients often permits establishment of a definitive diagnosis. The complete evaluation may vary from a brief assessment in the patient with advanced renal failure and markedly shrunken kidneys to an extensive workup in the patient who may have potentially reversible disease of recent onset. Most of the evaluation can be performed on an ambulatory basis.
History and Physical Examination
Findings in the history and on the physical examination can provide useful information that helps the clinician establish the nature of the kidney disease, estimate its duration, and determine its effect on the patient. One of the major goals in evaluating the patient with recently identified renal failure is to distinguish patients with primary, acquired kidney disease from those whose renal failure is caused by familial, congenital, or systemic illness.
The family history should be reviewed for the presence of polycystic kidney disease, Alport syndrome, medullary sponge kidney, hypertension, or DM. The presence of a genetically influenced form of renal disease in the family should help establish the etiology of the patient's kidney problem. Next, the patient's medical history should be reviewed carefully, with a particular emphasis on discovering the presence of a systemic illness that can cause renal failure (e.g., hypertension, DM, collagen vascular disorders).
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Patients with AIDS can develop a nephropathy that presents as a nephrotic syndrome and often progresses to renal failure. In the absence of symptoms related to a systemic illness, the patient should be questioned about symptoms associated with abnormalities of the urinary tract. Dysuria, frequency, renal colic, hesitancy, or urinary incontinence points to an abnormality of the lower urinary tract as the cause of the patient's renal dysfunction.
In addition to the symptoms that may prove useful in establishing a diagnosis, several symptoms (e.g., nausea, vomiting, fatigue, nocturia, itching, restless legs) are nonspecific. These “uremic” symptoms are present in most patients with stage 5 CKD.
Because symptoms of renal failure often do not appear until late in the course, it is sometimes difficult to pinpoint the time of onset of the disease. Important clues can occasionally be found when records of past physical examinations performed for work, insurance, or military purposes are reviewed.
Because certain drugs can cause renal dysfunction (e.g., heroin, nonsteroidal anti-inflammatory drugs [NSAIDs], aminoglycosides) or aggravate pre-existing renal insufficiency (e.g., diuretics) (Table 52.5), there should be a complete inventory of past and current drug use.
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TABLE 52.5 Some Commonly Used Drugs That May Adversely Affect Renal Function |
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The physical examination should be focused on a search for signs of systemic illnesses and for genitourinary structural abnormalities. These might include high blood pressure, hypertensive or diabetic retinopathy, vascular bruits, vasculitic skin rashes (palpable purpura), or gouty tophi. Enlarged kidneys on palpation may be found in patients with polycystic disease or hydronephrosis. A pelvic or rectal examination should be performed to evaluate causes of lower urinary tract obstruction, such as prostatic or cervical cancer. If obstruction or flaccid neurogenic bladder is suspected, the bladder should be catheterized or evaluated by sonography after the patient voids to measure residual volume (see Chapter 54). A residual volume that is larger than 200 to 300 mL should raise concern for bladder outlet obstruction (seeChapter 53) or neurogenic bladder (most commonly seen in diabetic patients). Signs of heart failure, pericarditis, or neuropathy are most often related to the stage of renal failure and are not helpful in establishing the cause.
Laboratory Investigation
Screening/Primary Prevention
There is evidence that kidney diseases are under-recognized, resulting in lost opportunities to prevent additional damage, treat comorbid conditions and refer expeditiously. Screening programs have been recommended in order to identify and treat patients in the early stages, at least for high-risk populations. The Kidney Early Evaluation Program (KEEP 2.0) is a screening program initiated by the National Kidney Foundation that evaluated adults with diabetes, hypertension, or those with a family history of diabetes, hypertension, or kidney disease (6). The screening program identified high numbers of patients with previously undetected microalbuminuria (29%) and calculated GFRs less than 60 mL/min/1.73 m2 (16%). Although the role of population-based screening has not been firmly proven (7), the laboratory evaluation of patients at risk for, or with, CKD (Table 52.6) should, at a minimum, include a urinalysis, measurement of protein excretion, estimate of GFR, and in many instances a renal ultrasound. The urine dipstick is only a rough guide to the amount of proteinuria (see Chapter 48). Most dipsticks are designed
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to detect only albumin and may therefore miss the presence of other proteins, such as light-chain proteins. The dipstick measures only the concentration of protein, so the reading must be interpreted in conjunction with the urine specific gravity. The finding of 1+ proteinuria on two consecutive tests taken 3 months apart is considered abnormal and requires further evaluation. Generally the threshold for detecting proteinuria by the standard dipstick is 300 mg/dL. Patients who are at high risk for the development of kidney disease (Table 52.6) should be checked for microalbuminuria (urine albumin excretion between 30 and 300 mg/day) by means of specific urinary dipsticks for albumin or by immunoassay. The finding of microalbuminuria in these populations is associated with an increased risk of renal and cardiovascular events and requires further evaluation and treatment.
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TABLE 52.6 Clinical and Socioeconomic Factors for Increased Susceptibility for Chronic Kidney Disease |
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The protein/creatinine ratio, which has replaced the 24-hour urine collection as the recommended way to quantitate proteinuria, may be determined in a specimen of urine as described in Chapter 48. The finding of nephrotic-range proteinuria (excretion of more than 3.5 g/day or a spot urine protein/creatinine ratio greater than 3) usually indicates a glomerular lesion, whereas lesser amounts are seen in some glomerular or vascular disorders and in most interstitial forms of nephritis. In patients older than 40 years of age with unexplained renal insufficiency, regardless of the amount of urinary protein detected by dipstick, a serum and urine electrophoresis should be obtained to exclude the possibility of multiple myeloma.
The urinalysis can often provide important diagnostic information. Red blood cells (RBCs), particularly when associated with RBC casts, are most indicative of a glomerular or vascular lesion. In the presence of isolated hematuria, dysmorphic RBCs in the urinalysis suggest a parenchymal source. Leukocytes, with or without casts, are found in the interstitial nephropathies. Hyaline or granular casts are not indicative of a specific pathologic process.
Some measure of overall kidney function is needed to determine the degree of impairment, monitor the progression of disease, assess the effects of therapy, and adjust the dosage of drugs that are excreted by the kidney. The GFR is the standard means of expressing the level of renal function. In clinical practice, the GFR may be estimated from the serum creatinine concentration, from the endogenous creatinine clearance (CrCl), or from formulas that incorporate the patient's serum creatinine level, age, and weight.
The normal GFR is approximately 100 to 140 mL/min/ 1.73 m2 in men and 85 to 115 mL/min/1.73 m2 in women. A gradual deterioration of GFR with age occurs, even in the absence of overt renal disease, in 70% of individuals (8,9). The following equation may be used for estimating the expected CrCl in healthy men.
GFR = 133 - 0.64 × Age
where the GFR is expressed in mL/minute, and the age is expressed in years. The clearance for women 50 years of age or older is approximately 5 to 10 mL/min/1.73 m2 less than for men. At age 70, for example, an individual without renal disease may have lost 30% of his or her previous GFR.
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FIGURE 52.4. Relationship of the serum creatinine concentration to glomerular filtration rate in patients with different muscle mass. |
Because of the difficulties in estimating the level of renal function from the serum creatinine concentration alone, alternative methods for estimating the GFR are available. These methods are used to categorize the stage of CKD and to adjust dosages of drugs that are excreted by the kidney or to assess renal function in elderly or small patients.
The serum creatinine concentration is a better indicator of renal function than is the level of serum urea nitrogen (SUN), because the latter is affected by such nonrenal factors as volume status, diet, intestinal bleeding, liver function, and protein catabolism. Figure 52.4 shows the general relationship between serum creatinine concentration and GFR. When trying to determine the extent of renal impairment, it is important to remember that the serum creatinine concentration for any given level of GFR varies among individuals, because the relationship between the two values is significantly influenced by nonrenal factors such as the patient's muscle mass and age. Creatinine is produced by muscle, and its production rate directly parallels the muscle mass. The amount of creatinine produced per day also falls with age. As can be seen in Fig. 52.4, a small or elderly patient may have a doubling of the serum creatinine concentration, from 0.8 to 1.6 mg/dL, and still be within the “normal” range. Also, a young, muscular patient who produces 1.5 g of creatinine per day will have a GFR of 30 mL/min/1.73 m2 when his or her serum creatinine concentration is 5 mg/dL, whereas an elderly, frail patient who produces only 0.5 g of creatinine per day will have a CrCl of only 10 mL/min/1.73 m2 at the same serum creatinine concentration. Therefore, although an elevated serum creatinine value almost always reflects abnormal renal function, a creatinine concentration
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in the “normal” range does not mean that GFR is normal, particularly if there is other evidence for the presence of renal disease. Once the factors affecting the level of serum creatinine concentration are understood, the clinician should have a clinically useful measure of overall renal function.
The endogenous CrCl is a reasonable approximation of GFR in patients with normal or modestly reduced function but overestimates the GFR in those with advanced renal failure. Because of the difficulties and errors associated with measuring CrCl with 24-hour urine collections, it is now recommended that formulas be used as the preferred method to estimate GFR. The Cockroft-Gault formula takes into account the patient's body weight (in kilograms) and age:
(The GFR value obtained should be multiplied by 0.85 in the case of a woman.) More recently, the Modification of Diet in Renal Disease (MDRD) formula has been developed, based on iothalamate clearances in a wide variety of kidney diseases (10). It should be recognized that the value of GFR determined by the preceding formulae or by measurement of the CrCl may vary significantly from the more accurate determination of GFR by inulin clearance. For clinical purposes, however, these differences are generally considered insignificant. The formulae have not been validated in all populations. For example, it may still be necessary to measure GFR via a 24-hour collection in emaciated or obese people as well as in those with amputations.
When monitoring the course of kidney disease, it should be recalled that the serum creatinine concentration increases in a nonlinear fashion as renal function declines (Fig. 52.4). In the early stages of renal insufficiency, when the GFR falls by 50%, the absolute increase in the serum creatinine concentration is small. Therefore, most of the loss of functioning nephrons occurs at levels of serum creatinine that would be considered only modestly increased. Once the GFR is reduced to 20% to 30% of normal, the curve expressing the relationship between serum creatinine and GFR rises steeply. The absolute changes in serum creatinine concentration that occur when ESRD is present are therefore less significant, in relation to losses of GFR, than those seen in early renal insufficiency. It is also important to understand that changes in GFR (reflected by an increasing serum creatinine concentration or by a falling CrCl) are not necessarily related to permanent changes in intrinsic kidney function and may be caused by other factors (see Treating Reversible Causes of Deterioration in Renal Functionbelow).
Selected additional tests should be ordered when an immunologically mediated disease is suspected, such as in a patient with vasculitis or an unexplained nephritic picture (RBC casts, nephrotic proteinuria). For example, measurement of the serum complement levels (C3 and C4) and screening for the presence of antistreptococcal antibodies, antinuclear antibodies, rheumatoid factor, and cryoglobulins may be of value when collagen vascular disease or poststreptococcal glomerulonephritis is suspected. Measurement of antineutrophil cytoplasmic antibodies (ANCAs) is useful in diagnosing cases of systemic vasculitis, including Wegener granulomatosis and polyarteritis nodosa. Hepatitis B surface antigen (see Chapter 47) can be demonstrated in the blood of some patients with membranous glomerulopathy and in those with some forms of vasculitic renal disease. Hepatitis C infections are associated with mixed cryoglobulinemia and membranoproliferative glomerulonephritis. Hepatitis B and C antigens and antibodies should also be assayed in any patient being referred for dialysis or transplantation, because precautions to prevent the spread of hepatitis must be taken if the patient is a potential carrier. A test for human immunodeficiency virus (HIV) antibodies (see Chapter 39) should be performed in patients with nephrotic syndrome or renal failure who are at risk for HIV infection. In general, a nephrologist should be consulted to help guide this workup.
The frequency of anemia (see Chapter 55) increases as GFR declines (Fig. 52.5). The absence of anemia in patients with renal insufficiency should suggest either recent onset, the presence of polycystic kidney disease, or hydronephrosis. Both polycystic kidney disease and hydronephrosis can be associated with normal or elevated hematocrit values. The peripheral blood smear should be examined carefully for abnormalities associated with diseases that can produce renal failure. Rouleaux formation may be present in multiple myeloma, and leukopenia may be associated with collagen vascular diseases. A microangiopathic hemolytic anemia may be seen in patients with thrombotic thrombocytopenic purpura, the hemolytic-uremic syndrome, postpartum renal failure, accelerated hypertension, or scleroderma.
Measurements of the concentrations of blood glucose, serum electrolytes (Na, K, Cl, HCO3, Ca, PO4), and uric acid are helpful in monitoring the patient's course. Hypercalcemia may suggest a tumor or hyperparathyroidism. The uric acid concentration is usually increased in patients with renal insufficiency, but a level greater than 12 mg/day may indicate the presence of primary hyperuricemia or a myeloproliferative disorder.
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FIGURE 52.5. Relationship between GFR and anemia in CKD. (From K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Am J Kidney Dis 2002;39:S124. ) |
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Renal Imaging Techniques
Anatomic and functional evaluation of the kidney can be obtained through a variety of tests, not all of which need be performed on any individual patient. Renal imaging techniques in CKD should be used to establish renal size, detect remediable lesions, and determine etiology.
Renal sonography is a reliable means of estimating kidney size and usually detects the presence of significant hydronephrosis. Because of the risk of radiocontrast dye toxicity in patients with renal impairment (discussed later in this section), the sonogram should be used rather than the intravenous pyelogram (IVP) as the initial imaging technique. Median kidney length as measured by sonography is 11.2 cm on the left and 10.9 cm on the right. Renal size is slightly less in women than in men and decreases with age in both sexes. Small kidneys usually indicate advanced chronic renal disease. However, normal or large kidneys may be seen in certain conditions associated with CKD (e.g., DM, amyloidosis, HIV-associated nephropathy [HIVAN]).
Hydronephrosis caused by obstruction should be ruled out in every patient with CKD. If the screening sonogram reveals the presence of hydronephrosis, a urologist should be consulted. Subsequent evaluation of the obstructed kidney by the urologist may include an IVP, a retrograde pyelogram, a computed tomographic (CT) scan, magnetic resonance imaging (MRI), or a sonographically guided percutaneous antegrade pyelogram. These evaluations are selected to localize the precise site of the obstruction and to identify its nature. The choice of the procedure depends on the preference of the urologist or radiologist. Occasional cases of nondilated hydronephrosis occur, so further evaluation is indicated, even when the sonogram is normal, if the suspicion of obstruction is high (e.g., a patient with a history of renal colic or intra-abdominal malignancy).
In the past, the IVP was the most useful radiographic test in determining the cause of renal failure in diseases that produce gross anatomic abnormalities such as chronic pyelonephritis, nephrolithiasis, or obstruction from papillary necrosis. Although the cysts in patients with polycystic kidney disease are detected by IVP, renal ultrasound or spiral CT (see next paragraph) are better screening techniques. The IVP is not useful in patients with parenchymal disorders that are not associated with gross anatomic defects or if the creatinine concentration is elevated (e.g., more than 2.0 to 2.5 g/dL).
CT scans, particularly the high-speed spiral CT scan, have proved useful for the evaluation of renal stones, renal masses, and cysts, and for visualizing the renal vessels. Nuclear medicine imaging techniques, useful in the evaluation of patients with hypertension caused by unilateral renal artery stenosis, have been found to be less reliable in detecting bilateral renovascular disease. Bilateral atheromatous renovascular disease (Table 52.7), an often overlooked cause of renal failure, is more difficult to diagnose with radionuclide studies because the standard renal scan relies on asymmetric blood flow as a diagnostic criterion. When blood flow to both kidneys is reduced, it is difficult to distinguish bilateral renal artery stenosis from parenchymal disease. Captopril renography,
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which depends on captopril-induced hemodynamic alterations (and is helpful in diagnosing unilateral renal artery stenosis in the absence of significant renal failure), is less valuable in patients with renal insufficiency and suspected bilateral renovascular disease, and often is not diagnostic. Doppler or duplex sonography has been used as a screening tool for diagnosing bilateral renal artery stenosis, but these modalities do not provide anatomic detail and are operator dependent. An arteriogram should be obtained if the index of suspicion is high and a therapeutic decision (e.g., balloon dilation, often with stent placement) would be made based on the results. Gadolinium-enhanced magnetic resonance imaging has become another less invasive means of assessing the renal arteries in high-risk patients with suspected renal artery stenosis. It avoids the use of potentially nephrotoxic radiographic dyes and the use of intra-arterial catheters and is recommended by many nephrologists as a screening test in patients suspected of having renovascular disease. Carbon dioxide angiographyprovides good definition without the use of traditional dyes. Intravenous digital subtraction angiography has been suggested as a lower-risk method of imaging the renal arteries, because the risks of dye-induced acute renal failure (ARF) or atheroembolic disease appear to be reduced, probably because of the lesser amount of dye given and the use of smaller catheters. Finally, high-speed spiral CT scans produce excellent images of the renal arteries and veins, but require a large infusion of radiocontrast material. Given the complex decisions encountered when evaluating patients with suspected ischemic renal artery disease, a vascular surgeon, a radiologist, or a nephrologist should be consulted before a modality for imaging the kidneys is selected. The most difficult decisions arise in patients with probable diabetic nephropathy, who often have significant peripheral arterial disease. The decision to perform angiography is usually based on the clinical judgment that the course deviates from what is usually seen in diabetics, or when the vascular component seems prominent (severe hypertension, claudication, bruits).
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TABLE 52.7 Clinical Presentations of Atheromatous Renal Disease |
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The incidence of radiocontrast-induced ARF seems highest in patients with serum creatinine concentrations greater than 1.6 mg/dL, diabetic patients, and in the elderly. The incidence of ARF ranges from 3% to 50% depending on the presence of risk factors, on the type of radiocontrast agent employed, and on whether prophylactic measures have been used (see below) (11,12). In most cases the rise in serum creatinine after administration of radiocontrast agents is transient and small. The use of a nonionic, iso-osmotic radiocontrast agent like iodixinol, appears to reduce the occurrence of postangiography ARF in patients with pre-existing renal insufficiency (13). The use of the antioxidant acetylcysteine (600 mg orally twice a day, the day before and the day of the study) in combination with intravenous saline has been shown to reduce the frequency of renal function deterioration after the administration of nonionic, iso-osmolar radiocontrast agents in patients with renal insufficiency (14). In one study, the use of sodium bicarbonate given as a 3 mL/kg bolus 1 hour prior to the procedure, followed by a 6-hour infusion, reduced the incidence of ARF as compared to a sodium chloride infusion (15). The benefits of giving mannitol infusions or other pretreatments prophylactically are still unsettled. In summary, the presence of renal insufficiency should not be considered an absolute contraindication to the performance of intravascular dye studies, particularly when the needed information cannot be obtained by alternative means. Because the decline in renal function after use of radiocontrast materials appears to be particularly preventable by avoiding volume depletion, patients should be instructed to maintain sodium intake (6 to 8 g/day) and fluid intake (1.5 to 2 L/day) both before and after the examination, unless this is otherwise not advisable (e.g., in a patient with congestive heart failure [CHF]). Iso-osmotic radiocontrast agents should be used for patients who have pre-existing renal insufficiency.
Renal Biopsy
Once the baseline data have been accumulated, a nephrologist should be consulted to help interpret the information and to decide whether a renal biopsy is indicated. Early consultation with a nephrologist (if the serum creatinine concentration is greater than 1.5 mg/dL or other signs of significant renal disease are present) is advisable. A complete record of past laboratory investigations, a recent urinalysis, and a recent renal ultrasound test should be provided for patients who are being referred for evaluation of chronic renal insufficiency. If the diagnosis remains unknown despite all available information, a renal biopsy provides histologic information and, for many disease entities, is the most specific diagnostic test available. The biopsy should be considered when the diagnosis is uncertain, to estimate prognosis, to help demonstrate renal involvement of a systemic illness, and to help make therapeutic decisions. Most renal biopsies can be performed percutaneously with the use of local anesthesia.
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Although overnight observation in the hospital is still common, many nephrologists perform renal biopsies in ambulatory surgery settings with 6 to 8 hours of postprocedure monitoring (see Chapter 48). If the kidneys are very small or if renal failure is advanced, a biopsy is usually not done.
Monitoring the Patient with Chronic Kidney disease
The interval between visits is determined by the stage of renal insufficiency, the rate of progression, and the presence of complicating disorders. Early in the course, patients should have office visits scheduled every 4 to 6 months for monitoring of their symptoms, signs (e.g., weight, blood pressure, edema), and laboratory data (e.g., serum creatinine concentration, SUN, electrolytes, complete blood count [CBC], urinalysis, and possibly CrCl). As renal failure progresses, visits must be spaced more closely, usually at 1-month intervals until dialysis becomes necessary. Drug dosages of prescription, over-the-counter (OTC), and herbal medications should be reviewed at each visit and adjusted according to the degree of renal dysfunction (see Drug Use in Chronic Kidney Disease, below).
Course and Prognosis
The underlying renal disease largely determines prognosis. Many renal diseases have characteristic rates of progression. For example, patients with polycystic kidney disease typically have very indolent courses and some never progress to ESRD. More aggressive courses, with advanced renal failure developing within months to a year, are more likely to occur in patients with diseases such as rapidly progressive glomerulonephritis, systemic sclerosis, or malignant hypertension. However, most renal diseases fall into an intermediate group, with ESRD developing within 1 to 5 years after the initial diagnosis.
Therapy
Goals
The goals of therapy fall into five major categories. The first is to treat the underlying renal disease, if possible, with specific therapies (e.g., corticosteroids or chlorambucil for membranous nephropathy). The second is to slow the progression of renal deterioration by modifying the known or suspected factors that aggravate the primary process. A number of potentially modifiable factors have been identified that if treated have been shown in animal or human studies to slow the progression of established renal disease (Table 52.8). The third goal is to identify and treat comorbidities that can lead to increased cardiovascular complications (e.g. hypertension, diabetes, hyperlipidemia, anemia). The fourth is to treat the specific complications of renal disease (e.g., acidosis) as they occur, and to prevent the long-term complications of uremia before they can become fully established (e.g., secondary hyperparathyroidism). Finally, the patient should be referred to a dialysis and transplantation center well before the need for renal replacement therapy (see Dialysis and Transplantation).
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TABLE 52.8 Modifiable Risk Factors for the Progression of Chronic Kidney Disease (CKD) |
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Specific Treatments
Once a diagnosis is established, a nephrologist should be consulted, if not already accomplished, to determine whether effective therapy is available for the patient's renal disease. In general, the earlier in the course a treatment is started, the more likely it is to be successful in halting or reversing the disease. When the patient's renal disease is advanced or the effectiveness of the treatment is not well established, it is often advisable to forgo potentially toxic therapies, because the hazards often outweigh the benefits.
Many immunologically mediated renal diseases (e.g., membranous nephropathy, Wegener granulomatosis, Goodpasture syndrome, lupus nephritis) may respond to treatment with corticosteroids, cytotoxic agents, or plasmapheresis. For others (e.g., immunoglobulin A nephropathy), there is no proven effective therapy. Patients with immunologically mediated renal disease who require therapy should be under the care of a rheumatologist or nephrologist.
When the renal disease is associated with a metabolic disorder such as occurs in DM, it is critical to treat the underlying abnormality (e.g., hyperglycemia). Treatment directed at metabolic control may slow the course of renal deterioration but is not likely to result in significant reversal of established disease.
When a drug (e.g., methicillin, indomethacin) or other toxic substance (e.g., a heavy metal) is identified as the
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cause of renal failure, the offending agent should be withheld. A trial of corticosteroids may be given to patients with drug-induced interstitial nephritis, but this treatment is still controversial and the decision should be made in conjunction with a nephrologist.
Vascular lesions in the kidney caused by malignant hypertension may resolve slowly, but usually only partially, with control of blood pressure. In some patients this correlates with significant improvement in the GFR. Patients with renal failure secondary to bilateral renal vascular disease may have significant improvement in their renal function after successful angioplasty or bypass surgery, particularly if intervention occurs before renal insufficiency becomes too far advanced (serum creatinine less than approximately 4 mg/dL).
Obstructing lesions of the urinary tract may require surgical excision (e.g., benign prostatic hypertrophy) or urinary diversion (e.g., retroperitoneal fibrosis) to preserve or improve renal function. Other cases can be managed more conservatively (e.g., intermittent straight catheterization of the bladder) if the lesion is not amenable to surgical therapy (e.g., flaccid neurogenic bladder).
Nonspecific Treatments to Prevent Progression of Renal Disease
There are important treatment options that can reduce the rate of renal deterioration even when no specific therapies can be directed at the primary renal disorder. These therapies are directed at treating the modifiable risk factors listed in Table 52.8. This section will focus on treatment guidelines for hypertension, the use of specific drugs (e.g., the angiotensin-converting enzyme inhibitors [ACEIs] and the angiotensin receptor blockers [ARBs]), reduction of proteinuria and protein-restricted diets. Systemic hypertension, which is present in most patients with stages 2 through 5 CKDs (Table 52.2), contributes to the progression of pre-existing kidney failure. Of the 1,795 patients with renal insufficiency admitted to the MDRD study, 83% were hypertensive at study entry (16). The factors that correlated with the prevalence of hypertension included older age, lower GFR, presence of glomerular disease, high body mass index (BMI), male sex, and African American race. The presence of hypertension in the MDRD study predicted a greater probability of progressive renal insufficiency with a faster rate of decline. That long-term control of hypertension slows the progression of renal insufficiency seems to be beyond debate (see Chapter 67), but a number of important clinical questions remain unresolved.
One important question is what levels of blood pressure should be targeted? Few studies have addressed the issue of whether renal function is better preserved by lowering blood pressure to less than the usual target of 140/90 mm Hg. In addition to varying the protein intake, patients in the MDRD study were randomly assigned to receive usual or aggressive antihypertension therapies. Patients in the aggressively treated group (mean arterial pressure [MAP] target, 92 mm Hg) whose GFRs were between 25 and 55 mL/min/1.73 m2 had a more rapid decline in renal function during the first 4 months than those in the usual care group (MAP target, 107 mm Hg), but a more gradual decline thereafter. It was postulated that the initial rapid decline was hemodynamically mediated and did not reflect actual kidney damage. The beneficial effect of aggressive blood pressure control was greatest in patients with proteinuria (greater than 1 g/day). These findings led to the recommendation that the target blood pressure should be 130/80 to 130/85 mmHg for patients with chronic renal disease without proteinuria, but that patients with proteinuria greater than 1 g/day should have their blood pressure lowered to levels near 125/75 mm Hg. Interestingly, the effectiveness of more aggressive lowering of blood pressure was not confirmed in African Americans with hypertensive nephrosclerosis, a population that seems to be most sensitive to the harmful effects of hypertension (17). The Ramipril Efficacy In Nephropathy 2 (REIN-2) study (18) also did not show an additional benefit when felodipine (a dihydropyridine calcium channel blocker [CCB]) was added to ramipril to see whether reducing blood pressure below 130/80 mm Hg was effective at slowing the rate of renal progression. One meta-analysis raised the possibility that lowering the systolic blood pressure below 110 mmHg could be associated with worse renal outcomes (19). Table 52.9 summarizes recommendations for blood pressure treatment goals. Achieving these goals generally requires multiple antihypertensive medications.
A second important question is whether certain antihypertensive agents offer advantages over others—that is, do some medications have beneficial effects beyond the consequences of lowering of blood pressure? Intraglomerular hypertension leading to hyperfiltration is believed to be
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an important factor leading to the progression of kidney disease. ACEIs and ARBs have the theoretical advantage of reducing both systemic and intraglomerular pressures. They also have the additional effects of reducing proteinuria, and the cytokine mediated effects of angiotensin, factors associated with renal injury.
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TABLE 52.9 Recommended Target Blood Pressures |
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Most studies comparing the use of various ACEIs with other antihypertensive medications in humans with nondiabetic renal failure show that ACEIs offer an advantage in slowing the progression of renal insufficiency (20, 21, 22). The general recommendations for treating hypertension in patients with renal insufficiency are to use an ACEI as initial therapy unless renal artery stenosis is suspected or the patient has hyperkalemia (serum potassium concentration greater than 5.0 mEq/L). The serum potassium and creatinine levels should be checked 1 to 2 weeks after initiating therapy and periodically thereafter. A small rise in creatinine (below 0.5 mg/dL) or potassium (below 0.5 mEq/L) may occur but does not necessarily mean that therapy should stop. ARBs, as primary therapy, have been shown to be effective in diabetic renal disease (see Diabetes Mellitus), but the data in nondiabetic renal disease is not as well established. Nevertheless, ARBs are recommended by K/DOQI as initial therapy, particularly if there are reasons not to use an ACEI. The COOPERATE study showed that the combination of an ACEI with an ARB resulted in less proteinuria and in fewer patients reaching the primary endpoint (doubling of serum creatinine) than when either therapy was used alone (Fig. 52.6) (23). ACEIs/ARBs can be used in all stages of CKD unless precluded by hyperkalemia. Since proteinuria is an independent risk factor for the progression of renal disease, minimizing proteinuria using combinations of drugs such as ACEIs, ARBs, and CCBs (see below) makes sense. Most studies show that proteinuria can be reduced by 50% to 60% by the use of ACEIs/ARBs.
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FIGURE 52.6. Effect of combined treatment on the course of CKD. (From Nakao N, Yoshimura A, Morita H, et al. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2003;361:117. ) |
CCBs seem to be an adequate alternative to ACEIs when the latter cannot be used or there are other reasons for choosing a CCB. Nondihydropyridine CCBs may also have specific local protective effects on the renal vasculature or glomerular basement membrane that could be advantageous beyond their systemic effects on hypertension. Dihydropyridine CCBs do not seem to offer additional benefit beyond their effects on systemic hypertension since they do not reduce proteinuria. Also, there are some concerns about their use since they cause arteriolar vasodilatation that can lead to intraglomerular hyperperfusion.
Diuretics are almost always needed as part of antihypertensive therapy, particularly as renal function deteriorates. Diuretic therapy in patients with stage 1through 3 CKD (Table 52.2) is similar to that for patients with normal renal function and hypertension. A sodium-restricted diet (e.g., 2 g/day) may be attempted as a first step. Loop diuretics such as furosemide, bumetanide, or torsemide can be added if sodium restriction is insufficient or if nondiuretic drugs (e.g., hydralazine, captopril) lead to secondary sodium retention. Thiazides are generally avoided in patients with GFRs lower than 30 mL/min/1.73 m2 because they often lose their diuretic effect. Spironolactone, a diuretic whose use is increasing, has been reported frequently (24) to cause hyperkalemia in patients with renal failure, especially if they also have been prescribed an ACEI. Therefore, it and other potassium-sparing diuretics (triamterene, amiloride) should be used only with extreme caution and careful monitoring in patients with significant renal impairment. In patients who have refractory edema or advanced renal failure with severe sodium retention, it may be necessary to use large daily doses of diuretic (furosemide up to 400 mg, bumetanide up to 10 mg, or torsemide up to 200 mg) or to use a combination of loop diuretic and thiazide (e.g., metolazone 2.5 to 5 mg). Patients need to have their body weight and blood chemistries closely monitored when they use combination diuretic therapy, because some patients experience exaggerated responses.
There is often a fine line between effective blood pressure control and hypotension when potent diuretics and antihypertensives are being used; therefore, careful monitoring of blood pressure (both supine and upright) and of serum creatinine concentration is necessary.
Nonpharmacologic therapy to reverse intraglomerular hypertension may involve the use of protein-restricted diets. The GFR in healthy animals and humans varies directly with protein intake. Dietary protein restriction has been shown in animal experiments, using various models
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of partial renal injury, to reduce the degree of compensatory hypertrophy and hyperperfusion (see Pathophysiology of CKD) and to forestall the development of glomerular sclerosis, proteinuria, and progressive renal failure. Dietary treatments have been extensively studied in humans as well.
Despite several small studies that seemed to confirm the benefits of dietary protein restriction in humans, questions remained about its value in the treatment of CKD. Some, but not all, of these questions were resolved by the Modification of Diet in Renal Disease (MDRD) Study (25). Patients with varying degrees of renal insufficiency (GFR, 25 to 55 mL/min/1.73 m2) were randomly assigned to a usual blood pressure group (mean arterial pressure [MAP], 107 mm Hg) or to a low blood pressure group (MAP, 92 mm Hg). ACEIs were used in a significant proportion of both groups. On the basis of an intention-to-treat analysis, despite the achievement of dietary and blood pressure goals, there were no significant differences between the interventions in rate of decline of GFR (as measured by radioisotope techniques), time until dialysis was required, or mortality. Although the mean protein intake between the groups was different, there was considerable variation and overlap among individual patients. When the data from the group with advanced renal failure were reanalyzed, correlating actual achieved dietary protein intake with GFR (controlling for other factors known to influence the rate of decline in GFR), it was concluded that, within the range 0.5 to 1.0 g/kg daily protein intake, a lower intake was associated with a slower rate of decline in GFR (26).
Based on current literature, a National Institutes of Health Consensus Conference (27) made the following recommendations for nutritional management of nondiabetic patients with renal insufficiency: There is insufficient evidence to warrant protein restriction in patients whose GFR is greater than 25 mL/min/1.73 m2, who therefore should be maintained on a normal protein intake of more than 0.8 g/kg daily. A diet restricted in protein (0.6 g/kg daily) should be prescribed for patients with a GFR less than 25 mL/min/1.73 m2, with the understanding that good dietary counseling should be available and that there should be careful monitoring for signs of malnutrition (weight loss, falling albumin concentration, transferrin less than 200 mg/dL). Given the remaining controversy about dietary protein restriction in patients with renal failure, consultation with a nephrologist should be obtained before embarking on such therapy.
Treating Reversible Causes of Deterioration of Renal Function
Before any change in serum creatinine concentration is attributed to natural progression of the underlying renal disease, several alternative possibilities should be considered.
Extracellular volume depletion is probably the most common cause for a fall in GFR. It may be related to an intercurrent illness associated with anorexia, fever, gastrointestinal (GI) losses of sodium and water, excessive sodium restriction, or diuretic use. The usual clinical signs of volume depletion (low jugular venous pressure, orthostatic hypotension, tachycardia, decreased skin turgor, and weight loss) may be absent. Weight loss between office visits is usually the most important diagnostic clue to the presence of volume depletion. The urinary sodium concentration or urine osmolality, usually helpful in establishing the diagnosis of volume depletion in oliguric patients, is of little value in the patient with chronic renal failure because concentrating and sodium-conserving abilities in these patients are often impaired.
Patients with decompensated CHF may also have superimposed prerenal azotemia because of diminished cardiac output and renal perfusion. Optimal treatment of heart failure may improve renal function in these patients (see Chapter 66).
Drugs given for treatment of various other disorders can be related to worsening of renal function (Table 52.5). A careful review of both prescribed and OTC medications is therefore necessary when assessing unexpected changes in kidney function. Of the drugs prescribed in the ambulatory setting, diuretics and NSAIDs are probably the most common offenders. Diuretics can aggravate pre-existing renal failure by inducing intravascular volume depletion and, less commonly, by producing an interstitial nephritis. Careful monitoring of the blood pressure, weight, SUN, and serum creatinine concentration helps detect early signs of prerenal azotemia in patients receiving diuretics. Withholding diuretic therapy for several days usually allows intravascular volume and GFR to return to baseline values. Use of NSAIDs can result in deterioration in kidney function, either by causing a reversible redistribution of renal blood flow or by producing an interstitial nephritis. NSAIDs are most likely to reduce GFR in patients with prerenal states (e.g., volume depletion, CHF, nephrosis). At this time it cannot be said that one nonsteroidal compound is safer to use in the patient with renal insufficiency than another. It is therefore best to avoid them altogether once the GFR is less than 50 mL/min/1.73 m2.
There are numerous reports of reversible renal dysfunction when ACEIs were administered to patients with bilateral renovascular disease or renal artery stenosis of a solitary kidney.
Obstruction, because of its reversibility, should always be considered in patients with a fall in the GFR. This is particularly true in elderly men who are predisposed to prostatic hypertrophy and in diabetic patients who may have autonomic neuropathy affecting bladder emptying. Drugs that reduce bladder tone (e.g., antidepressants,
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antispasmodics, antiparkinsonian drugs with anticholinergic properties) should always be considered as causes of urinary retention. If obstruction is a possibility, the postvoid residual volume should be measured (see Chapter 53).
Microcrystal deposition in the kidney has been suggested as a cause of progressive deterioration in patients with azotemia. Serum uric acid concentrations are often elevated in patients with renal insufficiency. However, there is no evidence that reducing the serum uric acid concentration will prevent further deterioration when the original kidney disease was not caused by tophaceous gout. Allopurinol therefore is not used unless it is needed to control symptomatic gout.
Dietary Management
In addition to the possible effects of slowing the progression of kidney disease (see Nonspecific Treatments to Prevent Progression of Renal Disease), the major goals of dietary management in the patient with chronic renal disease are to optimize intravascular volume, correct electrolyte abnormalities, and relieve uremic symptoms. The dietary and general treatment of nephrotic syndrome, occasionally a component of chronic renal failure, is discussed in Chapter 48.
The volume of the intravascular space is directly related to sodium balance, which is in turn regulated by the kidney. As renal function declines, the ability of the kidney to maintain sodium balance in response to changes in sodium intake becomes limited, especially when the changes occur abruptly. The intravascular volume may be depleted if the intake of sodium is reduced (e.g., excessive sodium restriction, anorexia) or if there are losses of sodium (e.g., vomiting, diarrhea, diuretics). A reduction in intravascular volume can lead to a further increase in the SUN and to serum creatinine concentrations above the baseline values (prerenal azotemia). Conversely, the intravascular volume will increase if the intake of sodium is suddenly augmented (dietary indiscretion), and the patient can develop hypertension, edema, or heart failure.
Most patients with chronic renal insufficiency maintain sodium balance on a sodium intake of 4 to 6 g/day. Patients with CHF or hypertension may need further limitation of sodium intake (2 g/day of sodium), whereas the rare patient with severe salt-wasting nephropathy may require salt supplements to prevent volume depletion. Most of these latter patients have some form of interstitial renal disease.
Salt intake should be adjusted to maintain intravascular volume at the level that maximizes the GFR for any given degree of renal failure. Assessment of the state of the intravascular volume can be aided by obtaining serial body weights (rapid changes in weight are usually caused by fluid gains or losses), performing a physical examination (e.g., orthostatic change of pulse and blood pressure, jugular venous pressure, skin turgor, edema), and by measuring changes in the SUN and serum creatinine concentrations (increases in the level of SUN are proportionately greater than those of the serum creatinine concentration in states of volume depletion). It is often useful to establish an “ideal weight.” This is the weight at which the patient has optimal renal function without overt signs of volume overload. For some patients (e.g., those with CHF or nephrotic syndrome), a small amount of edema is acceptable because worsening of azotemia may develop when further diuresis is attempted. Whenever there is a significant change in the GFR, the intravascular volume and the ideal weight should be re-evaluated.
If volume overload develops or persists despite sodium restriction, diuretics can be used to increase sodium excretion. Because the thiazide diuretics, with the exception of metolazone (Zaroxolyn), lose their effectiveness when the GFR falls below 30 mL/min/1.73 m2, it is often necessary to use a loop diuretic, such as furosemide (Lasix), torsemide (Demadex), or bumetanide (Bumex). Another loop diuretic, ethacrynic acid (Edecrin), has been associated with an unacceptable level of ototoxicity and should not be used in patients with renal insufficiency. The potassium-sparing diuretics spironolactone (Aldactone), triamterene (Dyrenium), and amiloride (Midamor; also in Moduretic) are also best avoided without consultation from a nephrologist when there is significant renal failure because of the risk of inducing serious hyperkalemia.
Potassium restriction is usually unnecessary until the late stages of renal failure (GFR less than 15 mL/min/1.73 m2), except in the small number of patients with the syndrome of hyporeninemic hypoaldosteronism (see next paragraph), but careful monitoring of serum potassium levels is indicated nonetheless. If hyperkalemia develops, potassium restriction to between 2 and 2.4 g/day (40 to 50 mEq/day) is necessary. A dietitian should be consulted to help plan a potassium-restricted diet. Foods with high potassium content include dairy products, many greens, beans, potatoes, tomatoes, bananas, dates, prunes, raisins, and citrus fruits. Patients who are on sodium-restricted diets must also be informed that many salt substitutes are unacceptable because they are often composed of potassium salts.
The association of hyperkalemia and hyperchloremic metabolic acidosis in patients with GFR greater than 25 mL/min/1.73 m2 should lead one to consider the presence of the hyporenin-hypoaldosterone syndrome (28). This syndrome occurs most often in azotemic patients with hypertension, DM, or interstitial nephritis. This disorder probably has many causes, but it is caused in part by a suppression of the renin–aldosterone axis. The diagnosis is usually made on clinical grounds, after excluding other reasons for hyperkalemia (e.g., severe renal failure, high potassium intake, drugs that reduce renal excretion of potassium), but it can be more firmly established by the
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demonstration of a low plasma renin concentration that fails to rise after stimulation with furosemide (Lasix, 40 mg orally) in a patient who has been upright posture for 2 or more hours. The patient should also have no evidence of glucocorticoid deficiency (random cortisol concentration, 15 to 25 mg/mL; see Chapter 81). Because, in the absence of aldosterone, potassium excretion by the kidney depends on an adequate urine flow rate (1.5 to 2 L/day), patients with this syndrome are at risk for development of severe hyperkalemia during periods of sodium restriction or volume depletion. Normotensive patients may be treated with a mineralocorticoid (fluorohydrocortisone [Florinef], 0.1-mg tablets, ½ to 1 tablet per day). Alternatively, if hypertension is present or develops after administration of the mineralocorticoid, the patient may be treated with a combination of furosemide (Lasix, 40 to 80 mg twice a day) plus sodium bicarbonate (600 mg four times a day). The furosemide is used to promote a good urine flow rate, whereas the sodium bicarbonate helps prevent sodium depletion and also is of use in correcting the associated metabolic acidosis. The goal of therapy is to keep the serum potassium concentration within the normal range. Because therapy is often complicated, these cases are best managed with the help of a nephrologist or endocrinologist.
Although diluting and concentrating abilities are impaired in renal failure, most patients can ingest 1 to 3 L of fluid daily without developing hyponatremia. If hyponatremia occurs, fluids should be limited to less than 1.5 L/day to prevent water intoxication.
As GFR falls, patients often consume less protein. Because protein deficient diets are often low in vitamins, calcium, and phosphorus, patients should receive a daily vitamin supplement and 1 to 1.5 g of elemental calcium per day (a single 600-mg calcium carbonate tablet provides 250 mg of elemental calcium). The reduction in dietary phosphorus is desirable (see later discussion), so phosphorus supplements are not given.
Considering the complexity of such diets and the need for individualization of salt, mineral, protein, and potassium intake, consultation with a dietitian or a nephrologist proficient in prescribing renal diets is suggested. Constant encouragement and supervision of dietary therapy are needed. The success of dietary treatment often depends on the involvement of family members as well as an enthusiastic dietitian.
Calcium and Phosphorus
Renal osteodystrophy is a general term that encompasses osteitis fibrosa, osteomalacia, adynamic bone disease, and a variety of other bone lesions that occur in patients with kidney failure. Many aspects of the diagnosis and treatment of renal osteodystrophy remain controversial. However, it is clear that the pathophysiologic factors that lead to osteodystrophy originate in the early stages of renal failure (stages 3 and 4, Table 52.2), although clinical manifestations generally do not develop until the patient is on dialysis.
The pathophysiology of renal osteodystrophy is complex but can be briefly summarized as follows: PTH hypersecretion occurs in response to an absolute or relative deficiency of the active form of vitamin D (see later discussion). The relative deficiency of vitamin D, in turn, leads to diminished calcium absorption, skeletal resistance to the effects of PTH, and resetting of the setpoint of PTH secretion in response to calcium.
The increased rate of PTH secretion keeps serum calcium and phosphorus levels within the normal range until the GFR is less than 30 mL/min/1.73m2. In more advanced renal failure, hypocalcemia and hyperphosphatemia develop. Hyperphosphatemia further blunts the calcemic response to PTH and diminishes vitamin D secretion. It also predisposes to tissue and vascular calcification. Hyperphosphatemia is linked to increased mortality in the dialysis population (29). A major consequence of prolonged secondary hyperparathyroidism is the development of bone disease (osteitis fibrosa cystica).
Osteomalacia, in renal insufficiency, is caused partly by the failure of the diseased kidney to convert 25-hydroxyvitamin D3 to its more active form, 1,25-dihydroxyvitamin D3. The active form of vitamin D is necessary for normal bone mineralization. Serum levels of vitamin D can be in the normal range in patients with renal failure, but with GFRs greater than 30 mL/min/1.73m2 such levels may still represent a relative deficiency of the vitamin, because increased levels of vitamin D would be expected in response to the low calcium concentration in renal failure. Absolute deficiencies of vitamin D are found once the GFR falls below 30 mL/min/1.73 m2 (Fig. 52.7). Abnormal collagen synthesis, titration of bone buffers, and accumulation of aluminum in the bone matrix have also been implicated in the pathogenesis of osteomalacia. A growing number of patients, mainly with stage 5 CKD (Table 52.2) who have been treated with vitamin D, have relatively low PTH values and show histomorphic evidence of low bone turnover or adynamic bone disease. Many will show a combination of histological patterns. The diagnosis of this condition can only reliably be made by bone biopsy.
Much of the current controversy in the diagnosis of renal osteodystrophy centers on the use of PTH measurements. Assays that measure the “intact hormone” have been used for years and were assumed to measure the level of active hormone. These assays only measured the 6–84 fragment and are being replaced by newer “biointact” assays that measure the complete hormone (1–84). In general, very high levels of hormone correlate with the presence of osteitis fibrosa cystica and very low levels are associated with adynamic bone disease. Many patients, unfortunately, have intermediate values that do not predict
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the bone histology pattern well. Because this is an area of great uncertainty and new information is accumulating rapidly, it would be advisable to discuss interpretation of PTH levels with a nephrologist before initiating therapy.
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FIGURE 52.7. Vitamin D and PTH in patients with CKD. (Modified from Friedman EA. Consequences and management of hyperphosphatemia in patients with renal insufficiency. Kidney Int 2005;95:S1. ) |
Patients with CKD should have periodic measurements of calcium, phosphorus, magnesium, and alkaline phosphatase once the GFR falls below 60 mL/min/1.73 m2 (Table 52.10). The clinical features of deranged calcium and phosphorus metabolism, including bone pain, fractures, and proximal myopathy, are not often seen until after the patient is on dialysis. However, it is generally acknowledged that preventing parathyroid hyperplasia is easier than reversing it once it is established. Therefore, therapy to correct these abnormalities should begin during the early stages of kidney disease.
The goals of therapy are to limit the rise in PTH secretion that usually accompanies renal failure, to prevent the development of osteomalacia, and to maintain normal calcium and phosphorus levels. Maintaining a positive calcium balance, providing vitamin D supplements, and reducing phosphorus intake can achieve these goals.
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TABLE 52.10 Frequency of Measurement of PTH and Calcium/Phosphorus by Stage of CKD |
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Treatment
Because calcium absorption is diminished in patients with CKD, the first step in treatment is to ensure an adequate intake of calcium. This is particularly important for patients on protein-restricted diets, which often contain only 300 to 400 mg of calcium per day (normal calcium intake is 800 to 1,000 mg/day). Supplements in the form of calcium carbonate (generic), 600 mg four times per day, provide 1,000 mg of elemental calcium per day. Calcium lactate (generic, 300 mg, in two tablets four times a day) may be substituted if the carbonate is not tolerated because of constipation or bloating.
Restriction of Dietary Phosphorous
Restriction of dietary phosphorus to approximately 800 mg/day (normal intake is 1 to 1.8 g/day) should be initiated when either the PTH begins to rise or when the serum phosphorus level first becomes elevated (stage 4). This degree of phosphorus restriction can be achieved by restricting the intake of protein to 60 g/day (foods such as eggs, meat, and fish contain 15 mg of phosphorus per gram of protein, and dairy products 20 to 30 mg/g). Despite restriction of phosphorus intake, the serum phosphorus level often becomes elevated when the GFR falls below 30 mL/min/1.73m2. At this juncture, it is necessary to start treatment with phosphate binders. Calcium-containing compounds such as calcium carbonate and calcium acetate, which bind phosphate in the intestine and thereby reduce phosphate absorption, have supplanted the use of oral antacids containing aluminum because aluminum from the antacids is absorbed and can accumulate in the brain and bones of patients with renal failure. This aluminum accumulation has been implicated in the pathogenesis of the dialysis
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dementia syndrome (myoclonus, seizures, and dementia), and in the development of anemia (see Chapter 55), and of a particular form of osteomalacia (characterized by the appearance of aluminum in the mineralization front of bone studied histochemically) that develop in some patients with ESRD. Nephrologists now recommend the addition of aluminum-containing compounds only in refractory cases of hyperphosphatemia. The initial dosage of calcium carbonate or calcium acetate should be 1 or 2 tablets or capsules given with meals; the dosage should be increased (at 2-week intervals) until the serum phosphorus concentration is reduced to between 4 and 6 mg/dL. Serum phosphorus levels should be monitored every 1 to 2 months to avoid the syndrome of phosphate depletion (low serum phosphorus), which may result in muscle weakness, osteomalacia, and fractures. Many patients report constipation with calcium salts and object to the number of pills they must take.
A serious concern has been raised about the use of calcium-containing phosphate binders in patients with renal failure. A study in which young dialysis patients were screened with electron-beam CT scans revealed significant cardiac calcification (which in the general population is associated with atherosclerosis) in 14 of 16 subjects who were between 20 and 30 years of age. One correlate of cardiac calcification was higher calcium intake (30). Therefore, it is recommended that the total amount of calcium intake in the form of binders be limited to 1,500 mg/day or patients whose serum calcium is greater than 10.2 mg/dL. Fortunately, new options for binding phosphate using calcium free binders are now available. One option is to use a non–calcium-containing, nonabsorbable resin called sevelamer hydrochloride (Renagel). The starting dose should be one 800 mg capsule taken three times per day with meals and titrated to normalize the phosphorus level. Sevelamer hydrochloride also lowers total and low-density lipoprotein (LDL) cholesterol concentrations, but can worsen acidosis. This product is as effective as calcium carbonate, but it is considerably more expensive and some patients complain of gastric bloating. Lanthanum carbonate (Fosrenol) is available in 250 and 500 mg tablets and appears to be as effective as the aluminum-containing binders. Doses are to be given with meals to maximize phosphorus binding and tablets need to be chewed before swallowing.
Vitamin D Therapy
If PTH levels remain elevated despite adequate calcium intake and control of serum phosphorus with diet and binders, consideration should be given to use of vitamin D therapy. Vitamin D can reduce PTH secretion by increasing serum calcium, but there is also a direct suppressive effect of vitamin D on the parathyroid gland. The normal kidney is responsible for the conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 (calcitriol), which is the active form. Low levels of 25-hydroxyvitamin D3 (<30 ng/mL) are common in patients with stage 3 or 4 CKD and result in low levels of 1,25-dihydroxyvitamin D3. Correction with ergocalciferol has been shown to ameliorate bone lesions.
Until now, the most commonly used vitamin D preparation that does not require renal activation was 1,25-dihydroxyvitamin D3 (Rocaltrol). When given orally, Rocaltrol (0.25 to 1.0 µg/day) is effective in improving calcium absorption and raising serum calcium levels in azotemic patients and can reverse some of the biochemical and histologic evidence of osteodystrophy (31). However, Rocaltrol also increases phosphorus absorption through the GI tract and can aggravate hyperphosphatemia. Newer vitamin D analogues have been developed that are effective in reducing PTH secretion, but do not promote calcium and phosphorus absorption to the extent that calcitriol does. Paricalcitol (Zemplar) is available in intravenously administered and oral formulations and is used extensively in patients on hemodialysis. Doxercalciferol or 1 α-hydroxyvitamin D2 (Hectorol) has been shown to reduce PTH levels in stage 3 or 4 patients (Fig. 52.8) with only minor effects on calcium and phosphorus concentrations (32). The recommended starting dose is 1 mg by mouth daily. If, after consultation with a nephrologist, it is decided to treat, the lowest dosage of the vitamin D preparation should be selected, and the dosage should be raised every 4 weeks until the PTH level is in the desired range (Table 52.11). Vitamin D doses should be reduced if the PTH levels fall below the target range or if serum calcium or phosphorus levels exceed 9.5 or 4.6 mg/dL respectively. Suppression of PTH to “normal” levels with vitamin D therapy leads to a syndrome of adynamic bone disease in dialysis patients who manifest a resistance to PTH.
Vitamin D therapy should not be initiated when serum calcium or phosphorus levels are greater than 10.5 and 6.0 mg/dL, respectively, because of the possibility of inducing metastatic calcification or renal dysfunction. If the serum phosphorus concentration is elevated, as is common in patients whose GFR is less than 30 mL/min/1.73 m2, it is necessary to first reduce the level of phosphorus to normal before starting vitamin D therapy.
The serum phosphorus concentration may rise after institution of vitamin D therapy because both calcium and phosphorus absorption are increased. If dietary phosphate restriction (approximately 800 mg/day) is not sufficient to maintain serum phosphorus levels within the normal range, phosphate binders must be used (see Restriction of Dietary Phosphorus). Patients who have elevated serum calcium levels or increased calcium X phosphorus products might not be candidates for vitamin D therapy. Cinacalcet (Sensipar), a calcium-sensing receptor antagonist (Fig. 52.9), has been used in both dialysis and
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pre-dialysis patients to treat hyperparathyroidism (33). This drug “fools” the parathyroid gland into thinking that the calcium level is higher than it actually is. The starting dose is 30 mg by mouth daily. The serum calcium and phosphorus levels typically fall after starting therapy and have to be monitored closely.
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FIGURE 52.8. Reduction in PTH in stages 3 and 4 CKD with doxercalciferol therapy. (From Coburn JW, Maung HM, Elangovan L, et al. Doxercalciferol safely suppresses PTH levels in patients with secondary hyperparathyroidism associated with chronic kidney disease stages 3 and 4. Am J Kidney Dis 2004;43:877. ) |
Acidosis
A mild hyperchloremic (normal anion gap) metabolic acidosis develops commonly in patients with stage 3 CKD (Fig. 52.10) (34). This occurs because the decrease in production of ammonia by the failing kidney results in inability of the kidney to excrete metabolically produced acids (sulfates and phosphates). The hypochloremic (with an abnormal anion gap) acidosis that is commonly associated with renal failure usually does not appear until the GFR has fallen below 20 mL/min/1.73 m2.
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TABLE 52.11 Target Range of Intact Plasma PTH by Stage of CKD |
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Chronic metabolic acidosis contributes to the long-term complications of patients who have renal failure by decreasing bone mineralization and suppressing protein synthesis. The goal of treating the acidosis is to maintain a serum bicarbonate level greater than 22 mEq/L. If protein restriction (see Dietary Management), which reduces the exogenous acid load, is insufficient to restore buffering capacity, base in the form of sodium citrate liquid (1 mL liquid = 1 mEq bicarbonate) can be given. Dosages of 30 to 60 mEq/day of base, given in divided doses, are generally sufficient to maintain acid–base balance. Sodium bicarbonate (600 mg = 14 mEq base) can also be used, but it is less well tolerated than citrate because of GI complaints such as belching and bloating. Finally, calcium carbonate, given as a calcium supplement and phosphate binder, may also be effective in correcting the acidosis.
Anemia
A normochromic, normocytic anemia typically develops in patients with chronic renal failure, and its severity is proportional to the degree of renal insufficiency (Fig. 52.5). Up to 45% of patients with a serum creatinine concentration of 2 mg/dL or more are anemic (35). The anemia of renal failure results mainly from decreased erythropoietin production. The presence of anemia in patients with CKD affects their quality of life, sexual function, and exercise capacity, and is a major contributor to left ventricular hypertrophy and heart failure. Other causes of anemia (e.g., iron deficiency, GI bleed, vitamin deficiencies) must also be considered.
All patients should be prescribed a multivitamin regimen that includes folate to replace the vitamins lacking
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in the restrictive diets. Iron deficiency is almost universal in patients on hemodialysis, but it may also occur in the predialysis patient, particularly if multiple blood samples have been taken or if there is bleeding. Iron deficiency is best diagnosed in patients with chronic renal failure by measuring the level of serum ferritin and/or iron saturation. The ferritin, serum iron and iron-binding capacity may be “normal” in CKD, but a transferrin saturation less than 20% or ferritin <100 nanograms per milliliter suggest the possibility of iron deficiency. Some CKD patients with “adequate” iron stores who do not respond to erythropoietin and oral iron may respond to intravenously administered iron (Venofer or Ferrlecit) (36) (see Chapter 55).
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FIGURE 52.9. Reduction in PTH in stages 3 and 4 CKD with cinacalcet. (Modified from Block GA, Martin KJ, de Francisco AL. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 2004;350:1516. ) |
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FIGURE 52.10. Relationship between serum bicarbonate and serum creatinine concentrations in patients with chronic renal insufficiency. (From Widmer B, et al. The influence of graded degrees of chronic renal failure. Arch Intern Med 1979;139:1099. ) |
Patients whose hemoglobin levels fall below 12 g/dL or who have symptoms related to anemia should be treated with recombinant human erythropoietin (Epogen, Procrit, Aranesp). Weekly doses of Procrit/ Epogen starting at 10,000 units given subcutaneously have been shown to be safe and effective (37). Darbepoetin alfa (Aranesp), a glycosylated form of erythropoietin with a longer half-life, can be given less frequently (0.45 µg/kg by subcutaneous injection weekly or 0.75 µg/kg by subcutaneous injection every other week). The hematocrit value or hemoglobin concentration should be measured every other week until stable and monthly thereafter. In general, dose titration should not be done more often than monthly. Most patients become asymptomatic when the hemoglobin level is between 11 and 12 g/dL. The optimal target value for hematocrit or hemoglobin is much debated. There has not been convincing evidence that increasing the hemoglobin above 12 g/dL is beneficial and there is even some evidence that in some patients, higher levels may be harmful (38,39).
Even patients who are not iron-deficient but are taking erythropoietin should be given ferrous sulfate 300 mg
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and 1 mg of folic acid daily because iron and vitamin stores can be depleted rapidly when red cell production is increased. In some patients, blood pressure may become more difficult to control with this treatment, and it is therefore recommended that blood pressure measurements be taken on a weekly basis until the hematocrit level stabilizes (usually 6 to 8 weeks). Despite evidence that correction of anemia improves quality of life and may reduce long-term cardiovascular complications, only a minority of uremic patients are treated with erythropoietin before starting dialysis treatment. The reasons for suboptimal use of erythropoietin in the predialysis population are not known, but they may be related to lack of familiarity with the use of erythropoietin or to difficulties in obtaining reimbursement. For the treatment to be reimbursable, Medicare rules require that the injections be given in the office or clinic. Many patients complain that there are many obstacles (i.e., large prepayments) to obtaining private insurance coverage for erythropoietin, given its expense.
Drug Use in Chronic kidney disease
The incidence of adverse drug effects is increased in patients with renal failure, a fact that is attributable largely to the alterations in pharmacokinetics that occur as renal function declines. Adverse drug effects in these patients can be divided into those that are caused by abnormal drug metabolism (e.g., increased incidence of digitalis toxicity) and those that are caused by an effect on renal function that is part of the anticipated pharmacologic action of the drug (e.g., reduction in GFR with diuretics or NSAIDs). In renal failure, drug bioavailability, volume of distribution, and protein binding may be abnormal; however, the most significant derangement is the prolongation of half-life of many drugs or their metabolites. Therefore, it is necessary to have a basic understanding of how a drug's administration should be modified when renal failure is present.
Because even OTC preparations (e.g., aspirin, ibuprofen, magnesium-containing antacids) have the potential for causing toxicity, patients should be reminded to telephone their primary care provider before using nonprescription drugs. Whenever possible, drugs that require no modification of dosage or that do not affect kidney function adversely should be substituted for those with a greater potential for inducing toxicity. The avoidance of drugs with marginal efficacy will help reduce the frequency of adverse effects.
A complete review of drug usage in renal failure may be found in Drug Prescribing in Renal Failure, published by the American College of Physicians (40) or by using on-line resources such as MicroMedix.
Before initiating therapy with a drug that requires dosage modification in renal failure, it is necessary to have an accurate estimation of GFR. Predicting the GFR from the serum creatinine level alone is not recommended; rather, one should either measure the CrCl directly or use one of the formulas for estimating GFR (see Screening and Primary Prevention and equations).
Depending on what modifications are required for a particular drug, an appropriate loading and maintenance dosage can be chosen. A loading dose must be given whenever rapid achievement of therapeutic drug levels is desired. Maintenance dosages are adjusted either by lengthening the interval between administrations or by reducing the size of each dose. The use of nomograms or tables does not guarantee that adverse drug effects will not occur. The monitoring of serum drug levels is often helpful, particularly when using drugs with low toxic/therapeutic ratios. Finally, the list of drugs should be reviewed periodically and the patient questioned specifically about side effects.
Chronic kidney disease and Coexisting Disorders
Nonrenal diseases often occur in patients with kidney disease. In some patients, such as those with SLE or DM, the renal disease is part of a generalized illness that affects many other organ systems. Other patients may have diseases unrelated to the kidneys, such as coronary artery disease (CAD), chronic obstructive pulmonary disease, or malignancy. The coexistence of multiple disorders often complicates management. For example, angina in patients with CAD may be aggravated by the anemia of CKD.
Diabetes Mellitus
Patients with diabetes represent a substantial portion of most primary care providers’ practices and clinical diabetic nephropathy, manifested by proteinuria with or without an elevated serum creatinine occurs in a significant proportion of this population. Overt nephropathy with persistent proteinuria occurs in up to 50% of patients with type 1 DM and more advanced nephropathy is seen in 10% to 20%, usually 15 to 20 years after the onset of diabetes. The pathology and natural history of the nephropathy associated with type 2 diabetes is similar to that associated with type 1 diabetes once overt proteinuria develops, with progression to ESRD within 5 years of the development of overt proteinuria. Patients with DM account for approximately 30% to 40% of many dialysis populations. Since type 2 diabetes is more common than type 1, the majority of diabetic patients requiring renal replacement therapy have type 2 diabetes. The pathophysiology of diabetic nephropathy is complex and involves genetic, metabolic, and hemodynamic factors. It is becoming increasingly
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important for the generalist to recognize and treat these patients, because efforts to prevent the development of advanced renal failure must take place early, usually before the patient is referred to the nephrologist.
Microalbuminuria (30 to 300 mg/24 hours), is the earliest clinical manifestation of diabetic nephropathy and identifies a subpopulation of patients who need more aggressive therapy, including tight glucose and blood pressure control. Without specific interventions, a high proportion of patients (50%) with type 1 disease who have microalbuminuria develop more advanced CKD. The predictive value of microalbuminuria in type 2 diabetes is weaker (20% to 40% who have microalbuminuria develop more advanced CKD). Overt proteinuria (greater than 300 mg/day), as detected by a urine dipstick is seen on average 10 to 15 years after the onset of type 1 DM and sooner in patients with type 2. By this time, pathologic changes of diabetic glomerulosclerosis are well established. The presence of proteinuria is also associated with an increased incidence of cardiovascular disease and death.
The Council on Diabetes Mellitus of the National Kidney Foundation has published guidelines for the screening and treatment of diabetic patients with microalbuminuria (41). Screening for microalbuminuria should be performed annually for all diabetics between the ages of 12 and 70 years. Measurement of a morning spot urine for albumin and creatinine, using a specific assay to detect microalbuminuria, is a practical screening method. Microalbuminuria is present if the albumin/creatinine ratio is between 30 and 300 mg/g on two occasions in a 3-month period. Urine protein may be falsely elevated if the patient is performing strenuous exercise, has a febrile illness, has a urinary tract infection, or is in heart failure. Studies have shown that treatments (usually involving the use of ACEIs or ARBs) that reduce proteinuria have significant renoprotective effects in patients with or without hypertension (42,43).
The prevention of progressive kidney disease and reduction of cardiovascular risks should be the major goals in treating patients with early diabetic nephropathy. Therapeutic strategies include glycemic control, lowering of blood pressure, reduction of proteinuria, use of protein restricted diets, treatment of dyslipidemia and smoking cessation.
Short-term studies of patients with early diabetes showed that tight glycemic control can reverse some of the abnormalities, such as hyperfiltration, which are thought to be important in the development of diabetic nephropathy. Most studies that have looked at the effects of glycemic control in diabetes are relatively short-term and use the development of proteinuria as a surrogate endpoint for nephropathy. There is relatively little information on the effects of tight glycemic control on GFR. The Diabetes Control and Complications Trial (DCCT) (44) showed that the rate of development of microalbuminuria and macroalbuminuria was reduced when intensive therapy (glycated or glycosylated hemoglobin [HgbA1c] value <7%) with multiple-dose insulin or an insulin pump was coupled with frequent glucose monitoring in patients with type 1 diabetes. In a study of 102 patients with uncontrolled type 1 diabetes initially without evidence of nephropathy, none of the patients in the intensive treated group developed an abnormal reduction in GFR as opposed to six in the standard treatment group (45). The effects of strict glycemic control on more advanced nephropathy are less certain, but reversal of histologic lesions have been seen after pancreas transplantation. Furthermore, strict glycemic control helps prevent other microvascular complications of diabetes.
Similar data are available for populations of patients with early type 2 diabetes. The Steno study (46), which included a group of patients with type 2 diabetes and microalbuminuria who received intensive therapy aimed at controlling glucose, blood pressure, and dyslipidemia, showed a reduced risk of developing nephropathy (>300 mg protein per day). The United Kingdom Prospective Diabetes Study (UKPDS) (47) also showed a reduced risk of developing proteinuria and of doubling of serum creatinine levels with more intensive glucose control. In a Japanese study of type 2 diabetics, similar in design to the DCCT, the progression of microvascular complications, including nephropathy, was delayed in patients treated with intensive regimens that included multiple doses of insulin as compared to conventional therapy (48). Based on the results of these studies, the American Diabetes Association recommends keeping HgbA1c levels less than 7% to prevent long-term diabetic complications including nephropathy. Attempts at preventing diabetic complications by using drugs that inhibit the formation of advanced glycation end products have only met with limited success and cannot yet be recommended for routine use.
Hypertension is often present in diabetic patients, particularly if they have evidence of nephropathy. A number of studies in both type 1 and type 2 diabetes have demonstrated that the speed of renal deterioration is correlated with the degree of hypertension and that reducing the blood pressure to normal levels slows the rate of deterioration. Animal studies and short-term human studies suggest that ACEIs, ARBs, and nondihydropyridine CCBs provide additional protective effects beyond those afforded by the lowering of blood pressure. These impressions have been confirmed in large-scale, randomized studies (49). Most nephrologists would now recommend the use of an ACEI as first-line antihypertensive therapy in diabetic patients with nephropathy (the earliest sign of which is microalbuminuria). Although hyperkalemia and renal insufficiency (in patients with bilateral renal artery stenosis) are uncommon complications of ACEI therapy, the serum potassium and creatinine levels should be checked approximately
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1 week after starting treatment. A decrease in GFR, reflected in a small but measurable increase in serum creatinine level, is expected and should not be a reason for discontinuing the ACEI. Clinical trials have demonstrated that the ARBs can reduce proteinuria and slow the progression of renal insufficiency in hypertensive, nephropathic patients with type 2 diabetes, even in patients with elevated creatinine levels (50,51). In at least one study, the nondihydropyridine CCBs verapamil and diltiazem were as effective as lisinopril in reducing protein excretion and the rate of decline in GFR in patients with type 2 DM, renal insufficiency, and proteinuria (52). The combination of an ACEI and an ARB has been shown to produce a greater reduction in proteinuria and blood pressure than either used alone. It is recommended that diabetic patients with proteinuria be started on an ACEI, since cardioprotective effects have been shown for this class of drug, and that an ARB be added for maximal effect on proteinuria. Regardless of which antihypertensive agent is used, it is important to maintain good control of the blood pressure (130/80 mm Hg or lower).
The renoprotective effect of ACEIs appears to extend to normotensive patients with type 1 diabetes and probably also to those with type 2 as well (53, 54, 55, 56). The Heart Outcomes Prevention Evaluation (HOPE) trial (57) demonstrated the value of using ramipril in reducing cardiovascular events in diabetic patients who were considered to be at high risk, including those with microalbuminuria. Therefore, the consensus recommendation is to treat all diabetic patients who have microalbuminuria or macroalbuminuria, regardless of blood pressure, with ACEIs or ARBs unless contraindicated. One study has shown that the use of trandolapril could reduce the incidence of microalbuminuria in type 2 diabetics with hypertension suggesting that an ACEI should be employed as initial antihypertensive therapy in these patients (58).
The burden of implementing the therapies shown to attenuate the course of diabetic nephropathy falls on the primary care provider. A study that compared intensified versus usual treatment for diabetics that focused on glucose, blood pressure, and lipid targets showed that to achieve a significant benefit in renoprotection and a reduction in hospitalization an average of 11 visits per year was required (59).
As in nondiabetic patients, the value of a low-protein diet in retarding the progression of renal damage in diabetic populations remains controversial. If such therapy is attempted, it is important to refer the patient to a dietitian who is familiar with the prescription of the diets and who will work with the patient over time to help with compliance.
Renal disease may reduce the requirement for insulin, an effect related at least in part to decreased hormone degradation in the renal tubules as nephrons are progressively lost. Some oral hypoglycemic agents, notably chlorpropamide and acetohexamide, also have prolonged half-lives in uremic patients. As a consequence of these pharmacologic abnormalities, the first overt manifestation of renal disease in some diabetic patients is the occurrence of hypoglycemia. Therefore, the dosage of insulin or oral hypoglycemic drugs should be assessed regularly in patients with renal impairment.
Diabetes per se is not a contraindication to dialysis or transplantation, although the course of diabetic patients is more complicated than that of patients with isolated renal failure. The form of therapy best suited for those patients with ESRD is uncertain. Hemodialysis, peritoneal dialysis, and transplantation have their proponents. Diabetic patients should be reminded that dialysis and transplantation are supportive therapies for renal dysfunction and will not improve their diabetes (see Dialysis and Transplantation). The vasculopathy that destroys the kidney also affects the retinal and peripheral vessels. Because blindness and peripheral arterial disease are important causes of morbidity and mortality in the dialysis and transplantation population, it is critical for these patients to have appropriate attention to their eyes (see Chapter 79) and feet (see Chapter 73).
Cardiovascular Disease
Cardiovascular complications (e.g. ischemic heart disease, left ventricular hypertrophy, CHF, sudden death) are common in patients with CKD and are a leading cause of morbidity and mortality (Fig. 52.11). A large proportion of patients with CKD die of cardiovascular causes before reaching ESRD. In addition to the usual risk factors (hypertension, hypercholesterolemia, smoking, diabetes), patients with CKD are predisposed to cardiovascular disease through “nontraditional” risk factors (hyperhomocysteinemia, systemic inflammation, calcium and phosphate abnormalities) (Table 52.12). CKD and proteinuria are also independent risk factors for the development of cardiovascular disease (60). Therefore, the primary care provider needs to identify these risk factors and to recognize that patients with CKD are at high risk for cardiovascular disease and must be treated aggressively.
The majority of patients with CKD develop hypertension during the course of their illness (Fig. 52.12). More than 70% of patients starting renal replacement therapy have LVH. Analysis of data from the Third National Health and Nutrition Examination Survey (NHANES III) on the adequacy of drug treatment of hypertension in patients with elevated serum creatinine revealed that only 75% of patients with hypertension and elevated serum creatinine had received treatment (61). Furthermore, only 11% had their blood pressure reduced to below 130/85 mmHg, the level recommended by the Sixth Report of the Joint National Committee (JNC VI) on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure (62)
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and by the NKF to slow the progression of chronic kidney disease. Only 27% had their blood pressure reduced to <140/90 mm Hg, the level recommended by JNC VI to prevent cardiovascular disease in individuals without pre-existing target organ damage. Thus, the goals of antihypertensive therapy should be to reduce the risk of cardiovascular disease (as part of an overall risk reduction program), in addition to slowing the progression of renal disease. In addition to lifestyle modifications, most patients will need more than one antihypertensive medication. The goal of therapy should be to lower the systolic pressure to below 130 mm Hg and diastolic pressure to below 80 mm Hg. The type of medication should be tailored to the individual, but most patients, particularly those with proteinuria, would benefit from an ACEI/ARB and a diuretic.
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FIGURE 52.11. Probability of cardiovascular mortality versus GFR. (From Manjunath G, Tighiouart H, Ibrahim H, et al. Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol 2003;41:47. ) |
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TABLE 52.12 Traditional vs. CKD-Related Factors Potentially Related to an Increased Risk for CVD |
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Lipid abnormalities are common in patients with CKD, particularly those with diabetes and/or proteinuria. The pattern of dyslipidemia differs depending on the stage of CKD and on associated disorders. Treatment of hypercholesterolemia in the general population has been shown to reduce cardiovascular mortality. Unfortunately, patients with CKD have generally been excluded from these studies; however, a secondary prevention study that included patients with GFRs below 75 mL/min/1.73 m2 showed a reduction in major coronary events, but not in all cause mortality (63). Therefore, recommendations for treating dyslipidemia in patients with CKD are largely based on extrapolations. Studies in predialysis populations are being done to provide better evidence to guide therapy. The K/DOQI guidelines recommend that all patients with CKD have a fasting lipid panel at least annually. Patients with hyperlipidemia and diabetes should have strict control of blood sugar and patients with nephrotic range proteinuria
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should be treated with an ACEI/ARB. Initial therapy should include weight loss, diet and exercise. Patients with elevated LDL cholesterol levels should be given a statin (there is some evidence that statin therapy can slow the progression of CKD) and those with triglycerides >500 mg/dL can be treated with a fibrate (gemfibrozil preferred) or with niacin (Fig. 52.13). Patients with stage 5 CKD should be considered at high risk for cardiovascular disease and targeted for LDL cholesterol levels of less than 100 mg/dL. Attention should be paid to adjusting drug dosages and monitoring for side effects (e.g., myopathy) (64). Combining a statin with a fibrate is problematic in patients with reduced GFRs. A pilot study has shown that statins (simvastatin 20 mg/day) and low dose aspirin therapy appear safe and that statins are effective in lowering cholesterol in predialysis patients with CKD (65).
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FIGURE 52.12. Prevalence of hypertension relative to GFR. (From K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Am J Kidney Dis 2002;39:S116. ) |
Human Immunodeficiency Virus Infection
A chronic, progressive nephropathy, human immunodeficiency virus-associated nephropathy (HIVAN) characterized by heavy proteinuria and renal failure can be seen in patients with the acquired immunodeficiency syndrome (AIDS). Most of these patients have a history of intravenous drug abuse, but AIDS nephropathy has also been found in patients with other HIV exposures. Small studies have reported a beneficial effect of steroids alone or in combination with highly active antiretroviral therapy
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(HAART) on the course of HIV nephropathy (66,67). The early experience with dialysis in AIDS patients was poor, but more recent reports suggest a more optimistic prognosis, particularly for asymptomatic patients and for those treated with HAART (68). The experience is best for patients who are HIV-positive but have unrelated renal failure. Some centers are performing kidney transplantation in patients with HIVAN who are on HAART and have low viral titers.
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FIGURE 52.13. Treatment algorithm for cholesterol in patients with CKD. (From K/DOQI Clinical Practice Guidelines for Management of Dyslipidemias in Patients with Kidney Disease. Am J Kidney Dis 2003;41;4 Suppl 3:I-IV, S1. ) |
Malignancy
Renal failure resulting from hypercalcemia, sepsis, or drug nephrotoxicity is not an uncommon occurrence in patients who are dying with a malignancy. In many of these patients it would be inappropriate to prolong their lives by initiating dialysis. However, patients with neoplasms, such as multiple myeloma, who may have a relatively long survival time, might benefit from dialysis. Dialysis in patients with neoplastic diseases should be recommended only after careful discussion with the patient, the family, an oncologist, and a nephrologist.
Pregnancy and Chronic Kidney Disease
The presence of even mild renal insufficiency has important ramifications for the health of the mother and baby. The frequency of hypertensive complications is increased and proteinuria is exacerbated in women with renal disease who become pregnant. Aside from the increased incidence of hypertension, women who have antepartum serum creatinine levels of 1.4 mg/dL or less do not generally experience a worsening of renal function during the pregnancy. The renal outcome for women with initial serum creatinine levels greater than 1.4 milligrams per deciliter is not as good; almost half experience a decline in renal function during pregnancy, a decline that persists in many (69). Prematurity and low birth weight are much more common in babies born to women with renal insufficiency, but fetal survival is greater than 90% in most series when women get appropriate prenatal attention and high-quality neonatal intensive care is available.
Symptomatic Therapy for Advanced (Stage 4 or 5) Chronic kidney disease
Initiation of Dialysis
Patients with advanced kidney disease (GFR less than 15 mL/min/1.73 m2) invariably develop a variety of uremic symptoms. GI disturbances such as nausea, anorexia, and vomiting are common. Although the patient and health care provider should try to minimize the symptoms of uremia with conservative therapy including protein-restricted diets, there is a point when this effort becomes counterproductive and dialysis should be started. There are no absolute laboratory criteria defining the time at which dialysis should be initiated. Delay in starting dialysis can lead to the development of severe peripheral neuropathy, malnutrition, or pericarditis from which complete recovery might not be possible. A falling serum albumin, reflecting malnutrition, has been shown to be a strong predictor for increased mortality in both dialysis and predialysis populations. As patients become uremic, there is a tendency for them to spontaneously decrease their food intake, which predisposes these patients to malnutrition. Most nephrologists would consider any sign of malnutrition, such as weight loss or low serum albumin (not attributable to other causes), to be an indication for starting dialysis (70). A National Kidney Foundation consensus group recommended that dialysis be started when the CrCl falls below that provided by peritoneal dialysis on a weekly basis (less than 9 to 14 mL/min/1.73 m2), particularly if there is evidence of malnutrition or signs of uremia (71).
The importance of timely referral to a nephrologist for dialysis planning cannot be overemphasized. Late referral, defined as less than 3 months before the actual initiation of dialysis, has been associated with poorer metabolic control, lower likelihood of being treated with erythropoietin for anemia, greater chance of starting hemodialysis with a temporary catheter, starting dialysis as an inpatient, and having higher medical care costs and higher mortality rates (72). If the patient is not already under the care of a nephrologist, referral for dialysis planning should take place when the CrCl is less than 30 mL/min/1.7 m2. In some instances the primary care provider may question whether referral for dialysis treatments is appropriate. This question most often arises in very old patients, those with severe heart disease, significant cognitive impairment, malignancies, or otherwise short life expectancies. Several sets of guidelines have been developed to help assist in these difficult decisions (73,74).
Dialysis and Transplantation
There are now more than 300,000 patients being maintained on dialysis in the United States. Most facilities provide hemodialysis, peritoneal dialysis, and transplantation (or referral to a transplantation center) for patients with ESRD. Either form of dialysis therapy can be performed at a center or at the patient's home. Some patients choose dialysis as a permanent form of treatment, whereas others undergo dialysis temporarily until they receive a kidney transplant. Although dialysis does not correct all of the metabolic abnormalities of chronic renal failure, it has enabled thousands of patients to lead productive lives. The nephrologist often serves as primary care provider for patients who do not have another. For those patients who
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do, it is important for the nephrologist and the generalist to coordinate care carefully.
Hemodialysis
The hemodialysis procedure involves circulating the patient's blood through a machine that corrects electrolyte abnormalities and can remove excess fluid and toxic metabolic wastes. In the case of slowly progressive renal failure, provisions for dialysis should be made months in advance of need. The goal of dialysis therapy is to maintain health at a level consistent with a normal lifestyle. Therefore, it is not advisable to wait for signs and symptoms of far-advanced uremia (e.g., pericarditis, seizures, coma, bleeding) to appear before initiating dialysis. The patient should be referred to a nephrologist associated with a dialysis center at a point that allows for sufficient time for the patient to become familiar with the various forms of therapy offered at that facility and to become acquainted with the staff.
Before starting dialysis, it is necessary to provide vascular access to allow for the repeated venipunctures required for this form of therapy. It is important that the access be placed well before the patient needs dialysis treatments; otherwise, it is necessary to use temporary access techniques (central vein or femoral vein cannulation), which are associated with both short-term problems (pneumothorax, infection) and long-term complications (subclavian vein stenosis or thrombosis). The preferred access is the arteriovenous fistula, which is usually created at the wrist of the nondominant arm. The creation of a fistula can be performed, in most instances, under local anesthesia and often in an outpatient surgical unit. Fistulas can also be created in the upper arm. An experienced vascular surgeon can almost always find a vein to create a fistula. Because a 2- to 3-month maturation period is often necessary before the fistula can be used, arrangements for the creation of the fistula should be made early, and always before the GFR falls to less than 10 to 15 mL/min/1.73 m2. If the patient's vessels are inadequate to support the creation of an arteriovenous fistula, an alternative would be to insert a synthetic (Dacron, Gore-Tex) graft under the skin of the forearm. In most cases the synthetic graft can be used within 3 weeks after placement. The most common complications after placement of a fistula or graft are clotting and infection.
Hemodialysis is performed in most centers three times a week, and each session lasts 3 to 4 hours. Except for needle insertion, the procedure is not painful, but some patients do experience muscle cramps, headaches, or nausea during or just after dialysis. Home dialysis is encouraged for patients with good home situations who have willing and able partners. Home dialysis patients have the advantage of more flexible schedules and a greater sense of control than do hospital-based patients; for these reasons, they have a greater chance of maintaining their previous lifestyle. The remainder of the patients can be treated at outpatient dialysis centers. Small, uncontrolled studies suggest that short daily or slow nocturnal hemodialysis offers better metabolic control and sense of well-being, compared with traditional intermittent hemodialysis.
As a group, hemodialysis patients have an 80% survival rate for the first year; by 5 years, the survival rate falls to approximately 55%. The development of long-term complications of chronic renal failure, including progressive neuropathy, osteodystrophy, cardiovascular disease, and an array of endocrine disturbances, reflects the fact that dialysis does not correct all of the metabolic disturbances of uremia.
Peritoneal Dialysis
Peritoneal dialysis procedures involve the instillation of dialysis fluid through a catheter into the abdominal cavity. Fluid and toxic solutes are transferred across the mesenteric capillary bed into the dialysis fluid, which is then removed through the catheter. Improvements in the techniques of peritoneal dialysis have increased its popularity among patients. Its simplicity and freedom from hemodynamic complications make this form of therapy attractive, particularly to the elderly and to those with heart disease. With continuous ambulatory peritoneal dialysis (CAPD) the patient constantly carries 2 to 3 L of dialysis solution in the abdomen (75). The fluid is exchanged four to five times a day, every day. However, because fluid movement is determined by gravity and no machine is necessary, the patient is able to perform dialysis at home, at work, or virtually anywhere. This degree of freedom is one of the most attractive aspects of CAPD. Its other attributes, at least theoretically, are that it provides greater removal of higher–molecular-weight substances than hemodialysis does and that the continuous nature of the dialysis eliminates the large swings in concentration of electrolytes and creatinine that occur with the more intermittent forms of therapy. Also, the abdominal catheter for CAPD can be placed at the time of the first dialysis and does not require a maturation period. The major difficulty associated with peritoneal dialysis is the development of peritonitis. The incidence in the typical patient is approximately one infection every 12 to 24 months, but these infections usually respond to antimicrobial therapy and continued peritoneal dialysis, and often treatment of peritonitis does not require hospitalization. However, the peritoneal dialysis catheter may need periodic replacement.
Continuous cyclic peritoneal dialysis (CCPD) is a variant of peritoneal dialysis in which the patient is connected to an automated cycling device that performs the exchanges while the patient is sleeping, further reducing the impact of dialysis on the patient's daytime schedule.
Comparative survival statistics between hemodialysis and peritoneal dialysis are difficult to interpret because of significant population selection biases. An increased risk
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of death in peritoneal dialysis as compared to hemodialysis patients after the first year of treatment was reported in a cohort study in which patients were not randomly assigned to their type of dialysis (76). Without a randomized study, however, firm conclusions about the superiority of one treatment over another will remain conjectural. The results of this study (76) should be interpreted in conjunction with previous studies that did not show a difference in survival between the two dialysis modalities. Whether hemodialysis or peritoneal dialysis is used depends on the center to which the patient is referred and on patient preference. Obese patients or those with previous abdominal surgery may not be candidates for peritoneal dialysis. At most dialysis facilities, the patient has a choice and may change dialysis modes if the outcome of one is unsatisfactory.
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FIGURE 52.14. Two-year kidney graft survival according to donor source in patients treated with cyclosporine. (Modified from Agodoa LYC, Held PJ, Port FK, eds.U.S. Renal Data System: USRDS 1996 annual data report. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases, 1996. ) |
Renal Transplantation
Of all available therapies, successful renal transplantation provides for the most complete correction of the uremic syndrome. Innovations in antirejection therapy, such as use of the potent immunosuppressant drugs cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, and monoclonal antibodies (OKT3), have improved the rate of graft survival.
The success of renal transplantation depends partly on the antigenic similarity between donor and recipient. Except in the case of identical twins (in which rejection does not occur), the best results are found with living related donor, human leukocyte antigen (HLA)–identical transplants. In this instance, kidney survival is greater than 90% at 2 years. More commonly performed are HLA-matched (but not identical) sibling-to-sibling or parent-to-child organ transplantations, with a kidney survival of 92% at 1 year and 87% at 2 years (Fig. 52.14). Patient survival for non–HLA-identical living related donor transplants is greater than 90% at both 1 year and 2 years. Living unrelated donor transplants are being done with greater frequency and also have excellent outcomes. Most patients (more than 75%) do not have the possibility of a living donor and must await a cadaveric transplant, which, despite the best tissue typing, has a significantly lower kidney survival of 83% at 1 year and 77% at 2 years. Patient survival rates for cadaveric transplants are 90% at 1 year and 88% at 2 years. Comparison of survival statistics between cadaveric transplants and dialysis patients is complicated because of selection bias. Transplant recipients tend to be younger, have better myocardial function, and have fewer coexisting illnesses than their dialysis counterparts. If these factors are taken into account, no significant difference in survival rate can be found between patients receiving cadaveric kidney transplants and those being treated by dialysis.
Patients with uncomplicated renal transplantation usually require a 3- to 5-day hospitalization. The use of laparoscopic donor nephrectomy has reduced the convalescence of donors and increased the frequency of living related and living unrelated donor transplants (77). After transplantation (except with identical twins), the patient requires lifelong immunosuppression, usually with a combination of cyclosporine (Sandimmune) or tacrolimus (Prograf); prednisone; and sirolimus (Rapamune), or mycophenolate mofetil (CellCept). The patient must understand that there is always the risk of rejection and the possibility of graft failure, with a return to dialysis. Although there is no doubt that a successfully functioning transplant restores health better than any other therapy, patients on
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immunosuppressive therapy have considerable risks from corticosteroid use and immunosuppressive therapy, including nephrotoxicity, obesity, diabetes, cataracts, osteoporosis, serious infections, and malignancies. Since patients who have received transplants will still need to be seen by their primary care providers for routine medical care, it is important to establish a relationship with the nephrologist caring for the patient in order to coordinate care. Discussion about medication changes is particularly important due to the frequency of potential drug interactions. The primary care provider should also be aware of long-term complications such as obesity, osteoporosis, hyperglycemia, opportunistic infections, post-transplant lymphoproliferative disease and other cancers that occur in higher frequency in this population. These patients are also at high risk for cardiovascular disease and should be treated accordingly (78).
The primary care provider can also be of great value in advising which forms of therapy might coincide best with the patient's expectations. Often, patients have a better understanding of their choices if they visit a dialysis or transplantation unit and talk with patients or staff. The decision to suggest renal transplantation is most clear-cut in adolescents or young adults who wish to pursue an active, vigorous life, have a job, and have intact sexual functions. This is particularly so if a well-matched living donor is available. Elderly patients and those with extensive multisystem disease may not be able to tolerate the rigors of transplantation. For others, a period of dialysis and assessment of the patient's adjustment to this therapy often helps in determining whether to continue dialysis or consider transplantation. Often, the patient who adjusts well to dialysis can be fully rehabilitated and can maintain a job as efficiently as the patient with a successful renal transplantation. At present it appears that quality of life is the most important criterion determining which form of therapy is selected, because survival appears to be similar in patients undergoing either cadaveric transplantation or dialysis.
The personal financial impact of chronic renal failure and the cost of hemodialysis and transplantation, which initially were prohibitively expensive, have been minimized for patients and their families by extension of the Medicare program to patients younger than 65 years of age with ESRD. Nevertheless, patients often have to leave their jobs because of chronic illness or because of the time requirements of therapy.
Despite advances in dialysis and transplantation in recent years, the best hope for patients with chronic renal disease lies in prevention and appropriate therapy in the early stages of renal insufficiency. The patient's primary care provider must accomplish these objectives.
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
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