IF The National Kidney Foundation

Am.erican Journal of Kidney Diseases

The Official Journal of

VOL XIX, NO 6, JUNE 1992

IN-DEPTH REVIEW

Cardiovascular Risk Factors in Chronic Renal Failure and Hemodialysis Populations King W. Ma, MD, Edward L. Greene, MD, and Leopoldo Raij, MD • Cardiovascular disease is the leading cause of death in patients with end-stage renal disease (ESRD). Risk factors for cardiovascular disease, including hypertension, lipid abnormalities, left ventricular hypertrophy (LVH), and glucose intolerance, are present more frequently in patients with chronic renal failure than in the general population, even before the onset of replacement therapy. The prevalence, pathogenesis, and significance of these factors in the uremic population are examined, and the potential roles of intervention are revieWed. Evidence suggests, but is not conclusive, that these factors are of predictive value for cardiovascular complications in patients with chronic renal failure. The effect of modification of these factors on cardiovascular morbidity and mortality in this population, especially in the early stages of renal failure, is an important area for further study. © 1992 by the National Kidney Foundation, Inc. INDEX WORDS: Cardiovascular risk factors; chronic renal failure; hypertension; dyslipoproteinemia; LVH; glucose intolerance.

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ARDIOVASCULAR disease has been the leading cause of death in patients receiving chronic hemodialysis therapy both in earlyl-3 and in more recent4 •5 reports. In large series, cardiovascular causes of death included conditions other than atherosclerosis-related complications, such as pericardial disease and heart failure unrelated to myocardial ischemia. 1,2 When the atherosclerosis-related complications were examined more specifically, their incidence was found to be significantly higher in dialysis patients than in nonuremic controls. 3,6,7 However, controversy exists over whether progression of atherosclerosis is accelerated in chronic hemodialysis patients. In an early retrospective study, Lindner et al 6 reviewed the cases of 39 patients on long-term hemodialysis whose predialysis clinical diagnosis was only "uremia." The patients were monitored for a mean of 6.5 years on dialysis; of 23 deaths, eight were secondary to myocardial infarction and three to stroke. It was concluded that accelerated atherosclerosis is a major complication of long-term dialysis. However, other studies have suggested that atherogenic factors were operative

before regular dialysis began and that the dialysis per se did not accelerate the process. S- IO Why is there a persistent increase in the incidence of atherosclerosis-related cardiovascular morbidity and mortality in patients with advanced renal failure, as well as in the dialysis population? Two factors can probably be implicated: first, change in demographic factors and primary etiologies of end-stage renal disease (ESRD) involving the dialysis population and, second, the continued presence of cardiovascular risk factors in patients with chronic renal failure. A recent report from the Medicare ESRD Program showed that the average age of the dialysis patient has increased by more than 5 years during the past decade and patients whose renal failure From the Department ofMedicine, Veterans Administration Medical Center and University of Minnesota, Minneapolis,

MN. Address reprint requests 10 Leopoldo Rai). MD, Chief, Nephrology/Hypertension-IIIJ, VA Medical Center, One Veterans Dr, Minneapolis. MN 5541 7. © 1992 by the National Kidney Foundation. Inc. 0272-6386/92/1906-0001$3.00/0

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is attributable to diabetes mellitus currently account for 30% of all patients on replacement therapy each year. II Similar data were obtained from the EDTA Registry. 12 Since aging and diabetes mellitus are both associated with an increase in atherosclerosis-related cardiovascular complications, they are contributing factors to the sustained increase in cardiovascular mortality and morbidity in the ESRD patient population. The classic Framingham study identified risk factors for atherosclerotic cardiovascular disease in the nonuremic population, namely, hypertension, lipid disturbances, left ventricular hypertrophy (LVH), and glucose intolerance. The study also found a synergistic interaction when several cardiovascular risk factors coexisted in the same patient. 13 These same risk factors occur frequently in the uremic population. In the following discussion, the prevalence and pathogenesis of these factors in patients with chronic renal failure and in those requiring chronic hemodialysis will be examined. The significance of these factors and the effect of their modification on cardiovascular complications will be assessed. HYPERTENSION

Hypertension secondary to renal parenchymal disease occurs in patients with a mild reduction in glomerular filtration rate, and it appears to increase in frequency as renal failure progresses. With the development of end-stage renal failure, the prevalence of hypertension reaches 75% to 80%.14 Hypertension is more frequently associated with glomerular diseases than with interstitial diseases. Moreover, its incidence appears to vary within different clinicopathologic types of glomerulonephritis. 15 The pathogenesis of hypertension in chronic renal failure is complex and multifactorial. The subject was recently reviewed by Smith and Dunn. 16 Factors implicated include positive sodium balance, increased activity of the renin-angiotensin-aldosterone system, and the sympathetic nervous system, and, possibly, reduced production of vasodilator substances by the uremic kidney. These factors affect systemic hemodynamics and cause hypertension by increasing either cardiac output or total peripheral resistance or both. Different disturbances may exist in different patients, and indeed in the same patient the causal factors may vary at different

stages in the course of renal parenchymal hypertension. Several studies of dialysis patients have examined the role of hypertension as a possible cardiovascular risk factor. Degoulet et al, 3 in a survival analysis of 1,453 dialysis patients, noted a correlation between significantly increased cardiovascular mortality and the mean levels of predialysis systolic and diastolic blood pressure. The relationship between elevated diastolic blood pressure and mortality associated with cerebrovascular accidents was particularly obvious. Rostand et al l7 examined risk factors for ischemic heart disease in 320 hemodialysis patients and concluded that elevated diastolic blood pressure at the initiation of dialysis was a significant risk factor. Vincenti et al lS assessed vascular atherosclerotic changes intraoperatively in 46 nondiabetic dialysis patients at the time of renal transplantation. Vascular segments from the iliac vessels were obtained and histologically examined. Hypertension was present in 90% of the patients with evidence of atherosclerotic changes noted in the vessels. In patients between the ages of 25 and 40, atherosclerosis was present only in previously hypertensive patients. Cardiovascular morbidity and mortality in patients with essential hypertension is decreased effectively with antihypertensive therapy. The incidence of stroke is clearly reduced with treatment, even though controversy still exists regarding the benefit of blood pressure control on coronary artery disease. 19 Similar data are not available for patients with hypertension secondary to renal parenchymal disease. A study of 84 patients with chronic glomerulonephritis showed improved patient survival when blood pressure was lowered. 20 The cause of death was not specified and the study was retrospective. Charra et al21 studied 44 chronic dialysis patients and noted a lO-year survival of 85%, with no deaths attributable to cerebrovascular accident or myocardial infarction. The duration of each dialysis treatment was longer than usual and effective blood pressure control was achieved entirely by adequate ultrafiltration and strict maintenance of dry weight. The investigators inferred that control of blood pressure was the major factor responsible for the lack of cardiovascular complications in their patient population. Retrospective analysis

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of their experience by others22 ,23 has resulted in similar conclusions. Carefully designed prospective and controlled studies are needed to more fully answer the question of whether hypertension control per se will lower cardiovascular morbidity and mortality in the uremic population. LIPOPROTEIN ABNORMALITIES

Lipoproteins are carriers for the hydrophobic lipids in the plasma. The lipoprotein molecule consists of a central core of cholesterol esters and triglycerides and an outer coating of free cholesterol, phospholipids, and apoproteins. The latter are important for activation of enzymes and recognition of lipoproteins by receptors. Lipoproteins are classified by their densities: chylomicrons, very-low density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). They have different protein and lipid contents and serve different functions. 24 Abnormalities in lipid and/or protein content of the lipoproteins have been described in patients with chronic renal failure. 24,25 Hypertriglyceridemia, the most common lipid abnormality, occurs in 50% to 75% of patients with chronic renal insufficiency. In general, the triglyceride elevation is modest and occurs mainly in the VLDL fraction. Hypercholesterolemia rarely occurs in uremic and dialyzed patients. However, decreased HDL-cholesterol concentration has been documented in 50% to 75% of patients with chronic renal failure. Racial differences in the various lipoprotein fractions have been noted. 26 Abnormal apoprotein profiles27 and specific types of potentially atherogenic lipoprotein particles derived from the catabolism of the triglyceride-rich lipoprotein have also been reported in the uremic population. 28 Recently, Parra et aJ29 noted an increase in the serum concentration of Lp(a) lipoprotein in chronically hemodialyzed patients. Lp(a) is a variant of the apoprotein B-containing lipoproteins reportedly associated with an increased risk of coronary and cerebral vascular diseases. 3o Finally, defect in cholesterol transport demonstrated in vitro, resulting in tissue cholesterol accumulation and possibly accelerated atherogenesis, has also been described in hemodialysis patients. 31,32 There are few prospective data regarding the stage of renal failure at which lipoprotein abnor-

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malities occur. Limited observations33-37 suggest that hypertriglyceridemia can occur in patients with a mild to moderate degree of renal insufficiency. Likewise, abnormal apoprotein profiles can be detected early in renal failure, even in patients who have normal or near-normal plasma lipid levels. 36,37 It has not been shown that hemodialysis consistently modifies the lipoprotein profile. 36-4o The mechanism(s) responsible for the hypertriglyceridemia in chronic renal failure have not been delineated. Available data derived from kinetic studies with intralipid administration 41 or labeled glycerol42 have demonstrated that reduced catabolism of the triglyceride-rich lipoprotein is the predominant defect. Reports have incriminated a deficiency of lipoprotein lipase;43,44 hepatic triglyceride lipase,45 or both46,47 these enzymes being the primary mediators of the process. The reason for the decrease in enzymatic activity is unclear. Possibilities include the presence of a circulating inhibitor of lipolytic enzymes in the uremic serum,48 changes in apoprotein concentrations, which can affect lipoprotein lipase activity,49 or the insulin resistance seen in renal insufficiency. 50 Factors other than changes in lipolytic enzyme activities that may contribute to decreased triglyceride catabolism, such as alteration of the lipoprotein substrate, have recently been reviewed by Attman and Alaupovic. 5o The decrease in HDL-cholesterollevel seen in patients with renal failure has not been fully explained. A recent kinetic study51 attributed the low plasma HDL level to a decrease in the rate of synthesis of the lipoprotein. A decrease in HDL-cholesterol concentration has been shown by some researchers,52,53 but not others,54 to be associated with hypertriglyceridemia. Clofibrate therapy, presumably by increasing lipoprotein lipase activity, lowered the triglycerides and raised the HDL level in a group of patients on hemodialysis. 53 These data suggest a causal relationship between elevated serum triglycerides and decreased HDLcholesterol concentrations. Finally, diminished hepatic protein synthesis has been described in the uremic state. 55 Decreased hepatic protein synthesis has been postulated to account for the altered apoprotein concentration and metabolism seen in patients with chronic renal failure. 25 Studies in the general population have demonstrated that hypercholesterolemia is associated

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with an increased risk of atherosclerotic cardiovascular complications. In addition, coronary risk has been found to be directly proportional to LDL-cholesterollevel and inversely proportional to HDL-cholesterollevel. 13 The relationship between hypertriglyceridemia and atherosclerotic heart disease is far less clear. 56 No large prospective study to date has examined whether the disturbances in lipoprotein metabolism constitute a significant cardiovascular risk factor in the uremic population. 57 Available studies, which have included small numbers of patients or been retrospective in nature, have yielded conflicting results. Hahn et al40 reviewed data in 252 chronic hemodialysis patients. They noted that the average VLDL-triglyceride value was significantly higher and the HDL-cholesterollevel significantly lower in patients with coronary artery disease than in those without. Ponticelli et al 58 and Brunzell et al 52 described higher plasma triglyceride levels in dialysis patients with atherosclerotic complications. Goldberg et at2 6 noted that white male dialysis patients had significantly higher levels of plasma triglycerides and lower levels of plasma HDL-cholesterol than black male hemodialysis patients. These researchers postulated that these abnormalities may explain the higher rate of cardiovascular mortality among white hemodialysis patients. Attman et al,27 in studying patients with chronic renal failure, concludedthat a characteristic apoprotein profile appears to be a predictor of coronary artery disease in dialysis patients. On the other hand, Rostand et aI, 17 Degoulet et at,3 and Vincenti et al 18 found no correlation between serum triglyceride levels and the incidence of atherosclerotic complications. The failure to find a relationship between hypertriglyceridemia and increased atherosclerotic risk may be due to the fact that other indices oflipid and lipoprotein metabolism were not evaluated and the time offollow-up may have been inadequate. Additional cross-sectional and long-term studies are needed to definitely answer the important question of whether the disturbances in lipoprotein metabolism seen in chronic renal failure are indeed cardiovascular risk factors. It has now been convincingly documented that lowering total cholesterol and LDL-cholesterol levels by diet or drug therapy reduces coronary morbidity and mortality in the general popula-

MA, GREENE, AND RAIJ

tionY Similar interventional studies of a much smaller magnitude have been reported in patients with ESRD. Dietary modification to alter the lipid profile has been attempted both in chronic renal failure patients on conservative treatment59,60 and in patients on hemodialysis. 61 -63 Reduction in triglyceride levels has been documented in most, but not all, studies. However, the number of patients studied was small, the duration of the studies was short, and the study designs varied. Moreover, this approach to reducing production ofVLDL-triglyceride does not alter an important component of the underlying defect, namely, the decreased catabolism of the VLDL-triglyceride. Experience with the use of lipid-lowering drugs in renal disease patients is limited. Fibric acids, whose major adion is to enhance the activity of lipoprotein lipase and hence to enhance lipolysis, are the drugs that have been most fully tested. Studies using clofibrate,53,58,64 gemfibrozil,47 and bezafibrate65 have shown a significant reduction in serum triglyceride levels and, when measured, an increase in HDL-cholesterollevels. Toxicity in the form of myopathy has been observed with these agents; dosage reduction in chronic renal failure patients has been emphasized, since the fibric acids are largely excreted by the kidney. Additional reports have described the use of fish oil,66 oral charcoal,67 carnitine,68,6910vastatin, 70 and endurance exercise training71 for lipid disturbances in uremic/hemodialysis patients. Overall, it should be noted that although advantageous changes in lipid profiles have been obtained in the various studies, convincing and clear beneficial effects of lipidlowering agents for the reduction of the incidence of atherosclerotic cardiovascular complications in chronic renal failure and/or hemodialysis patients have not been demonstrated. A prospective study of medical intervention and correction of lipid abnormalities early in the course of renal failure is needed. Until then, no specific recommendation(s) regarding the treatment of the lipoprotein disturbances can be made. LEFT VENTRICULAR HYPERTROPHY

Several reports using echocardiography as the method of evaluation have documented an incidence of LVH of 57% to 93% in the dialysis population. 72-75 Two studies have also shown that left ventricular mass determined by either an-

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giography or echocardiography was significantly increased in these patients compared with agematched controls. 76,77 Moreover, LVH has been noted at the start of dialysis, 78 suggesting that the factors responsible predated the onset of renal replacement therapy. Serial studies in patients on dialysis have demonstrated either progression78 or improvement72 ,79 of LVH. The pathogenesis ofLVH has not been clearly defined, but is most likely multifactorial. It is of interest that in a study of carefully selected hemodialysis patients without a history of cardiovascular disease, an increase in left ventricular mass occurred in 56.1%.77 Factors noted to be associated with LVH clinically include hypertension, age,72,73 anemia,80 and, most recently, aluminum accumulation. 81 The role of increased myocardial calcification, described in hemodialysis patients,82 in the pathogenesis of LVH is uncertain. Whether uremia per se is associated with an increase in left ventricular mass has been examined. In an experimental study, Rambausek et al 83 noted an increase in heart weight in rats with renal insufficiency despite normalization of blood pressure, effective (3- and al-adrenoreceptor blockade, correction of anemia, and parathyroidectomy. Of interest, the same group of investigators also described a reduced capillary cross-sectional area and an increase in the interstitial volume with fibrosis both in the hearts of the animals studied84 and in uremic patients. 85 The latter may account for the impaired cardiac compliance and diastolic dysfunction described in patients with ESRD (vide infra). Studies in the general population, including the Framingham study, have shown that asymptomatic LVH, as detected by either echocardiography or electrocardiography, is an independent predictor of cardiovascular disease. 13,86-88 The consequences of LVH are multifold. LVH has been associated with an increase in ventricular ectopic activity, 89 a possible cause of sudden death that has been reported to occur at a higher frequency in patients with LVH than those with normal myocardium. 9o Diastolic dysfunction of the left ventricle can be a consequence ofLVH.91 Finally, abnormalities of the coronary microcirculation can also occur secondary to cardiac hypertrophy.92 Impaired coronary reserve occurs, probably because growth of the coronary vascular bed does not keep pace with the increase in car-

diac mass, resulting in myocardial ischemia despite normal coronary arteries. In dialysis patients, congestive heart failure secondary to diastolic dysfunction resulting from LVH 93 and angina with normal coronary arteries94 have both been described. Silberberg et al 95 examined the prognostic significance of LVH detected by echocardiography in a group of patients beginning renal replacement therapy. LVH was found to be associated with an increased risk of mortality from all causes. The effect persisted after adjustments for other known cardiac risk factors. Regression of LVH in this patient population has been reported following adequate blood pressure control,79 erythropoietin treatment,96,97 and renal transplantation. 75 ,98 A recent report from the Framingham study99 has suggested that, in the general population, reversal of LVH may be associated with a reduction in cardiovascular risks. Whether a decrease in LVH in this population will result in reduced cardiovascular mortality requires further study.

GLUCOSE INTOLERANCE Mild glucose intolerance has been well documented to occur in greater than 50% of patients with chronic renal failure, including those not yet on replacement therapy. 100,101 Pathogenic mechanisms include peripheral resistance to the action of insulin and impaired insulin secretion.102 Experimental evidence suggests that insulin resistance in uremia is due to a postreceptor defect on the ability of insulin to stimulate glucose transport. 103 However, the primary defect and causative agents have not yet been defined. Tissue sensitivity to insulin has been reported to improve following the institution of hemodialysis therapy.102 Impaired insulin secretion, on the other hand, has been associated with the state of secondary hyperparathyroidism commonly seen in chronic renal failure. 104 Previous epidemiologic studies have established that abnormal glucose tolerance significantly increases the risk for cardiovascular complications related to atherosclerosis. 105 The mechanism whereby this occurs is unknown. Glucose intolerance is felt to be secondary to insulin resistance. Insulin resistance and hyperinsulinemia have been associated with cardiovascular risk factors such as hypertension and abnormal lipoprotein metabolism. 106 This may

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be postulated as the link between glucose intolerance and enhanced risk of atherosclerotic complications. In the uremic population, whether the abnormal glucose tolerance observed carries the same significance and implications is unclear at present. Further detailed evaluation is needed. OTHER FACTORS

Smoking has been implicated as a cardiovascular risk factor in the maintainance dialysis population in two studies. 94•107 The number of patients examined is small and confirmatory data from a larger number of patients are needed. Isolated reports have suggested that factors in the uremic serum may be atherogenic. Bagdade, for example, described factor(s) in the serum from chronic dialysis patients that stimulate the proliferation of human arterial smooth muscle cells in vitro. 108 This may be of significance, since recent evidence suggests that proliferation of the smooth muscle cells in the media oflarger arteries is a central process in atherogenesis. 109 Further studies directed at the mechanisms of atherosclerosis in the uremic population will be of immense interest and utmost importance.

SUMMARY

Morbidity and mortality rates related to cardiovascular complications remain elevated in the chronic dialysis population despite technological advances and overall improvement in patient management. The major cardiovascular risk factors in the general population include hypertension, lipid abnormalities, LYR, and glucose intolerance. These factors are present with increased frequency in patients with chronic renal failure, even before the onset of ESRD and dialysis therapy. Evidence suggests that these factors hold the same predictive value for atherosclerotic cardiovascular complications in the chronic renal failure-hemodialysis population as in the general population. Results of intervention trials in the general population are encouraging. Similar studies in uremic patients, especially those in the early stages of renal failure, are sparse to nonexistent. Further attempts that aim specifically at correction of these risk factors and at prevention of cardiovascular complications in patients with ESRD should be vigorously pursued.

REFERENCES 1. Gurland HJ, Brunner FP, Dehn HV, et al: Combined report on regular dialysis and transplantation in Europe. Proc Eur Dial Transplant Assoc 10:17-58, 1973 2. Burton BT, Krueger KK, Bryan FA Jr: National Registry oflong-term dialysis patients. JAMA 218:718-722, 1971 3. Degoulet P, Legrain M, Reach I, et al: Mortality risk factors in patients treated by chronic hemodialysis. Nephron 31:103-110, 1982 4. Disney APS: Dialysis treatment in Australia, 1982 to 1988. Am J Kidney Dis 15:402-409, 1990 5. Kjellstrand CM, Hylander B, Collins AC: Mortality on dialysis-On the influence of early start, patient characteristics, and transplantation and acceptance rates. Am J Kidney Dis 15:483-490, 1990 6. Lindner A, Charra B, Sherrard D, et al: Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Eng! J Med 290:697-701, 1974 7. Broyer M, Brunner FP, Brynger H, et al: Combined report on regular dialysis and transplantation in Europe. Proc Eur Dial Transplant Assoc 19:260, 1982 8. Rostand SG, Gretes JC, Kirk KA, et al: Ischemic heart disease in patients with uremia undergoing maintenance hemodialysis. Kidney Int 16:600-611, 1979 9. Ibels LS, Stewart JH, Mahony JF, et al: Occlusive arterial disease in uraemic and hemodialysis patients and renal transplant recipients. Q J Med 44:197-214, 1977 10. Burke JF, Francos GC, Moore LL, et al: Accelerated atherosclerosis in chronic dialysis patients-Another look. Nephron 21:181-185, 1978

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