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EDITORIALREVIEW

Cardiovascular risk in patients with end-stage renal disease FC Luft HELIOS Klinikum-Berlin, Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Humboldt University of Berlin, Germany

Abstract Cardiovascular disease is the major cause of death in patients with end-stage renal disease (ESRD). ESRD patients are almost invariably hypertensive. They all have acquired combined hyperlipidemia and increased Lp(a), hyperhomocysteinemia, decreased physical activity, pyschosocial stress, insulin resistance, procoagulant factors, left ventricular hypertrophy, and increased oxidative stress. Diabetes mellitus, a major risk factor for both cardiovascular disease and ESRD, has become the commonest cause of ESRD. If ESRD patients choose to smoke, the additive risk is profound. Moreover, ESRD patients are becoming older and are often menopausal if female. Finally, ESRD patients have a dramatic tendency for vascular and cardiac calcification, probably related to hyperphosphatemia and hyperparathyroidism. Cardiovascular disease is also a major risk in patients with decreased renal function of nearly any degree. Data from the HDFP Study showed that patients with a serum creatinine concentration >1.5 mg/dl had a profoundly higher risk of cardiovascular disease than patients with creatinine values below this value. These data were recently corroborated in the HOPE study. Microalbuminuria (MAU), with or without diabetes mellitus, indicates increased cardiovascular disease risk even without decrease in glomerular filtration rate. We found earlier that nondiabetic hypertensive patients with MAU had much higher rates of myocardial infarction, stroke, and peripheral vascular disease, than similar hypertensive patients without MAU. In conclusion, the presence of decreased renal function or MAU is a major cardiovascular risk factor. ESRD can be regarded as a catastrophic risk factor. Prophylactic measures known to be effective in reducing the risk from cardiovascular disease are grossly underused. Unfortunately, they are less effective in patients with renal disease and new strategies are needed. Key words: renal disease, end-stage renal disease, cardiovascular disease, atherosclerosis, hypertension, lipid disturbances, homocysteine, thrombosis

Introduction End-stage renal disease : Cardiovascular disease is the commonest cause of death in patients with end-stage renal disease (ESRD)1. The risk is far greater than in the general population. For example, among patients treated with hemodialysis or peritoneal dialysis, the prevalence of coronary artery disease is approximately 40% and the prevalence of left ventricular hypertrophy is approximately 75%2. Among dialysis patients in the United States in Address for Correspondence: Friedrich C. Luft, M.D. Charité Campus-Buch Franz Volhard Clinic Wiltberg Str. 50 13125 Berlin, Germany e-mail: [email protected]

1995, 16 000 died of heart disease that year. This means that about 10% of dialysis patients die from heart disease each year. This sad state-of-affairs caused Foley et al.3 to call for an important series of clinical recommendations worth repeating here: 1. Patients with ESRD should be considered in the highest risk group for subsequent cardiovascular disease events. 2. Congestive heart failure is far more common than in non ESRD patients and should be considered an independent risk factor for death. 3. Congestive heart failure may reflect left ventricular dysfunction or volume overload or both. Such ESRD patients should all be evaluated for cardiovascular disease. 4. The excess in cardiovascular disease deaths is in part a consequence of an increase in all the well recognized risk factors for cardiovascular disease in the ESRD patient population. 5. Hemodynamic, metabolic, and recently recognized inflammatory processes add Copyright © 2001 by The Indian Society of Nephrology

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greatly to this risk. Lesser degrees of decreased renal function : Patients with mild renal insufficiency are also at increased risk. However, the epidemiology of cardiovascular disease risk in patients with lesser degrees of renal insufficiency, with the exception perhaps of patients with diabetes mellitus, is less well studied. Shulman et al.4 analyzed the data from the HDFP study (hypertension detection and follow-up program) and found that a serum creatinine concentration >1.5 mg/dl was a strong predictor of cardiovascular disease. HDFP studied only patients with essential hypertension and the majority of the patients were African Americans. In HDFP, a linear relationship between serum creatinine concentrations and cardiovascular mortality was shown. Furthermore, there was a five-fold difference between the lowest and the highest blood pressure strata, indicating strong evidence for the notion that antihypertensive treatment might be helpful. The risk of cardiovascular disease in the HDFP study attributed to an increased creatinine concentration was independent of other risk factors. In line with these observations, preliminary data from the HOT Study (hypertension optimal treatment) showed an independent influence of elevated creatinine on cardiovascular disease morbidity and mortality5. Furthermore, in another report, an increase in creatinine was an independent risk factor for stroke6. A recent analysis of the HOPE (heart outcomes prevention evaluation) study data corroborated the importance of elevated creatinine in cardiovascular risk (Prof. Johannes F. Mann, personal communication). That study extended the information beyond patients with hypertension. Briefly, serum creatinine elevation >1.4 was an independent risk factor. Treatment of patients with a raised creatinine value with the angiotensin converting enzyme (ACE) inhibitor ramilpril decreased the risk of cardiovascular disease. If renal disease is defined even more subtly, namely the presence solely of microalbuminuria (MAU), similar information is accrued. We performed a cross-sectional study in over 11 000 nondiabetic hypertensive patients who were tested for MAU7. All had creatinine values below 1.2 mg/dl in their analysis. The presence of MAU was an independent risk factor for myocardial infarction, stroke, and peripheral vascular disease. Thus, beyond any doubt whatsoever, renal disease of any cause and at any severity, the presence of MAU, even when glomerular filtration rate is preserved, are independent risk factors for cardiovascular disease. To answer the question “why ?”, the risk factors must be assessed.

Hypertension The prevalence of hypertension in ESRD patients is 60100%, perhaps related to how diligently the condition is sought. Mailloux and Levey have recently reviewed the topic in detail8. They point out that hypertension is Copyright © 2001 by The Indian Society of Nephrology

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commonly not well controlled in ESRD patients. The preferred treatment is extracellular fluid volume maintenance through dietary salt reduction and strict attention to the dialysis regimen. The target blood pressures in ESRD patients should be no different than the targets recommended for the general population (JNC VI). In dialysis patients, particularly hemodialysis patients, the appropriate time to measure blood pressure for monitoring therapy is unknown, however, low blood pressure in ESRD patients is also associated with decreased survival (so-called J curve). This upward swing in the left-hand part of the curve may be due to the presence of underlying cardiovascular disease. Patients with hypotensive episodes on dialysis or hypotensive ESRD patients should be specifically evaluated for the presence of cardiovascular disease. One reason for the high prevalence of hypertension may have to do with inadequate dialysis. The drive to shorten dialysis times, which stems from both economic interests of health-care providers and from the patients, may have contributed to the problem. There is evidence that long (>6 hour), slower dialysis times are associated with improved blood pressure control.

Hyperlipidemia The prevalence of hyperlipidemia is increased in patients with chronic renal disease to the point of almost being universal. However the type and severity of lipid abnormalities vary among different chronic renal disease populations9. Every patient with renal disease should be screened for hyperlipidemia. The prevalence of lowdensity lipoprotein (LDL) cholesterol elevation is highest in patients with ESRD. The relationship of elevated triglycerides or low high-density lipoprotein (HDL) cholesterol to cardiovascular disease risk in ESRD patients is not entirely clear. Lp(a) concentrations are particularly elevated in ESRD patients and must also be noted. Kasiske has recommended that the National Cholesterol Education Program (NCEP) Adult Treatment Panel recommendations should be followed. HMG-CoA reductase inhibitors effectively lower LDL and triglyceride concentrations. In my view, ESRD patients have a risk for cardiovascular disease greater than cardiovascular disease patients themselves. Thus, lipid-lowering drugs should be considered in all these patients. In Germany, the first randomized controlled trial of HMG-CoA reductase inhibitors in ESRD patients is currently underway.

Hyperglycemia Diabetes mellitus is the commonest cause of ESRD10. In Germany, the average diabetic dialysis patient has a life expectancy of about five years. They die of cardiovascular disease. In an earlier study of non-renal disease patients, Haffner et al.11 showed that middleaged diabetic persons who have, not had a myocardial

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infarction have the same risk of having a myocardial infarction as nondiabetic patients who have already had one. For diabetic ESRD patients this risk is profoundly greater. Strict glycemic control is helpful but even more difficult than in patients without diminished renal function. Oral antihyperglycemic agents are often not suitable and insulin is the only therapeutic option. In an earlier study of diabetic patients with decreased renal function, we observed a profound cardiovascular mortality12. Most of the patients did not survive long enough to be dialyzed. They died of heart disease before their renal disease became severe.

Calcium and phosphate homeostasis The tendency of coronary arteries, heart valves, and the myocardium itself to calcify, may be an under-appreciated risk factor in ESRD patients. We studied this problem 10 years ago13. We used electron beam computed tomography (EBCT) as a noninvasive, quantitative method to search for coronary and cardiac calcifications in dialysis patients. We compared our results to those obtained in nondialysis patients with and without heart disease and performed an analysis of potential risk factors for cardiac calcifications. Then we repeated our measurements in the dialysis patients and observed a disturbing tendency for progression. There were 34 men and 15 women aged 32-73 years, who were treated with maintenance hemodialysis. We also used EBCT to examine 73 men and 29 women aged 32-73 years without renal disease, but who had undergone cardiac catheterization for suspected coronary artery disease. This allowed us to test the sensitivity and specificity of the EBCT method to detect coronary calcifications in nonuremic patients. The repeat study on the dialysis patients was performed after a short interval of 11 to 13 months. We were not only interested in reproducibility of the findings, but also in the possibility of detecting progression, despite the short time interval. Hemodialysis patients had a remarkably high incidence of calcified coronary artery, mitral, and aortic valve calcifications, compared to patients with suspected and documented coronary artery disease. The difference in magnitude ranged from 2.5 to 5-fold in the latter two groups. Furthermore, we found a profound age-related effect on coronary calcifications in dialysis patients. We also were able to show that hypertension had an independent effect on the total coronary calcification score. Parameters used to estimate the severity of hyperparathyroidism were not correlated with the total coronary calcium score; however, this negative result may be misleading, since we were also able to identify an inverse correlation between bone mass and the total coronary artery calcium score. Our findings suggest that a regular assessment of cardiac calcifications is desirable in dialysis patients. Those patients with valvular calcifications should have yearly examinations.

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Patients with coronary calcifications should be carefully evaluated for ischemic heart disease. Hypertensive dialysis patients warrant particular attention.

Smoking The prevalence of tobacco use in renal disease patients reflects the usage in the general population. Tobacco use accelerates both the progression of chronic renal disease and the occurrence of cardiovascular disease in patients with diminished renal function14. The adverse effects of smoking are profound. Ritz et al. studied the renal effects of smoking in normal persons and patients with IgA nephropathy15. They found that smoking increased blood pressure, vasopressin release, and renovascular resistance. Similarly, glomerular filtration rate decreased. The effects were reproduced with nicotinecontaining gum and were more profound in the patients with renal disease. The sympathetic nervous system was stimulated by smoking. Orth et al.16 performed a multicenter analysis of patients with primary renal disease and documented impressively that smoking increases the risk of end-stage renal disease, irrespective of the renal diagnosis. Thus, smoking is one of the most important, and one of the least appreciated, risk factor contributing to end-stage renal disease.

Other risk factors Most patients with decreased renal function are less active than the general population. An added cardiovascular risk from inactivity is well documented. The association of physical activity and cardiovascular disease in renal disease patients has not been well studied. Physical activity can be increased by counseling and maintenance of regular exercise. Obesity management, particularly of abdominal obesity, would appear to be important; however, no specific studies have been done in this area. Most women on dialysis are over 50 years old and therefore, are post-menopausal. The relationship between menopause and cardiovascular disease in chronic renal disease patients is not known. Hormone replacement can correct post menopausal hormone deficiency; however, the impact of this treatment in dialysis patients has not been studied. Patients with decreased renal function have elevated homocysteine levels. Elevated homocysteine levels are an independent risk factor for cardiovascular disease in the general population. In renal disease patients, elevated homocysteine concentrations probably represent an increased risk for cardiovascular disease. A combination of high-dose folic acid, vitamin B12, and B6 can lower homocysteine concentrations by about 25% but the effects of this approach in ESRD patients are unknown.

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Prevention and management A major aspect of avoiding cardiovascular disease in patients with chronic renal disease is the avoidance of chronic renal disease itself or when present, inhibiting its progression. Any detailed discussion goes beyond this report; however, decreasing proteinuria, attention to blood pressure control (125/75 mm Hg), management of hyperlipidemia, cessation of smoking, glycemic control in diabetic patients, and attention to potentially nephrotoxic agents form cornerstones of this preventative management. A specific case has been made for ACE inhibitor therapy in these patients. Obviously, all these strategies must be continued when patients develop ESRD. Special additional attention should be directed towards assessing the relevance of homocysteinuria and Lp(a), which may be particularly important; however, additional studies are necessary in this area. Many patients with renal insufficiency and ESRD have known coronary artery disease. The prevalence of coronary artery disease in ESRD patients is stated at 30-40%; however, the real value may be higher. Routine screening is not recommended in asymptomatic patients, although some transplant centers request coronary angiography in diabetic dialysis patients before considering them for transplantation. For noncardiac surgery, the screening recommendations are the same as for the general population. However, in patients with particular constellations of risk factors, the clinician will have to use personal judgment. Exercise testing, scintigraphy, dobutamine echocardiographic examination, and 24 h Holter monitoring for ischemia

are all employed. The sensitivity and specificity of exercise testing in ESRD patients are less than 50%. For dipyridamole radionuclide studies and dobutamine echocardiography, these values increase to 80% and greater. The use of antiplatelet therapy is controversial17; however, although a bleeding tendency may occur, low dose aspirin (75-162 mg/day) would appear reasonable. The use of warfarin for atrial fibrillation has also not been studied in ESRD patients. Their risk for stroke seems similar to age, and blood pressure-matched non ESRD patients. The medical management of coronary artery disease in ESRD patients is the same as in the general population. In addition, control of extracellular fluid volume and correction of anemia are important. The American guidelines suggest a hematocrit over 36%; however, many Europeans would set the goal at a higher value. The risks of coronary angiography in ESRD patients is higher, as are the risks of percutaneous angioplasty and coronary bypass grafting. Initial technical successes in ESRD patients are similar to the general population; however, recurrence rates are higher. Restenosis is more common after percutaneous angioplasty. However, the use of stents may provide a better outcome; the data are not yet forthcoming. As in the general population, patients should be considered for coronary revascularization if they remain symptomatic or are at high risk for a myocardial infarction. Coronary bypass surgery is currently regarded as the procedure of choice. Coronary stenting may be a perfectly reasonable alternative, if feasible and individually indicated.

References 1.

2.

3.

4.

5.

The USRDS Dialysis Morbidity and Mortality Study: Wave 2. US Renal Data Systems. Am J Kidney Dis 1997; 30(Suppl 1): S67-S85 Tucker B, Fabbian F, Giles M, Thuraisingham RC, Raine AE, Baker LR. Left ventricular hypertrophy and ambulatory blood pressure monitoring in chronic renal failure. Nephrol Dial Transplant 1997; 12: 724-728 Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998; 32(Suppl 3): S112-S119. Shulman NB, Ford CE, Hall WD, Blaufox WD, Simon D, Langford HG, Schneider KA. Prognostic value of serum creatinine and the effect of treatment of hypertension on renal function: HDFP results. Hypertension 1989; 13(Suppl 1): I-80-I-93. Ruilope LM, Salvetti A, Jamerson K, Hansson L, Warnold I, Wedel H, Zanchetti A. Renal function and intensive lowering of blood pressure in hypertensive participants of the hypertension optimal treatment (HOT) study. J Am Soc Nephrol. 2001;12:218-25.

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6.

Wannamethzee SG, Shaper AG, Perry IJ. Serum creatinine concentration and risk of cardiovascular disease: a possible marker of increased risk for stroke. Stroke 1997; 28: 557-63. 7. Agrawal B, Berger A, Wolf K, Luft FC. Microalbumin screening by reagent strip predicts cardiovascular risk in hypertension. J Hypertens 1996; 14: 223-228. 8. Mailloux LU, Levey AS. Hypertension in patients with chronic renal disease. Am J Kidney Dis 1998; 32(Suppl 3): S120-S141. 9. Kasiske BL. Hyperlipidemia in patients with chronic renal disease. Am J Kidney Dis 1998; 32(Suppl 3): S142S156. 10. Manske CL. Hyperglycemia and intensive glycemic control in diabetic patients with chronic renal disease. Am J Kidney Dis 1998; 32(Suppl. 3): S157-S171. 11. Haffner SM, Lehto S, Ronneman T, Pvorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339: 229-32

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12. Harris LE, Luft FC, Rudy DW, Kesterson JG, Tierney WM. Effects of multidisciplinary case management of patients with chronic renal insufficiency. Am J Med 1998; 105: 464-471. 13. Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC. Electron beam computed tomography in evaluation of cardiac calcifications in chronic dialysis patients. Am J Kidney Dis 1996; 27: 394-401. 14. Orth SR, Ritz E, Schrier RW. The renal risks of smoking. Kidney Int 1997; 51: 1678-1695. 15. Ritz E, Benck U, Franek E, Keller C, Seyfarth M, Clorius J. Effects of smoking on renal hemodynamics in healthy volunteers and in patients with glomerular disease. J Am Soc Nephrol. 1998 Oct;9(10):1798-804.

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16. Orth SR, Stockmann A, Conradt C, Ritz E, Ferro M, Kreusser W, Piccoli G, Rambausek M, Roccatello D, Schafer K, Sieberth HG, Wanner C, Watschinger B, Zucchelli P. Smoking as a risk factor for end-stage renal failure in men with primary renal disease. Kidney Int. 1998 Sep;54(3):926-31. 17. Murphy SW, Foley RN, Parfrey PS. Screening and treatment for cardiovascular disease in patients with chronic renal disease. Am J Kidney Dis 1998; 32(Suppl 3): S184-S199.

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