Cardiac Disease in Chronic Uremia: Epidemiology

Cardiac Disease in Chronic Uremia: Epidemiology Wendy E. Bloembergen Cardiac abnormalities develop during chronic renal failure. The prevalence of ischemic heart disease, cardiac failure, and left ventricular disorders is high among patients initiating end-stage renal disease (ESRD) therapy, and appears to be getting higher. Age, gender, race, diabetes, and possibly geographic location are predictive of the presence of several cardiac conditions. Cardiac morbidity after the initiation of ESRD therapy is high, and cardiac causes are the most common reported cause of death. Cardiac abnormalities present on starting dialysis contribute to this morbidity and mortality. In epidemiological studies, higher cardiac death rates have also been associated with dialysis rather than transplantation as mode of ESRD therapy, peritoneal rather than hemodialysis, lower dose of dialysis, and unmodified cellulose rather than modified cellulose/synthetic hemodialysis membranes. © 1997 by the National Kidney Foundation, Inc. Index Words: Cardiac disease; end-stage renal disease; prevalence; epidemiology; risk factor.

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espite renal replacement therapy, the mortality of patients with end-stage renal disease (ESRD) remains high. The projected expected remaining lifetime of a patient who develops ESRD is one third to one quarter of a similar-aged person in the general population.! The morbidity experienced by this population is also substantial. On average, a dialysis patient younger than age 65 is admitted to hospital 1.3 times per year with an average length of stay of 11.5 days. A patient older than 65 years is admitted on average 1.4 times per year with an average length of stay of 12 days.2 Much of this mortality and morbidity is attributable to cardiac disease, which is extremely prevalent in this population. This introductory article reviews the burden of cardiac disease from an epidemiological perspective, using data primarily from the United States Renal Data System (USRDS), from other national ESRD registries where available, as well as from large cohort studies.

Prevalence of Cardiac Disease in Chronic Uremia Established ESRD The dialysis population has a high degree of comorbidity, with cardiac disease particularly prevalent. In a USRDS special study, the Case Mix Adequacy Study (CMAS), data on demographics, comorbid conditions, laboratory values, and dialysis parameters were obtained by medical chart abstraction on a representative (randomly selected) sample of 4,790 U.s. pa-

tients who were on hemodialysis on December 31,1991. The high prevalence of cardiac conditions present in this prevalent sample are shown in Table 1. New ESRD A comparison of the prevalence of these cardiac comorbid conditions among new (incident) patients, however, shows that the bulk of cardiac disease is already present at the time patients initiate dialysis. The Case Mix Severity Study (CMSS) is a USRDS study that provides comorbidity data on 3,399 incident (new) hemodialysis patients who started di.alysis in 1986 and 1987. 4 This earlier study was similar to the CMAS (described previously), with the exception that comorbidity and other data were collected from the time of dialysis initiation for all patients, rather than at the start of the study. The prevalence of comorbid conditions present in this representative sample of new U.s. dialysis patients is shown in Table 2. All comorbid conditions were only slightly less than in the sample of patients established on ESRD therapy. Results of a prospective cohort study that screened for the presence of LVH by performing echocardiography on 433 new dialysis From the Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI. Address correspondence to Wendy E. Bloembergen, MD, MS, Kidney Epidemiology and Cost Center, University of Michigan, 315 W Huron St, Suite 240, Ann Arbor, MI48103. © 1997 by the National Kidney Foundation, Inc. 1073-4449/97/0403-0010$3.00/0

Advances in Renal Replacement Therapy, Vol 4, No 3 (July), 1997: pp 185-193

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Table 1. Cardiac Conditions and Associated Mortality Risk Among Prevalent Hemodialysis Patients3

Cardiac Condition

Percent

RR*

p

Myocardial infarction Coronary artery diseaset Congestive heart failure Cardiac arrest Arrhythmia/ atrial fibrillation Pericarditis

15 45 42 3

1.5 1.44 1.62 2.1

<.01 <.01 <.01 <.01

31 7

1.51 1.22

<.01 <.05

*Relative risk is adjusted for age, sex, race, and cause of ESRO. tCoronary artery disease is defined as any history of coronary artery disease, myocardial infarction, abnormal angiogram, angioplasty, or coronary artery bypass graft within the 10 years before the study start date.

patients in several Canadian centers suggests that the prevalence of this condition is considerably greater than that observed by chart review. s LVH, as defined by standard cardiology criteria, was present in 74% of patients starting dialysis. Pre-ESRD Many of the patients who develop ESRD do so because of systemic disease such as diabetes and hypertension, which also may be the cause of the cardiac abnormalities present among patients starting renal replacement therapy. However, recent epidemiological evidence suggests that the decline in renal function in the pre-ESRD stage also may playa role

in the development of cardiac abnormalities. As part of a prospective cohort study by Levin et al,6 175 patients with chronic renal failure (mean creatinine clearance, 25.5 mL/min at baseline) were evaluated with echocardiography. Among this cohort, 38.9% of patients had LVH as defined by standard echocardiography criteria. Of note, this study found that a higher prevalence of LVH was associated with lower degrees of renal function. In a multivariate analysis, there was a 3% higher risk of LVH for every 5 mL/min lower creatinine clearance. Whether the decline in renal function contributes to the increase in LVH, or the increase in LVH and decline in renal function are simultaneous effects of the underlying disease, has not been determined. However, the former explanation certainly warrants consideration and exploration. If true, interventions such as earlier initiation of dialysis may conceivably reduce the development of cardiac abnormalities. This study also found that for every 5 mm Hg lower systolic blood pressure and for every 10 gil (1 g/ dL) higher hemoglobin there was a 3% and 6% lower risk of LVH, thus identifying two modifiable factors as predictors of LVH in this population. Predictors of Cardiac Disease Several demographic and other factors have been shown to be predictive of certain cardiac conditions.

Table 2. Cardiac Conditions Among Incident Dialysis Patients

ESRD Registry USRDS (US)4

Cardiac Condition

Patient Population

Coronary artery disease* Myocardial infarction

All <45,DM >45,DM <45,nonDM >45,nonDM All All

40.8

All All

30.9 38.1

Angina Congestive heart failure Left ventricular hypertrophyt Cardiomegaly

CORR (Canada)5

ANZDATA (Aust&NZ)7

Cohort Study Foley et alB

36

14.1

9.2

24 2.2 19.2 41.1

18.8 30.8

74

*Includes suspected; USROS definition, any history of coronary artery disease, myocardial infarction, coronary artery bypass surgery, coronary angioplasty, or abnormal angiography; ANZOATA, not defined; Canadian Organ Replacement Registry (CORR), history of MI, coronary artery bypass surgery, or angioplasty. tUSROS, LVH by ECG or echo report available on chart review; CORR, LVH on echo performed on all included patients. Abbreviation: OM, diabetes mellitus.

Epidemiology in Cardiac Disease

Age. Increasing age has been shown to be a predictor of a number of cardiac conditions among ESRD patients. Among patients starting dialysis in Australia, coronary artery disease was reported or suspected in 21% of patients aged 35 to 54 years, 47% of patients aged 55 to 64 years, and 55% of patients aged 65 to 74.7 Similarly, in data from the Canadian ESRD registry, patients older than 45 years had a much higher prevalence of history of myocardial infarction than those younger than 45 (Table 2).8 Other smaller studies of ESRD patients have also shown increasing age to be predictive of coronary artery disease. 9,lo

In a prospective cohort study of 432 dialysis patients by Harnett et al,l1 increasing age was also shown to be predictive of the presence of congestive heart failure in patients starting dialysis. Similarly, in the same cohort of patients, increasing age was predictive of the presence of LVH as determined by an echocardiogram done within the first year of dialysis. s Gender, Male gender has been shown to be predictive of coronary artery disease in the dialysis population. 9 In the cohort study by Harnett et al,l1 gender was not predictive of congestive heart failure. In this same group of patients, female gender was predictive of LVH, but male gender was predictive of LVH dilatation. This may have been influenced by the definitions used in this study. In a recent analysis of data from the USRDS CMSS and CMAS, we compared comorbid conditions of approximately 5,000 patients starting dialysis by gender. Adjusted for age, race, and cause of ESRD, men starting dialysis were more likely to have had a history of coronary artery disease, arrhythmia/ atrial fibrillation or LVH by echocardiogram or electrocardiogram (ECG). Conversely, women were more likely to have cardiomegaly on chest radiograph or a history of congestive heart failure. 12 Some of these results are therefore seemingly contrary to those found by Harnett et al. l1 Race. Prior studies have shown a higher prevalence of coronary artery disease among whites than blacks with ESRD.9 We have also compared comorbidity differences by race among new dialysis patients, in a study similar to that described for gender. Adjusted for

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age, gender, and cause of ESRD, whites starting dialysis were more likely to have had a history of coronary artery disease and arrhythmia/ atrial fibrillation. Conversely, blacks were more likely to have cardiomegaly on chest radiograph, LVH by echocardiogram or ECG, or a history of congestive heart failure.1 3 Geography. Although not directly comparable because of differences in data availability, reporting, and collection, the prevalence of various cardiac conditions present at the start of ESRD among patients from several countries is shown in Table 2. The Canadian Organ Replacement Register (CaRR) has reported on comorbidity data collected for new patients by means of an annual form completed by the patient's physician or his or her designee. 8 Although these data are collected less rigorously than that collected in the USRDS CMSS (also shown), it indicates that among patients for whom comorbidity data are available, 24% of diabetics and 19.2% of nondiabetics aged 45 years and over had a history of myocardial infarction. Among patients younger than 45 years, 9.2% of diabetics and 2.2% of nondiabetics had a history of myocardial infarction. The prevalence of reported angina is approximately 30% higher than the prevalence of myocardial infarction in each of these subgroups (not shown). The Australian ESRD Registry (ANZDATA) has also started to collect data for dialysis patients since October 1991. Coronary artery disease was reported in 25% of this group of patients, and suspected in a further 11%, for a total of 36%.7 The prevalence of coronary artery disease among ESRD patients in Europe and Japan has not been routinely reported in their national registry data reports. The prevalence of coronary artery disease conditions present in new dialysis patients has also been documented in cohort studies. 5,14 In the prospective cohort study of new dialysis patients in Canada, 14.1% were found to have a history of coronary artery disease (CAD) defined as history of myocardial infarction, coronary artery bypass surgery, or angioplasty, and 18.8% had a history of angina defined as precordial chest pain, precipitated by exertion or stress and relieved by rest or nitrates. Therefore, it appears that the

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prevalence of CAD may be lower in Canada than in Australia and the United States. However, the absence of standard definitions makes these comparisons difficult. The prevalence of other cardiac conditions among ESRD patients is not routinely available in many of the registry reports to allow national comparisons. Available data suggest that LVH may be higher in the United States (43%)15 than in Europe (26% of females, 37% for males).1 6 This difference may be real, supporting the contention that the much higher incidence rates of treated ESRD in the United States may be attributable in part to the acceptance of patients with greater degrees of comorbidity or may be simply attributable to differences in the use of echocardiography or other investigative tests. The very high prevalence of LVH observed (74%) when echocardiogram is used for screening emphasizes this point. 5 Diabetes. Diabetes is also predictive of the presence of several cardiac conditions among patients starting dialysis, including CADS and congestive heart failure.1 1 Dialysis modality. Using data from the CMSS, the USRDS has previously analyzed selection of patients to peritoneal and hemodialysis according to comorbid conditions. 17 In this study, there was no significant difference in the prevalence of congestive heart failure or CAD between new patients treated with these two modalities. Cardiac Comorbidity: Time Trends A study by Young et aP8 has compared comorbidity in patients starting hemodialysis in 1986 to 1987 and 1990 using data from the USRDS CMSS and CMAS studies. 18 The prevalence of cardiovascular diseases increased over time, adjusted for age, race, sex, and diabetes as the cause of ESRD. In particular there were significant increases in the prevalence of congestive heart failure (48% to 52%, P = .019) and CAD (52% to 55%, P = .038), including increases in patients who had undergone angiography (4% to 9%, P = .0001), coronary artery bypass (3% to 5%, P = .0001), and coronary angioplasty (1 % to 2%). An unadjusted comparison of new patients starting dialysis during two 6-month periods in 1991 to 1992 and 1994 in Australia also

showed an increase in the percentage of patients with, or suspected to have, CAD (33.5% to 37.4%).1 9 These two reports suggest that the burden of cardiac comorbidity is increasing in the incident dialysis population.

Morbidity Caused by Cardiac Disease Although there are few published data from national ESRD registries describing the morbidity attributable to cardiac disease among ESRD patients, data from available cohort studies suggest that it is substantial. The Canadian Hemodialysis Study 14 was a large cohort study of 496 new hemodialysis patients who were followed prospectively for a mean of 218 days. During this follow-up period, there were 30 circulatory events, defined as nonfatal myocardial infarction or angina requiring hospitalization (probability 8% per year), and there were 40 episodes of pulmonary edema requiring hospitalization or additional ultrafiltration (probability 10% per year). The study by Harnett et aPl also prospectively followed new dialysis patients for the occurrence of congestive heart failure during a mean follow-up of 41 months. Among 299 patients who were initially free of congestive heart failure (CHF), 76 (25%) developed an episode of CHF. Among 133 patients who had CHF at baseline, 75 (56%) had recurrent episodes during the follow-up period.

Mortality Caused by Cardiac Disease Cardiac disease is the major cause of death among ESRD patients according to several national registries. 7,8,16,20,21 In the United States, cardiac causes reportedly accounted for 48% of deaths occurring from 1991 to 1993 (Fig 1).20 Of note, in one large single U.s. center examining cause of death, this was not confirmed, and infection was found to be the leading cause of death. 22 Nevertheless, relative to the general population, death rates attributable to cardiac causes are extremely high among ESRD patients. For example, the death rate attributable to myocardial ischemia/infarction has been shown to be 16 to 19 times higher among ESRD patients compared with the general

189

Epidemiology in Cardiac Disease

Malignancy Infection

Unknown

Cardiac 48%

7%

20%

6%

Figure 1. Percent distribution of causes of death for all Medicare ESRD patients over the age of 20 years, 1991 to 1993. Categories collapsed from Death Notification Form.

population, in both Italy and the United Kingdom. 16 In the USRDS database, cardiac deaths were previously broadly classified as attributable to acute myocardial infarction or other cardiac causes. However, recent revisions to the Death Notification Form have provided more detailed information on deaths attributed to cardiac causes. Figure 2 shows the percent distribution of specific cardiac causes among all deaths classified as cardiac. The "other" category includes pulmonary edema, valvular disease, and pericarditis, which are relatively uncommon reported cardiac causes of death, accounting for 2%, 1.5%, and 0.5% of cardiac deaths, respectively. Role of Demographic Factors on Cardiac Mortality

Deaths of cardiac causes previously have been shown to be associated with several demographic factors. In a comparison of demographic-adjusted cause-specific death rates by

gender and race, the risk of death attributable to acute myocardial infarction and other cardiac causes was shown to be higher among white than black dialysis patients (RR = 1.34 and RR = 1.30, respectively, p < .001) and higher among male than female dialysis patients (RR = 1.48 and RR = 1.3, respectively, p = .001).23 Subsequent analyses of the more detailed data on cardiac causes of death, available since the new Death Notification Form, found that males and females had quite similar demographic-adjusted death rates of cardiac arrest, but males had higher death rates of acute myocardial infarction and other cardiac causes. 20 Adjusted death rates attributable to acute MI, cardiac arrest, and other cardiac causes also have been shown to be considerably higher among diabetics than nondiabetics and, as expected, higher among older compared with younger patients. 2o However the percentage of all deaths attributed to cardiac causes combined is within the range of 45% to

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Wendy E. Bloembergen

Other Cardiac Arrhythmia

14%

Cardiac Arrest 39%

Atherosclerotic Heart Disease 9%

24%

Figure 2. Percent distribution of specific cardiac causes of death among all cardiac causes for all ESRD patients, 1991 to 1993. 49% for all racial, gender, age, and diabetic status subgroups. Role of Geography The proportion of deaths that are due to cardiac causes appears to vary by country. Table 3 summarizes cardiac causes of death data reported by a number of national registries to allow an international comparison. The absence of standard cause of death definitions necessitates cautious interpretation of these data. Cardiac arrest is reportedly the most common cardiac cause of death in New Zealand, Japan, and the United States. Because of

reporting methods, this category may perhaps include sudden deaths that are not truly cardiac in nature. In Europe, there is a well-known north/ south gradient in the prevalence of cardiovascular disease in the general population, such that Mediterranean countries have a lower prevalence and northern European countries have a higher prevalence. Death rates attributable to cardiovascular causes, particularly myocardial ischemia and infarction, have been observed to be much higher in northern than southern European dialysis populations as well. 16

Table 3. Percent of Deaths Due to Cardiac Causes for Various Countries Cause of Death Year

Age

Australia7 Canada8

1995 1981-94

Europe16 New Zealand 7 US2° Japan21

1990 1995 1991-93 1994

All 0-44yr 45 + yrs All All All All

Country

Myocardial Infarction

Cardiac Arrest

Other Cardiac

Total Cardiac

18

12

15

15 18 12 7

12 23 19 26

15 14 17

45 35 38.5 42 53 48 33

Epidemiology in Cardiac Disease

Role of Baseline Cardiac Conditions on Cardiac Mortality Most studies have evaluated the relationship of cardiac conditions on all-cause mortality, although a few have also evaluated the relationship of cardiac conditions to deaths specifically attributable to cardiac causes. Table 1 lists the cardiac conditions that were significantly associated with all-cause mortality in the USROS CMAS after adjustment for age, race, gender, and cause of ESRO with their associated mortality risk. 3 These included (in order of decreasing risk) cardiac arrest (RR = 2.1), congestive heart failure (RR = 1.62), arrhythmia/ atrial fibrillation (RR = 1.51), myocardial infarction (RR = 1.5), coronary artery disease (RR = 1.44), and pericarditis (RR = 1.22). Angina, LVH (by echo cardiogram or ECG), and cardiomegaly (by x-ray) were not independent predictors of mortality. Harnett et aPl have also found congestive heart failure to be an independent predictor of all-cause mortality and in the same cohort of patients, Foley et al5 have found several echocardiographic measurements to be predictive of both all-cause and cardiac mortality. Symptomatic ischemic heart disease (coronary artery disease and angina) was predictive of increased mortality in these analyses, but this prediction was not independent of the effect of cardiac failure. 24 Whether LVH is an independent predictor of mortality remains somewhat controversial. Early reports suggested that it was associated with an increased risk of death. 25 However, as mentioned, analyses of USROS have not found it to be an independent predictor. In the analyses of their prospective cohort study, Foley et al 5 found LVH (defined as LV mass index >100 g/m2 in females and >131 g/m2in males) was not an independent predictor of mortality. However, LV geometry has prognostic importance,26 particularly for late mortality. LV mass is associated with mortality in patients with normal LV cavity volume, and LV volume is associated with mortality only in patients with LV dilatation. Role of Treatment Parameters Dialysis Modality. A national study of over 40,000 dialysis patient deaths in the United

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States compared cause-specific death rates between patients treated with peritoneal and hemodialysis in the years 1987 to 1989. 27 Patients treated with peritoneal dialysis (PO) were found to have a 31 % higher risk of death (RR = 1.31, P < .05) attributable to acute myocardial infarction and an 8% (RR = 1.08, P < .05) higher risk of death attributable to other cardiac causes than patients treated with hemodialysis when adjusted for age, race, gender, cause of ESRO, and time on dialysis. The increased risk for these causes of death among PO patients was accentuated among diabetics. On average, there was one more death of acute myocardial infarction and 0.62 more deaths of other cardiac causes among PO compared with hemodialysis (HO)-treated patients per 100 patient-years. Cardiac causes were therefore major contributors to the total number of four excess deaths per 100 patientyears among PO- compared with HO-treated patients. A similar analysis of more recent data20 of deaths occurring from 1991 to 1993 continues to show higher death rates for acute myocardial infarction (31.5 v 24.8 per 100 patient-years), cardiac arrest (45.3 v 43.4 per 100 patient-years), and other cardiac causes (51.5 v 39.2 per 100 patient-years) among PO-compared with HO-treated patients. These observations may be attributable to differences in dose of dialysis or medical care received by PO compared to HO patients, because of differences in compliance, or baseline comorbidity, or they may be related to the many technical differences inherent in the two modalities. Transplantation. A comparison of patients with similar age, race, gender, and diabetes status shows that death rates caused by acute myocardial infarction, cardiac arrest, and other cardiac causes are markedly lower among patients with a functioning transplant compared with dialysis patients. 20 However, this is undoubtedly attributable in part to the selection of healthier patients for transplantation. Dose of dialysis. A number of studies have found a relationship of lower all-cause mortality risk for dialysis patients treated with a higher dose of dialysis. 28,29 Using data from the USROS CMAS, we have also evaluated the relationship of delivered dose of dialysis with

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cause-specific mortality and found that higher doses of dialysis are associated with a lower risk of death of cardiac causes. IS Adjusting for demographics, comorbid diseases present at the start of the study, functional status, laboratory values, and other dialysis parameters, for 0.1 higher Kt/V, there was a 9% lower risk of death of CAD and a 12% lower risk of death of other cardiac causes (excluding cardiac arrest). Dialysis membrane. In a separate analysis that has evaluated the effect of dialysis membrane type on cause-specific mortality among hemodialysis patients, the use of modified cellulose and synthetic membranes was associated with a 26% lower risk of death attributable to coronary artery disease compared with unmodified cellulosic membranes. 3o Possible explanations for this observed mortality difference are several and include that it may be caused by greater biocompatibility, flux, or efficiency of the modified cellulose and synthetic membranes, because of the greater use of volumetric machines with the use of these membranes, or may simply be a center effect (facilities with otherwise superior outcomes happen to use modified cellulose and synthetic membranes).

References 1. u.s. Renal Data System: Patient mortality and survival. Am J Kidney Dis 28:579-592, 1996 2. U.s. Renal Data System: Hospitalization. Am J Kidney Dis 28:5114-5126, 1996 3. U.s. Renal Data System: Patient mortality and survival. Am J Kidney Dis 26:569-584, 1995 4. U.s. Renal Data System: Comorbid conditions and correlations with mortality risk among 3,399 incident hemodialysis patients. Am J Kidney Dis 20:32-38, 1992 5. Foley RN, Parfrey PS, Harnett JD, et al: Clinical and echocardiographic disease in patients starting endstage renal disease therapy. Kidney Int 47:186-192, 1995 6. Levin A, Singer J, Thompson CR, et al: Prevalent left ventricular hypertrophy in the predialysis population: Identifying opportunities for intervention. Am J Kidney Dis 27:347-354, 1996 7. Disney APS (ed): ANZDATA Report 1996, Australia and New Zealand Dialysis and Transplant Registry. Adelaide, South Australia 8. Annual Report 1996, Volume 1: Dialysis and Renal Transplantation, Canadian Organ Replacement Register, Canadian Institute for Health Information, Ontario, Don Mills, March 1996

9. Rostand SG, Kirk KA, Rutsky EA: Dialysis-associated ischemic heart disease: Insights from coronary angiography. Kidney Int 25:653-659,1984 10. Rostand SG, Kirk KA, Rutsky EA: Relationship of coronary risk factors to hemodialysis-associated ischemic heart disease. Kidney Int 22:302-308, 1982 11. Harnett JD, Foley R, Kent GM, et al: Congestive heart failure in dialysis patients: Prevalence, incidence, prognosis and risk factors. Kidney Int 47:884-890,1995 12. Bloembergen WE, Carroll C, Gillespie B, et al: Why do males with ESRD have higher mortality rates than females? J Am Soc NephroI7:1440, 1996 13. Carroll C, Bloembergen WE, Gillespie B, et al: Do racial differences in comorbidity or treatment explain higher mortality observed among whites with ESRD? J Am Soc NephroI7:1441, 1996 14. Churchill DN, Taylor DW, Cook RJ, et al: Canadian Hemodialysis Morbidity Study. Am J Kidney Dis 19:214-234,1992 15. Bloembergen WE, Stannard DC, Port FK, et al: The relationship of dose of hemodialysis and causespecific mortality. Kidney Int 50:557-565,1996 16. Raine AEG, Margreiter R, Brunner FP, et al: Report on management of renal failure in Europe, XXII, 1991. Nephrol Dial Transplant SuppI2:7-35, 1992 17. U.s. Renal Data System: 1992 Annual Data Report. Patient selection to peritoneal dialysis versus hemodialysis according to comorbid conditions. Am J Kidney Dis 20:20-26,1992 18. Young EW, Carroll CE, Wolfe RA, et al: Trends in comorbidity and residual renal function in patients starting treatment for end-stage renal disease. J Am Soc NephroI6:897, 1995 19. Disney APS (ed): ANZDATA Report 1995: Australia and New Zealand Dialysis and Transplant Registry, Adelaide, South Australia 20. U.s. Renal Data System: Causes of Death. Am J Kidney Dis 28:593-5102, 1996 21. Japanese Society for Dialysis Therapy: An Overview of Regular Dialysis Treatment in Japan (as of December 31,1994), Tokyo, Japan 22. Mailloux LU, Belluci AG, Wilkes BM, et al: Mortality in dialysis patients: Analyses of the causes of death. Am J Kidney Dis 18:326-335, 1991 23. Bloembergen WE, Port FK, Mauger EA, et al: Causes of death in dialysis patients: Racial and gender differences. J Am Soc NephroI5:1231-1242, 1994 24. Parfrey PS, Foley RN, Harnett JD, et al: Outcome and risk factors of ischemic heart disease in chronic uremia. Kidney Int 49:1425-1434,1996 25. Silberberg JS, Barre P, Prichard 5, et al: Left ventricular hypertrophy: An independent determinant of survival in end-stage renal failure. Kidney Int 36:286-290, 1989 26. Foley RN, Parfrey PS, Harnett JD, et al: The prognostic importance of left ventricular geometry in uremic cardomyopathy. J Am Soc NephroI5:2024-2031, 1995 27. Bloembergen WE, Port FK, Mauger EA, et al: A

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comparison of cause of death between patients treated with hemodialysis and peritoneal dialysis. J Am Soc NephroI6:184-191, 1995 28. Owen WF, Lew NL, Liu Y, et al: The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis. N Engl J Med 329:1001-1006,1993

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29. Held PJ, Port FK, Wolfe RA, et al: The dose of hemodialysis and patient mortality. Kidney Int 50:550556,1996 30. Bloembergen WE, Port FK, Hakim RM, et al: The relationship of dialysis membrane and cause-specific mortality in chronic hemodialysis patients. J Am Soc NephroI6:521,1995