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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2554-2558.)
© 1997 American Heart Association, Inc.

Articles

Elevated Fasting Total Plasma Homocysteine Levels and Cardiovascular Disease Outcomes in Maintenance Dialysis Patients

A Prospective Study

Andrew G. Bostom; Douglas Shemin; Petra Verhoef; Marie R. Nadeau; Paul F. Jacques; Jacob Selhub; Lance Dworkin; ; Irwin H. Rosenberg

From the Vitamin Bioavailability Laboratory (A.G.B., M.R.N., P.F.J., J.S., I.H.R.), Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts New England Medical Center, Boston, Mass; the Division of Renal Diseases (D.S., L.D.), Rhode Island Hospital, Providence, RI; and the Department of Nutrition (P.V.), Agricultural University, Wageningen, Netherlands.

	Abstract

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Abstract There is an excess prevalence of hyperhomocysteinemia in dialysis-dependent end-stage renal disease (ESRD) patients. Cross-sectional studies of the relationship between elevated total homocysteine (tHcy) levels and prevalent cardiovascular disease (CVD) in this patient population suffer from severe methodologic limitations. No prospective investigations examining the association between tHcy levels and the subsequent development of arteriosclerotic CVD outcomes among maintenance dialysis patients have been reported. To assess whether elevated plasma tHcy is an independent risk factor for incident CVD in dialysis-dependent ESRD patients, we studied 73 maintenance peritoneal dialysis or hemodialysis patients who received a baseline examination between March and December 1994, with follow-up through April 1, 1996. We determined the incidence of nonfatal and fatal CVD events, which included all validated coronary heart disease, cerebrovascular disease, and abdominal aortic/lower-extremity arterial disease outcomes. After a median follow-up of 17.0 months, 16 individuals experienced at least one arteriosclerotic CVD event. Cox proportional-hazards regression analyses, unadjusted and individually adjusted for creatinine, albumin, and total cholesterol levels, total/HDL cholesterol ratio, dialysis adequacy/residual renal function, baseline CVD, and the established CVD risk factors (ie, age, sex, smoking, hypertension, diabetes/glucose intolerance, and dyslipidemia) revealed that tHcy levels in the upper quartile (27.0 µmol/L) versus the lower three quartiles (<27.0 µmol/L) were associated with relative risk estimates (hazards ratios, with 95% confidence intervals for the occurrence of (pooled) nonfatal and fatal CVD ranging from 3.0 to 4.4; 95% confidence intervals (1.1-8.1) to (1.6-12.2). We conclude that the markedly elevated fasting tHcy levels found in dialysis-dependent ESRD patients may contribute independently to their excess incidence of fatal and nonfatal CVD outcomes.

Key Words: hyperhomocysteinemia • end-stage renal disease • arteriosclerosis • longitudinal study

	Introduction

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End-stage renal disease patients in the United States undergoing maintenance peritoneal or hemodialysis experience excess morbidity and mortality due to arteriosclerotic CVD.^{1 2 3 4 5} Specifically, event rates for MI and stroke are 5- to 10-fold higher in ESRD patients versus general populations.^{1 2 3 4 5} Risk factors linked to increased overall mortality in prospective studies of maintenance dialysis cohorts include age, prevalent CVD, diabetes, low serum albumin, low serum creatinine, and reduced indices of dialysis adequacy/residual renal function.^{1 5 6} Despite their widespread prevalence,⁷ traditional CVD risk factors⁸ such as smoking, hypertension, glucose intolerance/diabetes, and dyslipidemia are relatively limited predictors of CVD-specific mortality and morbidity in the ESRD population.^{4 9 10 11}

Earlier we provided evidence¹² that hyperhomocysteinemia, ie, elevated total plasma levels of the atherothrombotic^{13 14} sulfur amino acid homocysteine (tHcy), occurs more commonly than any of the other traditional CVD risk factors in maintenance dialysis patients. However, published cross-sectional investigations^{15 16 17 18} of the relationship between tHcy levels and prevalent CVD outcomes in ESRD populations have yielded conflicting results, characterized by inconsistencies both between and within studies.

No prospective data examining the association between tHcy levels and the subsequent development of CVD outcomes among maintenance dialysis patients have been reported. Accordingly, we conducted a longitudinal study of the relationship between plasma tHcy levels and the development of fatal and nonfatal CVD outcomes in 73 maintenance dialysis patients who were followed up for a median of 17.0 months. We controlled for age, sex, baseline CVD, the traditional CVD risk factors, serum albumin and creatinine, and dialysis adequacy/residual renal function to clarify the independent effect of tHcy levels on the prospective development of arteriosclerotic CVD outcomes.

	Methods

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Study Participants
A detailed description of the study population has been provided elsewhere,¹⁷ including specific data on the etiology of ESRD. In brief, 73 of 75 Rhode Island maintenance dialysis patients described earlier (after a priori exclusion of two subjects 35 years old at the baseline examination) were studied.

CVD Outcomes
Criteria for establishing the presence of preexisting CVD at the baseline examination (March 1994 to December 1994) or of CVD events that occurred during the follow-up period (through April 1, 1996) are described below. MI was confirmed by serial ECG evidence of a Q-wave or non–Q-wave MI and appropriate creatine phosphokinase MB fraction elevations; unstable angina, by chest pain/shortness of breath with new-onset ischemic ECG changes unrelated to clinical volume overload and/or accompanied by angiographic evidence of new, significant epicardial coronary artery stenoses of 50% occlusion; stroke (including hemorrhagic, as elevated tHcy levels have been associated with both nonhemorrhagic and hemorrhagic stroke¹⁹ was confirmed by computerized tomographic or magnetic resonance imaging evidence of cerebral infarction and neurological examination findings consistent with new-onset focal neurological deficits lasting >24 hours; TIA, by neurological examination findings consistent with new-onset focal neurological deficits lasting <24 hours; new-onset significant coronary artery, extracranial carotid artery, vertebrobasilar artery, thoracoabdominal aortic (see Reference²⁰ ), or major lower-extremity arterial disease was confirmed by B-mode/Doppler ultrasound, magnetic resonance angiography, or invasive angiographic evidence of new 50% arterial stenosis and/or documented surgical revascularization, percutaneous angioplasty, or lower-extremity amputation. CVD death was confirmed when in-hospital death related acutely or subacutely to documented (as above) MI or stroke or when out-of-hospital sudden death occurred in a stable patient with no clinical or laboratory evidence of uncontrolled uremia, sepsis, or gastrointestinal bleeding in the previous 24 to 48 hours. For example, patients hospitalized for sepsis due to peritonitis who subsequently died form "cardiopulmonary arrest" did not have their deaths classified as CVD deaths. All CVD outcome determinations were performed by a single investigator (A.G.B.) blinded to the potential independent predictor variables.

Biochemical Analyses
Plasma levels of tHcy and those of the B vitamin cofactors/substrates for Hcy metabolism,²¹ ie, PLP (active B-6), B-12, and folate and the presence of the C677T transition in thermolabile MTHFR) were determined as described in detail earlier.²² Plasma HDL cholesterol and total cholesterol levels were determined by routine precipitation and/or enzymatic methods,²³ and plasma glucose and serum albumin and creatinine levels were assessed by standard automated clinical chemistry laboratory methods. The tHcy, B vitamin, total and HDL cholesterol, glucose, and creatinine determinations were made in fasting (10 to 14 hours) specimens, whereas albumin was measured in the nonfasting state.

Other Covariate Measures
URRs for hemodialysis patients and weekly CCrs for peritoneal dialysis patients were determined as previously described,²² and dialysis adequacy/residual renal function was dichotomized by comparing those in the lowest quartile for either URR or CCr to those in the upper three quartiles. A positive smoking history was recorded when an individual was a current smoker or had quit <1 year prior to being interviewed. Hypertension was considered present based on current use of antihypertensive medication or two resting (predialysis for hemodialysis patients) systolic blood pressures >140 mm Hg or diastolic blood pressures >90 mm Hg. Clinical diabetes was considered present if the fasting plasma glucose level was >140 mg/dL or the individual was currently using insulin preparations or oral hypoglycemic medications, whereas glucose intolerance was designated if the patient had a fasting plasma glucose level >110 mg/dL or clinical diabetes (as defined above). Additional covariates examined included age, sex, race (white or black), dialysis mode (peritoneal or hemodialysis), and dialysis duration (months since first initiation).

Statistical Analyses
Differences for continuous variables were assessed by t tests (if normally distributed) or Wilcoxon rank-sum tests (if skewed) and for discrete variables by ² or Fisher's exact tests according to the presence or absence of our a priori definition of hyperhomocysteinemia (tHcy in the upper quartile, ie, 27 µmol/L versus the lower three quartiles, ie, <27 µmol/L). Subjects contributed the time (in person-months) until their initial CVD event (nonfatal or fatal), death from any cause, or the end of the follow-up period. Crude and adjusted relative risk estimates (hazards ratios) for any initial CVD event during the follow-up period (fatal or nonfatal) were calculated using Cox proportional-hazards regression modeling.²⁴ Owing to the relatively limited number of events, no more than two potential independent predictor variables were added to the models also containing hyperhomocysteinemia as a dichotomous variable. Evaluation of effect modification by sex was accomplished by formal testing with and without a hyperhomocysteinemiaxsex interaction term in two otherwise equivalent proportional-hazards models. In additional crude proportional-hazards analyses, hyperhomocysteinemia was arbitrarily defined as greater than or equal to the median (22.3 µmol/L), the upper tertile (26.0 µmol/L), and the upper quintile (29.7 µmol/L). All analyses, including checking the assumption of constant proportional hazards, were performed using SAS software.²⁵

	Results

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There was no patient lost to follow-up, and after a median follow-up of 17.0 months, 16 patients experienced nonfatal and/or fatal CVD events. The nonfatal CVD outcomes (n=10 total) included 6 cases of unstable angina/coronary artery disease, 5 of which resulted in coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty; 2 cases of lower-extremity arterial disease resulting in below-knee amputations, 1 thoracoabdominal aortic aneurysm; and 1 TIA caused by arteriosclerosis of the basilar artery. The fatal CVD outcomes (n=9 total) included 4 MIs, 4 sudden cardiac deaths, and 1 cerebral infarction. Covariate measures according to the presence or absence of hyperhomocysteinemia are displayed in Table 1. The hyperhomocysteinemic patients tended to have higher total cholesterol (P=.05) and lower folate (P=.0002), PLP (P=.02), and B-12 levels (P=.05), along with an increased percent cumulative incidence of both fatal CVD events (P=.002) and pooled nonfatal and fatal CVD events (P=.008). Results of the crude and adjusted proportional-hazards analyses are presented in Table 2. These data indicate that hyperhomocysteinemia was associated with relative risk estimates ranging from 3.0 to 4.4 (95% confidence intervals, 1.1 to 8.1 and 1.6 to 12.2 for pooled nonfatal and fatal CVD). Comparison of the crude and adjusted relative risk estimates revealed that the association between hyperhomocysteinemia and incident CVD outcomes was not appreciably confounded by preexisting CVD, the established CVD risk factors, albumin or creatinine levels, or dialysis adequacy/residual renal function. B-vitamin status (ie, comparing the lowest versus the upper three quartiles of folate, PLP, and B-12) was not a predictor of CVD occurrence during follow-up (data not shown) in either crude analyses or models that also included hyperhomocysteinemia. Data available from a subset (n=66) of patients for whom MTHFR C677T genotyping was performed revealed that homozygosity for this point mutation was not associated with an increased risk for the incidence of pooled nonfatal and fatal CVD (crude relative risk estimate, 0.9 [0.2 to 4.0]; relative risk estimate adjusted for tHcy 27.0 µmol/L, 0.9 [0.2 to 4.0]). In contrast to earlier unadjusted post hoc analyses^{16 26} suggesting that hyperhomocysteinemia was more predictive of CVD in men than in women, we found no evidence of effect modification by sex. The coefficient for the sexxhyperhomocysteinemia interaction term was nonsignificant, and a model including three independent variables (ie, hyperhomocysteinemia, sex, and the sexxhyperhomocysteinemia interaction term) did not significantly increase the log-likelihood estimate for CVD occurrence compared with a model containing only hyperhomocysteinemia and sex (data not shown). Finally, crude proportional-hazards analyses using other cutpoints for hyperhomocysteinemia yielded the following relative risk estimates for pooled nonfatal and fatal CVD occurrence: the median (22.3 µmol/L, 1.7 (0.6 to 4.6); the upper tertile (26.0 µmol/L, 2.2 (0.8 to 6.0); and the upper quintile (29.7 µmol/L, 3.6 (1.4 to 9.6). These data suggest that most of the increased risk for prospectively ascertained CVD was associated with fasting tHcy levels in the upper 20th- to 25th-percentile distribution.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of ESRD Patients Stratified by Levels of tHcy 27 µmol/L vs <27 µmol/L

View this table: [in this window] [in a new window]   Table 2. Relative Risk Estimates (Hazards Ratios) for Occurrence of CVD During Follow-up Associated With Plasma tHcy levels 27 µmol/L in Dialysis-Dependent ESRD Patients

	Discussion

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Wu²⁷ reported that the 2-year cumulative incidence of de novo CHD in ESRD patients undergoing chronic peritoneal (18.0%) and hemodialysis (15.0%) exceeded the 6-year cumulative incidence (12.7%) of de novo CHD among original Framingham Study participants who were also free of CHD at baseline, and by matched frequency to that of dialysis patients for the prevalence of established risk factors. In the present study, we evaluated the association between elevated fasting tHcy levels at a baseline examination and the subsequent development of CVD in a convenience sample of ESRD patients undergoing chronic dialysis therapy. Our findings provide the initial prospective evidence that the markedly elevated tHcy levels characteristically found in dialysis-dependent ESRD patients^{15 16 17 18} may contribute independently to the excess risk for CVD outcomes in this population. These prospective data strongly suggest that hyperhomocysteinemia warrants further study of its role as an important "nontraditional" risk factor for incident CVD in ESRD populations.

Earlier we demonstrated that 83% of dialysis-dependent ESRD patients had fasting tHcy levels >90th percentile value (ie, >13.9 µmol/L) for age-, sex-, and race-matched population-based control subjects free of renal disease.¹² ESRD hyperhomocysteinemia is due primarily to loss of renal Hcy uptake and metabolism, which normally accounts for 70% of daily Hcy removal from the plasma.^{28 29} Elimination of the substantial Hcy-metabolizing capacity of normal kidneys also likely accounts for the refractoriness of ESRD hyperhomocysteinemia to routine supplementation with near-physiological doses of folic acid, B-6, and B-12.¹² We have previously reported placebo-controlled data indicating that adding a combination of 15 mg/d folic acid, 100 mg/d B-6, and 1 mg/d B-12 (versus placebo) to the baseline regimen of 1 mg/d folic acid, 10 mg/d B-6, and 12 µg/d B-12 already prescribed for maintenance dialysis patients lowered nonfasting tHcy levels by a mean of 25% to 30% over 4 to 8 weeks of treatment.³⁰ Only one third of the patients randomized to the high-dose combination B vitamin therapy, however, reduced their nonfasting tHcy levels to within the normative range (ie, <15 µmol/L). In a separate preliminary investigation,³¹ we have further demonstrated that oral N-acetylcysteine administration (1200 mg/d) causes an apparent short-term reduction in nonfasting predialysis tHcy levels of 15% to 20% among hemodialysis patients. Long-term tHcy-lowering treatment with N-acetylcysteine, given in conjunction with folic acid, B-6, and B-12, requires further study, given the relative refractoriness of maintenance dialysis patients to even very high dose of folic acid–based B vitamin regimens alone.

Previous analyses have provided conflicting data regarding the association between tHcy levels and the prevalence of arteriosclerotic outcomes in ESRD patients.^{15 16 17 18} Intractable survivorship effects due to the excess yearly mortality in dialysis-dependent ESRD^{1 3 4 5 6} and the failure to establish whether or not arteriosclerotic outcomes antedated the development of ESRD render invalid any inference about tHcy-CVD associations suggested by published cross-sectional reports.^{15 16 17 18} As noted earlier, no prospective study has examined the association between tHcy levels and CVD occurrence in ESRD patients undergoing chronic maintenance dialysis. One prospective study relating baseline tHcy levels to CVD occurrence, a preliminary nested case-control analysis of 42 renal-transplant recipients, has been reported.²⁶ Although the main findings were negative, post hoc subgroup analyses of this investigation²⁶ indicated that elevated tHcy levels predicted CVD incidence in men but not in women. These findings are discordant with data from much larger studies conducted in general populations, where sex was not an effect modifier of the relationship between Hcy and CVD.³² Furthermore, missing baseline information regarding the presence or absence of preexisting CVD made it impossible to discern whether the reported association between tHcy levels and the development of CVD, even within the subgroup of renal-transplant–recipient men, was free of important confounding.²⁶ In contrast, we demonstrated in our dialysis-dependent study population that hyperhomocysteinemia conferred a significant independent risk for incident CVD (ie, 3- to 4.5-fold for pooled nonfatal and fatal events) after adjustment for preexisting CVD, the established arteriosclerotic risk factors, albumin and creatinine levels, and dialysis adequacy/residual renal function. Additional analyses suggested that hyperhomocysteinemia conferred a similar risk for CVD occurrence in women and men. Given the limited overall size of the maintenance dialysis population we studied and the modest number of CVD outcomes that accrued, the external validity of our findings needs to be established in prospective investigations of larger ESRD cohorts. If subsequent, more extensive longitudinal studies of ESRD cohorts confirm our present findings, clinical trials examining the effect of tHcy-lowering interventions (eg, high-dose folic acid–based B vitamin treatment³⁰ with the possible addition of oral N-acetylcysteine³¹ ) on CVD event rates in this patient population should be considered.

We conclude that the markedly elevated fasting tHcy levels found in dialysis-dependent ESRD patients may contribute independently to their excess incidence of arteriosclerotic CVD outcomes. Confirmation of these findings in more sizable ESRD cohorts is urgently required.

	Selected Abbreviations and Acronyms

 

CCr = creatinine clearance CVD = cardiovascular disease ECG = electrocardiogram ESRD = end-stage renal disease MI = myocardial infarction MTHFR = methylenetetrahydrofolate reductase PLP = pyridoxal 5'-phosphate (t)Hcy = (total) homocysteine TIA = transient ischemic attack URR = urea reduction ratios

	Acknowledgments

 
Support for this investigation was provided by a Rhode Island Hospital Developmental Grant Award (to Drs Shemin and Bostom).

	Footnotes

 
Reprint requests to Andrew G. Bostom, MD, Division of General Internal Medicine, Memorial Hospital of Rhode Island, 111 Brewster St, Pawtucket, RI 02860.

Presented in part at the American Heart Association 69th Scientific Sessions, New Orleans, La, November 12, 1996, and published in Abstract form in Circulation. 1996; 94(suppl I): I-457.

Received March 13, 1997; accepted April 30, 1997.

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