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(Circulation. 1996;94:2743-2748.)
© 1996 American Heart Association, Inc.

Articles

Hyperhomocysteinemia Confers an Independent Increased Risk of Atherosclerosis in End-Stage Renal Disease and Is Closely Linked to Plasma Folate and Pyridoxine Concentrations

Killian Robinson, MD; Anjan Gupta, MD; Vincent Dennis, MD; Kristopher Arheart, DEd; Debashish Chaudhary, MD; Ralph Green, MD; Paul Vigo, MD; Ellen L. Mayer, MD; Jacob Selhub, PhD; Michael Kutner, PhD; Donald W. Jacobsen, PhD

the Departments of Cardiology (K.R., E.L.M.), Internal Medicine (A.G., P.V., D.C.), Nephrology and Hypertension (V.D.), Biostatistics and Epidemiology (K.A., M.K.), Clinical Pathology (R.G.), and Cell Biology (D.W.J.), the Cleveland (Ohio) Clinic Foundation, and the United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Mass (J.S.).

Correspondence to Killian Robinson, MD, Desk F15, Department of Cardiology, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail robinsk@ccsmtp.ccf.org.

	Abstract

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Background A high level of total plasma homocysteine is a risk factor for atherosclerosis, which is an important cause of death in renal failure. We evaluated the role of this as a risk factor for vascular complications of end-stage renal disease.

Methods and Results Total fasting plasma homocysteine and other risk factors were documented in 176 dialysis patients (97 men, 79 women; mean age, 56.3±14.8 years). Folate, vitamin B₁₂, and pyridoxal phosphate concentrations were also determined. The prevalence of high total homocysteine values was determined by comparison with a normal reference population, and the risk of associated vascular complications was estimated by multiple logistic regression. Total homocysteine concentration was higher in patients than in the normal population (26.6±1.5 versus 10.1±1.7 µmol/L; P<.01). Abnormally high concentrations (>95th percentile for control subjects, 16.3 µmol/L) were seen in 149 patients (85%) with end-stage renal disease (P<.001). Patients with a homocysteine concentration in the upper two quintiles (>27.8 µmol/L) had an independent odds ratio of 2.9 (CI, 1.4 to 5.8; P=.007) of vascular complications. B vitamin levels were lower in patients with vascular complications than in those without. Vitamin B₆ deficiency was more frequent in patients than in the normal reference population (18% versus 2%; P<.01).

Conclusions A high total plasma homocysteine concentration is an independent risk factor for atherosclerotic complications of end-stage renal disease. Such patients may benefit from higher doses of B vitamins than those currently recommended.

Key Words: risk factors • coronary disease • kidney

	Introduction

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Vascular disease is a major complication of end-stage renal disease. Cardiac arrest, myocardial infarction, and other cardiac events combined are the most commonly reported causes of death in these patients.¹ Known risk factors include hypertension, hyperlipidemia, smoking, and diabetes.^{2 3 4} Concentrations of homocysteine, a sulfur-containing amino acid, rise in chronic renal failure.^{5 6 7 8 9 10 11 12 13 14 15 16 17} Increased plasma levels of this amino acid are associated with atherosclerosis,^{18 19 20 21 22 23 24 25 26 27 28} including coronary artery disease.^{18 21 22 25 26 27} This cross-sectional study documents the increased risk of prevalent atherosclerotic complications associated with high total homocysteine concentrations in patients with end-stage renal disease. In addition, a strong linear relationship between the concentrations of total homocysteine and the B vitamins, which are essential for its metabolism, is demonstrated.

	Methods

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Subjects
Patients with renal disease
One hundred seventy-six patients (97 men and 79 women; mean age, 56.3±14.8 years) with established end-stage renal disease were studied. All patients were either on hemodialysis or peritoneal dialysis. Table 1 summarizes their demographic and laboratory features. To examine the relationship between homocysteine and atherosclerosis, consecutive patients with end-stage renal disease were divided into two groups based on the presence of a clinically documented vascular event as described below.

View this table: [in this window] [in a new window]   Table 1. Demographic Characteristics of Patients With ESRD and the Normal Reference Population

Normal reference population
To define the prevalence of high total homocysteine concentrations in patients with end-stage renal disease, consecutive subjects attending an executive health screening program at the Cleveland Clinic Foundation served as normal control subjects. Individuals with clinical or ECG evidence of vascular disease or renal failure were excluded.

Diagnosis of End-Stage Renal Disease
End-stage renal disease was defined as a requirement for maintenance dialysis. All were on a schedule of chronic ambulatory peritoneal dialysis (CAPD) or were receiving thrice-weekly 4-hour sessions of hemodialysis using high-flux membranes. All were counseled to a protein intake of 1 g·kg body wt^-1·d^-1. By chart review, there was 71.5% compliance with multivitamin supplementation administered as Nephrocaps.

Diagnostic Criteria for Vascular Events
When clinically appropriate, the following diagnostic tests were applied.

Thromboembolic Episodes
Venous thrombosis was diagnosed by duplex ultrasound and/or contrast venography. Pulmonary embolism was diagnosed by high-probability ventilation perfusion scanning and/or pulmonary angiography. Peripheral arterial thrombosis was diagnosed by contrast arteriography. Device-related thrombosis was diagnosed by contrast angiography and/or duplex ultrasound. Unexplained ischemic stroke was diagnosed by clinical presentation, computerized tomography, and MRI. All those with stroke had normal carotid ultrasound examinations.

Atherosclerotic Disease
Coronary artery disease
Coronary artery disease was diagnosed in the presence of (1) a documented myocardial infarction, (2) a stenosis of 70% of at least one major epicardial coronary vessel documented at the time of coronary angiography carried out in standard manner, or (3) an abnormal cardiac functional test.

Peripheral vascular disease
Peripheral vascular disease was diagnosed by diminished pulses on clinical examination combined with measurements of peripheral vascular resistance and/or peripheral angiography.

Cerebrovascular disease
Cerebrovascular disease was suspected on clinical grounds, and the diagnosis was confirmed by computerized tomography, MRI, and duplex carotid ultrasonography.

Risk factors for vascular disease
Total fasting cholesterol concentrations in blood drawn at the same time as the sample for measurement of homocysteine were measured in all subjects. A high cholesterol concentration was defined as the presence of a total serum concentration >200 mg/dL. Subjects were classified either as nonsmokers (if they had never smoked) or ever-smokers (if they were current smokers or if they had quit). Hypertension was defined as a blood pressure >140/90 mm Hg or, in the presence of a history of hypertension, if the patient was also taking antihypertensive medications. Fasting glucose concentrations were measured in all subjects.

Diabetes mellitus was diagnosed if patients were using insulin or oral hypoglycemic agents or if the fasting glucose concentration was >140 mg/dL.

Determination of Total Plasma Homocysteine
Total fasting plasma homocysteine was measured on samples drawn at the time of the study by the technique of Jacobsen et al.²⁹ All forms of plasma homocysteine are determined in this assay, including reduced (homocysteine) and oxidized (homocystine, homocysteine-cysteine mixed disulfide, and protein-bound homocysteine mixed disulfide) forms. These forms are collectively referred to as total homocysteine.

Measurement of Vitamin Concentrations
Vitamin levels were measured in blood samples drawn at the time of the study. A commercial radioligand binding assay (Becton Dickinson, Simultrac) was used for the measurement of the concentrations of folic acid and vitamin B₁₂. The technique of Camp et al³⁰ was used to determine the concentrations of pyridoxal 5'-phosphate. Deficiency of folic acid was defined as a folate concentration of <6.4 nmol/L. Deficiency of vitamin B₁₂ was defined as a concentration of <125 pmol/L. Deficiency of pyridoxal 5'-phosphate was defined as a level of <20 nmol/L.

Statistical Analysis
Descriptive statistics are reported as frequency and percent for categorical data and as mean and SD for continuous data. The data for total homocysteine, creatinine, total cholesterol, folate, vitamin B₆, and vitamin B₁₂ were transformed to natural logarithms for analysis. The logarithmic transformation reduced the pronounced positive skew and decreased the variation, making the data more nearly normally distributed. The antilogs of the mean and SD of the logarithmically transformed data are reported for these variables. The reported mean and SD for total homocysteine are adjusted for age and sex. Percentages were compared by Pearson's ² test or Fisher's exact test, depending on the frequencies. Continuous variables were compared by Student's t test, ANOVA, or ANCOVA. Planned multiple comparisons among study group means were used to compare groups. Pearson correlations were used to assess linear associations. Odds ratios and 95% CIs were computed on the basis of the parameter estimates and SEEs from a multiple logistic regression model. Age, sex, smoking, hypercholesterolemia, diabetes, hypertension, and time since first dialysis were used as covariates in all logistic regression models. Values above the 95th percentile value for total homocysteine concentration in normal individuals were arbitrarily selected as abnormal to allow the calculation of prevalence of elevated concentrations in patients with end-stage renal disease. Since total homocysteine concentrations were frequently elevated above this level in patients with end-stage renal disease, odds ratios were also calculated on the basis of comparisons across the range of plasma values. Values of P<.05 were used to define statistical significance.

	Results

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Distribution of Total Plasma Homocysteine Concentrations, Prevalence of Hyperhomocysteinemia, and Effects of Age and Sex
On average, total homocysteine concentrations adjusted for age and sex were higher in end-stage renal disease patients than in the normal population (26.6±1.5 versus 10.1±1.7 µmol/L, P<.01). Elevated concentrations (>95th percentile for normal control subjects, 16.3 µmol/L) were seen in 149 patients with end-stage renal disease (85%, P<.001). Levels were higher in men than in women both in normal subjects (10.8±1.5 versus 9.4±1.5 µmol/L, P=.04) and in patients with end-stage renal disease (33.8±1.5 versus 26.5±1.6 µmol/L, P<.05) and correlated weakly with age (r=.14, P<.01). End-stage renal disease patients with atherosclerotic and thromboembolic vascular events had higher concentrations than did end-stage renal disease control subjects without vascular events (29.9±1.3 versus 23.9±1.5 µmol/L, P<.001; see Table 2).

View this table: [in this window] [in a new window]   Table 2. Comparisons of Homocysteine Concentrations (µmol/L) in Patients With ESRD With and Without Vascular Events and a Normal Reference Population

Relationship of Odds Ratios of Vascular End Points to Total Plasma Homocysteine Concentration
All Vascular Disease
Among patients with end-stage renal disease, a total homocysteine concentration in the upper two quintiles (>27.8 µmol/L) compared with the lower three quintiles resulted in an odds ratio of 2.9 (CI, 1.4 to 5.8; P<.01) for any thromboembolic or atherosclerotic vascular event, adjusted for age, sex, hypertension, diabetes mellitus, hypercholesterolemia, smoking, and time from first dialysis (Table 3). Similar observations were made when patients with homocysteine concentrations in the upper tertile were compared with those in the lower two tertiles (OR, 2.8; CI, 1.3 to 5.9; P=.01). Increases in total homocysteine concentrations on a logarithmic scale resulted in an odds ratio of 2.3 (CI, 1.1 to 4.5; P=.02; see Fig 1 and Table 3) for vascular complications.

View this table: [in this window] [in a new window]   Table 3. Odds Ratios and 95% CIs for the Association Between Vascular Events and Homocysteine Concentrations Adjusted for Age, Sex, Hypertension, Diabetes, Hypercholesterolemia, Smoking, and Time From First Dialysis

View larger version (28K): [in this window] [in a new window]   Figure 1. Odds ratios for increases in homocysteine concentrations for any thromboembolic or atherosclerotic vascular complication, adjusted for age, sex, hypertension, diabetes mellitus, hypercholesterolemia, smoking, and time from first dialysis compared with normal subjects and end-stage renal disease (ESRD) patients without vascular complications.

Atherosclerotic Disease
To exclude the possible confounding effects of arteriovenous fistula thrombosis in hemodialysis patients and the lower total homocysteine concentrations seen in patients on CAPD, hemodialysis patients with atherosclerosis (n=36) were analyzed separately. An odds ratio of 2.9 (CI, 1.1 to 7.9; P=.04) for atherosclerotic disease was seen for the upper tertile (total homocysteine, >30.2 µmol/L) compared with the lower two tertiles, adjusted for all other risk factors. An odds ratio of 2.6 (CI, 1.0 to 7.3; P=.06) for atherosclerotic disease was seen for the upper two quintiles compared with the lower three (total homocysteine, >27.8 µmol/L). In contrast, the risk of thromboembolic events in hemodialysis patients was 0.98 (CI, 0.5 to 2.2; P=.96) for the upper tertile compared with the bottom two tertiles.

Effect of Dialysis Type on Atherosclerotic Risk Factors, Total Homocysteine Levels, and Vascular Events
Risk factors for atherosclerosis for both hemodialysis and peritoneal dialysis are shown in Table 4. There was no significant difference between the hemodialysis and CAPD groups in the distribution of sex, smoking, or diabetes mellitus. Hypercholesterolemia occurred more frequently in the CAPD group than in the hemodialysis group (65% versus 24%, P<.01). Time since first dialysis was longer for the hemodialysis group than for the CAPD group (58±5 versus 32±4 months, P<.01). Adjusted for age and sex, total homocysteine levels were significantly higher in the patients undergoing hemodialysis (29.5±1.7 versus 19.5±1.7 µmol/L, P<.01).

View this table: [in this window] [in a new window]   Table 4. Comparisons Between Hemodialysis and Chronic Ambulatory Peritoneal Dialysis Patients in Cardiovascular Risk Factor Profile and Vitamin Status

Vascular complications, including all forms of atherosclerosis, as well as thromboembolic episodes occurred in a higher proportion of the hemodialysis group than of the CAPD group (62% versus 9%, P<.01).

Vitamins
Mean Vitamin Concentrations
Mean vitamin B₁₂ and folate concentrations were higher in patients with end-stage renal disease than in the normal reference population (441.5±1.6 versus 256.6±1.5 pmol/L and 56.5±2.9 versus 15.6±1.7 nmol/L, respectively, P<.01). Mean pyridoxal phosphate levels were not significantly different in the two groups (56.0±2.9 versus 64.9±2.0 nmol/L, P=.22). Folate levels were lower in patients with end-stage renal disease with vascular complications than in those without (48.4±2.5 versus 65.2±2.9 nmol/L), although this was of borderline significance (P=.06). Mean vitamin B₁₂ levels were lower in patients with vascular events than in those without (382.0±1.6 versus 504.7±1.6 pmol/L, P<.01; see Table 5). Similar findings were seen in relation to pyridoxal concentrations (43.8±3 versus 73.9±2.6 nmol/L, P<.01).

View this table: [in this window] [in a new window]   Table 5. Comparisons of Vitamin Concentrations Between ESRD Patients With and Without Vascular Events and Normal Control Subjects

Prevalence of Vitamin Deficiencies
In all patients with end-stage renal disease, deficiency of folate was <2% and was not different from the normal reference population (see Table 6). Vitamin B₁₂ deficiency was seen in 1% of end-stage renal disease patients, compared with 5% of the normal reference population (P=.03). In contrast, pyridoxal phosphate deficiency was seen in 18% of end-stage renal disease patients, compared with 2% of normal subjects (P<.01). Deficiency was seen in 18% of patients taking supplements, compared with 17% in those not taking supplements. Excluding those on vitamin supplements, pyridoxal deficiency was seen in 4 end-stage renal disease patients (21%) who had also suffered a vascular event, 2 end-stage renal disease patients (12%) without vascular events, but only 4 normal subjects (3%, P<.01).

View this table: [in this window] [in a new window]   Table 6. Comparisons of Frequency of Vitamin Deficiencies in Patients With ESRD Both With and Without Vitamin Supplementation and Normal Subjects

Relationship Between Plasma Concentrations of Vitamins and Total Homocysteine
There were negative correlations between total homocysteine and folate in end-stage renal disease patients with vascular events, those without vascular events, and normal subjects (r=-.48, -.48, and -.43, respectively; P<.05; see Figs 2, 3, and 4). Similar correlations were also seen between total homocysteine and vitamin B₁₂ (r=-.25, -.47, and -.37, respectively; P<.05) as well as pyridoxal 5'-phosphate (r=-.41, -.33, and -.29, respectively; P<.05).

View larger version (25K): [in this window] [in a new window]   Figure 2. Concentrations of folate and homocysteine (hcy) in patients with end-stage renal disease (ESRD) and normal subjects.

View larger version (24K): [in this window] [in a new window]   Figure 3. Concentrations of vitamin B12 and homocysteine (hcy) in patients with end-stage renal disease (ESRD) and normal subjects.

View larger version (22K): [in this window] [in a new window]   Figure 4. Concentrations of pyridoxal phosphate (B6) and homocysteine (hcy) in patients with end-stage renal disease (ESRD) and normal subjects.

	Discussion

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These data demonstrate that high total plasma homocysteine concentrations are associated with an increased risk of atherosclerosis independent of traditional risk factors in patients with end-stage renal disease. Although high homocysteine concentrations occur frequently in patients with renal failure,^{5 6 7 8 9 10 11 12 13 14 15 16 17} the relationship with vascular disease has remained unclear. In this study, high total homocysteine concentrations (>95th percentile of normal subjects) were seen in >80% of patients. To avoid difficulties based on the use of arbitrary definitions of high levels, data were analyzed across the range of plasma homocysteine concentrations. Because concentrations were not normally distributed, the data were log-transformed where appropriate. Using these approaches, we observed increasing odds ratios of vascular events with increasing homocysteine concentrations. To exclude the possible confounding effects of arteriovenous fistula thrombosis, which occurs frequently in patients on hemodialysis, the risk of atherosclerosis alone, excluding these subjects, was assessed. In this analysis, the increased risk of atherosclerosis associated with higher homocysteine concentrations prevailed.

Recently, attention has focused on homocysteine as a risk factor for atherosclerosis,^{18 19 20 21 22 23 24 25 26 27 28} and a number of studies have shown possible adverse effects of homocysteine on endothelium, platelets, and coagulation factors.^{31 32} Effects on lipids have also been noted,^{33 34} consistent with clinical observations.³⁵ In addition, lipoprotein (a) values rise in renal failure,³⁶ and interactions between this and homocysteine have been reported.³⁷ Other sulfur-containing amino acids are also elevated in patients with chronic renal failure,^{5 6 8 16 17 38} and we have made similar observations (unpublished data). The prevalence of high concentrations of these other compounds and their role, if any, in predisposing to atherosclerosis require further study.

Higher total homocysteine concentrations were noted in patients undergoing hemodialysis compared with those undergoing peritoneal dialysis. The reason for this is unclear, but it may be related to the higher folate and vitamin B₁₂ levels seen in peritoneal dialysis patients. The groups were similar in the distribution of other major risk factors, including sex, smoking, diabetes mellitus, and hypertension, although hypercholesterolemia occurred more frequently in the CAPD group than in the hemodialysis group. The prevalence of atherosclerosis was lower in patients with CAPD than in patients on hemodialysis. Although this could be related to the lower homocysteine concentrations seen in these patients, numbers were small, and they had been followed for a shorter period of time.

The mechanism for the high plasma concentration seen in patients with renal failure is not completely understood. Recently, Bostom et al³⁹ demonstrated substantial homocysteine uptake and metabolism by the rat kidney in vivo, with only trivial urinary excretion. Extrapolating these findings to humans suggests that two thirds of plasma homocysteine elimination may be related to renal metabolism. Data consistent with these findings have recently been reported by Guttormsen et al.⁴⁰ Pharmacokinetic modeling of homocysteine loading data revealed that plasma elimination was reduced by 70% in patients with end-stage renal disease compared with both well-nourished and B₁₂/folate-deficient control subjects who were free of renal disease. Folic acid, vitamin B₁₂, and vitamin B₆ are also essential for the metabolism of homocysteine, and deficiencies are associated with high concentrations.³² In this study, plasma levels of these vitamins were actually higher in patients than in normal subjects, reflecting the widespread use of supplements. Negative correlations were seen between concentrations of folate, vitamin B₁₂, vitamin B₆, and total homocysteine. Lower levels of all three vitamins were seen in patients with vascular complications than in those without. In patients with end-stage renal disease with the highest folate concentrations, total homocysteine levels were similar to those in the upper limits of the normal range (see Fig 2). Mean concentrations of pyridoxal phosphate were similar in patients and normal subjects, but the overall prevalence of frank deficiency was higher in patients with renal failure, consistent with the findings of others, and may possibly be due to disturbed pyridoxine metabolism.⁴¹ Moreover, the prevalence of pyridoxal deficiency was similar in patients with and without supplementation (18%, data not shown). Not only may current dosage recommendations for vitamin B₆ supplementation be inadequate, but such patients also may be at higher risk of developing future coronary artery disease.²⁷ Several uncontrolled, open-label studies have shown the feasibility of lowering of homocysteine in patients with renal failure.^{7 10 42 43 44} In a placebo-controlled study, Bostom et al recently demonstrated that much larger daily doses of folic acid (15 mg/d) significantly augmented the homocysteine-lowering effect of near physiological doses of folate, B₁₂, and B₆.⁴⁵ Mean homocysteine was lowered by an additional 30% in patients receiving folic acid and was reduced to the normative range in one third. These findings and those of the present study suggest that supplementation with doses of folic acid even greater than 15 mg/d may possibly reverse this risk factor. If prospective studies confirm the association between homocysteine and vascular disease, the effects of treatment with folic acid, either alone or combined with the other B vitamins, and methionine restriction will require further study.

	Acknowledgments

 
This study was funded by The Baxter Extramural Grant Program and also, in part, by grant HL-52234 (to Dr Jacobsen) from the Heart, Lung, and Blood Institute of the National Institutes of Health. We wish to acknowledge the secretarial assistance of Marie Scott and the assistance of Dr Richard Lang of the Section of Preventive Medicine, the Cleveland Clinic Foundation, for permission to study patients under his care. The authors also acknowledge the expert technical assistance provided by Diane Pexa, Susan R. Savon, and Ruth V. Earley.

Received February 5, 1996; revision received September 6, 1996; accepted September 9, 1996.

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