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A Low, Rather than a High, Total Plasma Homocysteine Is an Indicator of Poor Outcome in Hemodialysis Patients

Kamyar Kalantar-Zadeh^*,, Gladys Block, Michael H. Humphreys, Charles J. McAllister and Joel D. Kopple^*,||

*Division of Nephrology and Hypertension, Harbor-UCLA Medical Center, Torrance, California, and David Geffen School of Medicine at UCLA, Los Angeles, California; Division of Public Health Nutrition and Epidemiology, School of Public Health, University of California, Berkeley, California; University of California, San Francisco, San Francisco, California, and Division of Nephrology, San Francisco General Hospital, San Francisco, California; DaVita, Inc., Torrance, California; and ^||UCLA School of Public Health, Los Angeles, California

Correspondence to Dr. Kamyar Kalantar-Zadeh, Departments of Medicine and Pediatrics, Division of Nephrology and Hypertension, Harbor-UCLA Medical Center, Harbor Mailbox 406, 1000 West Carson Street, Torrance, CA 90509-2910. Phone: 310-222-3891; Fax: 310-782-1837; E-mail: kamkal{at}ucla.edu

ABSTRACT. An increased level of total plasma homocysteine (tHcy) is a risk factor for poor cardiovascular outcome in the general population. However, a decreased, rather than an increased, tHcy concentration may predict poor outcome in maintenance hemodialysis (MHD) patients, a phenomenon referred to as reverse epidemiology. Associations were examined between tHcy level and markers of malnutrition-inflammation complex syndrome and 12-mo prospective hospitalization and mortality in 367 MHD patients, aged 54.5 ± 14.7 (mean ± SD) years, who included 199 men and 55% individuals with diabetes. tHcy was 24.4 ± 11.8 µmol/L, and 94% of the patients had hyperhomocysteinemia (tHcy >13.5 µmol/L). tHcy had weak to moderate but statistically significant bivariate and multivariate correlations with some laboratory markers of nutrition (serum albumin, prealbumin, creatinine, and urea nitrogen) but no significant correlation with serum C-reactive protein or two proinflammatory cytokines (IL-6 and TNF-). During 12 mo of follow-up, 191 MHD patients were hospitalized, 37 died, nine underwent renal transplantation, and 38 transferred out. Hospitalization rates were significantly higher in patients with lower tHcy levels. Mortality rate in the lowest tHcy quartile (17.4%) was significantly higher compared with other three quartiles (6.5 to 9.8%; Kaplan-Meier P = 0.04). Relative risk of death for the lowest tHcy quartile, even after adjustment for case-mix and serum albumin, was 2.27 (95% confidence interval, 1.14 to 4.53; P = 0.02). Hence, tHcy may be a more exclusive nutritional marker in MHD patients with no association with inflammatory measures. Despite a very high prevalence of hyperhomocysteinemia in MHD patients, lower values of tHcy are paradoxically associated with increased hospitalization and mortality. The lowest tHcy quartile confers a twofold increase in risk of death independent of hypoalbuminemia. The nutritional feature of tHcy in MHD patients may explain its reverse association with outcome.

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