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(Circulation. 2006;113:1572-1577.)
© 2006 American Heart Association, Inc.

Epidemiology

Relationship Between Homocysteine and Mortality in Chronic Kidney Disease

Vandana Menon, MD; Mark J. Sarnak, MD; Tom Greene, PhD; Xuelei Wang, MS; Arema A. Pereira, MD; Gerald J. Beck, PhD; John W. Kusek, PhD; Jacob Selhub, PhD; Allan J. Collins, MD; Andrew S. Levey, MD; Michael G. Shlipak, MD

From the Department of Medicine, Division of Nephrology, Tufts–New England Medical Center, Boston, Mass (V.M., M.J.S., A.A.P., A.S.L.); the Department of Biostatistics and Epidemiology, Cleveland Clinic Foundation, Cleveland, Ohio (T.G., X.W., G.J.B.); the National Institutes of Health, Bethesda, Md (J.W.K.); Jean Mayer USDA Human Nutrition Research Center on Aging, Boston, Mass (J.S.); the Division of Nephrology, Hennepin County Medical Center, Minneapolis, Minn (A.J.C.); and General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco, Calif (M.G.S.).

Correspondence to Dr Mark J. Sarnak, 750 Washington Street, #391, Boston, MA 02111. E-mail msarnak{at}tufts-nemc.org

Received June 20, 2005; revision received January 23, 2006; accepted January 27, 2006.

Background— The relationship between total homocysteine (tHcy) and outcomes has not been investigated in patients with chronic kidney disease stages 3 to 4.

Methods and Results— The Modification of Diet in Renal Disease Study was a randomized, controlled trial of 840 patients. Serum tHcy was measured in frozen samples collected at baseline (n=804). Survival status and cause of death were obtained from the National Death Index. To evaluate its association with all-cause and cardiovascular disease (CVD) mortality, tHcy was evaluated both as tertiles (<14.7, 14.7 to 19.5, 19.6 µmol/L) and as a continuous variable (per 10/µmol/L). Participants had a mean age of 52±12 years and glomerular filtration rate (GFR) of 33±12 mL/min per 1.73 m²; 60% were male, and 85% were white. During a median follow-up of 10 years, 195 (24%) died from any cause, and 118 (15%) from CVD. The level of GFR was lower and proteinuria higher in the highest tHcy tertile. There was no association between the highest tertile of tHcy and all-cause (hazard ratio [HR]; 95% confidence interval [CI[, 1.32, 0.94 to 1.85) or CVD (HR; 95% CI, 1.50, 0.96 to 2.34) mortality in univariate analyses; this association was further attenuated by adjustment for GFR (HR; 95% CI all-cause, 1.04, 0.72 to 1.51; CVD, 1.20, 0.73 to 1.95). There was no association between tHcy as a continuous variable and all-cause (0.98, 0.83 to 1.16) or CVD (1.04, 0.85 to 1.27) mortality.

Conclusions— Hyperhomocystinemia does not appear to be a risk factor for all-cause or CVD mortality in the Modification of Diet in Renal Disease Study. Prior studies demonstrating an association between tHcy and CVD risk may have inadequately adjusted for the confounding effects of kidney function.

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