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Total Plasma Homocysteine and Arteriosclerotic Outcomes in Type 2 Diabetes with Nephropathy

Allon N. Friedman^*, Lawrence G. Hunsicker, Jacob Selhub, Andrew G. Bostom^, for the Collaborative Study Group

^* Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana; Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa; Vitamin Metabolism and Aging, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts; and Division of Renal Diseases, Rhode Island Hospital, Providence, Rhode Island

Address correspondence to: Dr. Allon N. Friedman, Division of Nephrology, Indiana University School of Medicine, 1481 W. 10th Street-111N, Indianapolis, IN 46202. Phone: 317-554-0000, ext. 5453; Fax: 317-554-0298; E-mail: allfried{at}iupui.edu

Received for publication October 13, 2004. Accepted for publication July 25, 2005.

Total serum homocysteine (tHcy) has been shown to predict de novo and recurrent cardiovascular events in many studies. However, results in diabetic populations with minimal nephropathy are mixed. The independent relationship between tHcy and arteriosclerotic outcomes and congestive heart failure (CHF) events in a population with high cardiovascular risk and diabetic nephropathy was examined. A total of 1575 individuals were enrolled in the international Irbesartan Diabetic Nephropathy Trial (IDNT) and followed for 2.6 yr. All participants had baseline diabetic nephropathy, overt proteinuria, and hypertension and were recruited between 1996 and 1999. A total of 492 total arteriosclerotic outcomes (primary outcome) and 317 CHF events (secondary outcome) were tallied. Established cardiovascular risk factors were highly prevalent, as were high tHcy levels (quintiles [µM]: first 4.5 to 11; second >11 to 13; third >13 to 15; fourth >15 to 19; fifth >19). No association between tHcy and arteriosclerotic outcomes was observed in a univariate model or after adjustment for study randomization and established cardiovascular risk factors. The strongest outcome predictor was the presence of baseline cardiovascular disease, followed by an inverse relationship to diastolic BP. The significant univariate association between tHcy and CHF events disappeared when serum creatinine alone was added to the model. These findings question the utility of tHcy in predicting de novo or recurrent cardiovascular events in individuals with diabetic nephropathy. Further studies are needed to confirm whether these negative results apply to other populations with heavy cardiovascular risk burdens. Previous positive findings can potentially be explained through tHcy’s role as a sensitive surrogate marker for kidney disease, itself a recognized cardiovascular risk factor.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673