Bilirubin and Progression of Nephropathy in Type 2 Diabetes: A Post Hoc Analysis of RENAAL With Independent Replication in IDNT

  1. Hiddo J. Lambers Heerspink4
  1. 1Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
  2. 2Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia
  3. 3Division of Nephrology, Vanderbilt University, Nashville, TN
  4. 4Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
  1. Corresponding author: Dick de Zeeuw,{at}


Bilirubin, a potent endogenous antioxidant, was found to protect against the development of diabetic nephropathy (DN) in rodents. In humans, cross-sectional studies found an inverse relation between bilirubin and DN. We prospectively investigated whether bilirubin is associated with progression of DN toward end-stage renal disease (ESRD). To this end, we performed a post hoc analysis in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial with independent replication in the Irbesartan Diabetic Nephropathy Trial (IDNT). Subjects with type 2 diabetes and nephropathy with alanine aminotransferase, aspartate aminotransferase (AST), and bilirubin levels <1.5 times the upper limit of normal were included. The renal end point was defined as the composite of confirmed doubling of serum creatinine or ESRD. Bilirubin was inversely associated with the renal end point in RENAAL independent of age, sex, race, BMI, smoking, total cholesterol, diastolic blood pressure, HbA1c, treatment, estimated glomerular filtration rate, albumin-to-creatinine ratio, and AST. These results were confirmed in IDNT. This study indicates an independent inverse association of bilirubin with progression of nephropathy in RENAAL and IDNT. These data suggest a protective effect of bilirubin against progression of nephropathy in type 2 diabetes. The well-established role of bilirubin as an antioxidant is a potential explanation for the findings.


  • Received October 24, 2013.
  • Accepted March 24, 2014.
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