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

  1. Hiddo J. Lambers Heerspink, PharmD, PhD4
  1. 1 Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands;
  2. 2 Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia;
  3. 3 Division Nephrology, VanderBilt University, Nashville, TN, USA;
  4. 4 Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
  1. Corresponding address: Prof. Dr. D. de Zeeuw, E-mail:{at}


Bilirubin, a potent endogenous antioxidant, was found to protect against 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 towards 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 ALT, AST, and bilirubin levels <1.5 times the ULN were included. The renal endpoint was defined as the composite of confirmed doubling of serum creatinine (DSCR) or ESRD. Bilirubin was inversely associated with the renal endpoint in RENAAL independent of age, gender, race, BMI, smoking, total cholesterol, diastolic blood pressure, HbA1c, treatment, eGFR, ACR, and AST. These results were confirmed in IDNT. In conclusion, we found 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 our findings.

  • Received October 24, 2013.
  • Accepted March 23, 2014.

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