Bilirubin: A Potential Biomarker and Therapeutic Target for Diabetic Nephropathy

  1. Anupam Agarwal1,3
  1. 1Division of Nephrology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL
  2. 2Division of Cardiothoracic Surgery, Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL
  3. 3Birmingham Veterans Administration Medical Center, Birmingham, AL
  1. Corresponding author: Anupam Agarwal, agarwal{at}

Diabetic nephropathy (DN), which is a major end-organ complication in diabetes, continues to be the most common cause of end-stage renal disease and accounts for >40% of patients on renal replacement therapy (1). Currently available factors that are routinely used in clinical practice to predict and monitor the progression of DN include degree of proteinuria and both glycemic and blood pressure control. In this issue of Diabetes, Riphagen et al. (2) performed a post hoc analysis of two large clinical trials—Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan (RENAAL) and Irbesartan Diabetic Nephropathy Trial (IDNT)—and demonstrated that serum bilirubin levels are inversely correlated with progression of DN. These findings are clinically important because they identify a potential biomarker and/or therapeutic target for DN, a disease that causes significant morbidity and mortality.

Bilirubin is generated when heme oxygenase (HO) catalyzes the degradation of heme (derived from heme proteins). This results in formation of biliverdin, which is rapidly converted into bilirubin by biliverdin reductase (Fig. 1) (3). Further processing of bilirubin occurs in hepatocytes, where unconjugated (lipid-soluble) bilirubin is conjugated by uridine diphosphate–glucuronosyl transferase (UDP-GT) to a water-soluble form for excretion. Total bilirubin is the sum of conjugated (direct) and unconjugated (indirect) bilirubin and generally ranges from 0.3 to 1.2 mg/dL in healthy individuals. In conditions such as erythroblastosis fetalis, hemolysis results in markedly elevated bilirubin, which causes kernicterus and neurological damage in neonates. Furthermore, genetic deficiency of UDP-GT in Crigler-Najjar syndrome type I results in severely elevated total bilirubin and is incompatible with life. Given the outcomes of these conditions, it is not surprising that bilirubin was long considered to be merely a toxic byproduct of heme degradation. However, unconjugated bilirubin levels are positively correlated with plasma antioxidant capacity (4), and moderate elevations in serum total bilirubin …

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