Bilirubin: A Potential Biomarker and Therapeutic Target for Diabetic Nephropathy

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 have been associated with reduced susceptibility to several common diseases (Table 1). Although a protective role for bilirubin in kidney disease has been established in animal studies (5,6), human data are lacking in this area. Riphagen et al. (2) investigated the association between serum bilirubin levels and progression of DN in a post hoc analysis of 1,498 patients in the RENAAL trial (7). Data from this study were then independently verified using the IDNT (8). In both trials, the renal end point was examined over a $2.5-year follow-up period and defined as a doubling of serum creatinine or end-stage renal disease requiring dialysis or transplantation. The authors’ findings demonstrate, for the first time, a significant and graded inverse association between baseline total bilirubin levels and progression of DN in patients between 30 and 70 years of age. This association remained significant after adjustment for potentially confounding patient characteristics and risk factors for renal disease, and it was independent of treatment with placebo or angiotensin receptor blocker. While serum total bilirubin levels decreased significantly from baseline during the first year of the study, this change was not associated with progression of DN and may be explained by the observed concomitant decrease in serum hemoglobin levels, an observation that was exacerbated by angiotensin receptor blocker therapy (losartan, RENAAL; irbesartan, IDNT) relative to control (2). These findings suggest that measurement of bilirubin levels may identify subjects at risk for progression of DN. Confirmation of initial findings using the IDNT and the relatively large sample size strengthens the findings