Bilirubin and Progression of Nephropathy in Type 2 Diabetes

A Post Hoc Analysis of RENAAL With Independent Replication in IDNT

Ineke J. Riphagen; Petronella E. Deetman; Stephan J.L. Bakker; Gerjan Navi; Mark E. Cooper; Julia B. Lewis; Dick de Zeeuw; Hiddo J. Lambers Heerspink

Disclosures

Diabetes. 2014;63(8):2613-2616. 

In This Article

Abstract and Introduction

Abstract

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.

Introduction

The incidence of type 2 diabetes and its complications are increasing worldwide. One of the major complications of type 2 diabetes is diabetic nephropathy (DN). Nephropathy develops in ~20–40% of patients with diabetes and is the single leading cause of end-stage renal disease (ESRD) around the world.[1]

Bilirubin is a product of heme catabolism and is known to be a potent endogenous antioxidant.[2] As such, bilirubin has consistently been associated with protection against the development of cardiovascular disease (CVD).[3,4] A study in rodents suggested that bilirubin is also protective against progression of DN.[5] This notion is supported by several cross-sectional studies in humans demonstrating that low levels of bilirubin are associated with DN.[6–8]

To our knowledge, there are no prospective studies to date that investigated whether bilirubin levels are associated with progression of DN toward ESRD. Therefore, our primary objective was to prospectively investigate the association of bilirubin with progression of nephropathy in patients with type 2 diabetes. To this end, we performed a historical prospective study in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial.[9,10] Subsequently, independent replication was sought in the Irbesartan Diabetic Nephropathy Trial (IDNT).[11,12]

In the RENAAL and IDNT studies, patients were treated with an angiotensin receptor blocker (ARB) (losartan in RENAAL and irbesartan in IDNT). Several studies have shown that ARBs reduce hemoglobin levels.[13–15] Because bilirubin is a product of heme catabolism, the use of ARBs could consequently reduce bilirubin levels. Therefore, our secondary aim was to investigate the effect of ARB treatment on serum concentrations of hemoglobin and bilirubin.

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