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Nephropathy Progression Reduced with Bilirubin

Treatments raising serum bilirubin levels may protect against diabetic nephropathy….

Ineke Riphagen, MD, from the Departments of Clinical Pharmacology and Internal Medicine at University Medical Center, Groningen, the Netherlands, and colleagues reported findings at Kidney Week 2012: American Society of Nephrology 45th Annual Meeting.

When they prospectively investigated the relation in a post hoc analysis of the results of the Reduction of Endpoints in Noninsulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan trial (RENAAL) and the Irbesartan Diabetic Nephropathy Trial (IDNT), they found an inverse relationship of baseline serum bilirubin with the doubling of serum creatinine and end-stage renal disease during a median follow-up of about 3 years. The 2 trials tested their respective angiotensin receptor antagonists against placebo on renal outcome in diabetic nephropathy.

Serum bilirubin values were available for 3205 patients (RENAAL, n = 1498; IDNT, n = 1707), with mean values of 0.57 ± 0.19 mg/dL and 0.54 ± 0.21 mg/dL, respectively. In both trials, the serum bilirubin level was significantly associated with age, sex, smoking, total serum cholesterol level, and the log albumin-to-creatinine ratio.

After adjustment for various factors, regression analyses showed that (log2 transformed) bilirubin values were inversely associated with the renal endpoint.

Table. Adjusted Hazard Ratios

Hazard Ratio (95% Confidence Interval)*

P Value

Hazard Ratio (95% Confidence Interval)**

P Value

0.44 (0.35 – 0.55)

< .001

0.68 (0.54 – 0.86)


0.53 (0.45 – 0.64)

< .001

0.79 (0.65 – 0.96)


* Adjusted for age and sex ** Adjusted for age, sex, race, body mass index, smoking, total cholesterol level, systolic blood pressure, HbA1c, treatment, estimated glomerular filtration rate, and log albumin-to-creatinine ratio

The investigators concluded that higher baseline bilirubin values were associated with lower risk of doubling of serum creatinine and end-stage renal disease in both trials. They speculated that treatments that raise serum bilirubin levels could be renoprotective.

The researchers noted that bilirubin, a powerful endogenous antioxidant, has been seen in animal trials to protect against the progression of diabetic nephropathy, and in human cross-sectional studies, there was an inverse relationship between bilirubin levels and diabetic nephropathy.

Kidney Week 2012: American Society of Nephrology 45th Annual Meeting. Abstract TH-PO510. Presented November 1, 2012.