Elevated bilirubin levels are associated with a better renal prognosis and ameliorate kidney fibrosis

• Published in: PloS one 2017-02, Vol.12 (2), p.e0172434-e0172434
• Main Authors: Park, Sehoon, Kim, Do Hyoung, Hwang, Jin Ho, Kim, Yong-Chul, Kim, Jin Hyuk, Lim, Chun Soo, Kim, Yon Su, Yang, Seung Hee, Lee, Jung Pyo
• Format: Article
• Language: English
• Subjects: Aged; Analysis; Animal experimentation; Animals; Apoptosis; Apoptosis - drug effects; Bilirubin; Bilirubin - blood; Bilirubin - pharmacology; Biology and Life Sciences; Cardiovascular disease; Care and treatment; Cell cycle; Complications and side effects; Confidence intervals; Coronary vessels; Creatinine; Creatinine - blood; Development and progression; Diabetes; Dialysis; Disease Models, Animal; Disease Progression; Dosage and administration; Epidermal growth factor receptors; Epithelial cells; Female; Fibronectin; Fibronectins; Fibrosis; Fibrosis - blood; Fibrosis - pathology; Fibrosis - physiopathology; Glomerular filtration rate; Glomerular Filtration Rate - physiology; Health aspects; Humans; Hyperbilirubinemia; Hypertension; Internal medicine; Kidney - drug effects; Kidney - pathology; Kidney - physiopathology; Kidney diseases; Kidney Diseases - blood; Kidney Diseases - pathology; Kidney Diseases - physiopathology; Kidney Function Tests; Laboratory animals; Liver cirrhosis; Male; Medical imaging; Medical prognosis; Medicine; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Middle Aged; Oxidative stress; Patients; Prognosis; Prospective Studies; Renal function; Renal Insufficiency, Chronic - blood; Renal Insufficiency, Chronic - pathology; Renal Insufficiency, Chronic - physiopathology; Rodents; Studies; Ureteral Obstruction - blood; Ureteral Obstruction - pathology; Ureteral Obstruction - physiopathology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0172434

Bilirubin has been reported to protect against kidney injury. However, further studies highlighting the beneficial effects of bilirubin on renal fibrosis and chronic renal function decline are necessary. We assessed a prospective cohort with a reference range of total bilirubin levels. The primary outcome was a 30% reduction in the estimated glomerular filtration rate (eGFR) from baseline, and the secondary outcome was a doubling of the serum creatinine levels, halving of the eGFR and the initiation of dialysis. In addition, experiments with tubular epithelial cells and C57BL/6 mice were performed to investigate the protective effects of bilirubin on kidney fibrosis. As a result, 1,080 patients were included in the study cohort. The study group with relative hyperbilirubinemia (total bilirubin 0.8-1.2 mg/dL) showed a better prognosis in terms of the primary outcome (adjusted hazard ratio (HR) 0.33, 95% confidence interval (CI) 0.19-0.59, P < 0.001) and the secondary outcome (adjusted HR 0.20, 95% CI 0.05 to 0.71, P = 0.01) than that of the control group. Moreover, the bilirubin-treated mice showed less fibrosis in the unilateral ureteral obstruction (UUO) model (P < 0.05). In addition, bilirubin treatment decreased fibronectin expression in tubular epithelial cells in a dose-dependent manner (P < 0.05). Mildly elevated serum bilirubin levels were associated with better renal prognosis, and bilirubin treatment induced a beneficial effect on renal fibrosis. Therefore, bilirubin could be a potential therapeutic target to delay fibrosis-related kidney disease progression.