Abstract
BackgroundBilirubin 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.MethodsWe 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.ResultsAs 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).ConclusionsMildly 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.
Highlights
Chronic kidney disease (CKD) is currently a major morbidity in medicine
Elevated serum bilirubin levels were associated with better renal prognosis, and bilirubin treatment induced a beneficial effect on renal fibrosis
There were conflicting results regarding the effects of bilirubin on the development of kidney fibrosis [16,17,18], animal studies have suggested that bilirubin prevents fibrosis-related mechanisms [17,19,20]
Summary
Chronic kidney disease (CKD) is currently a major morbidity in medicine. Prevention of CKD progression is crucial to avoid end-stage renal disease (ESRD), which severely impairs the patient’s quality of life and increases mortality [1]. Among the many mechanisms related to renal function decline, the development of fibrosis has been considered the major terminal pathway of CKD progression [2]. Bilirubin induced a protective effect against kidney and cardiovascular disease [6]. There were conflicting results regarding the effects of bilirubin on the development of kidney fibrosis [16,17,18], animal studies have suggested that bilirubin prevents fibrosis-related mechanisms [17,19,20]. Additional studies with a generalized patient population that investigate the impacts of bilirubin on renal outcome are warranted to clarify the protective effects of bilirubin on renal outcomes. Further studies highlighting the beneficial effects of bilirubin on renal fibrosis and chronic renal function decline are necessary
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