Our study demonstrated individuals with elevated serum IBIL concentrations are at reduced risk of cardiovascular death among MHD patients followed for 53 months. This relationship also remained significant even after adjusting for potential confounding factors, including age, serum uric acid, hemoglobin, serum albumin, eGFR, serum calcium, serum phosphorus. However, there was no relationship between circulation IBIL and all-cause mortality in this study.
Our finding that a high serum IBIL level was a protective factor for cardiovascular death in MHD patients is consistent with the results in previous studies. A cohort study followed for 12 years comprised 661 chronic hemodialysis patients demonstrated that individuals with bilirubin in the upper tertile had an adjusted hazard ratio of 0.32 for cardiovascular event, compared with those in the lower tertile . Additionally, in 1,419 patients with angina pectoris undergoing percutaneous coronary intervention, those with higher bilirubin concentrations (༞8.4 µmol/L) experienced significantly fewer long-term MACEs (cardiac death, myocardial infarction, target-vessel revascularization, or unstable angina pectoris/heart failure, over 2.4-yr follow up) than patients with lower bilirubin concentrations. Moreover, investigation of 3,316 Ludwigshafen Risk and Cardiovascular Health Study participants revealed that increased bilirubin predicted lower overall mortality over a period of 10.4 yr. Furthermore, a study included 2936 subjects followed for 5.4 years showed that higher serum concentrations of bilirubin were associated with a decreased risk of developing cardiovascular death in asymptomatic diabetic patients . However, few studies drew opposite conclusions. A large retrospective study investigating 1111 patients indicated that patients with ST-segment elevation myocardial infarction with higher bilirubin undergoing percutaneous coronary intervention and stent placement had increased MACE and rate of cardiac death during their hospital admission. The discrepancies in ethnicity and inclusion criteria may be confounding factors that caused these different results.
The high risk of cardiovascular morbidity and mortality in MHD individuals is associated with a high prevalence of traditional risk factors for cardiovascular disease (hypertension, diabetes, dyslipidemia). Apart from these risk factors, a series of nontraditional risk factors[29, 30] including calcium and phosphate abnormalities, oxidative stress, inflammation, and malnutrition may render ESRD patients more prone to develop excess risks of cardiovascular death. The recognition of bilirubin as an important endogenous anti-inflammatory and antioxidant molecule has increased in recent decades. Bilirubin affects atherosclerosis by several inhibiting mechanisms, including low-density lipoprotein oxidation, vascular smooth muscle cell proliferation, and endothelial dysfunction . Additionally, elevated bilirubin concentrations are associated with decreased oxidative stress status and augmented endothelium dependent vasodilation in male gilbert syndrome subjects. Moreover, in spontaneously hypertensive rats, the administration of hemin for 3 months elevated bilirubin levels and total antioxidant capacity and reduced left ventricular hypertrophy, hypertension, ventricular phospholipase C activity, circulating aldosterone, and urinary excretion of oxidized lipids. Furthermore, lipid soluble antioxidant bilirubin prevents the oxidation of cardiolipin and decreases the infarct size in the heart during ischemia. Considered together, the antioxidative characteristic of bilirubin might protect against the cardiovascular death.
The present study has some limitations. First, this was a retrospective study, and therefore, larger clinical prospective studies are required to validate our results. Second, the relatively small sample size, single-center study might have selection bias and reduce the statistical power. Third, potential mechanism behind the relationship between serum bilirubin and cardiovascular mortality in MHD individuals was not clarified, and thus, persistent uncertainty is a call to arms for scientists and researchers in this neglected area.