Beyond a Measure of Liver Function—Bilirubin Acts as a Potential Cardiovascular Protector in Chronic Kidney Disease Patients

Tsai, Ming-Tsung; Tarng, Der Cherng

doi:10.3390/ijms20010117

Cited by 35 publications

(29 citation statements)

References 144 publications

(172 reference statements)

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“…The potential mechanisms behind the protective role of serum bilirubin are as follows: First, serum bilirubin is seen as a potent, endogenous antioxidant reagent because of persistent recovery in intracellular bilirubin redox metabolism. Second, it has been previously demonstrated that STB has a positive association with anti-inflammatory effects, which are a protective factor of CKD ( 37 ). Zucker et al supported the finding that bilirubin could prevent an inflammatory reaction in a mice model of inflammatory colitis by preventing vascular cell adhesion molecule 1 (VCAM-1) -mediated leukocyte infiltration in target tissues ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

Serum Total Bilirubin and Progression of Chronic Kidney Disease and Mortality: A Systematic Review and Meta-Analysis

Liu

2021

Front. Med.

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Background: Previous studies have suggested that serum total bilirubin (STB) levels are associated with heightened chronic kidney disease (CKD) and mortality in both the general population and nephropathy patients. However, these results remain inconsistent. The aim of our study was to investigate whether STB was a predictor for progression of CKD and mortality by meta-analysis.Methods: We performed a systematic literature search in PubMed, Web of Science, MEDLINE, EMBASE, Google Scholar, and Cochrane Library's database up to June 30, 2019. Pooled risk ratios (RR) and corresponding 95% confidence intervals (CI) were extracted for the highest vs. lowest category STB levels within the physiological range, and a random-effects model was applied to calculate the dose–response relationships. A pooled hazard ratio (HR) was used to investigate the association between STB levels and mortality in dialysis patients.Results: A total of 16 studies, wherein participants were followed from 21 months to 7 years, were eligible for inclusion in the study. For the categorized STB, 11 studies with 41,188 participants were identified and analyzed. Patients with the highest STB levels were associated with a lower risk of CKD (RR = 0.64; 95% CI 0.55–0.73) compared to those with the lowest STB levels. Furthermore, based on seven studies, a pooled RR of 0.89, 95% CI (0.80–0.99) was observed for the continuous STB levels (per 0.2 mg/dL increase). Four studies that included 51,764 participants illustrated that there was no association between STB levels and all-cause mortality (HR = 0.77; 95% CI 0.42–1.41). A prominent negative linear relationship (X2 = 14.70; P = 0.0001) was found between STB levels and risk of CKD. Subgroup analyses showed that there were no significant differences in the subgroup adjustment factor except for sample size.Conclusions: Elevated STB levels within a physiological range are associated with lower risk of CKD regardless of the study characteristics and coincide with a liner dose–response relationship. However, whether high STB levels are a protective factor against mortality remains inconclusive. Large-scale randomized controlled trails are needed to target STB levels for predicting renal outcomes.

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Section: Discussionmentioning

confidence: 99%

Serum Total Bilirubin and Progression of Chronic Kidney Disease and Mortality: A Systematic Review and Meta-Analysis

Liu

2021

Front. Med.

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“…Increased HO-1 enzymatic activity is not only essential for MSC maturation, but is also cytoprotective against oxidative stress [58,59]. The antioxidant effects of HO-1 arise from its ability to increase reduced glutathione levels and degrade heme, as well as its ability to increase biliverdin and bilirubin, which have potent antioxidant properties [60,61]. In IR-AKI models, the increased production of HO-1 after MSC administration correlated with decreased levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) and ROS [62].…”

Section: Oxidative Stress In Ir-akimentioning

confidence: 99%

The Anti-Inflammatory, Anti-Oxidative, and Anti-Apoptotic Benefits of Stem Cells in Acute Ischemic Kidney Injury

Lee

Tseng

Yang

et al. 2019

IJMS

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Ischemia-reperfusion injury (IRI) plays a significant role in the pathogenesis of acute kidney injury (AKI). The complicated interaction between injured tubular cells, activated endothelial cells, and the immune system leads to oxidative stress and systemic inflammation, thereby exacerbating the apoptosis of renal tubular cells and impeding the process of tissue repair. Stem cell therapy is an innovative approach to ameliorate IRI due to its antioxidative, immunomodulatory, and anti-apoptotic properties. Therefore, it is crucial to understand the biological effects and mechanisms of action of stem cell therapy in the context of acute ischemic AKI to improve its therapeutic benefits. The recent finding that treatment with conditioned medium (CM) derived from stem cells is likely an effective alternative to conventional stem cell transplantation increases the potential for future therapeutic uses of stem cell therapy. In this review, we discuss the recent findings regarding stem cell-mediated cytoprotection, with a focus on the anti-inflammatory effects via suppression of oxidative stress and uncompromised immune responses following AKI. Stem cell-derived CM represents a favorable approach to stem cell-based therapy and may serve as a potential therapeutic strategy against acute ischemic AKI.

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“…As mentioned above, accumulating evidence has shown that bilirubin exerts a protective role against renal disease progression, through various mechanisms 10,11 . Bilirubin also has an immunomodulatory effect, which is expected to reduce graft rejection after kidney transplantation 14,15 . However, scarce data exist regarding the association between serum bilirubin levels and kidney transplant outcomes 19 .…”

Section: Discussionmentioning

confidence: 99%

“…These bene cial effects have largely been attributed to the antioxidant property of bilirubin 12,13 . Recent studies have further suggested that bilirubin may exert anti-in ammatory, immunomodulatory, and endothelial protective effects 14 .…”

Section: Introductionmentioning

confidence: 99%

Clinical Impact of Serum Bilirubin Levels on Kidney Transplant Outcomes

Lee

Kim

Lee

et al. 2021

Preprint

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Serum bilirubin, a potent endogenous antioxidant, has been associated with decreased risks of cardiovascular disease, diabetes, and kidney disease. However, the effects of serum bilirubin on kidney transplant outcomes remain undetermined. We analyzed 1628 patients who underwent kidney transplantations between 2003 and 2017. Patients were grouped into sex-specific quartiles according to mean serum bilirubin levels, 3-12 months post-transplantation. Median bilirubin levels were 0.66 mg/dL in males and 0.60 mg/dL in females. The intra-individual variability of serum bilirubin levels was low (9%). Serum bilirubin levels were inversely associated with graft loss, death-censored graft failure, and all-cause mortality, independent of renal function, donor status, and transplant characteristics. Multivariable analysis revealed that the lowest serum bilirubin quartile was associated with increased risk of graft loss (HR 2.63, 95% CI 1.67-4.16, P < 0.001), death-censored graft failure (HR 2.96, 95% CI 1.62-5.40, P < 0.001), and all-cause mortality (HR 2.07, 95% CI 1.01-4.23, P = 0.046). Patients with lower serum bilirubin were also at greater risk of late-onset rejection and exhibited consistently lower glomerular filtration rates than those with higher serum bilirubin. Serum bilirubin levels were significantly associated with transplantation outcomes, suggesting that bilirubin could represent a therapeutic target for improving long-term transplant outcomes.

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Beyond a Measure of Liver Function—Bilirubin Acts as a Potential Cardiovascular Protector in Chronic Kidney Disease Patients

Cited by 35 publications

References 144 publications

Serum Total Bilirubin and Progression of Chronic Kidney Disease and Mortality: A Systematic Review and Meta-Analysis

Serum Total Bilirubin and Progression of Chronic Kidney Disease and Mortality: A Systematic Review and Meta-Analysis

The Anti-Inflammatory, Anti-Oxidative, and Anti-Apoptotic Benefits of Stem Cells in Acute Ischemic Kidney Injury

Clinical Impact of Serum Bilirubin Levels on Kidney Transplant Outcomes

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