Low serum bilirubin concentration is a novel risk factor for the development of albuminuria in patients with type 2 diabetes

doi:10.1016/j.metabol.2013.11.011

Metabolism

Volume 63, Issue 3, March 2014, Pages 409-414

https://doi.org/10.1016/j.metabol.2013.11.011 Get rights and content

Abstract

Objective

Bilirubin has been recognized as an important endogeneous antioxidant. Previous studies reported that bilirubin could prevent atherosclerosis. The aim of this study was to investigate if serum bilirubin concentration could be a predictor for the development of albuminuria in patients with type 2 diabetes.

Materials and Methods

We measured serum bilirubin in 320 consecutive patients with normoalbuminuria. We performed follow-up study to assess the development of albuminuria, mean interval of which was 3.2 ± 0.9 years. Cox proportional hazards regression was used to examine the relationship between serum bilirubin concentration and the development of albuminuria.

Results

During follow-up duration, 43 patients have developed albuminuria. In multivariate analysis, after adjusting for comprehensive risk factors, the risk of developing albuminuria was higher in the lowest quartile of serum bilirubin concentrations than that in the highest quartile of serum bilirubin concentrations (Hazard ratio, 5.76; 95% CI, 1.65 to 24.93).

Conclusions

Low serum bilirubin concentration could be a novel risk factor for the development of albuminuria in patients with type 2 diabetes.

Introduction

Cardiovascular disease (CVD) has become the most common cause of mortality and morbidity in patients with type 2 diabetes, and several risk factors including smoking, hypertension and dyslipidemia have been shown to accelerate the progression of CVD [1], [2]. Albuminuria, the earliest manifestation of nephropathy, is a marker of increased cardiovascular mortality and the progression of CVD [3], [4]. The finding of microalbuminuria is an indication for screening for possible vascular disease and aggressive intervention to reduce all cardiovascular risk factors [5].

Bilirubin has been shown to be an effective endogenous antioxidant [6], [7], [8], [9], to suppress the oxidation of lipids and lipoproteins, especially low-density lipoprotein cholesterol [10], and to be directly related to the total serum antioxidant capacity in humans [9]. Because of its antioxidant, bilirubin could act against plaque formation and subsequent atherosclerosis [11]. Previous studies reported that serum bilirubin has been consistently shown to be inversely related to CVD [12], [13], [14]. Inoguchi et al. [15] reported lower prevalence of vascular complications such as coronary artery disease, cerebrovascular disease, retinopathy, or macroalbuminuria in patients with diabetes and Gilbert syndrome, a congenital hyperbilirubinemia. Moreover, recent studies showed serum bilirubin to be associated with CVD-related factors such as hypertension [16], [17], abnormal glucose tolerance [18], body mass index [16], [19], [20], metabolic syndrome [19], [21], and coronary artery calcification scores [22]. Serum bilirubin has also been inversely related to the severity of nonalcoholic fatty liver disease, a condition closely related to type 2 diabetes and CVD [23]. And, we previously reported that the serum bilirubin concentration is associated with urinary albumin excretion (UAE) in patients with type 2 diabetes in a cross-sectional study [24]. However, a relationship between serum bilirubin concentration and the development of albuminuria in patients with type 2 diabetes has not been investigated. Therefore, we evaluated the relationship between serum bilirubin concentration and the development of albuminuria in patients with type 2 diabetes.

Section snippets

Patients and study design

We performed a retrospective cohort study with 320 participants recruited from the outpatient clinic at the Kyoto Prefectural University of Medicine and Kyoto Yamashiro General Medical Center from April, 2006 to June, 2013. Type 2 diabetes was diagnosed according to the Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus [25]. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Patients were classified as never

Results

Characteristics of the 320 patients with type 2 diabetes enrolled in this study are shown in Table 1. Mean serum bilirubin was 0.77 ± 0.28 mg/dL. The average duration of follow up was 3.2 ± 0.9 years. During the study period, 50 patients have developed albuminuria. Age (P = 0.01), average SBP (P = 0.0002) and baseline UAE (P < 0.0001) were higher at baseline in patients with the development of albuminuria than those without. Duration of diabetes was longer at baseline in patients with the development of

Discussion

The major finding of our study is that low serum bilirubin concentration is a risk factor for the development of albuminuria after adjustment for the other risk factors. Previous studies reported that low serum bilirubin concentration has been associated with a risk of CVD [12], [13], [14], CVD-related factors [16], [17], [18], [19], [20], [22] and diabetic complications including nephropathy in a cross-sectional study [24] and retinopathy in a cohort study [26]. Then, to the best of our

Author contributions

H.O. researched data and wrote manuscript. M.F., M.T. and G.H. researched data and contributed to discussion. S.M., K.K., H.I. K.T. and K.N. researched data. N.N. researched data and reviewed and edited the manuscript. M.F. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Conflict of interest

No potential conflicts of interest relevant to this article were reported.

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Cited by (23)

Association between serum bilirubin levels and progression of albuminuria in Taiwanese with type 2 diabetes mellitus
2021, Biomedical Journal
Citation Excerpt :
The renal protective effect of BIL has recently attracted much attention. Higher serum BIL within the normal range is associated with less ABU and less deterioration in glomerular function in both type 1 and type 2 diabetic patients [11–14,18–20]. Because most of the relevant studies have been reported in Japanese populations, a large-scale single-center database cohort study from Taiwan was conducted to evaluate a possible ethnic difference in results and to assess the relationship between serum BIL and AUPr in type 2 diabetes.
To investigate the association between serum bilirubin (BIL) levels and the progression of albuminuria in type 2 diabetic Taiwanese.
Longitudinal data from January 2001 to June 2015 were retrospectively reviewed from Chang Gung Memorial Hospital in Taiwan. A total of 2877 type 2 diabetic patients with normal total BIL levels were divided into 4 groups according to BIL, with the highest BIL in the fourth group. The urinary albumin/creatinine ratio (UACR) trend and progression, as well as other laboratory measurements, were evaluated among the four groups. The cumulative incidence and Cox proportional hazard model analysis were performed to examine the relationship between BIL and the risk of albuminuria progression (AUPr).
The mean duration of follow-up was 1.5 years (±1.37 years). The mean patient age, glycosylated hemoglobin level, and duration of diabetes were 62.52 years, 7.9%, and 3.94 years, respectively. A significant correlation was observed between BIL and both the UACR at baseline (P < 0.001) and the cumulative incidence of AUPr (log–rank test, P = 0.031). Hazard ratio (HR) analysis revealed that patients in the fourth BIL quartile had the lowest HR risk of AUPr among the four groups (adjusted HR = 0.70; 95% Confidence Interval = 0.56–0.89, P < 0.05).
Higher serum BIL levels are associated with a lower risk of AUPr in type 2 diabetes patients in Taiwan.
Association between serum total bilirubin levels and the risk of type 2 diabetes mellitus
2019, Diabetes Research and Clinical Practice
Citation Excerpt :
Moreover, low level of bilirubin is a risk factor of diabetic nephropathy and hemoglobin is associated with diabetic nephropathy and the association might play its role through bilirubin metabolism [32]. Small-scale cross-sectional studies of patients with T2DM indicated that serum bilirubin levels are negatively correlated with urinary albumin, renal function, and eGFR [19,33–35]. The Hisayama Study by Yasuda et al. [36] indicated that among patients with T2DM and those with IGT, the increase in bilirubin levels might be a protective factor.
To confirm whether serum bilirubin is an independent risk factor of type 2 diabetes mellitus (T2DM) onset in patients with impaired fasting glycemia (IFG) and impaired glucose tolerance (IGT).
This was a prospective cohort study carried out at the Diabetic Identification Center of Tianjin Metabolic Diseases Hospital. Serum total bilirubin (TBIL) was measured at baseline and the patients were grouped according to baseline bilirubin quartiles. The outcome was the confirmation of T2DM by oral glucose tolerance test (OGTT) during the 3-year follow-up. Logistic regression was used to determine the risk factors for T2DM development and whether bilirubin levels are independently associated with T2DM development.
Finally, 523 patients were analyzed. After 3 years, 310 participants were diagnosed with diabetes based on OGTT. Baseline quartiles of total bilirubin were inversely associated with diabetes risk, even after multivariable adjustment. The adjusted ORs for diabetes were 1.0 (reference), 0.83 (95% CI 0.74–0.96), 0.78 (95% CI 0.68–0.90), 0.74 (95% CI 0.64–0.87) for the 1st, 2nd, 3rd, and 4th quartiles of baseline serum total bilirubin, respectively (P < 0.001).
In patients with IFG or IGT, low levels of serum total bilirubin were associated with a significantly increased risk of T2DM.
Association of serum bilirubin with renal outcomes in Han Chinese patients with chronic kidney disease
2018, Clinica Chimica Acta
Citation Excerpt :
Serum bilirubin concentrations are higher in patients with diabetic nephropathy than in those without diabetic nephropathy, and prospective studies have demonstrated that serum bilirubin is negatively correlated with the progression of renal function in type 2 diabetes [35–37]. In addition, several studies have suggested that low serum bilirubin levels are a risk factor for the development of renal function in patients with diabetes [19,21,38]. In this study, there were no significant differences in serum bilirubin levels between patients with and without type 2 diabetes.
Oxidative stress and inflammation play pivotal roles in chronic kidney disease (CKD). Bilirubin is an endogenous anti-inflammatory antioxidant. However, the relationship between serum bilirubin and renal outcomes in CKD is controversial. We explored the association of serum bilirubin levels with renal outcomes in Han Chinese patients with CKD.
Clinical and laboratory data were collected from 316 patients with CKD. The primary clinical endpoint was renal replacement therapy or death. The association between serum bilirubin and clinical parameters was assessed by correlation analysis. Multiple Cox regression analysis was used to explore the relationship between serum bilirubin and renal outcomes in patients with CKD.
Serum total and indirect bilirubin were positively correlated with estimated glomerular filtration rate, but negatively correlated with 24-h urine protein in patients with CKD. Serum total and indirect bilirubin were inversely associated with CKD stages in patients with CKD stages 1–5. Multiple Cox regression analysis demonstrated that the higher concentration of serum total bilirubin was independently associated with better renal outcomes in CKD.
Our results suggest that serum total bilirubin may have protective effects on kidneys.
Association between serum bilirubin levels and decline in estimated glomerular filtration rate among patients with type 2 diabetes
2016, Journal of Diabetes and its Complications
Studies indicate that elevated serum total bilirubin (TBil) levels are associated with lower risk of diabetic kidney disease (DKD). Few studies examined the associations of direct bilirubin (DBil) and indirect bilirubin (IBil) with the development of DKD.
Type 2 diabetes patients (n = 2,958) with estimated glomerular filtration (eGFR) ≥ 60 ml min^− 1 1.73 m^− 2 from the Dongfeng–Tongji cohort were selected and followed up for 5 years. Development of DKD was defined as decline in eGFR ≥ 30% during follow-up. Generalize linear model was used to assess the associations of bilirubin levels with DKD development.
Compared with those in the first tertile of serum TBil, the relative risks (RRs) and 95% confidence intervals (CIs) of incident eGFR decline for tertile 2 to 3 were 0.83 (0.64–1.09) and 0.74 (0.56–0.98), P _trend = 0.04. The counterpart RRs (95% CIs) in IBil were 0.74 (0.57–0.97) and 0.75 (0.57–0.98), P_trend = 0.04. No significant associations were observed in DBil. Moreover, TBil and IBil interacted with smoking, the bilirubin-DKD associations were evident in ever smokers.
Our findings suggest that elevation of serum TBil or IBil levels are independent protective factors for development of DKD, particularly in smokers.
Serum bilirubin concentration is associated with EGFR and urinary albumin excretion in patients with type 1 diabetes mellitus
2015, Journal of Diabetes and its Complications
Citation Excerpt :
Meanwhile, in patients with type 1 diabetes, we showed a significant inverse relationship between total bilirubin concentration and severity of retinopathy and nephropathy (Sekioka, Tanaka, Nishimura, & Itoh, 2015). In these reports concerning the relationship between bilirubin concentration and diabetic nephropathy (Mashitani et al., 2014; Okada et al., 2014; Sekioka et al., 2015; Toya et al., 2014), only total bilirubin was investigated. In other words, direct and indirect bilirubin concentrations were not investigated separately.
Although relationships of serum bilirubin concentration with estimated glomerular filtration rate (eGFR) and urinary albumin excretion (UAE) in patients with type 2 diabetes have been reported, whether such relationships exist in patients with type 1 diabetes is unknown.
A total of 123 patients with type 1 diabetes were investigated in this cross-sectional study. The relationship between bilirubin (total and indirect) concentrations and log(UAE) as well as eGFR was examined by Pearson’s correlation analyses. Multivariate regression analyses were used to assess the association of bilirubin (total and indirect) with eGFR as well as log(UAE).
A positive correlation was found between serum bilirubin concentration and eGFR; total bilirubin (r = 0.223, p = 0.013), indirect bilirubin (r = 0.244, p = 0.007). A negative correlation was found between serum bilirubin concentration and log(UAE); total bilirubin (r = − 0.258, p = 0.005), indirect bilirubin (r = − 0.271, p = 0.003). Multivariate regression analyses showed that indirect bilirubin concentration was an independent determinant of eGFR and log(UAE).
Bilirubin concentration is associated with both eGFR and log(UAE) in patients with type 1 diabetes. Bilirubin might have a protective role in the progression of type 1 diabetic nephropathy.
Association of serum total bilirubin with renal outcome in Japanese patients with stages 3-5 chronic kidney disease
2015, Metabolism: Clinical and Experimental
Serum bilirubin has been reported to be associated with the progression of kidney disease in patients with diabetic nephropathy. Less is known, however, about the relationship between bilirubin and chronic kidney disease (CKD) of other etiologies. This study was designed to clarify whether serum total bilirubin concentration is associated with kidney disease progression in patients with CKD independent of etiology.
This prospective observational study enrolled 279 consecutive patients with stages 3–5 CKD. The renal endpoint was the composite of the doubling of serum creatinine or end-stage renal disease requiring dialysis. Patients were divided into three groups by their serum total bilirubin concentrations: ≤ 0.3 (lowest), 0.4–0.5 (middle), and ≥ 0.6 (highest) mg/dL. A Cox proportional hazards model was applied to determine the risk factors for poor renal outcome.
The median follow-up period was 21 months. One-hundred and three patients reached renal end points. After multivariable adjustment, a 0.1 mg/dL increase in serum bilirubin was associated negatively with poor renal outcome (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.60–0.87). In addition, after adjustment for confounding factors, including traditional and nontraditional cardiovascular risk factors, the middle (HR 3.14, 95% CI 1.36–8.57) and lowest (HR 4.22, 95% CI 1.81–11.59) bilirubin groups had significantly higher HRs for renal outcome than the highest bilirubin group.
Lower serum bilirubin concentration was independently associated with adverse renal outcomes, suggesting that the measurement of serum bilirubin is useful for predicting kidney disease progression in patients with moderate to severe CKD.

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Clinical ScienceLow serum bilirubin concentration is a novel risk factor for the development of albuminuria in patients with type 2 diabetes

Abstract

Objective

Materials and Methods

Results

Conclusions

Introduction

Section snippets

Patients and study design

Results

Discussion

Author contributions

Conflict of interest

J Biol Chem

Biochem Pharmacol

Atherosclerosis

Am J Cardiol

Metabolism

Am J Hypertens

Atherosclerosis

Metabolism

Metabolism

Atherosclerosis

Kidney Int

Ophthalmology

Diabetes Res Clin Pract

Biochem Biophys Res Commun

Kidney Int

Biochem Biophys Res Commun

Clin Biochem

Cardiovascular morbidity and mortality associated with the metabolic syndrome

Diabetes Care

Multiple risk factor intervention trial. Risk factor changes and mortality results

JAMA

Estimated glomerular filtration rate and albuminuria are independent predictors of cardiovascular events and death in type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

Diabetologia

The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus. A systematic overview of the literature

Arch Intern Med

American Diabetes Association. Diabetic nephropathy

Diabetes Care

Clinical Science
Low serum bilirubin concentration is a novel risk factor for the development of albuminuria in patients with type 2 diabetes