DOI QR코드

DOI QR Code

Low serum bilirubin level predicts the development of chronic kidney disease in patients with type 2 diabetes mellitus

  • Ahn, Kang Hee (Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Hospital) ;
  • Kim, Sang Soo (Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Hospital) ;
  • Kim, Won Jin (Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Hospital) ;
  • Kim, Jong Ho (Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Hospital) ;
  • Nam, Yun Jeong (Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Hospital) ;
  • Park, Su Bin (Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Hospital) ;
  • Jeon, Yun Kyung (Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Hospital) ;
  • Kim, Bo Hyun (Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Hospital) ;
  • Kim, In Joo (Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Hospital) ;
  • Kim, Yong Ki (Kim Yong Ki Internal Medicine Clinic)
  • Received : 2015.06.03
  • Accepted : 2016.05.17
  • Published : 2017.09.01

Abstract

Background/Aims: We evaluated whether serum bilirubin levels can predict the development of chronic kidney disease (CKD) in patients with type 2 diabetes mellitus (T2DM). Methods: This was a retrospective observational longitudinal study of patients presenting at the Pusan National University Hospital. A total of 349 patients with T2DM and preserved kidney function (estimated glomerular filtration rate ${\geq}60mL/min/1.73m^2$) were enrolled. The main outcome was the development of CKD stage 3 or greater. The patients were divided into four groups according to the quartiles of the total serum bilirubin levels at baseline. Results: The group with the lowest range of total serum bilirubin level (Q1) showed the highest cumulative incidence of CKD stage 3 or greater than that of the other lower quartiles (Q1 vs. Q4; hazard ratio [HR], 6.75; 95% confidence interval [CI], 1.54 to 29.47; p = 0.011). In multivariate analysis, the risk of developing CKD stage 3 or greater was higher in the second lowest quartile of the serum bilirubin level than that in the highest quartile of the serum bilirubin level (Q2 vs. Q4; HR, 9.36; 95% CI, 1.33 to 65.73; p = 0.024). In the normoalbuminuria subgroup (n = 236), multivariate analysis showed that the risk of developing CKD stage 3 or greater was higher in the lowest quartile of the serum bilirubin level than that in the highest quartile of the serum bilirubin level (Q1 vs. Q4; HR, 7.36; 95% CI, 1.24 to 35.82; p = 0.019). Conclusions: Serum bilirubin might be an early clinical marker for predicting the progression of CKD in patients with T2DM and preserved renal function.

Keywords

Acknowledgement

Supported by : Pusan National University Hospital

References

  1. Ahn JH, Yu JH, Ko SH, et al. Prevalence and determinants of diabetic nephropathy in Korea: Korea National Health and Nutrition Examination Survey. Diabetes Metab J 2014;38:109-119. https://doi.org/10.4093/dmj.2014.38.2.109
  2. American Diabetes Association. (9) Microvascular complications and foot care. Diabetes Care 2015;38 Suppl:S58-S66. https://doi.org/10.2337/dc15-S012
  3. Kim WJ, Kim SS, Bae MJ, et al. High-normal serum uric acid predicts the development of chronic kidney disease in patients with type 2 diabetes mellitus and preserved kidney function. J Diabetes Complications 2014;28:130-134. https://doi.org/10.1016/j.jdiacomp.2013.11.006
  4. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res 2010;107:1058-1070. https://doi.org/10.1161/CIRCRESAHA.110.223545
  5. Arias IM. The excretion of conjugated bilirubin by the liver cell. Medicine (Baltimore) 1966;45:513-515. https://doi.org/10.1097/00005792-196645060-00015
  6. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science 1987;235:1043-1046. https://doi.org/10.1126/science.3029864
  7. Inoguchi T, Sasaki S, Kobayashi K, Takayanagi R, Yamada T. Relationship between Gilbert syndrome and prevalence of vascular complications in patients with diabetes. JAMA 2007;298:1398-1400.
  8. Fukui M, Tanaka M, Shiraishi E, et al. Relationship between serum bilirubin and albuminuria in patients with type 2 diabetes. Kidney Int 2008;74:1197-1201. https://doi.org/10.1038/ki.2008.398
  9. Zelle DM, Deetman N, Alkhalaf A, Navis G, Bakker SJ. Support for a protective effect of bilirubin on diabetic nephropathy in humans. Kidney Int 2011;79:686.
  10. Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function: measured and estimated glomerular filtration rate. N Engl J Med 2006;354:2473-2483. https://doi.org/10.1056/NEJMra054415
  11. Molitch ME, DeFronzo RA, Franz MJ, et al. Diabetic nephropathy. Diabetes Care 2003;26 Suppl 1:S94-S98. https://doi.org/10.2337/diacare.26.2007.S94
  12. Madsen-Bouterse SA, Kowluru RA. Oxidative stress and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Rev Endocr Metab Disord 2008;9:315-327. https://doi.org/10.1007/s11154-008-9090-4
  13. Fujii M, Inoguchi T, Sasaki S, et al. Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase. Kidney Int 2010;78:905-919. https://doi.org/10.1038/ki.2010.265
  14. Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes 1991;40:405-412.
  15. Sonta T, Inoguchi T, Matsumoto S, et al. In vivo imaging of oxidative stress in the kidney of diabetic mice and its normalization by angiotensin II type 1 receptor blocker. Biochem Biophys Res Commun 2005;330:415-422. https://doi.org/10.1016/j.bbrc.2005.02.174
  16. Sasaki S, Inoguchi T. The role of oxidative stress in the pathogenesis of diabetic vascular complications. Diabetes Metab J 2012;36:255-261. https://doi.org/10.4093/dmj.2012.36.4.255
  17. Riphagen IJ, Deetman PE, Bakker SJ, et al. Bilirubin and protection against progression of diabetic nephropathy. Proceedings of the Kidney Week 2012: American Society of Nephrology 45th Annual Meeting; 2012 Oct 30-Nov 4; San Diego, CA.
  18. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-869. https://doi.org/10.1056/NEJMoa011161
  19. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-860. https://doi.org/10.1056/NEJMoa011303
  20. Toya K, Babazono T, Hanai K, Uchigata Y. Association of serum bilirubin levels with development and progression of albuminuria, and decline in estimated glomerular filtration rate in patients with type 2 diabetes mellitus. J Diabetes Investig 2014;5:228-235. https://doi.org/10.1111/jdi.12134
  21. Mashitani T, Hayashino Y, Okamura S, Tsujii S, Ishii H. Correlations between serum bilirubin levels and diabetic nephropathy progression among Japanese type 2 diabetic patients: a prospective cohort study (Diabetes Distress and Care Registry at Tenri [DDCRT 5]). Diabetes Care 2014;37:252-258. https://doi.org/10.2337/dc13-0407
  22. Mazzone GL, Rigato I, Ostrow JD, et al. Bilirubin inhibits the TNFalpha-related induction of three endothelial adhesion molecules. Biochem Biophys Res Commun 2009;386:338-344. https://doi.org/10.1016/j.bbrc.2009.06.029
  23. Hirata K, Shikata K, Matsuda M, et al. Increased expression of selectins in kidneys of patients with diabetic nephropathy. Diabetologia 1998;41:185-192. https://doi.org/10.1007/s001250050888
  24. Okada S, Shikata K, Matsuda M, et al. Intercellular adhesion molecule-1-deficient mice are resistant against renal injury after induction of diabetes. Diabetes 2003;52:2586-2593. https://doi.org/10.2337/diabetes.52.10.2586

Cited by

  1. Serum bilirubin level and its impact on the progression of chronic kidney disease vol.50, pp.9, 2017, https://doi.org/10.1007/s11255-018-1923-9
  2. Urinary liver-type fatty acid-binding protein levels as a potential risk factor for renal dysfunction in male HIV-infected Japanese patients receiving antiretroviral therapy: a pilot study vol.29, pp.14, 2017, https://doi.org/10.1177/0956462418788432
  3. Renal impairment markers in type 2 diabetes patients with different types of hyperuricemia vol.10, pp.1, 2017, https://doi.org/10.1111/jdi.12850
  4. Main Risk Factors Related to Activities of Daily Living in Non-Dialysis Patients with Chronic Kidney Disease Stage 3–5: A Case–Control Study vol.15, pp.None, 2017, https://doi.org/10.2147/cia.s249137
  5. Serum Total Bilirubin and Progression of Chronic Kidney Disease and Mortality: A Systematic Review and Meta-Analysis vol.7, pp.None, 2017, https://doi.org/10.3389/fmed.2020.00549
  6. Bilirubin as a metabolic hormone: the physiological relevance of low levels vol.320, pp.2, 2017, https://doi.org/10.1152/ajpendo.00405.2020