Diabetology International

, Volume 7, Issue 4, pp 432–439 | Cite as

Relationship between kidney function decline and initial risk factors for the progression of diabetic kidney disease: a retrospective analysis of 91 Japanese patients with type 2 diabetes

  • Toshiharu Ishizuka
  • Yoshiharu Tokuyama
  • Atsuya Horie
  • Yukiko Hatanaka
  • Sumihiko Sato
  • Azuma Kanatsuka
Original Article



Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) in Japan. The clinical course and factors related to the progression of DKD to ESRD are important issues when treating patients with DKD.


Ninety-one type 2 diabetic patients with DKD that had progressed from chronic kidney disease (CKD) stages G1–3 on their initial clinical visit to ESRD were enrolled. The decline in the estimated glomerular filtration rate (eGFR) was analyzed and the initial clinical factors that influenced the decline rate were explored.


There was a linear decline in eGFR before progression to ESRD, with a median annual decline rate (∆eGFR) of 9.2 mL/min/1.73 m2. In all patients, a history of coronary artery disease and increased levels of initial eGFR and high-density lipoprotein cholesterol (HDL-C) were positive predictors of log ∆eGFR, whereas age, history of cerebral infarction (CI), and an increased level of serum albumin were negative predictors of log ∆eGFR. In patients with CKD stages G1–2 on their first visit, male sex and increased diastolic blood pressure were positive predictors. In patients with CKD stage G3 on their first visit, an increased level of LDL-C was a positive predictor, whereas a history of CI and an increased level of serum total bilirubin (TBil) were negative predictors.


In addition to the common risk factors, initial eGFR, HDL-C, and TBil were identified as novel risk factors for ESRD. These risk factors may differ between patients with early and advanced stages of CKD.


Diabetic kidney disease eGFR decline rate Multivariate linear regression analysis High-density lipoprotein cholesterol Bilirubin 


Compliance with ethical standards

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent or its substitute was obtained from all patients before they were included in the study.

Conflict of interest

There was no financial sponsor for this study.

Financial disclosure

Toshiharu Ishizuka, none. Yoshiharu Tokuyama, none. Atsuya Horie, none. Yukiko Hatanaka, none. Sumihiko Sato, none. Azuma Kanatsuka, none.


  1. 1.
    Nakai S, Watanabe Y, Masakane I, Wada A, Shoji T, Hasegawa T, et al. Overview of regular dialysis treatment in Japan (as of 31 December 2011). Ther Apher Dial. 2013;17:567–611.Google Scholar
  2. 2.
    Molitch M, DeFronzo R, Franz M, Keane W, Mogensen CE, Parving HH, et al. Nephropathy in diabetes. Diabetes Care. 2004;27:S579–83.CrossRefGoogle Scholar
  3. 3.
    Skupien J, Warram JH, Smiles AM, Niewczas MA, Gohda T, Pezzolesi MG, et al. The early decline in renal function in patients with type 1 diabetes and proteinuria predicts the risk of end-stage renal disease. Kidney Int. 2012;82:589–97.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Krolewski AS, Niewczas MA, Skupien J, Gohda T, Smiles A, Eckfeldt JH, et al. Early progressive renal decline precedes the onset of microalbuminuria and its progression to macroalbuminuria. Diabetes Care. 2014;37:226–34.CrossRefPubMedGoogle Scholar
  5. 5.
    Krolewski AS. Progressive renal decline: the new paradigm of diabetic nephropathy in type 1 diabetes. Diabetes Care. 2015;38:954–62.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    KDIGO. Clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2012;2013:3.Google Scholar
  7. 7.
    Sheen Y-J, Sheu WH. Risks of rapid decline renal function in patients with type 2 diabetes. World J. Diabetes. 2014;5:835–46.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    The National Kidney Foundation. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis. 2012;60:850–86.Google Scholar
  9. 9.
    Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92.CrossRefPubMedGoogle Scholar
  10. 10.
    Fukuda M. Classification and treatment of diabetic retinopathy. Diabetes Res Clin Pract. 1994;24:S171–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Shimamoto K, Ando K, Fujita T, Hasebe N, Higaki J, Horiuchi M, Imai Y, Imaizumi T, Ishimitsu T, Ito M, Ito S. The Japanese Society of Hypertension guidelines for the management of hypertension. Hypertens Res. 2014;37:253.Google Scholar
  12. 12.
    Björck S, Mulec H, Johnsen SA, Nordén G, Aurell M. Renal protective effect of enalapril in diabetic nephropathy. BMJ. 1992;304:339–43.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hillege HL, van Gilst WH, van Veldhuisen DJ, Navis G, Grobbee DE, de Graeff PA, et al. Accelerated decline and prognostic impact of renal function after myocardial infarction and the benefits of ACE inhibition: the CATS randomized trial. Eur Heart J. 2003;24:412–20.CrossRefPubMedGoogle Scholar
  14. 14.
    Tarnow L, Rossing P, Jensen C, Hansen BV, Parving HH, Cooper ME. Long-term renoprotective effect of nisoldipine and lisinopril in type 1 diabetic patients with diabetic nephropathy: response to Tarnow et al. Diabetes Care. 2000;23:1723–4.CrossRefGoogle Scholar
  15. 15.
    Holtkamp FA, de Zeeuw D, Thomas MC, Cooper ME, de Graeff PA, Hillege HJL, et al. An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function. Kidney Int. 2011;80:282–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Pavkov ME, Bennett PH, Knowler WC, Krakoff J, Sievers ML, Nelson RG. Effect of youth-onset type 2 diabetes mellitus on incidence of end-stage renal disease and mortality in young and middle-aged Pima Indians. JAMA. 2006;296:421–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Dart AB, Martens PJ, Rigatto C, Brownell MD, Dean HJ, Sellers E. Earlier onset of complications in youth with type 2 diabetes. Diabetes Care. 2014;37:436–43.CrossRefPubMedGoogle Scholar
  18. 18.
    Levin A, Rocco M. KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis. 2007;49:12–154.CrossRefGoogle Scholar
  19. 19.
    Bouchi R, Babazono T, Yoshida N, Nyumura I, Toya K, Hayashi T, et al. Silent cerebral infarction is associated with the development and progression of nephropathy in patients with type 2 diabetes. Hypertens Res. 2010;33:1000–3.Google Scholar
  20. 20.
    Babazono T, Nyumura I, Toya K, Hayashi T, Ohta M, Suzuki K, et al. Higher levels of urinary albumin excretion within the normal range predict faster decline in glomerular filtration rate in diabetic patients. Diabetes Care. 2009;32:1518–20.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Keane WF, Brenner BM, de Zeeuw D, Grunfeld J-P, McGill J, Mitch WE, et al. The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy: the RENAAL study. Kidney Int. 2003;63:1499–507.CrossRefPubMedGoogle Scholar
  22. 22.
    Chang Y-H, Chang D-M, Lin K-C, Hsieh C-H, Lee Y-J. High-density lipoprotein cholesterol and the risk of nephropathy in type 2 diabetic patients. Nutr Metab Cardiovasc Dis. 2013;23:751–7.Google Scholar
  23. 23.
    Zewinger S, Speer T, Kleber ME, Scharnagl H, Woitas R, Lepper PM, et al. HDL cholesterol is not associated with lower mortality in patients with kidney dysfunction. J Am Soc Nephrol. 2014;25:1073–82.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Schuchardt M, Tölle M, van der Giet M. High-density lipoprotein: structural and functional changes under uremic conditions and the therapeutic consequences. Handb Exp Pharmacol. 2015;224:423–53.CrossRefPubMedGoogle Scholar
  25. 25.
    Speer T, Rohrer L, Blyszczuk P, Shroff R, Kuschnerus K, Kränkel N, et al. Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2. Immunity. 2013;38:754–68.Google Scholar
  26. 26.
    Adin C, Croker B, Agarwal A. Protective effects of exogenous bilirubin on ischemia-reperfusion injury in the isolated, perfused rat kidney. Am J Physiol Renal Physiol. 2005;0126:778–84.Google Scholar
  27. 27.
    Fujii M, Inoguchi T, Sasaki S, Maeda Y, Zheng J, Kobayashi K, et al. Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase. Kidney Int. 2010;78:905–19.CrossRefPubMedGoogle Scholar
  28. 28.
    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;298:1398–400.CrossRefPubMedGoogle Scholar
  29. 29.
    Fukui M, Tanaka M, Shiraishi E, Harusato I, Hosoda H, Asano M, et al. Relationship between serum bilirubin and albuminuria in patients with type 2 diabetes. Kidney Int. 2008;74:1197–201.CrossRefPubMedGoogle Scholar
  30. 30.
    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;37:252–8.Google Scholar
  31. 31.
    Riphagen IJ, Deetman PE, Bakker SJL, Navis G, Cooper ME, Lewis JB, et al. Bilirubin and progression of nephropathy in type 2 diabetes: a post hoc analysis of RENAAL with independent replication in IDNT. Diabetes. 2014;63:2845–53.CrossRefPubMedGoogle Scholar
  32. 32.
    Stukel TA, Fisher ES, Wennberg DE, Alter DA, Gottlieb DJ, Vermeulen MJ. Analysis of observational studies in the presence of treatment selection bias: effects of invasive cardiac management on AMI survival using propensity score and instrumental variable methods. JAMA. 2007;297:278–85.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Japan Diabetes Society 2016

Authors and Affiliations

  • Toshiharu Ishizuka
    • 1
  • Yoshiharu Tokuyama
    • 2
  • Atsuya Horie
    • 3
  • Yukiko Hatanaka
    • 3
  • Sumihiko Sato
    • 1
  • Azuma Kanatsuka
    • 3
  1. 1.Sato ClinicChibaJapan
  2. 2.Kashiwado HospitalChibaJapan
  3. 3.Chiba Central Medical Center, Diabetes CenterChibaJapan

Personalised recommendations