The Search for Molecular Prognostic Markers of Diabetic Nephropathy in Patients with Type 2 Diabetes Mellitus

V. M. Ibragimov, PhD¹; I.V. Sarvilina, PhD, ScD²*; M.M. Batyushin, PhD, ScD³

1Dagestan State Medical Academy, the Republic of Dagestan, Makhachkala, the Russian Federation; 2Medical Centre "Novomeditsina", Rostov-on-Don, the Russian Federation; 3Rostov-on-Don State Medical University, Rostov-on-Don, the Russian Federation

*Corresponding author: Irina V. Sarvilina, PhD, ScD. CEO of Medical Centre «Novomeditsina», Rostov-on-Don, Russian Federation..E-mail:

Published: March 16, 2016. DOI: 10.21103/Article6(1)_OA14


The purpose of this study was to search for molecular prognostic markers of diabetic nephropathy (DN) in patients with type 2 diabetes mellitus (T2DM).

The study included 205 patients with T2DM and DN (stages 1 to 4). All patients were stratified by the MDRD equation. The control group included 30 healthy individuals. All T2DM patients were divided into 4 groups depending on the DN stages. Group 1 included 42 patients with DN-Stage 1 (prenephropathy), Group 2 included 48 patients with DN-Stage 2 (incipient nephropathy); Group 3 included 65 patients with DN-Stage 3 (overt nephropathy), and Group 4 included 50 patients with DN-Stage 4 (kidney failure).

Molecular phenotyping of urine was processed with methods of proteomics: the prefractionation, the separation of proteins with standard sets (MB-HIC C8 Kit, MB-IMAC Cu, MB-Wax Kit, «Bruker», USA), matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF-MS/MS, Ultraflex II, «Bruker», USA). The data of the molecular interactions and functional features of proteins were received with STRING 10.0 database.

Potentially new molecular markers of DN development were identified. The research into signaling pathways and the molecules that are involved in ECM formation may help in developing strategies to prevent DN.

type 2 diabetes mellitus; diabetic nephropathy; proteomics; molecular markers.
  1. IDF Diabetes Atlas, Fifth Edition. International Diabets Federation, Brussels, Belgium; 2011.
  2. Shestakova M, Shamalova M. Diabetic nephropathy: clinic, diagnostic, therapy. Dedov II, editor. M: Medicine; 2009. [in Russian].
  3. Shlipak M. Diabetic nephropathy: preventing progression. BMJ Clin Evid. 2010;2010. pii: 0606.
  4. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update. Am J Kidney Dis. 2012;60(5):850-86.
  5. King, P, Peacock I,  Donnelly R. The UK Prospective Diabetes Study (UKPDS): clinical and therapeutic implications for type 2 diabetes / P. King, I.Peacock,  R. Donnelly. Br J Clin Pharmacol. 1999; 48(5):643–8.
  6. Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes. ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al. N Engl J Med. 2008;358(24):2560-72.
  7. Wood AJ, Churilov L, Perera N, Thomas D, Poon A, MacIsaac RJ,  et al. Estimating glomerular filtration rate: Performance of the CKD-EPI equation over time in patients with type 2 diabetes.  J Diabetes Complications. 2016;30(1):49-54.
  8. Hall J, Brands M, Dixon W, Smith MJJr. Obesity-induced hypertension. Renal function and systemic hemodynamics. Hypertension. 1993;22(3):292–9.
  9. Rask-Madsen C, King GL. Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab. 2013;17(1):20-33.
  10. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al.; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861-9.
  11. Van Buren PN, Toto R.Hypertension in diabetic nephropathy: epidemiology, mechanisms, and management. Adv Chronic Kidney Dis. 2011;18(1):28-41.
  12. Stauffer ME,  Fan T.  Prevalence of Anemia in Chronic Kidney Disease in the United States. PLoS One. 2014;9(1): e84943.
  13. Ha SK, Seo JK. Insertion/deletion polymorphism in ACE gene as a predictor for progression of diabetic nephropathy. Kidney Int Suppl.1997;60:S28-32.
  14. Haneda M, Utsunomiya K, Koya D, Babazono T, Moriya T, Makino H, et al.; Joint Committee on Diabetic Nephropathy. A new Classification of Diabetic Nephropathy 2014: a report from Joint Committee on Diabetic Nephropathy. J Diabetes Investig. 2015;6(2):242-6.
  15. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al.; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. JAMA. 200321;289(19):2560-72
  16. Kim SS, Song SH, Kim IJ, Jeon YK, Kim BH, Kwak IS, et al. Urinary cystatin C and tubular proteinuria predict progression of diabetic nephropathy. Diabetes Care. 2013;36(3):656-61.
  17. Conti M, Moutereau S, Zater M, Lallali K, Durrbach A, Manivet P, et al. Urinary cystatin C as a specific marker of tubular dysfunction. Clin Chem Lab Med. 2006;44(3):288–91.
  18.   Lan HY. Diverse roles of TGF-beta/Smads in renal fibrosis and inflammation. Int J Biol Sci 2011;7:1056-67.
  19. Bottinger EP. TGF-beta in renal injury and disease. Semin Nephrol 2007;27:309-20.
  20. Lan HY. Tubular epithelial-myofibroblast transdifferentiation mechanisms in proximal tubule cells. Curr Opin Nephrol Hypertens 2003;12:25-29.
  21. Yanagita M. Inhibitors/antagonists of TGF-β system in kidney fibrosis. Nephrol Dial Transplant. 2012;27(10):3686-91.
  22. Bolignano D, Donato V, Coppolino G, Campo S, Buemi A, Lacquaniti A, Buemi M. Neutrophil gelatinase-associated lipocalin (NGAL) as a marker of kidney damage. Am J Kidney Dis. 2008;52(3):595-605.
  23. Jim B, Ghanta M, Qipo A, Fan Y, Chuang PY, Cohen HW, et al. Dysregulated nephrin in diabetic nephropathy of type 2 diabetes: a cross sectional study. PLoS One. 2012;7(5):e36041.
  24. Nakamura T, Ushiyama C, Suzuki S, Hara M, Shimada N, Ebihara I, et al. Urinary excretion of podocytes in patients with diabetic nephropathy. Nephrol Dial Transplant. 2000;15(9):1379-83.
  25. White KE, Bilous RW, Marshall SM, El Nahas M, Remuzzi G, Piras G, et al. Podocyte number in normotensive type 1 diabetic patients with albuminuria. Diabetes. 2002;51(10):3083-9.
  26. Doublier S, Salvidio G, Lupia E, Ruotsalainen V, Verzola D, Deferrari G, et al. Nephrin expression is reduced in human diabetic nephropathy: evidence for a distinct role for glycated albumin and angiotensin II. Diabetes. 2003; 52(4):1023–30.

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