Urinary biomarkers in the early diagnosis of diabetic kidney disease and diabetic retinopathy
Abstract
Introduction/Aim
Urinary biomarkers are increasingly recognized as important indicators of renal injury in type 2 diabetes mellitus (T2DM), and some may also serve as early predictors of microvascular complications. Diabetic kidney disease (DKD) is the most common microvascular complication of type 2 diabetes mellitus and a leading cause of chronic kidney disease and end-stage renal failure. Although microalbuminuria is the established early marker of renal injury, its limited sensitivity and specificity necessitate novel urinary biomarkers for earlier detection. This study aimed to assess whether urinary type IV collagen, transferrin, and liver-type fatty acid–binding protein (L-FABP) could serve as early biomarkers of DKD and to evaluate their association with diabetic retinopathy.
MethodsEighty T2DM patients were divided into two groups: normoalbuminuric (≤30 mg/day) and microalbuminuric (30–300 mg/day). Ten healthy individuals served as controls. All participants were older than 18 years, had diabetes duration >1 year, and an estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m². Urinary concentrations of type IV collagen, transferrin, and L-FABP were measured in 24-hour and first-morning urine samples using ELISA. Statistical analyses included group comparisons, correlation testing, and receiver operating characteristic (ROC) curve assessment.
ResultsUrinary levels of all biomarkers were negligible in controls but significantly higher in microalbuminuric compared with normoalbuminuric patients (p < 0.05). Type IV collagen showed the highest diagnostic accuracy (90.4%) for early DKD. All biomarkers correlated positively with DKD, while urinary transferrin was additionally associated with diabetic retinopathy
ConclusionUrinary type IV collagen, transferrin, and L-FABP are promising early biomarkers of diabetic kidney disease, demonstrating superior diagnostic potential to albuminuria. Moreover, urinary transferrin may serve as a noninvasive marker for early detection of diabetic retinopathy, supporting its role in monitoring microvascular complications in T2DM
References
1. International Diabetes Federation (IDF). IDF Diabetes Atlas 11th edition. idf.org. 2025.
2. Dash S, Chougule A, Mohanty S. Correlation of Albuminuria and Diabetic Retinopathy in Type-II Diabetes Mellitus Patients. Cureus. 2022 Feb 5;14(2):e21927. doi: 10.7759/cureus.21927.
3. Zhen LT, Yih-Chung T, Marco YM Li Chee, Tyler HR, Ning C, Mukharram M.B, Xing YW, et al.Global Prevalence of Diabetic Retinopathy and Projection of Burden through 2045: Systematic Review and Meta-analysis,Ophthalmology,Volume 128, Issue 11,2021, Pages 1580-1591,ISSN 0161-6420, https://doi.org/10.1016/j.ophtha.2021.04.027.76
4. Li et al. Research progress on the pathogenesis of diabetic retinopathy BMC Ophthalmology (2023) 23:372 https://doi.org/10.1186/s12886-023-03118-6
5. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney DiseaseVOL 105 | ISSUE 4S | APRIL 2024Kidney International (2024) 105 (Suppl 4S), S117–S314
6. Gupta S, Dominguez M, Golestaneh L. Diabetic Kidney Disease: An Update. Med Clin North Am. 2023 Jul;107(4):689-705. doi: 10.1016/j.mcna.2023.03.004
7. AS L, Coresh J, Balk E, Al E. National kidney foundation practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Ann Intern Med. 2003;139(2):137–47
8. Samsu N. Diabetic Nephropathy: Challenges in Pathogenesis, Diagnosis, and Treatment. Biomed Res Int. 2021 Jul 8;2021:1497449. doi: 10.1155/2021/1497449.
9. Gaydarski, L., Petrova, K., Angushev, I., Stanchev, S., Iliev, A., Stamenov, N., Kirkov, V., & Landzhov, B. (2025). Exploring the Molecular Modalities in the Pathogenesis of Diabetic Kidney Disease with a Focus on the Potential Therapeutic Implications. Biomedicines, 13(1), 50. https://doi.org/10.3390/biomedicines13010050
10. McGill JB, Haller H, Roy-Chaudhury P, Cherrington A, Wada T, Wanner C, Ji L, Rossing P. Making an impact on kidney disease in people with type 2 diabetes: the importance of screening for albuminuria. BMJ Open Diabetes Res Care. 2022 Jul;10 (4):e002806. doi: 10.1136/bmjdrc-2022-002806.
11. Uchenna A. N, Jeanne A. D, Kenneth K. C, Zeng B, Arzumanyan H, Joan C. Lo, Zheng S; Prevalence of Albuminuria Among Adults With Diabetes and Preserved Estimated Glomerular Filtration Rate by Race and Ethnicity. Diabetes Care 1 March 2023; 46 (3): e78–e80. https://doi.org/10.2337/dc22-1871
12. Scilletta, S., Di Marco, M., Miano, N., Filippello, A., Di Mauro, S., Scamporrino, A., Musmeci, M., Coppolino, G., Di Giacomo Barbagallo, F., Bosco, G., Scicali, R., Piro, S., Purrello, F., & Di Pino, A. (2023). Update on Diabetic Kidney Disease (DKD): Focus on Non-Albuminuric DKD and Cardiovascular Risk. Biomolecules, 13(5), 752. https://doi.org/10.3390/biom13050752
13. Zhang C, Liu T, Wang X, Yang J, Qin D, Liang Y, Wang X. Urine biomarkers in type 2 diabetes mellitus with or without microvascular complications. Nutr Diabetes. 2024 Jul 10;14(1):51. doi: 10.1038/s41387-024-00310-5
14. Swaminathan SM, Rao IR, Shenoy SV, Prabhu AR, Mohan PB, Rangaswamy D, Bhojaraja MV, Nagri SK, Nagaraju SP. Novel biomarkers for prognosticating diabetic kidney disease progression. Int Urol Nephrol. 2023 Apr;55(4):913-928. doi: 10.1007/s11255-022-03354-7
15. Mahendran KB, Bhaskar MV, Santha K, Inmozhi R, Perumal KK. Plasma and Urinary Type IV Collagen Levels for Early Detection of Nephropathy in Type 2 Diabetes Mellitus Patients. Int J Health Sci (Qassim). 2016 Oct;10(4):492-498. PMID: 27833513; PMCID: PMC50853
16. Uwaezuoke SN. The role of novel biomarkers in predicting diabetic nephropathy: a review. Int J Nephrol Renovasc Dis. 2017 Aug 17;10:221-231. doi: 10.2147/IJNRD.S143186.
17. Claudia G a, Sara N. de O.C., Sabrina R. G. and Jackson de S.M. Urinary Transferrin as a Marker of Renal Injury in Diabetic Individuals: An Integrative Review.Journal of Advances in Medicine and Medical Research Volume 36, Issue 6, Page 141-152, 2024; DOI: 10.9734/jammr/2024/v36i65459
18. Li B, Wang J, Ye W. A meta-analysis of urinary transferrin for early diagnosis of diabetic nephropathy. Lab Med. 2024 Jul 3;55(4):413-419. doi: 10.1093/labmed/lmad115
19. A P, C VK, Kalra P. Urinary transferrin as early marker of renal damage in type II diabetes mellitus: A case–control study [Internet]. Int J Clin Biochem Res. 2021 [cited 2025 Sep 16];8(1):33-39. Available from: https://doi.org/10.18231/j.ijcbr.2021.008
20. Tanaka T, Doi K, Maeda-Mamiya R, Negishi K, Portilla D, Sugaya T, Fujita T, Noiri E. Urinary L-type fatty acid-binding protein can reflect renal tubulointerstitial injury. Am J Pathol. 2009 Apr;174(4):1203-11. doi: 10.2353/ajpath.2009.080511. Epub 2009 Mar 5.
21. Kamijo-Ikemori A, Sugaya T, Yasuda T, Kawata T, Ota A, Tatsunami S, Kaise R, Ishimitsu T, Tanaka Y, Kimura K. Clinical significance of urinary liver-type fatty acid-binding protein in diabetic nephropathy of type 2 diabetic patients. Diabetes Care. 2011 Mar;34(3):691-6. doi: 10.2337/dc10-1392. Epub 2011 Jan 27
22. Zhang L, Xue S, Wu M, Dong D. Performance of urinary liver-type fatty acid-binding protein in diabetic nephropathy: A meta-analysis. Front Med (Lausanne). 2022 Sep 2;9:914587. doi: 10.3389/fmed.2022.914587.
23. Terzic B, Stanojevic I, Radojicic Z, Resan M, Petrovic D, Maksic Dj et al.; Urinary transferrin as an early biomarker of diabetic nephropathy: Vojnosanit pregled 2019; 76(6): 616-9; DOI: https://doi.org/10.2298/VSP170808138T
24. Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum? Indian J Endocrinol Metab. 2016 Jul-Aug;20(4):546-51. doi: 10.4103/2230-8210.183480.
25. Rico-Fontalvo J, Aroca-Martínez G, Daza-Arnedo R, Cabrales J, Rodríguez-Yanez T, Cardona-Blanco M et al. Novel Biomarkers of Diabetic Kidney Disease. Biomolecules. 2023 Mar 31;13(4):633. doi: 10.3390/biom13040633.
26. Jha R, Lopez-Trevino S, Kankanamalage HR, Jha JC. Diabetes and Renal Complications: An Overview on Pathophysiology, Biomarkers and Therapeutic Interventions. Biomedicines. 2024 May 15;12(5):1098. doi: 10.3390/biomedicines12051098.
27. Chen C, Wang C, Hu C, Han Y, Zhao L, Zhu X, Xiao L, Sun L. Normoalbuminuric diabetic kidney disease. Front Med. 2017 Sep;11(3):310-318. doi: 10.1007/s11684-017-0542-7. Epub 2017 Jul 18.
28. Yamanouchi M, Furuichi K, Hoshino J, Ubara Y, Wada T. Nonproteinuric diabetic kidney disease. Clin Exp Nephrol. 2020 Jul;24(7):573-581. doi: 10.1007/s10157-020-01881-0. Epub 2020 Mar 31.
29. Wang C, Li C, Gong W, Lou T. New urinary biomarkers for diabetic kidney disease. Biomark Res. 2013 Feb 4;1(1):9. doi: 10.1186/2050-7771-1-9.
30. Tomino Y, Suzuki S, Azushima C, Shou I, Iijima T, Yagame M, Wang LN, Chen HC, Lai KN, Tan SY, Kim MJ. Asian multicenter trials on urinary type IV collagen in patients with diabetic nephropathy. J Clin Lab Anal. 2001;15(4):188-92. doi: 10.1002/jcla.1026.
31. Hassan, Marwa E.; Mahfouz, Mohamed H.; and Shoman, Mohamed S. (2020) "Assessment of urinary type IV collagen, alpha-1 microglobulin, and transferrin in type 2 diabetes mellitus with nephropathy," Journal of Medicine in Scientific Research: Vol. 3: Iss. 1, Article 4. DOI: https://doi.org/10.4103/JMISR.JMISR_74_19
32. Claudia Gusmão, Sara Nállia de Oliveira Costa, Sabrina Ribeiro Gonsalez, and Jackson de Souza-Menezes. 2024. “Urinary Transferrin As a Marker of Renal Injury in Diabetic Individuals: An Integrative Review”. Journal of Advances in Medicine and Medical Research 36 (6):141–152. https://doi.org/10.9734/jammr/2024/ v36i65459
33. Narita T, Hosoba M, Kakei M, Ito S. Increased urinary excretions of immunoglobulin g, ceruloplasmin, and transferrin predict development of microalbuminuria in patients with type 2 diabetes. Diabetes Care. 2006 Jan;29(1):142-4. doi: 10.2337/diacare.29.1.142.
34. Bangjian Li, Jieying Wang, Wen Ye, A meta-analysis of urinary transferrin for early diagnosis of diabetic nephropathy, Laboratory Medicine, Volume 55, Issue 4, July 2024, Pages 413–419, https://doi.org/10.1093/labmed/lmad115
35. Viswanathan V, Sivakumar S, Sekar V, Umapathy D, Kumpatla S. Clinical significance of urinary liver-type fatty acid binding protein at various stages of nephropathy. Indian J Nephrol. 2015 Sep-Oct;25(5):269-73. doi: 10.4103/0971-4065.145097.
36. Thi TND, Gia BN, Thi HLL, Thi TNC, Thanh HP. Evaluation of urinary L-FABP as an early marker for diabetic nephropathy in type 2 diabetic patients. J Med Biochem. 2020 Jan 23;39(2):224-230. doi: 10.2478/jomb-2019-0037.
37. Panduru NM, Forsblom C, Saraheimo M, Thorn L, Bierhaus A, Humpert PM, Groop PH; FinnDiane Study Group. Urinary liver-type fatty acid-binding protein and progression of diabetic nephropathy in type 1 diabetes. Diabetes Care. 2013 Jul;36(7):2077-83. doi: 10.2337/dc12-1868. Epub 2013 Feb 1.
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