Skip to main content

Advertisement

Log in

Review and discussion of tubular biomarkers in the diagnosis and management of diabetic nephropathy

  • Review
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

The prevalence of diabetic nephropathy has tremendously increased with the relentless rise in the incidence of diabetes over the last couple decades. Diabetic nephropathy is a leading cause of morbidity and mortality, and it invariably leads to an end-stage renal disease (ESRD). In an effort to delay the onset of ESRD systematic screening and appropriate management are needed to evaluate the progression of renal damage in diabetic nephropathy. The reliability of current tests in predicting the onset, progression and response to various regimens for diabetic nephropathy is still under debate; and it has engendered a search for more sensitive and specific urinary biomarkers, especially those reflective of tubular dysfunctions. It is well-known that there is a good correlation between the degree of damage to the tubulo-interstitial compartment and the deterioration of renal functions. In view of this, the utility of urinary biomarkers, reflective of tubular injury, reported in the literature is discussed in this brief review.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. A.J. Collins, R.N. Foley, B. Chavers, D. Gilbertson, C. Herzog, K. Johansen, United States Renal Data System 2011 Annual Data Report: atlas of chronic kidney disease & end-stage renal disease in the United States. Am. J. Kidney Dis. 59([1 Suppl 1] A7), e1–e420 (2012)

    Google Scholar 

  2. Y.S. Kanwar, L. Sun, P. Xie, F.-Y. Liu, S. Chen, A glimpse of various pathogenetic mechanisms of diabetic nephropathy. Annu. Rev. Pathol. 6, 395–423 (2011)

    Article  PubMed  CAS  Google Scholar 

  3. C.C. Tisher, R.C. McCoy, Diabetes mellitus and the kidney. Perspect. Nephrol. Hypertens. 3, 105–128 (1976)

    PubMed  CAS  Google Scholar 

  4. C.E. Hills, P.E. Squires, The role of TGF-beta and epithelial-to mesenchymal transition in diabetic nephropathy. Cytokine Growth Factor Rev. 22, 131–139 (2011)

    PubMed  CAS  Google Scholar 

  5. W.J. Fu, B.L. Li, S.B. Wang, M.L. Chen, R.T. Deng, C.Q. Ye, Changes of the tubular markers in type 2 diabetes mellitus with glomerular hyperfiltration. Diabetes Res. Clin. Pract. 95, 105–109 (2012)

    Article  PubMed  CAS  Google Scholar 

  6. V. Vallon, S.C. Thomson, Renal function in diabetic disease models: the tubular system in the pathophysiology of the diabetic kidney. Annu. Rev. Physiol. 74, 351–375 (2012)

    Article  PubMed  CAS  Google Scholar 

  7. B. Fabris, R. Candido, L. Armini, F. Fischetti, M. Calci, M. Bardelli, Control of glomerular hyperfiltration and renal hypertrophy by an angiotensin converting enzyme inhibitor prevents the progression of renal damage in hypertensive diabetic rats. J. Hypertens. 17, 1925–1931 (1999)

    Article  PubMed  CAS  Google Scholar 

  8. C.E. Mogensen, A. Chachati, C.K. Christensen, C.F. Close, T. Deckert, E. Hommel, Microalbuminuria: an early marker of renal involvement in diabetes. Urem. Invest. 9, 85–95 (1985)

    Google Scholar 

  9. J.M. Halimi, The emerging concept of chronic kidney disease without clinical proteinuria in diabetic patients. Diabetes Metab. 38(4), 291–297 (2012)

    Article  PubMed  CAS  Google Scholar 

  10. M.C. Thomas, W.C. Burns, M.E. Cooper, Tubular changes in early diabetic nephropathy. Adv. Chronic Kidney Dis. 12, 177–186 (2005)

    Article  PubMed  CAS  Google Scholar 

  11. S.C. Tang, J.C. Leung, K.N. Lai, Diabetic tubulopathy: an emerging entity. Contrib. Nephrol. 170, 124–134 (2011)

    Article  PubMed  Google Scholar 

  12. R.J. Baines, N.J. Brunskill, Tubular toxicity of proteinuria. Nat. Rev. Nephrol. 7, 177–180 (2011)

    Article  PubMed  CAS  Google Scholar 

  13. Y.C. Liao, Y.H. Lee, L.Y. Chuang, J.Y. Guh, M.D. Shi, J.S. Huang, Advanced glycation end products-mediated hypertrophy is negatively regulated by tetrahydrobiopterin in renal tubular cells. Mol. Cell. Endocrinol. 355, 71–77 (2012)

    Article  PubMed  CAS  Google Scholar 

  14. A. Matheson, M.D. Willcox, J. Flanagan, B.J. Walsh, Urinary biomarkers involved in type 2 diabetes: a review. Diabetes Metab. Res. Rev. 26, 150–171 (2010)

    Article  PubMed  CAS  Google Scholar 

  15. W.J. Fu, S.L. Xiong, Y.G. Fang, S. Wen, M.L. Chen, R.T. Deng, Urinary tubular biomarkers in short-term type 2 diabetes mellitus patients: a cross-sectional study. Endocrine 41, 82–88 (2012)

    Article  PubMed  CAS  Google Scholar 

  16. F. Waanders, G. Navis, H. van Goor, Urinary tubular biomarkers of kidney damage: potential value in clinical practice. Am. J. Kidney Dis. 2010(55), 813–816 (2010)

    Article  Google Scholar 

  17. V.S. Vaidya, M.A. Niewczas, L.H. Ficociello, A.C. Johnson, F.B. Collings, J.H. Warram, Regression of microalbuminuria in type 1 diabetes is associated with lower levels of urinary tubular injury biomarkers, kidney injury molecule-1, and N-acetyl-beta-d-glucosaminidase. Kidney Int. 79, 464–470 (2011)

    Article  PubMed  CAS  Google Scholar 

  18. S.E. Nielsen, S. Andersen, D. Zdunek, G. Hess, H.H. Parving, P. Rossing, Tubular markers do not predict the decline in glomerular filtration rate in type 1 diabetic patients with overt nephropathy. Kidney Int. 79, 1113–1118 (2011)

    Article  PubMed  CAS  Google Scholar 

  19. D. Bolignano, A. Lacquaniti, G. Coppolino, S. Campo, A. Arena, M. Buemi, Neutrophil gelatinase-associated lipocalin reflects the severity of renal impairment in subjects affected by chronic kidney disease. Kidney Blood Press. Res. 31, 255–258 (2008)

    Article  PubMed  CAS  Google Scholar 

  20. T. Kuwabara, K. Mori, M. Mukoyama, M. Kasahara, H. Yokoi, Y. Saito, Urinary neutrophil gelatinase-associated lipocalin levels reflect damage to glomeruli, proximal tubules, and distal nephrons. Kidney Int. 75, 285–294 (2009)

    Article  PubMed  CAS  Google Scholar 

  21. W.S. Waring, A. Moonie, Earlier recognition of nephrotoxicity using novel biomarkers of acute kidney injury. Clin. Toxicol. (Phila) 49, 720–728 (2011)

    Article  CAS  Google Scholar 

  22. K. Mori, K. Nakao, Neutrophil gelatinase-associated lipocalin as the real-time indicator of active kidney damage. Kidney Int. 71, 967–970 (2007)

    Article  PubMed  CAS  Google Scholar 

  23. J. Mishra, K. Mori, Q. Ma, C. Kelly, J. Yang, M. Mitsnefes, Amelioration of ischemic acute renal injury by neutrophil gelatinase-associated lipocalin. J. Am. Soc. Nephrol. 15, 3073–3082 (2004)

    Article  PubMed  Google Scholar 

  24. P. Devarajan, Neutrophil gelatinase-associated lipocalin (N-GAL): a new marker of kidney disease. Scand. J. Clin. Lab. Invest. Suppl. 241, 89–94 (2008)

    Article  PubMed  Google Scholar 

  25. K.M. Schmidt-Ott, K. Mori, J.Y. Li, A. Kalandadze, D.J. Cohen, P. Devarajan, Dual action of neutrophil gelatinase-associated lipocalin. J. Am. Soc. Nephrol. 18, 407–413 (2007)

    Article  PubMed  CAS  Google Scholar 

  26. G.J. Ko, D.N. Grigoryev, D. Linfert, H.R. Jang, T. Watkins, C. Cheadle, Transcriptional analysis of kidneys during repair from AKI reveals possible roles for N-GAL and KIM-1 as biomarkers of AKI-to-CKD transition. Am. J. Physiol. Renal Physiol. 298, F1472–F1483 (2010)

    Article  PubMed  CAS  Google Scholar 

  27. P. Devarajan, Biomarkers for the early detection of acute kidney injury. Curr. Opin. Pediatr. 23, 194–200 (2011)

    Article  PubMed  CAS  Google Scholar 

  28. Y.H. Yang, X.J. He, S.R. Chen, L. Wang, E.M. Li, L.Y. Xu, Changes of serum and urine neutrophil gelatinase-associated lipocalin in type-2 diabetic patients with nephropathy: one year observational follow-up study. Endocrine 36, 45–51 (2009)

    Article  PubMed  Google Scholar 

  29. K. Mori, H.T. Lee, D. Rapoport, I.R. Drexler, K. Foster, J. Yang, Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J. Clin. Invest. 115, 610–621 (2005)

    PubMed  CAS  Google Scholar 

  30. N.A. Bhavsar, A. Kottgen, J. Coresh, B.C. Astor, Neutrophil gelatinase-associated lipocalin (N-GAL) and kidney injury molecule 1 (KIM-1) as predictors of incident CKD Stage 3: the atherosclerosis risk in communities (ARIC) study. Am. J. Kidney Dis. 60, 233–240 (2012)

    Article  PubMed  CAS  Google Scholar 

  31. B. Lisowska-Myjak, Serum and urinary biomarkers of acute kidney injury. Blood Purif. 29, 357–365 (2010)

    Article  PubMed  CAS  Google Scholar 

  32. M.M. van Timmeren, S.J. Bakker, V.S. Vaidya, V. Bailly, T.A. Schuurs, J. Damman, Tubular kidney injury molecule-1 in protein-overload nephropathy. Am. J. Physiol. Renal Physiol. 291, F456–F464 (2006)

    Article  PubMed  Google Scholar 

  33. Y. Huang, A.C. Don-Wauchope, The clinical utility of kidney injury molecule 1 in the prediction, diagnosis and prognosis of acute kidney injury: a systematic review. Inflamm. Allergy Drug Targets 10, 260–271 (2011)

    Article  PubMed  CAS  Google Scholar 

  34. V. Bailly, Z. Zhang, W. Meier, R. Cate, M. Sanicola, J.V. Bonventre, Shedding of kidney injury molecule-1, a putative adhesion protein involved in renal regeneration. J. Biol. Chem. 277, 39739–39748 (2002)

    Article  PubMed  CAS  Google Scholar 

  35. M.M. van Timmeren, M.C. van den Heuvel, V. Bailly, S.J. Bakker, H. van Goor, C.A. Stegeman, Tubular kidney injury molecule-1 (KIM-1) in human renal disease. J. Pathol. 212, 209–217 (2007)

    Article  PubMed  Google Scholar 

  36. W. Huo, K. Zhang, Z. Nie, Q. Li, F. Jin, Kidney injury molecule-1 (KIM-1): a novel kidney-specific injury molecule playing potential double-edged functions in kidney injury. Transpl. Rev. (Orlando) 24, 143–146 (2010)

    Article  Google Scholar 

  37. X. Zhao, Y. Zhang, L. Li, D. Mann, D. Imig, N. Emmett, Glomerular expression of kidney injury molecule-1 and podocytopenia in diabetic glomerulopathy. Am. J. Nephrol. 34, 268–280 (2011)

    Article  PubMed  CAS  Google Scholar 

  38. G. Tramonti, Y.S. Kanwar, Tubular biomarkers to assess progression of diabetic nephropathy. Kidney Int. 79, 1042–1044 (2011)

    Article  PubMed  CAS  Google Scholar 

  39. P. Devarajan, The use of targeted biomarkers for chronic kidney disease. Adv Chronic Kidney Dis. 17, 469–479 (2010)

    Article  PubMed  Google Scholar 

  40. A. Kamijo-Ikemori, T. Sugaya, K. Kimura, Urinary fatty acid binding protein in renal disease. Clin. Chim. Acta 374, 1–7 (2006)

    Article  PubMed  CAS  Google Scholar 

  41. A. Kamijo-Ikemori, T. Sugaya, A. Obama, J. Hiroi, H. Miura, M. Watanabe, Liver-type fatty acid-binding protein attenuates renal injury induced by unilateral ureteral obstruction. Am. J. Pathol. 169, 1107–1117 (2006)

    Article  PubMed  CAS  Google Scholar 

  42. T. Yokoyama, A. Kamijo-Ikemori, T. Sugaya, S. Hoshino, T. Yasuda, K. Kimura, Urinary excretion of liver type fatty acid binding protein accurately reflects the degree of tubulointerstitial damage. Am. J. Pathol. 174, 2096–2106 (2009)

    Article  PubMed  CAS  Google Scholar 

  43. A. Kamijo, K. Kimura, T. Sugaya, M. Yamanouchi, A. Hikawa, N. Hirano, Urinary fatty acid-binding protein as a new clinical marker of the progression of chronic renal disease. J. Lab. Clin. Med. 143, 23–30 (2004)

    Article  PubMed  CAS  Google Scholar 

  44. Y. Kanaguchi, Y. Suzuki, K. Osaki, T. Sugaya, S. Horikoshi, Y. Tomino, Protective effects of L-type fatty acid-binding protein (L-FABP) in proximal tubular cells against glomerular injury in anti-GBM antibody-mediated glomerulonephritis. Nephrol. Dial. Transpl. 26, 3465–3473 (2011)

    Article  CAS  Google Scholar 

  45. A. Kamijo-Ikemori, T. Sugaya, T. Yasuda, T. Kawata, A. Ota, S. Tatsunami, Clinical significance of urinary liver-type fatty acid-binding protein in diabetic nephropathy of type 2 diabetic patients. Diabetes Care 34, 691–696 (2011)

    Article  PubMed  CAS  Google Scholar 

  46. C.C. Wu, H.K. Sytwu, Y.F. Lin, Cytokines in diabetic nephropathy. Adv. Clin. Chem. 56, 55–74 (2012)

    Article  PubMed  CAS  Google Scholar 

  47. L. Chen, J. Zhang, Y. Zhang, Y. Wang, B. Wang, Improvement of inflammatory responses associated with NF-kappa B pathway in kidneys from diabetic rats. Inflamm. Res. 57, 199–204 (2008)

    Article  PubMed  CAS  Google Scholar 

  48. M. Buraczynska, P. Zukowski, P. Wacinski, B. Berger-Smyka, M. Dragan, S. Mozul, Chemotactic cytokine receptor 5 gene polymorphism: relevance to microvascular complications in type 2 diabetes. Cytokine 58, 213–217 (2012)

    Article  PubMed  CAS  Google Scholar 

  49. K. Kalantarinia, A.S. Awad, H.M. Siragy, Urinary and renal interstitial concentrations of TNF-alpha increase prior to the rise in albuminuria in diabetic rats. Kidney Int. 64, 1208–1213 (2003)

    Article  PubMed  CAS  Google Scholar 

  50. Y. Moriwaki, T. Inokuchi, A. Yamamoto, T. Ka, Z. Tsutsumi, S. Takahashi, Effect of TNF-alpha inhibition on urinary albumin excretion in experimental diabetic rats. Acta Diabetol. 44, 215–218 (2007)

    Article  PubMed  CAS  Google Scholar 

  51. M.A. Niewczas, T. Gohda, J. Skupien, A.M. Smiles, W.H. Walker, F. Rosetti, Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes. J. Am. Soc. Nephrol. 23, 507–515 (2012)

    Article  PubMed  CAS  Google Scholar 

  52. J. Liu, Z. Zhao, M.D. Willcox, B. Xu, B. Shi, Multiplex bead analysis of urinary cytokines of type 2 diabetic patients with normo- and microalbuminuria. J. Immunoass. Immunochem. 31, 279–289 (2010)

    Article  Google Scholar 

  53. S. Jain, A. Rajput, Y. Kumar, N. Uppuluri, A.S. Arvind, U. Tatu, Proteomic analysis of urinary protein markers for accurate prediction of diabetic kidney disorder. J. Assoc. Physicians India 53, 513–520 (2005)

    PubMed  Google Scholar 

  54. R. Ben Ameur, L. Molina, C. Bolvin, C. Kifagi, F. Jarraya, H. Ayadi, Proteomic approaches for discovering biomarkers of diabetic nephropathy. Nephrol. Dial. Transplant. 25, 2866–2875 (2010)

    Article  PubMed  CAS  Google Scholar 

  55. A. Alkhalaf, P. Zurbig, S.J. Bakker, H.J. Bilo, M. Cerna, C. Fischer, Multicentric validation of proteomic biomarkers in urine specific for diabetic nephropathy. PLoS ONE 5, e13421 (2010)

    Article  PubMed  Google Scholar 

  56. H. Jiang, G. Guan, R. Zhang, G. Liu, H. Liu, X. Hou, Increased urinary excretion of orosomucoid is a risk predictor of diabetic nephropathy. Nephrology (Carlton) 14, 332–337 (2009)

    Article  CAS  Google Scholar 

  57. A. Lapolla, L. Molin, R. Seraglia, A. Sechi, C. Cosma, L. Bonfantel, Urinary peptides as a diagnostic tool for renal failure detected by matrix-assisted laser desorption/ionisation mass spectrometry: an evaluation of their clinical significance. Eur. J. Mass Spectrom. (Chichester, Eng.) 17, 245–253 (2011)

    Article  CAS  Google Scholar 

  58. H. Dihazi, G.A. Muller, S. Lindner, M. Meyer, A.R. Asif, M. Oellerich, Characterization of diabetic nephropathy by urinary proteomic analysis: identification of a processed ubiquitin form as a differentially excreted protein in diabetic nephropathy patients. Clin. Chem. 2007(53), 1636–1645 (2007)

    Article  Google Scholar 

  59. W.G. Fisher, J.E. Lucas, U.F. Mehdi, D.W. Qunibi, H.R. Garner, K.P. Rosenblatt, A method for isolation and identification of urinary biomarkers in patients with diabetic nephropathy. Proteomics Clin. Appl. 5, 603–612 (2011)

    Article  PubMed  CAS  Google Scholar 

  60. H. Jiang, G. Guan, R. Zhang, G. Liu, J. Cheng, X. Hou, Identification of urinary soluble E-cadherin as a novel biomarker for diabetic nephropathy. Diabetes Metab. Res. Rev. 25, 232–241 (2009)

    Article  PubMed  CAS  Google Scholar 

  61. S.C. Lim, D.Q. Liying, W.C. Toy, M. Wong, L.Y. Yeoh, C. Tan, Adipocytokine zinc alpha(2) glycoprotein (ZAG) as a novel urinary biomarker for normo-albuminuric diabetic nephropathy. Diabet. Med. 29, 945–949 (2012)

    Article  PubMed  CAS  Google Scholar 

  62. S. Chen, B. Jim, F.N. Ziyadeh, Diabetic nephropathy and transforming growth factor-beta: transforming our view of glomerulosclerosis and fibrosis build-up. Semin. Nephrol. 23, 532–543 (2003)

    Article  PubMed  CAS  Google Scholar 

  63. T.J. Cawood, M. Bashir, J. Brady, B. Murray, P.T. Murray, D. O’Shea, Urinary collagen IV and piGST: potential biomarkers for detecting localized kidney injury in diabetes–a pilot study. Am. J. Nephrol. 32, 219–225 (2010)

    Article  PubMed  CAS  Google Scholar 

  64. C.R. Ban, S.M. Twigg, Fibrosis in diabetes complications: pathogenic mechanisms and circulating and urinary markers. Vasc. Health Risk Manag. 4, 575–596 (2008)

    PubMed  CAS  Google Scholar 

  65. P. Sthaneshwar, S.P. Chan, Urinary type IV collagen levels in diabetes mellitus. Malays. J. Pathol. 32, 43–47 (2010)

    PubMed  Google Scholar 

  66. P. Katavetin, Susantitaphong, N. Townamchai, K. Tiranathanagul, K. Tungsanga, S. Eiam-Ong, Urinary type IV collagen excretion predicts subsequent declining renal function in type 2 diabetic patients with proteinuria. Diabetes Res. Clin. Pract. 89, e33–e35 (2010)

    Article  PubMed  CAS  Google Scholar 

  67. N. Kashihara, Y. Haruna, V.K. Kondeti, Y.S. Kanwar, Oxidative stress in diabetic nephropathy. Curr. Med. Chem. 17, 4256–4269 (2010)

    Article  PubMed  CAS  Google Scholar 

  68. Y. Hinokio, S. Suzuki, M. Hirai, C. Suzuki, M. Suzuki, T. Toyota, Urinary excretion of 8-oxo-7, 8-dihydro-2′-deoxyguanosine as a predictor of the development of diabetic nephropathy. Diabetologia 45, 877–882 (2002)

    Article  PubMed  CAS  Google Scholar 

  69. M.T. Coughlan, S.K. Patel, G. Jerums, S.A. Penfold, T.V. Nguyen, K.C. Sourris, Advanced glycation urinary protein-bound biomarkers and severity of diabetic nephropathy in man. Am. J. Nephrol. 34, 347–355 (2011)

    Article  PubMed  CAS  Google Scholar 

  70. M. Zheng, L.L. Lv, J. Ni, H.F. Ni, Q. Li, K.L. Ma, Urinary podocyte-associated mRNA profile in various stages of diabetic nephropathy. PLoS ONE 6, e20431 (2011)

    Article  PubMed  CAS  Google Scholar 

  71. H. Chen, Z. Zheng, R. Li, J. Lu, Y. Bao, X. Ying, Urinary pigment epithelium-derived factor as a marker of diabetic nephropathy. Am. J. Nephrol. 32, 47–56 (2010)

    Article  PubMed  CAS  Google Scholar 

  72. A.J. Branten, G. Vervoort, J.F. Wetzels, Serum creatinine is a poor marker of GFR in nephrotic syndrome. Nephrol. Dial. Transplant. 20, 707–711 (2005)

    Article  PubMed  CAS  Google Scholar 

  73. O.F. Laterza, C.P. Price, M.G. Scott, Cystatin C: an improved estimator of glomerular filtration rate? Clin. Chem. 48, 699–707 (2002)

    PubMed  CAS  Google Scholar 

  74. L.A. Stevens, C.H. Schmid, T. Greene, L. Li, G.J. Beck, M.M. Joffe, Factors other than glomerular filtration rate affect serum cystatin C levels. Kidney Int. 75, 652–660 (2009)

    Article  PubMed  CAS  Google Scholar 

  75. G. Tramonti, I. Cipollini, C. Annichiarico, P. Lorusso, E. Panicucci, G. Mariani, Creatinine clearance, cystatin C, beta2-microglobulin and TATI as markers of renal function in patients with proteinuria. J. Nephrol (2012). doi:10.5301/jn.5000078

    PubMed  Google Scholar 

  76. C. Bianchi, C. Donadio, G. Tramonti, Noninvasive methods for the measurement of total renal function. Nephron 28, 53–57 (1981)

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Supported by NIH grant DK60635. We thank Dr. Elisabeth I. Wallner for proof-reading the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yashpal S. Kanwar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tramonti, G., Kanwar, Y.S. Review and discussion of tubular biomarkers in the diagnosis and management of diabetic nephropathy. Endocrine 43, 494–503 (2013). https://doi.org/10.1007/s12020-012-9820-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-012-9820-y

Keywords

Navigation