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.
Similar content being viewed by others
References
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)
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)
C.C. Tisher, R.C. McCoy, Diabetes mellitus and the kidney. Perspect. Nephrol. Hypertens. 3, 105–128 (1976)
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)
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)
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)
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)
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)
J.M. Halimi, The emerging concept of chronic kidney disease without clinical proteinuria in diabetic patients. Diabetes Metab. 38(4), 291–297 (2012)
M.C. Thomas, W.C. Burns, M.E. Cooper, Tubular changes in early diabetic nephropathy. Adv. Chronic Kidney Dis. 12, 177–186 (2005)
S.C. Tang, J.C. Leung, K.N. Lai, Diabetic tubulopathy: an emerging entity. Contrib. Nephrol. 170, 124–134 (2011)
R.J. Baines, N.J. Brunskill, Tubular toxicity of proteinuria. Nat. Rev. Nephrol. 7, 177–180 (2011)
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)
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)
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)
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)
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)
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)
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)
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)
W.S. Waring, A. Moonie, Earlier recognition of nephrotoxicity using novel biomarkers of acute kidney injury. Clin. Toxicol. (Phila) 49, 720–728 (2011)
K. Mori, K. Nakao, Neutrophil gelatinase-associated lipocalin as the real-time indicator of active kidney damage. Kidney Int. 71, 967–970 (2007)
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)
P. Devarajan, Neutrophil gelatinase-associated lipocalin (N-GAL): a new marker of kidney disease. Scand. J. Clin. Lab. Invest. Suppl. 241, 89–94 (2008)
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)
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)
P. Devarajan, Biomarkers for the early detection of acute kidney injury. Curr. Opin. Pediatr. 23, 194–200 (2011)
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)
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)
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)
B. Lisowska-Myjak, Serum and urinary biomarkers of acute kidney injury. Blood Purif. 29, 357–365 (2010)
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)
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)
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)
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)
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)
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)
G. Tramonti, Y.S. Kanwar, Tubular biomarkers to assess progression of diabetic nephropathy. Kidney Int. 79, 1042–1044 (2011)
P. Devarajan, The use of targeted biomarkers for chronic kidney disease. Adv Chronic Kidney Dis. 17, 469–479 (2010)
A. Kamijo-Ikemori, T. Sugaya, K. Kimura, Urinary fatty acid binding protein in renal disease. Clin. Chim. Acta 374, 1–7 (2006)
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)
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)
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)
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)
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)
C.C. Wu, H.K. Sytwu, Y.F. Lin, Cytokines in diabetic nephropathy. Adv. Clin. Chem. 56, 55–74 (2012)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
P. Sthaneshwar, S.P. Chan, Urinary type IV collagen levels in diabetes mellitus. Malays. J. Pathol. 32, 43–47 (2010)
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)
N. Kashihara, Y. Haruna, V.K. Kondeti, Y.S. Kanwar, Oxidative stress in diabetic nephropathy. Curr. Med. Chem. 17, 4256–4269 (2010)
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)
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)
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)
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)
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)
O.F. Laterza, C.P. Price, M.G. Scott, Cystatin C: an improved estimator of glomerular filtration rate? Clin. Chem. 48, 699–707 (2002)
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)
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
C. Bianchi, C. Donadio, G. Tramonti, Noninvasive methods for the measurement of total renal function. Nephron 28, 53–57 (1981)
Acknowledgments
Supported by NIH grant DK60635. We thank Dr. Elisabeth I. Wallner for proof-reading the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-012-9820-y