Skip to main content

Advertisement

SpringerLink
Log in

Urinary biomarkers for early diabetic nephropathy: beyond albuminuria

  • Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Diabetic nephropathy (DN) is the most common cause of end-stage kidney disease in the USA and accounts for a significant increase in morbidity and mortality in patients with diabetes. Early detection is critical in improving clinical management. Although microalbuminuria is regarded as the gold standard for diagnosing the onset of DN, its predictive powers are limited. Consequently, great efforts have been made in recent years to identify better strategies for the detection of early stages of DN and progressive kidney function decline in diabetic patients. Here, we review the various urinary biomarkers that have emerged from these studies which hold promise as more sensitive diagnostic tools for the earlier detection of diabetic kidney disease and the prediction of progression to end-stage kidney disease. A number of key biomarkers present in the urine have been identified that reflect kidney injury at specific sites along the nephron, including glomerular/podocyte damage and tubular damage, oxidative stress, inflammation and activation of the intrarenal renin–angiotensin system. We also describe newer approaches, including urinary microRNAs, which are short noncoding mRNAs that regulate gene expression, and urine proteomics, that can be used to identify potential novel biomarkers in the development and progression of diabetic kidney disease.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Imperatore G, Boyle JP, Thompson TJ, Case D, Dabelea D, Hamman RF, Lawrence JM, Liese AD, Liu LL, Mayer-Davis EJ, Rodriguez BL, Standiford D (2012) SEARCH for diabetes in youth study group. Projections of type 1 and type 2 diabetes burden in the U.S. Population aged <20 years through 2050: dynamic modeling of incidence, mortality, and population growth. Diabetes Care 35:2515–2520

    Article  PubMed Central  PubMed  Google Scholar 

  2. Stanton RC (2014) Frontiers in diabetic kidney disease: introduction. Am J Kidney Dis 63[2 Suppl 2]:S1–2

    Article  PubMed  Google Scholar 

  3. Perkins BA, Ficociello LH, Roshan B, Warram JH, Krolewski AS (2010) In patients with type 1 diabetes and new-onset microalbuminuria the development of advanced chronic kidney disease may not require progression to proteinuria. Kidney Int 77:57–64

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR; UKPDS GROUP (2003) Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 63:225–232

  5. Zachwieja J, Soltysiak J, Fichna P, Lipkowska K, Stankiewicz W, Skowronska B, Kroll P, Lewandowska-Stachowiak M (2010) Normal-range albuminuria does not exclude nephropathy in diabetic children. Pediatr Nephrol 25:1445–1451

    Article  PubMed  Google Scholar 

  6. Fioretto P, Steffes MW, Mauer M (1994) Glomerular structure in nonproteinuric IDDM patients with various levels of albuminuria. Diabetes 43:1358–1364

    Article  CAS  PubMed  Google Scholar 

  7. Kramer HJ, Nguyen QD, Curhan G, Hsu CY (2003) Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. JAMA 289:3273–3277

    Article  PubMed  Google Scholar 

  8. MacIsaac RJ, Tsalamandris C, Panagiotopoulos S, Smith TJ, McNeil KJ, Jerums G (2004) Nonalbuminuric renal insufficiency in type 2 diabetes. Diabetes Care 27:195–200

    Article  PubMed  Google Scholar 

  9. Araki S, Haneda M, Sugimoto T, Isono M, Isshiki K, Kashiwagi A, Koya D (2005) Factors associated with frequent remission of microalbuminuria in patients with type 2 diabetes. Diabetes 54:2983–2987

    Article  CAS  PubMed  Google Scholar 

  10. Glassock RJ (2010) Is the presence of microalbuminuria a relevant marker of kidney disease? Curr Hypertens Rep 12:364–368

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Lewis EJ, Xu X (2008) Abnormal glomerular permeability characteristics in diabetic nephropathy: implications for the therapeutic use of low-molecular weight heparin. Diabetes Care 31[Suppl 2]:S202–S207

    Article  CAS  PubMed  Google Scholar 

  12. Memişoğullari R, Bakan E (2004) Levels of ceruloplasmin, transferrin, and lipid peroxidation in the serum of patients with Type 2 diabetes mellitus. J Diabetes Complicat 18:193–197

    Article  PubMed  Google Scholar 

  13. Narita T, Sasaki H, Hosoba M, Miura T, Yoshioka N, Morii T, Shimotomai T, Koshimura J, Fujita H, Kakei M, Ito S (2004) Parallel increase in urinary excretion rates of immunoglobulin G, ceruloplasmin, transferrin, and orosomucoid in normoalbuminuric type 2 diabetic patients. Diabetes Care 27:1176–1181

    Article  CAS  PubMed  Google Scholar 

  14. Cheung CK, Cockram CS, Yeung VT, Swaminathan R (1989) Urinary excretion of transferrin by non-insulin-dependent diabetics: a marker for early complications? Clin Chem 35:1672–1674

    CAS  PubMed  Google Scholar 

  15. Kazumi T, Hozumi T, Ishida Y, Ikeda Y, Kishi K, Hayakawa M, Yoshino G (1999) Increased urinary transferrin excretion predicts microalbuminuria in patients with type 2 diabetes. Diabetes Care 22:1176–1180

    Article  CAS  PubMed  Google Scholar 

  16. Narita T, Hosoba M, Kakei M, Ito S (2006) Increased urinary excretions of immunoglobulin G, ceruloplasmin, and transferrin predict development of microalbuminuria in patients with type 2 diabetes. Diabetes Care 29:142–144

    Article  CAS  PubMed  Google Scholar 

  17. Martin P, Walton C, Chapman C, Bodansky HJ, Stickland MH (1990) Increased urinary excretion of transferrin in children with type 1 diabetes mellitus. Diabet Med 7:35–40

    Article  CAS  PubMed  Google Scholar 

  18. Mackinnon B, Shakerdi L, Deighan CJ, Fox JG, O’Reilly DS, Boulton-Jones M (2003) Urinary transferrin, high molecular weight proteinuria and the progression of renal disease. Clin Nephrol 59:252–258

    Article  CAS  PubMed  Google Scholar 

  19. Su J, Li SJ, Chen ZH, Zeng CH, Zhou H, Li LS, Liu ZH (2010) Evaluation of podocyte lesion in patients with diabetic nephropathy: Wilms’ tumor-1 protein used as a podocyte marker. Diabetes Res Clin Pract 87:167–175

    Article  CAS  PubMed  Google Scholar 

  20. Pätäri A, Forsblom C, Havana M, Taipale H, Groop PH, Holthofer H (2003) Nephrinuria in diabetic nephropathy of type 1 diabetes. Diabetes 52:2969–2974

    Article  PubMed  Google Scholar 

  21. Kalani A, Mohan A, Godbole MM, Bhatia E, Gupta A, Sharma RK, Tiwari S (2013) Wilm’s tumor-1 protein levels in urinary exosomes from diabetic patients with or without proteinuria. PLoS One 8:e60177

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Wang SX, Rastaldi MP, Patari A, Ahola H, Heikkila E, Holthofer H (2002) Patterns of nephrin and a new proteinuria-associated protein expression in human renal diseases. Kidney Int 61:141–147

    Article  CAS  PubMed  Google Scholar 

  23. Jim B, Ghanta M, Qipo A, Fan Y, Chuang PY, Cohen HW, Abadi M, Thomas DB, He JC (2012) Dysregulated nephrin in diabetic nephropathy of type 2 diabetes: a cross sectional study. PLoS One 7:e36041

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Hara M, Yamagata K, Tomino Y, Saito A, Hirayama Y, Ogasawara S, Kurosawa H, Sekine S, Yan K (2012) Urinary podocalyxin is an early marker for podocyte injury in patients with diabetes: establishment of a highly sensitive ELISA to detect urinary podocalyxin. Diabetologia 55:2913–2919

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Zheng M, Lv LL, Ni J, Ni HF, Li Q, Ma KL, Liu BC (2011) Urinary podocyte-associated mRNA profile in various stages of diabetic nephropathy. PLoS One 6:e20431

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Wickman L, Afshinnia F, Wang SQ, Yang Y, Wang F, Chowdhury M, Graham D, Hawkins J, Nishizono R, Tanzer M, Wiggins J, Escobar GA, Rovin B, Song P, Gipson D, Kershaw D, Wiggins RC (2013) Urine podocyte mRNAs, proteinuria, and progression in human glomerular diseases. J Am Soc Nephrol 24:2081–2095

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Nielsen JS, McNagny KM (2009) The role of podocalyxin in health and disease. J Am Soc Nephrol 20:1669–1676

    Article  CAS  PubMed  Google Scholar 

  28. Kubo K, Miyagawa K, Yamamoto R, Hamasaki K, Kanda H, Fujita T, Yamamoto K, Yazaki Y, Mimura T (1999) Detection of WT1 mRNA in urine from patients with kidney diseases. Eur J Clin Investig 29:824–826

    Article  CAS  Google Scholar 

  29. Kim NH, Oh JH, Seo JA, Lee KW, Kim SG, Choi KM, Baik SH, Choi DS, Kang YS, Han SY, Han KH, Ji YH, Cha DR (2005) Vascular endothelial growth factor (VEGF) and soluble VEGF receptor FLT-1 in diabetic nephropathy. Kidney Int 67:167–177

    Article  CAS  PubMed  Google Scholar 

  30. Karalliedde J, Gnudi L (2011) Endothelial factors and diabetic nephropathy. Diabetes Care 34:S291–S296

    Article  PubMed Central  PubMed  Google Scholar 

  31. Singh A, Fridén V, Dasgupta I, Foster RR, Welsh GI, Tooke JE, Haraldsson B, Mathieson PW, Satchell SC (2011) High glucose causes dysfunction of the human glomerular endothelial glycocalyx. Am J Physiol Renal Physiol 300:F40–F48

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Nieuwdorp M, Mooij HL, Kroon J, Atasever B, Spaan JA, Ince C, Holleman F, Diamant M, Heine RJ, Hoekstra JB, Kastelein JJ, Stroes ES, Vink H (2006) Endothelial glycocalyx damage coincides with microalbuminuria in type 1 diabetes. Diabetes 55:1127–1132

    Article  CAS  PubMed  Google Scholar 

  33. Popławska-Kita A, Mierzejewska-Iwanowska B, Szelachowska M, Siewko K, Nikołajuk A, Kinalska I, Górska M (2008) Glycosaminoglycans urinary excretion as a marker of the early stages of diabetic nephropathy and the disease progression. Diabetes Metab Res Rev 24:310–317

    Article  PubMed  Google Scholar 

  34. Torffvit O (1999) Urinary sulphated glycosaminoglycans and Tamm-Horsfall protein in type 1 diabetic patients. Scand J Urol Nephrol 33:328–332

    Article  CAS  PubMed  Google Scholar 

  35. Iijima T, Suzuki S, Sekizuka K, Hishiki T, Yagame M, Jinde K, Saotome N, Suzuki D, Sakai H, Tomino Y (1998) Follow-up study on urinary type IV collagen in patients with early stage diabetic nephropathy. J Clin Lab Anal 12:378–382

    Article  CAS  PubMed  Google Scholar 

  36. Kotajima N, Kimura T, Kanda T, Obata K, Kuwabara A, Fukumura Y, Kobayashi I (2000) Type IV collagen as an early marker for diabetic nephropathy in non-insulin-dependent diabetes mellitus. J Diabetes Complicat 14:13–17

    Article  CAS  PubMed  Google Scholar 

  37. Cawood TJ, Bashir M, Brady J, Murray B, Murray PT, O’Shea D (2010) Urinary collagen IV and πGST: potential biomarkers for detecting localized kidney injury in diabetes—a pilot study. Am J Nephrol 32:219–225

    Article  CAS  PubMed  Google Scholar 

  38. Morita M, Uchigata Y, Hanai K, Ogawa Y, Iwamoto Y (2011) Association of urinary type IV collagen with GFR decline in young patients with type 1 diabetes. Am J Kidney Dis 58:915–920

    Article  CAS  PubMed  Google Scholar 

  39. Araki S, Haneda M, Koya D, Isshiki K, Kume S, Sugimoto T, Kawai H, Nishio Y, Kashiwagi A, Uzu T, Maegawa H (2010) Association between urinary type IV collagen level and deterioration of renal function in type 2 diabetic patients without overt proteinuria. Diabetes Care 33:1805–1810

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Zheng M, Lv LL, Cao YH, Zhang JD, Wu M, Ma KL, Phillips AO, Liu BC (2012) Urinary mRNA markers of epithelial mesenchymal transition correlate with progression of diabetic nephropathy. Clin Endocrinol 76:657–664

    Article  CAS  Google Scholar 

  41. McKittrick IB, Bogaert Y, Nadeau K, Snell-Bergeon J, Hull A, Jiang T, Wang X, Levi M, Moulton KS (2011) Urinary matrix metalloproteinase activities: biomarkers for plaque angiogenesis and nephropathy in diabetes. Am J Physiol Renal Physiol 301:F1326–F1333

    Article  PubMed Central  PubMed  Google Scholar 

  42. Fagerudd JA, Groop PH, Honkanen E, Teppo AM, Gronhagen-Riska C (1997) Urinary excretion of TGF-β1, PDGFBB and fibronectin in insulin-dependent diabetes mellitus patients. Kidney Int 51:S195–S197

    Article  Google Scholar 

  43. Takahashi M (1995) Increased urinary fibronectin excretion in type II diabetic patients with microalbuminuria. Nihon Jinzo Gakkai Shi 37:336–342

    CAS  PubMed  Google Scholar 

  44. Gilbert RE, Wilkinson BJL, Johnson DW, Cox J, Soulis T, Wu LL, Kelly DJ, Jerums G, Pollock CA, Cooper ME (1998) Renal expression of transforming growth factor-β-inducible gene-h3 (βig-h3) in normal and diabetic rats. Kidney Int 54:1052–1062

    Article  CAS  PubMed  Google Scholar 

  45. Ha SW, Kim HJ, Bae JS, Jeong GH, Chung SC, Kim JG, Park SH, Kim YL, Kam S, Kim IS, Kim BW (2004) Elevation of urinary βig-h3, transforming growth factor-β-induced protein in patients with type 2 diabetes and nephropathy. Diabetes Res Clin Pract 65:167–173

    Article  CAS  PubMed  Google Scholar 

  46. Cha DR, Kim IS, Kang YS, Han SY, Han KH, Shin C, Ji YH, Kim NH (2005) Urinary concentration of transforming growth factor-β-inducible gene-h3(βig-h3) in patients with Type 2 diabetes mellitus. Diabet Med 22:14–20

    Article  CAS  PubMed  Google Scholar 

  47. Sharma K, Ziyadeh FN, Alzahabi B, McGowan TA, Kapoor S, Kurnik BR, Kurnik PB, Weisberg LS (1997) Increased renal production of transforming growth factor-beta1 in patients with type II diabetes. Diabetes 46:854–859

    Article  CAS  PubMed  Google Scholar 

  48. Korpinen E, Teppo AM, Hukkanen L, Akerblom HK, Grönhagen-Riska C, Vaarala O (2000) Urinary transforming growth factor-beta1 and alpha1-microglobulin in children and adolescents with type 1 diabetes. Diabetes Care 23:664–668

    Article  CAS  PubMed  Google Scholar 

  49. Gilbert RE, Akdeniz A, Allen TJ, Jerums G (2001) Urinary transforming growth factor-β in patients with diabetic nephropathy: implications for the pathogenesis of tubulointerstitial pathology. Nephrol Dial Transplant 16:2442–2443

    Article  CAS  PubMed  Google Scholar 

  50. Sato H, Iwano M, Akai Y, Kurioka H, Kubo A, Yamaguchi T, Hirata E, Kanauchi M, Dohi K (1998) Increased excretion of urinary transforming growth factor beta 1 in patients with diabetic nephropathy. Am J Nephrol 18:490–494

    Article  CAS  PubMed  Google Scholar 

  51. Verhave JC, Bouchard J, Goupil R, Pichette V, Brachemi S, Madore F, Troyanov S (2013) Clinical value of inflammatory urinary biomarkers in overt diabetic nephropathy: a prospective study. Diabetes Res Clin Pract 101:333–340

    Article  CAS  PubMed  Google Scholar 

  52. Titan SM, Vieira JM Jr, Dominguez WV, Moreira SR, Pereira AB, Barros RT, Zatz R (2012) Urinary MCP-1 and RBP: independent predictors of renal outcome in macroalbuminuric diabetic nephropathy. J Diabetes Complicat 26:546–553

    Article  CAS  PubMed  Google Scholar 

  53. Nguyen TQ, Tarnow L, Andersen S, Hovind P, Parving HH, Goldschmeding R, van Nieuwenhoven FA (2006) Urinary connective tissue growth factor excretion correlates with clinical markers of renal disease in a large population of type 1 diabetic patients with diabetic nephropathy. Diabetes Care 29:83–88

    Article  CAS  PubMed  Google Scholar 

  54. Tam FW, Riser BL, Meeran K, Rambow J, Pusey CD, Frankel AH (2009) Urinary monocyte chemoattractant protein-1 (MCP-1) and connective tissue growth factor (CCN2) as prognostic markers for progression of diabetic nephropathy. Cytokine 47:37–42

    Article  CAS  PubMed  Google Scholar 

  55. Kalansooriya A, Holbrook I, Jennings P, Whiting PH (2007) Serum cystatin C, enzymuria, tubular proteinuria and early renal insult in type 2 diabetes. Br J Biomed Sci 64:121–123

    CAS  PubMed  Google Scholar 

  56. Kim SS, Song SH, Kim IJ, Jeon YK, Kim BH, Kwak IS, Lee EK, Kim YK (2013) Urinary cystatin C and tubular proteinuria predict progression of diabetic nephropathy. Diabetes Care 36:656–661

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Herget-Rosenthal S, Feldkamp T, Volbracht L, Kribben A (2004) Measurement of urinary cystatin C by particle-enhanced nephelometric immunoassay: precision, interferences, stability and reference range. Ann Clin Biochem 41:111–118

    Article  CAS  PubMed  Google Scholar 

  58. White KE, Bilous RW (2000) Type 2 diabetic patients with nephropathy show structural-functional relationships that are similar to type 1 disease. J Am Soc Nephrol 11:1667–1673

    CAS  PubMed  Google Scholar 

  59. Dickson LE, Wagner MC, Sandoval RM, Molitoris BA (2014) The proximal tubule and albuminuria: really! J Am Soc Nephrol 25:443–453

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Russo LM, Sandoval RM, Campos SB, Molitoris BA, Comper WD, Brown D (2009) Impaired tubular uptake explains albuminuria in early diabetic nephropathy. J Am Soc Nephrol 20:489–494

    Article  PubMed Central  PubMed  Google Scholar 

  61. Christensen EI, Birn H (2001) Megalin and cubilin: synergistic endocytic receptors in renal proximal tubule. Am J Physiol Renal Physiol 280:F562–F573

    CAS  PubMed  Google Scholar 

  62. Amsellem S, Gburek J, Hamard G, Nielsen R, Willnow TE, Devuyst O, Nexo E, Verroust PJ, Christensen EI, Kozyraki R (2010) Cubilin is essential for albumin reabsorption in the renal proximal tubule. J Am Soc Nephrol 21:1859–1867

  63. Thrailkill KM, Nimmo T, Bunn RC, Cockrell GE, Moreau CS, Mackintosh S, Edmondson RD, Fowlkes JL (2009) Microalbuminuria in type 1 diabetes is associated with enhanced excretion of the endocytic multiligand receptors megalin and cubilin. Diabetes Care 32:1266–1268

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Ogasawara S, Hosojima M, Kaseda R, Kabasawa H, Yamamoto-Kabasawa K, Kurosawa H, Sato H, Iino N, Takeda T, Suzuki Y, Narita I, Yamagata K, Tomino Y, Gejyo F, Hirayama Y, Sekine S, Saito A (2012) Significance of urinary full-length and ectodomain forms of megalin in patients with type 2 diabetes. Diabetes Care 35:1112–1118

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Hong CY, Hughes K, Chia KS, Ng V, Ling SL (2003) Urinary alpha1-microglobulin as a marker of nephropathy in type 2 diabetic Asian subjects in Singapore. Diabetes Care 26:338–342

    Article  CAS  PubMed  Google Scholar 

  66. Salem MA, el-Habashy SA, Saeid OM, el-Tawil MM, Tawfik PH (2002) Urinary excretion of n-acetyl-beta-D-glucosaminidase and retinol binding protein as alternative indicators of nephropathy in patients with type 1 diabetes mellitus. Pediatr Diabetes 3:37–41

  67. Koh KT, Chia KS, Tan C (1993) Proteinuria and enzymuria in non-insulin-dependent diabetics. Diabetes Res Clin Pract 20:215–221

    Article  CAS  PubMed  Google Scholar 

  68. Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, Ruff SM, Zahedi K, Shao M, Bean J, Mori K, Barasch J, Devarajan P (2005) Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 365:1231–1238

    Article  CAS  PubMed  Google Scholar 

  69. Nielsen SE, Schjoedt KJ, Astrup AS, Tarnow L, Lajer M, Hansen PR, Parving HH, Rossing P (2010) Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Injury Molecule 1 (KIM1) in patients with diabetic nephropathy: a cross-sectional study and the effects of lisinopril. Diabet Med 27:1144–1150

    Article  CAS  PubMed  Google Scholar 

  70. Nielsen SE, Reinhard H, Zdunek D, Hess G, Gutierrez OM, Wolf M, Parving HH, Jacobsen PK, Rossing P (2012) Tubular markers are associated with decline in kidney function in proteinuric type 2 diabetic patients. Diabetes Res Clin Pract 97:71–76

    Article  CAS  PubMed  Google Scholar 

  71. Fu WJ, Xiong SL, Fang YG, Wen S, Chen ML, Deng RT, Zheng L, Wang SB, Pen LF, Wang Q (2012) Urinary tubular biomarkers in short-term type 2 diabetes mellitus patients: a cross-sectional study. Endocrine 41:82–88

    Article  CAS  PubMed  Google Scholar 

  72. Kanauchi M, Nishioka H, Hashimoto T (2002) Oxidative DNA damage and tubulointerstitial injury in diabetic nephropathy. Nephron 91:327–329

    Article  CAS  PubMed  Google Scholar 

  73. Leinonen J, Lehtimaki T, Toyokuni S, Okada K, Tanaka T, Hiai H, Ochi H, Laippala P, Rantalaiho V, Wirta O, Pasternack A, Alho H (1997) New biomarker evidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitus. FEBS Lett 417:150–152

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  75. Broedbaek K, Weimann A, Stovgaard ES, Poulsen HE (2011) Urinary 8-oxo-7,8-dihydro-2 deoxyguanosine as a biomarker in type 2 diabetes. Free Radic Biol Med 51:1473–1479

    Article  CAS  PubMed  Google Scholar 

  76. Serdar M, Sertoglu E, Uyanik M, Tapan S, Akin K, Bilgi C, Kurt I (2012) Comparison of 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels using mass spectrometer and urine albumin creatinine ratio as a predictor of development of diabetic nephropathy. Free Radic Res 46:1291–1295

    Article  CAS  PubMed  Google Scholar 

  77. Wolkow PP, Niewczas MA, Perkins B, Ficociello LH, Lipinski B, Warram JH, Krolewski AS (2008) Association of urinary inflammatory markers and renal decline in microalbuminuric type 1 diabetics. J Am Soc Nephrol 19:789–797

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Timoshanko JR, Sedgwick JD, Holdsworth SR, Tipping PG (2003) Intrinsic renal cells are the major source of tumor necrosis factor contributing to renal injury in murine crescentic glomerulonephritis. J Am Soc Nephrol 14:1785–1793

    Article  CAS  PubMed  Google Scholar 

  79. Navarro JF, Mora C, Gomez M, Muros M, Lopez-Aguilar C, Garcia J (2008) Influence of renal involvement on peripheral blood mononuclear cell expression behaviour of tumour necrosis factor-alpha and interleukin-6 in type 2 diabetic patients. Nephrol Dial Transplant 23:919–926

    Article  CAS  PubMed  Google Scholar 

  80. Lu X, Roksnoer LC, Danser AH (2013) The intrarenal renin-angiotensin system: does it exist? Implications from a recent study in renal angiotensin-converting enzyme knockout mice. Nephrol Dial Transplant 28:2977–2982

    Article  CAS  PubMed  Google Scholar 

  81. Pohl M, Kaminski H, Castrop H, Bader M, Himmerkus N, Bleich M, Bachmann S, Theilig F (2010) Intrarenal renin angiotensin system revisited: role of megalin-dependent endocytosis along the proximal nephron. J Biol Chem 285:41935–41946

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Nishiyama A, Konishi Y, Ohashi N, Morikawa T, Urushihara M, Maeda I, Hamada M, Kishida M, Hitomi H, Shirahashi N, Kobori H, Imanishi M (2011) Urinary angiotensinogen reflects the activity of intrarenal renin-angiotensin system in patients with IgA nephropathy. Nephrol Dial Transplant 26:170–177

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Yamamoto T, Nakagawa T, Suzuki H, Ohashi N, Fukasawa H, Fujigaki Y, Kato A, Nakamura Y, Suzuki F, Hishida A (2007) Urinary angiotensinogen as a marker of intrarenal angiotensin II activity associated with deterioration of renal function in patients with chronic kidney disease. J Am Soc Nephrol 18:1558–1565

    Article  CAS  PubMed  Google Scholar 

  84. van den Heuvel M, Batenburg WW, Jainandunsing S, Garrelds IM, van Gool JM, Feelders RA, van den Meiracker AH, Danser AH (2011) Urinary renin, but not angiotensinogen or aldosterone, reflects the renal renin-angiotensin-aldosterone system activity and the efficacy of renin-angiotensin-aldosterone system blockade in the kidney. J Hypertens 29:2147–2155

    Article  PubMed  Google Scholar 

  85. Persson F, Lu X, Rossing P, Garrelds IM, Danser AH, Parving HH (2013) Urinary renin and angiotensinogen in type 2 diabetes: added value beyond urinary albumin? J Hypertens 31:1646–1652

    Article  CAS  PubMed  Google Scholar 

  86. McClelland A, Hagiwara S, Kantharidis P (2014) Where are we in diabetic nephropathy: microRNAs and biomarkers? Curr Opin Nephrol Hypertens 23:80–86

    Article  CAS  PubMed  Google Scholar 

  87. Szeto CC, Ching-Ha KB, Ka-Bik L, Mac-Moune LF, Cheung-Lung CP, Gang W, Kai-Ming C, Kam-Tao LP (2012) Micro-RNA expression in the urinary sediment of patients with chronic kidney diseases. Dis Markers 33:137–144

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  88. Argyropoulos C, Wang K, McClarty S, Huang D, Bernardo J, Ellis D, Orchard T, Galas D, Johnson J (2013) Urinary microRNA profiling in the nephropathy of type 1 diabetes. PLoS One 8:e54662

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Rossing K, Mischak H, Dakna M, Zürbig P, Novak J, Julian BA, Good DM, Coon JJ, Tarnow L, Rossing P; Network PREDICTIONS (2008) Urinary proteomics in diabetes and CKD. J Am Soc Nephrol 19:1283–1290

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  90. Alkhalaf A, Zürbig P, Bakker SJ, Bilo HJ, Cerna M, Fischer C, Fuchs S, Janssen B, Medek K, Mischak H, Roob JM, Rossing K, Rossing P, Rychlík I, Sourij H, Tiran B, Winklhofer-Roob BM, Navis GJ; PREDICTIONS Group (2010) Multicentric validation of proteomic biomarkers in urine specific for diabetic nephropathy. PLoS One 5:e13421

  91. Papale M, Di Paolo S, Magistroni R, Lamacchia O, Di Palma AM, De Mattia A, Rocchetti MT, Furci L, Pasquali S, De Cosmo S, Cignarelli M, Gesualdo L (2010) Urine proteome analysis may allow noninvasive differential diagnosis of diabetic nephropathy. Diabetes Care 33:2409–2415

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Zürbig P, Jerums G, Hovind P, Macisaac RJ, Mischak H, Nielsen SE, Panagiotopoulos S, Persson F, Rossing P (2012) Urinary proteomics for early diagnosis in diabetic nephropathy. Diabetes 61:3304–3313

    Article  PubMed Central  PubMed  Google Scholar 

  93. Roscioni SS, de Zeeuw D, Hellemons ME, Mischak H, Zürbig P, Bakker SJ, Gansevoort RT, Reinhard H, Persson F, Lajer M, Rossing P, Lambers Heerspink HJ (2013) A urinary peptide biomarker set predicts worsening of albuminuria in type 2 diabetes mellitus. Diabetologia 56:259–267

    Article  CAS  PubMed  Google Scholar 

  94. Wong MG, Perkovic V, Woodward M, Chalmers J, Li Q, Hillis GS, Yaghobian Azari D, Jun M, Poulter N, Hamet P, Williams B, Neal B, Mancia G, Cooper M, Pollock CA (2013) Circulating bone morphogenetic protein-7 and transforming growth factor-β1 are better predictors of renal end points in patients with type 2 diabetes mellitus. Kidney Int 83:278–284

    Article  CAS  PubMed  Google Scholar 

  95. Niewczas MA, Gohda T, Skupien J, Smiles AM, Walker WH, Rosetti F, Cullere X, Eckfeldt JH, Doria A, Mayadas TN, Warram JH, Krolewski AS (2012) Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes. J Am Soc Nephrol 23:507–515

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Gohda T, Niewczas MA, Ficociello LH, Walker WH, Skupien J, Rosetti F, Cullere X, Johnson AC, Crabtree G, Smiles AM, Mayadas TN, Warram JH, Krolewski AS (2012) Circulating TNF receptors 1 and 2 predict stage 3 CKD in type 1 diabetes. J Am Soc Nephrol 23:516–524

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Supported in part by the National Institutes of Health grants R01-DK57661, R01-HL079904, and P01-HL114501 to M.E.C.

Author information

Authors and Affiliations

  1. Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    So-Young Lee & Mary E. Choi

  2. Department of Internal Medicine, Bundang CHA Medical Center, CHA University, Seongnam, South Korea

    So-Young Lee

  3. Division of Nephrology & Hypertension, Department of Medicine, Weill Cornell Medical College, 525 East 68th Street, Box 3, New York, NY, 10065, USA

    Mary E. Choi

Authors
  1. So-Young Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mary E. Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mary E. Choi.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, SY., Choi, M.E. Urinary biomarkers for early diabetic nephropathy: beyond albuminuria. Pediatr Nephrol 30, 1063–1075 (2015). https://doi.org/10.1007/s00467-014-2888-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-014-2888-2

Keywords

Search

Navigation