Journal of IMAB - Annual Proceeding (Scientific Papers)
Publisher: Peytchinski, Gospodin Iliev
ISSN: 1312 773X (Online)
Issue: 2016, vol. 22, issue 2
Subject Area: Medicine
Pages: 1139-1148
DOI: 10.5272/jimab.2016222.1139
Published online: 08 June 2016

J of IMAB 2016 Apr-Jun;22(2):1139-1148
Goran Nikolov1 Corresponding Autor, Margaritka Boncheva2, Todor Gruev1, Katerina T. Trajkovska3, Irena Kostovska3.
1) University Clinic of Clinical Biochemistry, Skopje, Macedonia,
2) Department of General Medicine and Clinical Laboratory, Medical University of Varna, Bulgaria,
3) Institute of medical & experimental biochemistry, Medical Faculty – Skopje, Macedonia.

Early diagnosis of renal allograft dysfunction is crucial for the management and long-term survival of the transplanted kidney. Early after transplantation, acute tubular necrosis (ATN) manifesting as delay graft function (DGF) or slow graft function, acute rejection (AR) or drug toxicity (e.g. calcineurin inhibitor) are the leading causes of Acute kidney injury (AKI). Acute rejection, ATN, and calcineurin inhibitor toxicity continue to be major causes of renal allograft dysfunction along with other causes like infections (e.g. BK and CMV viruses, pyelonephritis), obstruction, and recurrence of the original disease. Clinicians have been searching for non-invasive tools that would allow the diagnosis of acute renal allograft dysfunction early and accurately without performing a kidney biopsy. The following comprehensive review will describe the latest findings on urinary biomarkers in acute allograft dysfunction.

Key words: Acute kidney injury (AKI), urinary biomarkers, renal transplantation,

- Download FULL TEXT /PDF 534 KB/
Please cite this article in PubMed Style or AMA (American Medical Association) Style:
Nikolov G, Boncheva M, Gruev T, Trajkovska KT, Kostovska I. URINARY BIOMARKERS FOR FOLLOW-UP OF RENAL TRANSPLANTATION - WHERE WE ARE! J of IMAB. 2016 Apr-Jun;22(2):1139-1148.

Correspondence to: Goram Nikolov, MD; University Clinic of Clinical Biochemistry, Skopje, Macedonia.; E-mail:

1. Alachkar N, Rabb H, Jaar BG. Urinary Biomarkers in Acute Kidney Transplant Dysfunction. Nephron Clin Pract. 2011; 118(2):c173-181. [PubMed]
2. Ge F, Dai Q, Gong W. Biomarkers for renal transplantation: where are we? Int J Nephrol Renovasc Dis. 2013 Oct:6;187-191. [PubMed]
3. Gong W, Whitcher GH, Townamchai N, Xiao X, Ge F. Biomarkers for monitoring therapeutic side effects or various supratherapeu­tic confounders after kidney transplantation. Transplant Proc. 2012 Jun;44(5):1265–1269. [PubMed]
4. Kotsch K, Mashreghi MF, Bold G, Tretow P, Beyer J, Matz M, et al. Enhanced granulysin mRNA expression in urinary sediment in early and delayed acute renal allograft rejection. Transplantation. 2004 Jun;77(12):1866–1875. [PubMed]
5. Bestard O, Crespo E, Stein M, Lúcia M, Roelen DL, de Vaal YJ, et al. Cross-validation of IFN-γ Elispot assay for measuring alloreactive memory/effector T cell responses in renal transplant recipients. Am J Transplant. 2013 Jul;13(7):1880-1890. [PubMed]
6. Dieterle F, Perentes E, Cordier A, Roth DR, Verdes P, Grenet O, et al. Urinary clusterin, cystatin C, beta2 microglobulin and total protein as markers to detect drug-induced kidney injury. Nat Biotechnol.2010 May;28(5):463-469. [PubMed]
7. Sawitzki B, Pascher A, Babel N, Reinke P, Volk HD. Can we use biomarkers and functional assays to implement personalized therapies in transplantation? Transplantation. 2009 Jun;87(11):1595–1601. [PubMed]
8. Li L, Khatri P, Sigdel TK, Tran T, Ying L, Vitalone MJ,  et al. A peripheral blood diagnostic test for acute rejection in renal transplantation. Am J Transplant. 2012 Oct;12(10):2710-2718. [PubMed]
9. Hoogland ER, de Vries EE, Christiaans MH, Winkens B, Snoeijs MG, van Heurn LW. The value of machine perfusion biomarker con­centration in DCD kidney transplantations. Transplantation. 2013 Feb;95(4):603-610. [PubMed]
10. Scian MJ, Maluf DG, Archer KJ, Turner SD, Suh JL, Krystle G David, et al. Identification of biomarkers to assess organ quality and predict posttransplantation outcomes. Transplantation. 2012 Oct;94(8):851-858. [PubMed]
11. Wen R, Wu V, Dmitrienko S, Yu A, Balshaw R, Keown PA, et al. Biomarkers in trans­plantation: prospective, blinded measurement of predictive value for the flow cytometry crossmatch after negative antiglobulin crossmatch in kidney transplantation. Kidney Int. 2006 Oct;70(8):1474-1481. [PubMed]
12. Vyas S, Roberti I. Lymphocyte ATP immune cell function assay in pedi­atric renal transplants: is it useful? Transplant Proc.  2011 Dec;43(10): 3675–3678. [PubMed]
13. Perera FP, Weinstein IB. Molecular epidemiology: recent advances and future directions. Carcinogenesis.2000 Mar;21(3):517-524. [PubMed]
14. Mayeux R. Biomarkers: Potential Uses and Limitations. NeuroRx. 2004 Apr;1(2):182-188. [PubMed]
15. Hoogland ER, de Vries EE, Christiaans MH, Winkens B, Snoeijs MG, van HeurLW. The value of machine perfusion biomarker con­centration in DCD kidney transplantations. Transplantation. 2013 Feb;95(4):603–610. [PubMed]
16. Scian MJ, Maluf DG, Archer KJ Stephen DT, Jihee LS,Krystle GD, et al. Identification of biomarkers to assess organ quality and predict posttransplantation outcomes. Transplantation. 2012 Oct;94(8):851-858. [PubMed]
17. Welberry Smith MP, Zougman A, Cairns DA, Wilson M, Wind T, Wood SL, et al. Serum aminoacylase-1 is a novel biomarker with potential prognostic utility for long-term outcome in patient with delayed graft function following renal transplantation. Kidney Int. 2013 Dec;84(6):1214-25. [PubMed]
18. Matas AJ, Payne WD, Sutherland DE Humar A, Gruessner RW, Kandaswamy R, et al. 2,500 living donor kid­ney transplants:  a single-center experience. Ann Surg. 2001 Aug;234(2): 149–164. [PubMed]
19. Devarajan P. Emerging Biomarkers of Acute Kidney Injury. Contrib Nephrol. 2007; 156:203-212. [PubMed]
20. Devarajan P. Emerging Urinary Biomarkers in the Diagnosis of Acute Kidney Injury. Expert Opin Med Diagn. 2008 Apr;2(4):387-398. [PubMed]
21. Tolkoff-Rubin NE, Rubin RH, Bonventre JV. Noninvasive Renal Diagnostic Studies. Clin Lab Med. 1988 Sep;8(3):507-526. [PubMed]
22. Bazzi C, Petrini C, Rizza V. Urinary Excretion of IgG and Alpha(1)-Microglobulin Predicts Clinical Course Better than Extent of Proteinuria in Membranous Nephropathy. Am J Kidney Dis. 2001 Aug;38(2):240-248. [PubMed]
23. Taniguchi N, Tanaka M, Kishihara C, Ohno H, Kondo T, Matsuda I, et al. Determination of carbonic anhydrase C and beta 2-microglobulin by radioimmunoassay in urine of heavy-metal-exposed subjects and patients with renal tubular acidosis.. Environ Res. 1979 Oct;20(1):154-161. [PubMed]
24. Mutti A, Lucertini S, Valcavi P, Neri TM, Fornari M, Alinovi R, et al. Urinary Excretion of Brush-Border Antigen Revealed by Monoclonal Antibody: Early Indicator of Toxic Nephropathy. Lancet. 1985 Oct;2(8461):914-917.  [PubMed]
25. Boldt J, Brenner T, Lang J, Kumle B, Isgro F. Kidney-Specific Proteins in Elderly Patients Undergoing Cardiac Surgery with Cardiopulmonary Bypass. Anest Analg. 2003 Dec;97(6):1582-1589. [PubMed]
26. Westhuyzen J, Endre Z, Reece G, Reith D, Saltissi D, Morgan T. Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive careunit. Nephrol Dial Transplant. 2003 Mar; 18(3):543-551. [PubMed]
27. Herget-Rosenthal S, Poppen D, Husing J, Marggraf G, Pietruck F, Jakob HG, et al. Prognostic value of tubular proteinuria and enzymuria in nonoliguric acute tubular necrosis. Clin Chem. 2004 Mar;50(3):552-558. [PubMed]
28. Chew SL, Lins RL, Daelemans R, Nuyts GD, De Broe ME. Urinary enzymes in acute renal failure. Nephrol Dial Transplant. 1993; 8(6):507-511. [PubMed]
29. Liangos O, Perianayagam MC, Vaidya VS, Han WK, Wald R, Tighiouart H, et al. Urinary N-acetyl-beta-(D)-glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure. J Am Soc Nephrol. 2007 Mar;18(3):904-912. [PubMed]
30. Eijkenboom JJ, van Eijk LT, Pickkers P, Peters WH, Wetzels JF, van der Hoeven HG. Small increases in the urinary excretion of glutathione S-transferase A1 and P1 after cardiac surgery are not associated with clinically relevant renal injury. Intensive CareMed. 2005 May;31(5):664-667. [PubMed]
31. Hamada Y, Kanda T, Anzai T, Kobayashi I, Morishita Y. N-acetyl-beta-D-glucosaminidase is not a predictor, but an indicator of kidney injury in patients with cardiac surgery. J Med. 1999; 30(5-6):329336. [PubMed]
32. Ichimura T, Bonventre JV, Bailly V, Wei H, Hession CA, Cate RL, et al. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem. 1998 Feb;273(7):4135-4142. [PubMed]
33. Bailly V, Zhang Z, Meier W, Cate R, Sanicola M, Bonventre JV. Shedding of kidney injury molecule-1, a putative adhesion protein involved in renal regeneration. J Biol Chem. 2002 Oct;277(42):39739-39748. [PubMed]
34. Vaidya VS, Ramirez V, Ichimura T, Bobadilla NA, Bonventre JV. Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury. Am J Physiol Renal Physiol. 2006 Feb;290(2):517-529. [PubMed]
35. Dieterle F, Staedtler F, Grenet O, Cordier A, Perentes E, Roth D, et al. Qualification of biomarkers for regulatory decision making: a kidney safety biomarker project. Toxicologist. 2007; 96: 383.
36. Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV. Kidney injury molecule- 1 (KIM-1): a novel biomarker for human renal proximal tubule injury. KidneyInt. 2002 Jul;62(1):237-244. [PubMed]
37. Han WK, Alinani A, Wu CL, Michaelson D, Loda M, McGovern FJ, et al. Human kidney injury molecule-1 is a tissue and urinary tumor marker of renal cell carcinoma. J Am Soc Nephrol. 2005 Apr;16(4):1126-1134. [PubMed]
38. Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, et al. Identification of neutrophilgelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol. 2003 Oct;14(10):2534-2543. [PubMed]
39. Mishra J, Dent C, Tarabishi R, Mark MM, Qing M,Caitlin K, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet. 2005 Apr;365(9466):1231-1238. [PubMed]
40. Dent CL, Ma Q, Dastrala S, Bennett M, Mitsnefes MM, Barasch J, et al. Plasma neutrophil gelatinase-associated lipocalin predicts acute kidney injury, morbidity and mortality after pediatric cardiac surgery: a prospective uncontrolled cohort study. Crit Care. 2007; 11(6):R127. [PubMed]
41. Parikh CR, Jani A, Mishra J, Ma Q, Kelly C, Barasch J, et al. Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation. Am J Transplant. 2006; 6:1639-1645.
42. Ling W, Zhaohui N, Ben H, Leyi G, Jianping L, Huili D, et al. Urinary IL-18 and NGAL as early predictive biomarkers in contrastinduced  nephropathy after coronary angiography. Nephron Clin Pract. 2008; 108:176-181.
43. Whittle C, Gillespie K, Harrison R, Mathieson PW, Harper SJ. Heterogeneous vascular endothelial growth factor (VEGF) isoform mRNA and receptor mRNA expression in human glomeruli, and the identification of VEGF148 mRNA, a novel truncated splice variant. Clin Sci. 1999; 97:303-312.
44. Rintala SE, Savikko J, Rintala JM, von Willebrand E: Vascular endothelial growth factor ligand and receptor induction in rat renal allograft rejection. Transplant Proc 2006; 38:3236-323845.
45. Xiong M, Elson G, Legarda D, Leibovich SJ. Production of vascular endothelial growth factor by murine macrophages: regulation by hypoxia, lactate, and the inducible nitric oxide synthase pathway. Am J Pathol. 1998; 153:587-598.
46. Sunderkötter C, Steinbrink K, Goebeler M, Bhardwaj R, Sorg C. Macrophages and angiogenesis. J Leukoc Biol. 1994; 55:410-422.
47. Shahbazi M, Fryer AA, Pravica V, Brogan IJ, Ramsay HM, Hutchinson IV,et al. Vascular endothelial growth factor gene polymorphisms are associated with acute renal allograft rejection. J Am Soc Nephrol. 2002; 13:260-264.
48. Watson CJ, Webb NJ, Bottomley MJ, Brenchley PE. Identification of polymorphisms within the vascular endothelial growth factor gene: correlation with variation in VEGF protein production. Cytokine. 2000; 12:1232-1235.
49. Peng W, Chen J, Jiang Y, Shou Z, Chen Y, Wang H. Acute renal allograft rejection is associated with increased levels of vascular endothelial growth factor in the urine. Nephrology (Carlton). 2008; 13:73-79.
50.Hancock WW, Wang L, Ye Q, Han R, Lee I. Chemokines and their receptors as markers of allograft rejection and targets for immunosuppression. Curr Opin Immunol .2003; 15:479–486.
51. Akalin E, Hendrix RC, Polavarapu RG, Pearson TC, Neylan JF, Larsen CP,et al. Gene expression analysis in human renal allograft biopsy samples using high-density oligoarray technology. Transplantation. 2001; 72:948–953.
52. Jiménez R, Ramírez R, Carracedo J, Agüera M, Navarro D, Santamaría R, et al. Cytometric bead array for the measurement of cytokines in urine and plasma of patients undergoing renal rejection. Cytokine. 2005; 32:45-50.
53. Smith SD, Wheeler MA, Lorber MI, Weiss RM. Temporal changes of cytokines and nitric oxide products in urine from renal transplant patients. Kidney Int. 2000; 58:829–837.
54. Di Paolo S, Gesualdo L, Stallone G, Ranieri E, Schena FP. Renal expression and urinary concentration of EGF and IL-6 in acutely dysfunctioning kidney transplanted patients. Nephrol Dial Transplant. 1997; 12:2687-2693.
55. Kaden J, Priesterjahn R. Increasing urinary IL-6 levels announce kidney graft rejection. Transpl Int. 2000; 13(suppl 1):S34-S41.
56.Prodjosudjadi W, Daha MR, Gerritsma JS, Florijn KW, Barendregt JN, Bruijn JA,et al. Increased urinary excretion of monocyte chemoattractant protein-1 during acute renal allograft rejection. Nephrol Dial Transplant. 1996; 11:1096-1103.
57. Dubiński B, Boratyńska M, Kopeć W, Szyber P, Patrzałek D, Klinger M. Activated cells in urine and monocyte chemotactic peptide-1-sensitive rejection markers in renal graft recipients. Transpl Immunol. 2008; 18:203-207.
58. Brown FG, Nikolic-Paterson DJ, Chadban SJ, Dowling J, Jose M, Metz CN, Bucala R, et al. Urine macrophage migration inhibitory factor concentrations as a diagnostic tool in human renal allograft rejection. Transplantation. 2001; 71:1777-1783.
59. Hauser IA, Spiegler S, Kiss E, Gauer S, Sichler O, Scheuermann EH, et al. Prediction of acute renal allograft rejection by urinary monokine induced by IFN-α. J Am Soc Nephrol. 2005; 34:589-91
60. Sarwal MM, Li L. Designer genes: filling the gap in transplantation. Transplantation. 2006; 82:1261-1272.
61. Larson RS, Springer TA. Structure and function of leukocyte integrins. Immunol Rev. 1990; 114:181-217.
62. Ding R, Li B, Muthukumar T, Dadhania D, Medeiros M, Hartono C, Serur D, et al. CD103 mRNA levels in urinary cells predict acute rejection of renal allografts. Transplantation. 2003; 75:1307–1312.
63. Parikh, E. Abraham, M. Ancukiewicz, C. L. Edelstein. Urine IL-18 Is an Early Diagnostic Marker for Acute Kidney Injury and Predicts Mortality in the Intensive Care Unit. J American Society of Nephrology. 2005; 16(10): 3046-3052.
64. Parikh CR, Mishra J, Thiessen-Philbrook H, Dursun B, Ma Q, Kelly C, et al. Urinary IL-18 Is an Early Predictive Biomarker of Acute Kidney Injury after Cardiac Surgery. Kidney Int. 2006 Jul;70(1)199-203. [PubMed]
65. Coll EA, Botey L, Alvarez K. Serum Cystatin C as a New Marker for Noninvasive Estimation of Glomerular Filtration Rate and as a Marker for Early Renal Impairment. Am J of Kidney Diseases. 2000; 36(1):29-34.
66. Dharnidharka VR, Kwon C, Stevens G. Serum Cystatin C Is Superior to Serum Creatinine as a Marker of Kidney Function: A Meta-Analysis. Am J Kidney Dis. 2002; 40(2):221-226
67. Song S, Meyer M, Turk TR. Serum Cystatin C in Mouse Models: A Reliable and Precise Marker for Renal Function and Superior to Serum Creatinine. Nephrol Dial Transplantation. 2009; 24(4):1157-1161.
68. Herget-Rosenthal S, Marggraf G, Husing J. Early Detection of Acute Renal Failure by Serum Cystatin C. Kidney Int. 2004; 66(3):1115-1122.
69. Shlipak MG, Sarnak MJ, Katz R. Cystatin C and the Risk of Death and Cardiovascular Events among Elderly Persons. The New England Journal of Medicine. 2005; 352(20):2049-2060
70. Sarnak MJ, Katz R, Stehman-Breen CO. Cystatin C Concentration as a Risk Factor for Heart Failure in Older Adults. Annals of Internal Medicine. 2005; 142(7):497-505.
71. Shlipak MG, Fried LF, Crump C, Anthony JB, Teri AM,  Russell PT, et al. Cardiovascular Disease Risk Status in Elderly Persons with Renal Insufficiency. Kidney Int. 2002; 62(3):997-1004.
72. Shlipak MG, Katz R, Sarnak MJ, Fried LF, Newman AB, Stehman-Breen C, et al. Cystatin C and Prognosis for Cardiovascular and Kidney Outcomes in Elderly Persons without Chronic Kidney Disease. Annals of Internal Medicine. 2006; 145(4):237-246.
73. Koyne JL, Bennett MR, Worcester EM, Qing  M, Jai R, Valluvan J, et al. Urinary Cystatin C as an Early Biomarker of Acute Kidney Injury Following Adult Cardiothoracic Surgery. Kidney Int. 2008; 74(8):1059- 1069.
74. Washburn KK, Zappitelli M, Arikan AA, Loftis L, Yalavarthy R, Parikh CR,et al. Urinary interleukin-18 is an acute kidney injury biomarker in critically ill children. Nephrol Dial Transplant. 2008; 23:566–572.
75. Melnikov VY, Ecder T, Fantuzzi G, Siegmund B, Lucia MS, Dinarello CA, et al. Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. J Clin Invest. 2001; 107:1145–1152.
76. Parikh CR, Mishra J, Thiessen-Philbrook H, Dursun B, Ma Q, Kelly C, et al. Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery. Kidney Int. 2006; 70: 199-203.
77. Parikh CR, Abraham E, Ancukiewicz M, Edelstein CL. Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit. J Am Soc Nephrol. 2005; 16:3046–3052.
79. Parikh CR, Jani A, Melnikov VY, Faubel S, Edelstein CL. Urinary interleukin-18 is a marker of human acute tubular necrosis. AmJ Kidney Dis. 2004; 43:405–414.
80.Yannaraki M, Rebibou J, Ducloux D, Saas P, Duperrier A, Felix S, et al. Urinary cytotoxic molecular markers for a noninvasive diagnosis in acute renal transplant rejection. Transpl Int. 2006; 19:759-768.
81. Fischer K, Hamza A, Eismann R, Amoury M, Heynemann H, Fornara P. Differential diagnostic use of interleukin patterns in patients being monitored after transplantation. Clin Chim Acta. 2001; 310:71-80
82. Boratyńska M. Monitoring of interleukin-8 in urine and in serum of patients after kidney transplantation. Przegl Lek. 1998; 55:576-580.
83. Smith SD, Wheeler MA, Lorber MI, Weiss RM. Temporal changes of cytokines and nitric oxide products in urine from renal transplant patients. Kidney Int. 2000; 58:829-837.

Received: 14 April 2016
Published online: 08 June 2016

back to Online Journal