[en] Kidney transplantation (KTx) represents the best available treatment for patients with end-stage renal disease. Still, the full benefits of KTx are undermined by acute rejection (AR). The diagnosis of AR ultimately relies on transplant needle biopsy. However, such an invasive procedure is associated with a significant risk of complications and is limited by sampling error and interobserver variability. In the present review, we summarize the current literature about non-invasive approaches for the diagnosis of AR in kidney transplant recipients (KTRs), including in vivo imaging, gene-expression profiling and omics analyses of blood and urine samples. Most imaging techniques, such as contrast-enhanced ultrasound and magnetic resonance, exploit the fact that blood flow is significantly lowered in case of AR-induced inflammation. In addition, AR-associated recruitment of activated leucocytes may be detectable by 18F-fluorodeoxyglucose positron emission tomography. In parallel, urine biomarkers, including CXCL9/CXCL10 or a three-gene signature of CD3ε, CXCL10 and 18S RNA levels, have been identified. None of these approaches has yet been adopted in the clinical follow-up of KTRs, but standardization of analysis procedures may help assess reproducibility and comparative diagnostic yield in large, prospective, multicentre trials.
Suthanthiran M, Schwartz JE, Ding R et al. Urinary-cell mRNA profile and acute cellular rejection in kidney allografts. N Engl J Med 2013; 369: 20-31
WilliamsWW, Taheri D, Tolkoff-Rubin N et al. Clinical role of the renal transplant biopsy. Nat Rev Nephrol 2012; 8: 110-121
Rush D, Nickerson P, Gough J et al. Beneficial effects of treatment of early subclinical rejection: a randomized study. J Am Soc Nephrol 1998; 9: 2129-2134
Loupy A, Vernerey D, Tinel C et al. Subclinical rejection phenotypes at 1 year post-transplant and outcome of kidney allografts. J Am Soc Nephrol 2015; 26: 1721-1731
Gigliotti P, Lofaro D, Leone F et al. Early subclinical rejection treated with low dose i.v. steroids is not associated to graft survival impairment: 13-years' experience at a single center. J Nephrol 2016; 29: 443-449
Thomas ME, Blaine C, Dawnay A et al. The definition of acute kidney injury and its use in practice. Kidney Int 2015; 87: 62-73
Haas M, Sis B, Racusen LC et al. Banff 2013 meeting report: inclusion of C4d-negative antibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant 2014; 14: 272-283
Furness PN, Taub N. International variation in the interpretation of renal transplant biopsies: report of the CERTPAP Project. Kidney Int 2001; 60: 1998-2012
Azancot MA, Moreso F, Salcedo M et al. The reproducibility and predictive value on outcome of renal biopsies from expanded criteria donors. Kidney Int 2014; 85: 1161-1168
Einollahi B, Bakhtiari P, Simforoosh N et al. Renal allograft accumulation of technetium-99m sulfur colloid as a predictor of graft rejection. Transplant Proc 2005; 37: 2973-2975
Khalifa F, Beache GM, El-Ghar MA et al. Dynamic contrast-enhanced MRI-based early detection of acute renal transplant rejection. IEEE Trans Med Imaging 2013; 32: 1910-1927
Blydt-Hansen TD, Sharma A, Gibson IW et al. Urinary metabolomics for noninvasive detection of borderline and acute T cell-mediated rejection in children after kidney transplantation. Am J Transplant 2014; 14: 2339-2349
Ong S, Mannon RB. Genomic and proteomic fingerprints of acute rejection in peripheral blood and urine. Transplant Rev 2015; 29: 60-67
Pawelski H, Schnöckel U, Kentrup D et al. SPECT-and PETbased approaches for noninvasive diagnosis of acute renal allograft rejection. Biomed Res Int 2014; 2014: 874785
Hirt-Minkowski P, De Serres SA, Ho J. Developing renal allograft surveillance strategies-urinary biomarkers of cellular rejection. Can J Kidney Heal Dis 2015; 2: 28
Lovinfosse P, Weekers L, Bonvoisin C et al. Fluorodeoxyglucose F(18) positron emission tomography coupled with computed tomography in suspected acute renal allograft rejection. Am J Transplant 2016; 16: 310-316
Kurian SM,Williams AN, Gelbart T et al. Molecular classifiers for acute kidney transplant rejection in peripheral blood by whole genome gene expression profiling. Am J Transplant 2014; 14: 1164-1172
Banham GD, Clatworthy MR. B-cell biomarkers in transplantation- from genes to therapy. Tissue Antigens 2015; 85: 82-92
McGettigan PA. Transcriptomics in the RNA-seq era. Curr Opin Chem Biol 2013; 17: 4-11
Wang Z, Gerstein M, Snyder M. RNA-seq: a revolutionary tool for transcriptomics. Nat Rev Genet 2009; 10: 57-63
Ding R, Li B, Muthukumar T et al. CD103 mRNA levels in urinary cells predict acute rejection of renal allografts. Transplantation 2003; 75: 1307-1312
Matz M, Beyer J, Wunsch D et al. Early post-transplant urinary IP-10 expression after kidney transplantation is predictive of short-and long-term graft function. Kidney Int 2006; 69: 1683-1690
Rabant M, Amrouche L, Morin L et al. Early lowurinary CXCL9 and CXCL10 might predict immunological quiescence in clinically and histologically stable kidney recipients. Am J Transplant 2016; 16: 1868-1891
Tatapudi RR, Muthukumar T, Dadhania D et al. Noninvasive detection of renal allograft inflammation by measurements of mRNA for IP-10 and CXCR3 in urine. Kidney Int 2004; 65: 2390-2397
Muthukumar T, Dadhania D, Ding R et al. Messenger RNA for FOXP3 in the urine of renal-allograft recipients. N Engl J Med 2005; 353: 2342-2351
Kotsch K, Mashreghi MF, Bold G et al. Enhanced granulysin mRNA expression in urinary sediment in early and delayed acute renal allograft rejection. Transplantation 2004; 77: 1866-1875
Seiler M, Brabcova I, Viklicky Oet al. Heightened expression of the cytotoxicity receptor NKG2D correlates with acute and chronic nephropathy after kidney transplantation. Am J Transplant 2007; 7: 423-433
van Ham SM, Heutinck KM, Jorritsma T et al. Urinary granzyme A mRNA is a biomarker to diagnose subclinical and acute cellular rejection in kidney transplant recipients. Kidney Int 2010; 78: 1033-1040
Li B, Hartono C, Ding R et al. Noninvasive diagnosis of renalallograft rejection by measurement of messenger RNA for perforin and granzyme B in urine. N Engl J Med 2001; 344: 947-954
Muthukumar T, Ding R, Dadhania D et al. Serine proteinase inhibitor-9, an endogenous blocker of granzyme B/perforin lytic pathway, is hyperexpressed during acute rejection of renal allografts. Transplantation 2003; 75: 1565-1570
Lorenzen JM, Volkmann I, Fiedler J et al. Urinary miR-210 as a mediator of acute T-cell mediated rejection in renal allograft recipients. Am J Transplant 2011; 11: 2221-2227
Renesto PG, Ponciano VC, Cenedeze MAet al. High expression of Tim-3 mRNA in urinary cells from kidney transplant recipients with acute rejection. AmJ Transplant 2007; 7: 1661-1665
Manfro RC, Aquino-Dias EC, Joelsons G et al. Noninvasive Tim-3 messenger RNA evaluation in renal transplant recipients with graft dysfunction. Transplantation 2008; 86: 1869-1874
Afaneh C, Muthukumar T, LubetzkyMet al. Urinary cell levels of mRNAfor OX40, OX40L, PD-1, PD-L1, or PD-L2 and acute rejection of human renal allografts. Transplantation 2010; 90: 1381-1387
Matignon M, Ding R, Dadhania DM et al. Urinary cellmRNA profiles and differential diagnosis of acute kidney graft dysfunction. J Am Soc Nephrol 2014; 25: 1586-1597
Shoker A, George D, Yang H et al. Heightened CD40 ligand gene expression in peripheral CD4+ T cells from patients with kidney allograft rejection. Transplantation 2000; 70: 497-505
Mao Y,Wang M, Zhou Q et al. CXCL10 and CXCL13 expression were highly up-regulated in peripheral blood mononuclear cells in acute rejection and poor response to anti-rejection therapy. J Clin Immunol 2011; 31: 414-418
Vasconcellos LM, Schachter AD, Zheng XX et al. Cytotoxic lymphocyte gene expression in peripheral blood leukocytes correlates with rejecting renal allografts. Transplantation 1998; 66: 562-566
WangW, Li X-B, Yang X-Y et al. Forkhead box protein 3 mRNA expression in the peripheral blood of kidney-transplant recipients with acute rejection. Chin Med J (Engl) 2011; 124: 1775-1778
Sarwal MM, Jani A, Chang S et al. Granulysin expression is a marker for acute rejection and steroid resistance in human renal transplantation. Hum Immunol 2001; 62: 21-31
Dugré FJ, Gaudreau S, Belles-Isles M et al. Cytokine and cytotoxic molecule gene expression determined in peripheral blood mononuclear cells in the diagnosis of acute renal rejection. Transplantation 2000; 70: 1074-1080
Sabek O, Dorak MT, Kotb M et al. Quantitative detection of Tcell activation markers by real-time PCR in renal transplant rejection and correlation with histopathologic evaluation. Transplantation 2002; 74: 701-707
Simon T, Opelz G,Wiesel M et al. Serial peripheral blood perforin and granzyme B gene expression measurements for prediction of acute rejection in kidney graft recipients. Am J Transplant 2003; 3: 1121-1127
Lee B, Oh CK, Kim MS et al. Cytokine gene expression in peripheral blood mononuclear cells during acute renal allograft rejection. Transplant Proc 2012; 44: 236-240
Striz I, Krasna E, Eliska K et al. Interleukin 18 (IL-18) upregulation in acute rejection of kidney allograft. Immunol Lett 2005; 99: 30-35
Simon T, Opelz G,WieselMet al. Serial peripheral blood interleukin-18 and perforin gene expression measurements for prediction of acute kidney graft rejection. Transplantation 2004; 77: 1589-1595
Soltaninejad E, Nicknam MH, Nafar M et al. Differential expression of microRNAs in renal transplant patients with acute T-cell mediated rejection. Transpl Immunol 2015; 33: 1-6
Zheng K, Sun X, Wu Wet al. A new index for acute rejection after renal transplant: Notch receptor-1. Exp Clin Transplant 2012; 10: 433-438
Wang Y-L, Fu Y-X, Zhu Z-J et al. OX40 mRNA in peripheral blood as a biomarker of acute renal allograft rejection. Chin Med J (Engl) 2012; 125: 3786-3790
Wang Y-W, Wang Z, Shi B-Y. Programmed death 1 mRNA in peripheral blood as biomarker of acute renal allograft rejection. Chin Med J (Engl) 2011; 124: 674-678
Shin G-T, Kim S-J, Lee T-S et al. Gene expression of perforin by peripheral blood lymphocytes as a marker of acute rejection. Nephron Clin Pract 2005; 100: c63-c70
Luo Y, Shi B, Qian Yet al. Sequential monitoring of TIM-3 gene expression in peripheral blood for diagnostic and prognostic evaluation of acute rejection in renal graft recipients. Transplant Proc 2011; 43: 3669-3674
Hancock WW, Lu B, Gao Wet al. Requirement of the chemokine receptor CXCR3 for acute allograft rejection. J Exp Med 2000; 192: 1515-1520
Liu CC,Walsh CM, Young JD. Perforin: structure and function. Immunol Today 1995; 16: 194-201
Atkinson EA, Barry M, Darmon AJ et al. Cytotoxic T lymphocyte-assisted suicide: caspase 3 activation is primarily the result of the direct action of granzyme B. J Biol Chem 1998; 273: 21261-21266
Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol 2010; 40: 1830-1835
Shalev I, Selzner N, Shyu Wet al. Role of regulatory T cells in the promotion of transplant tolerance. Liver Transpl 2012; 18: 761-770
Buckingham S, Buckingham S. The major world of micro-RNAs. Nature 2003; 1-3
Harris A, Krams SM, Martinez OM. MicroRNAs as immune regulators: implications for transplantation. Am J Transplant 2010; 10: 713-719
Anglicheau D, Sharma VK, Ding R et al. MicroRNA expression profiles predictive of human renal allograft status. Proc Natl Acad Sci USA 2009; 106: 5330-5335
Gough MJ, Weinberg AD. OX40 (CD134) and OX40L. Adv Exp Med Biol 2009; 647: 94-107
Li L, Khush K, Hsieh S-C et al. Identification of common blood gene signatures for the diagnosis of renal and cardiac acute allograft rejection. PLoS One 2013; 8: e82153
Roedder S, Sigdel T, Salomonis N et al. The kSORT assay to detect renal transplant patients at high risk for acute rejection: results of the multicenter AART study. PLoS Med 2014; 11: e1001759
Alachkar N. Serum and urinary biomarkers in acute kidney transplant rejection. Nephrol Ther 2012; 8: 13-19
Betts G, Shankar S, Sherston S et al. Examination of serum miRNA levels in kidney transplant recipients with acute rejection. Transplantation 2014; 97: e28-e30
Srivastava M, Eidelman O, Torosyan Y et al. Elevated expression levels of ANXA11, integrins β3 and α3, and TNF-α contribute to a candidate proteomic signature in urine for kidney allograft rejection. Proteomics Clin Appl 2011; 5: 311-321
Oetting WS, Rogers TB, Krick TP et al. Urinary beta2-microglobulin is associated with acute renal allograft rejection. Am J Kidney Dis 2006; 47: 898-904
O'Riordan E, Orlova TN, Podust VN et al. Characterization of urinary peptide biomarkers of acute rejection in renal allografts. Am J Transplant 2007; 7: 930-940
Lederer SR, Friedrich N, Regenbogen C et al. Non-invasive monitoring of renal transplant recipients: urinary excretion of soluble adhesion molecules and of the complement-split product C4d. Nephron Clin Pract 2003; 94: c19-c26
Hricik DE, Nickerson P, Formica RN et al. Multicenter validation of urinary CXCL9 as a risk-stratifying biomarker for kidney transplant injury. Am J Transplant 2013; 13: 2634-2644
Hu H, Aizenstein BD, Puchalski A et al. Elevation of CXCR3-binding chemokines in urine indicates acute renal-allograft dysfunction. Am J Transplant 2004; 4: 432-437
Jackson JA, Kim EJ, Begley B et al. Urinary chemokines CXCL9 and CXCL10 are noninvasive markers of renal allograft rejection and BK viral infection. Am J Transplant 2011; 11: 2228-2234
Schaub S, Nickerson P, Rush D et al. Urinary CXCL9 and CXCL10 levels correlate with the extent of subclinical tubulitis. Am J Transplant 2009; 9: 1347-1353
Hauser IA, Spiegler S, Kiss E et al. Prediction of acute renal allograft rejection by urinary monokine induced by IFNgamma (MIG). J Am Soc Nephrol 2005; 16: 1849-1858
Blydt-Hansen TD, Gibson IW, Gao A et al. Elevated urinary CXCL10-to-creatinine ratio is associated with subclinical and clinical rejection in pediatric renal transplantation. Transplantation 2015; 99: 797-804
PengW, Chen J, Jiang Y et al. Urinary fractalkine is a marker of acute rejection. Kidney Int 2008; 74: 1454-1460
Heyne N, Kemmner S, Schneider C et al. Urinary neutrophil gelatinase-associated lipocalin accurately detects acute allograft rejection among other causes of acute kidney injury in renal allograft recipients. Transplant J 2012; 93: 1252-1257
Sigdel TK, Salomonis N, Nicora CD et al. The identification of novel potential injury mechanisms and candidate biomarkers in renal allograft rejection by quantitative proteomics. Mol Cell Proteomics 2014; 13: 621-631
Zhang Q, Liu Y-F, Su Z-X et al. Serum fractalkine and interferon-gamma inducible protein-10 concentrations are early detection markers for acute renal allograft rejection. Transplant Proc 2014; 46: 1420-1425
Nafar M, Farrokhi F, Vaezi M et al. Pre-transplant and posttransplant soluble CD30 for prediction and diagnosis of acute kidney allograft rejection. Int Urol Nephrol 2009; 41: 687-693
Pelzl S, Opelz G, Daniel V et al. Evaluation of posttransplantation soluble CD30 for diagnosis of acute renal allograft rejection. Transplantation 2003; 75: 421-423
Shooshtarizadeh T, Mohammadali A, Ossareh S et al. Relation between pretransplant serum levels of soluble CD30 and acute rejection during the first 6 months after a kidney transplant. Exp Clin Transplant 2013; 11: 229-233
Kutukculer N, Clark K, Rigg KM et al. The value of posttransplant monitoring of interleukin (IL)-2, IL-3, IL-4, IL-6, IL-8, and soluble CD23 in the plasma of renal allograft recipients. Transplantation 1995; 59: 333-340
Le Meur Y, Leprivey-Lorgeot V, Mons S et al. Serum levels of macrophage-colony stimulating factor (M-CSF): a marker of kidney allograft rejection. Nephrol Dial Transplant 2004; 19: 1862-1865
Freue GVC, Sasaki M, Meredith A et al. Proteomic signatures in plasma during early acute renal allograft rejection. Mol Cell Proteomics 2010; 9: 1954-1967
Xu X, Huang H, Cai M et al. Combination of IL-1 receptor antagonist, IL-20 and CD40 ligand for the prediction of acute cellular renal allograft rejection. J Clin Immunol 2013; 33: 280-287
Panzer U, Reinking RR, Steinmetz OM et al. CXCR3 and CCR5 positive T-cell recruitment in acute human renal allograft rejection. Transplantation 2004; 78: 1341-1350
Rabant M, Amrouche L, Lebreton X et al. Urinary C-X-C motif chemokine 10 independently improves the noninvasive diagnosis of antibody-mediated kidney allograft rejection. J Am Soc Nephrol 2015; 26: 2840-2851
Gwinner W, Metzger J, Husi H et al. Proteomics for rejection diagnosis in renal transplant patients: where are we now? World J Transplant 2016; 6: 28-41
Voshol H, Brendlen N, Müller D et al. Evaluation of biomarker discovery approaches to detect protein biomarkers of acute renal allograft rejection. J Proteome Res 2005; 4: 1192-1199
Cibrik DM,Warner RL, KommareddiMet al. Identification of a protein signature in renal allograft rejection. Proteomics Clin Appl 2013; 7: 839-849
Horie R, Watanabe T. CD30: expression and function in health and disease. Semin Immunol 1998; 10: 457-470
Trailin AV. [Estimation of soluble serum CD30 in the diagnosis of early renal allograft dysfunction]. Klin Khir 2009; 10: 44-46
Weiss RH, Kim K. Metabolomics in the study of kidney diseases. Nat Rev Nephrol 2011; 8: 22-33
Weekers L, de Tullio P, Bovy C et al. Activation of the calciumsensing receptor before renal ischemia/reperfusion exacerbates kidney injury. Am J Transl Res 2015; 7: 128-138
Suhre K, Schwartz JE, Sharma VK et al. Urine metabolite profiles predictive of human kidney allograft status. J Am Soc Nephrol 2016; 27: 626-636
Zhao X, Chen J, Ye L et al. Serum metabolomics study of the acute graft rejection in human renal transplantation based on liquid chromatography-mass spectrometry. J Proteome Res 2014; 13: 2659-2667
Mao Y-Y, Bai J-Q, Chen J-H et al. A pilot study of GC/MS-based serum metabolic profiling of acute rejection in renal transplantation. Transpl Immunol 2008; 19: 74-80
Ammerlaan W, Trezzi J-P, Mathay C et al. Method validation for preparing urine samples for downstream proteomic and metabolomic applications. Biopreserv Biobank 2014; 12: 351-357
Shebel HM, Akl A, Dawood A et al. Power Doppler sonography in early renal transplantation: does it differentiate acute graft rejection from acute tubular necrosis? Saudi J Kidney Dis Transpl 2014; 25: 733-740
Chow L, Sommer FG, Huang J et al. Power Doppler imaging and resistance index measurement in the evaluation of acute renal transplant rejection. J Clin Ultrasound 2001; 29: 483-490
Liu G, Han F, XiaoWet al. Detection of renal allograft rejection using blood oxygen level-dependent and diffusion weighted magnetic resonance imaging: a retrospective study. BMC Nephrol 2014; 15: 158
Bohra R, Klepacki J, Klawitter J et al. Proteomics and metabolomics in renal transplantation-quo vadis? Transpl Int 2013; 26: 225-241
Sigdel TK, Gao Y, He J et al. Mining the human urine proteome for monitoring renal transplant injury. Kidney Int 2016; 89: 1244-1252
