Optimizing the approach to monitoring allograft inflammation using serial urinary CXCL10/creatinine testing in pediatric kidney transplant recipients.
CXCL10
biomarkers
graft rejection
kidney
kidney transplant
pediatric kidney transplant
subclinical rejection
Journal
Pediatric transplantation
ISSN: 1399-3046
Titre abrégé: Pediatr Transplant
Pays: Denmark
ID NLM: 9802574
Informations de publication
Date de publication:
May 2024
May 2024
Historique:
revised:
04
01
2024
received:
25
10
2023
accepted:
05
02
2024
medline:
30
3
2024
pubmed:
30
3
2024
entrez:
30
3
2024
Statut:
ppublish
Résumé
Urinary CXCL10/creatinine (uCXCL10/Cr) is proposed as an effective biomarker of subclinical rejection in pediatric kidney transplant recipients. This study objective was to model implementation in the clinical setting. Banked urine samples at a single center were tested for uCXCL10/Cr to validate published thresholds for rejection diagnosis (>80% specificity). The positive predictive value (PPV) for rejection diagnosis for uCXCL10/Cr-indicated biopsy was modeled with first-positive versus two-test-positive approaches, with accounting for changes associated with urinary tract infection (UTI), BK and CMV viremia, and subsequent recovery. Seventy patients aged 10.5 ± 5.6 years at transplant (60% male) had n = 726 urine samples with n = 236 associated biopsies (no rejection = 167, borderline = 51, and Banff 1A = 18). A threshold of 12 ng/mmol was validated for Banff 1A versus no-rejection diagnosis (AUC = 0.74, 95% CI = 0.57-0.92). The first-positive test approach (n = 69) did not resolve a clinical diagnosis in 38 cases (55%), whereas the two-test approach resolved a clinical diagnosis in the majority as BK (n = 17/60, 28%), CMV (n = 4/60, 7%), UTI (n = 8/60, 13%), clinical rejection (n = 5/60, 8%), and transient elevation (n = 18, 30%). In those without a resolved clinical diagnosis, PPV from biopsy for subclinical rejection is 24% and 71% (p = .017), for first-test versus two-test models, respectively. After rejection treatment, uCXCL10/Cr level changes were all concordant with change in it-score. Sustained uCXCL10/Cr after CMV and BK viremia resolution was associated with later acute rejection. Urinary CXCL10/Cr reliably identifies kidney allograft inflammation. These data support a two-test approach to reliably exclude other clinically identifiable sources of inflammation, for kidney biopsy indication to rule out subclinical rejection.
Sections du résumé
BACKGROUND
BACKGROUND
Urinary CXCL10/creatinine (uCXCL10/Cr) is proposed as an effective biomarker of subclinical rejection in pediatric kidney transplant recipients. This study objective was to model implementation in the clinical setting.
METHODS
METHODS
Banked urine samples at a single center were tested for uCXCL10/Cr to validate published thresholds for rejection diagnosis (>80% specificity). The positive predictive value (PPV) for rejection diagnosis for uCXCL10/Cr-indicated biopsy was modeled with first-positive versus two-test-positive approaches, with accounting for changes associated with urinary tract infection (UTI), BK and CMV viremia, and subsequent recovery.
RESULTS
RESULTS
Seventy patients aged 10.5 ± 5.6 years at transplant (60% male) had n = 726 urine samples with n = 236 associated biopsies (no rejection = 167, borderline = 51, and Banff 1A = 18). A threshold of 12 ng/mmol was validated for Banff 1A versus no-rejection diagnosis (AUC = 0.74, 95% CI = 0.57-0.92). The first-positive test approach (n = 69) did not resolve a clinical diagnosis in 38 cases (55%), whereas the two-test approach resolved a clinical diagnosis in the majority as BK (n = 17/60, 28%), CMV (n = 4/60, 7%), UTI (n = 8/60, 13%), clinical rejection (n = 5/60, 8%), and transient elevation (n = 18, 30%). In those without a resolved clinical diagnosis, PPV from biopsy for subclinical rejection is 24% and 71% (p = .017), for first-test versus two-test models, respectively. After rejection treatment, uCXCL10/Cr level changes were all concordant with change in it-score. Sustained uCXCL10/Cr after CMV and BK viremia resolution was associated with later acute rejection.
CONCLUSIONS
CONCLUSIONS
Urinary CXCL10/Cr reliably identifies kidney allograft inflammation. These data support a two-test approach to reliably exclude other clinically identifiable sources of inflammation, for kidney biopsy indication to rule out subclinical rejection.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e14718Subventions
Organisme : BC Children's Hospital Foundation
Informations de copyright
© 2024 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.
Références
Hoffmann AJ, Gibson IW, Ho J, et al. Early surveillance biopsy utilization and management of pediatric renal allograft acute T cell–mediated rejection in Canadian centers: observations from the PROBE multicenter cohort study. Pediatr Transplant. 2021;25:e13870.
Landsberg A, Riazy M, Blydt‐Hansen TD. Yield and utility of surveillance kidney biopsies in pediatric kidney transplant recipients at various time points post‐transplant. Pediatr Transplant. 2020;25:e13869.
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(7):1721‐1731.
Seifert ME, Agarwal G, Bernard M, et al. Impact of subclinical borderline inflammation on kidney transplant outcomes. Transplant Direct. 2021;7(2):e663.
Cosio FG, El Ters M, Cornell LD, Schinstock CA, Stegall MD. Changing kidney allograft histology early posttransplant: prognostic implications of 1‐year protocol biopsies. Am J Transplant. 2016;16(1):194‐203.
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(11):2129‐2134.
Seifert ME, Yanik MV, Feig DI, et al. Subclinical inflammation phenotypes and long‐term outcomes after pediatric kidney transplantation. Am J Transplant. 2018;18(9):2189‐2199.
Fadel FI, Abd ElBaky AM, Mawla MAA, Moustafa WI, Saadi GE, Salah DM. Subclinical rejection and immunosuppression in pediatric kidney transplant recipients: single centre study. Biomed Pharmacol J. 2021;14(3):1149‐1159.
Hymes LC, Warshaw BL, Hennigar RA, Amaral SG, Greenbaum LA. Prevalence of clinical rejection after surveillance biopsies in pediatric renal transplants: does early subclinical rejection predispose to subsequent rejection episodes? Pediatr Transplant. 2009;13(7):823‐826.
Hymes LC, Greenbaum L, Amaral SG, Warshaw BL. Surveillance renal transplant biopsies and subclinical rejection at three months post‐transplant in pediatric recipients. Pediatr Transplant. 2007;11(5):536‐539.
Shapiro R, Randhawa P, Jordan ML, et al. An analysis of early renal transplant protocol biopsies—the high incidence of subclinical Tubulitis. Am J Transplant. 2001;1(1):47‐50.
Gloor JM, Cohen AJ, Lager DJ, et al. Subclinical rejection in tacrolimus‐treated renal transplant recipients. Transplantation. 2002;73(12):1965‐1968.
Shishido S, Asanuma H, Nakai H, et al. The impact of repeated subclinical acute rejection on the progression of chronic allograft nephropathy. J Am Soc Nephrol. 2003;14(4):1046‐1052.
Nankivell BJ, Borrows RJ, Fung CLS, O'Connell PJ, Allen RDM, Chapman JR. Natural history, risk factors, and impact of subclinical rejection in kidney transplantation. Transplantation. 2004;78(2):242‐249.
Kee TY, Chapman JR, O'Connell PJ, et al. Treatment of subclinical rejection diagnosed by protocol biopsy of kidney transplants. Transplantation. 2006;82(1):36‐42.
Scholten EM, Rowshani AT, Cremers S, et al. Untreated rejection in 6‐month protocol biopsies is not associated with fibrosis in serial biopsies or with loss of graft function. J Am Soc Nephrol. 2006;17(9):2622‐2632.
Moreso F, Ibernon M, Gomà M, et al. Subclinical rejection associated with chronic allograft nephropathy in protocol biopsies as a risk factor for late graft loss. Am J Transplant. 2006;6(4):747‐752.
Anil Kumar MS, Khan S, Ranganna K, Malat G, Sustento‐Reodica N, Meyers WC. Long‐term outcome of early steroid withdrawal after kidney transplantation in African American recipients monitored by surveillance biopsy. Am J Transplant. 2008;8(3):574‐585.
Kurtkoti J, Sakhuja V, Sud K, et al. The utility of 1‐ and 3‐month protocol biopsies on renal allograft function: a randomized controlled study. Am J Transplant. 2008;8(2):317‐323.
Heilman RL, Devarapalli Y, Chakkera HA, et al. Impact of subclinical inflammation on the development of interstitial fibrosis and tubular atrophy in kidney transplant recipients. Am J Transplant. 2010;10(3):563‐570.
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(3):443‐449.
Hull KL, Adenwalla SF, Topham P, Graham‐Brown MP. Indications and considerations for kidney biopsy: an overview of clinical considerations for the non‐specialist. Clin Med (Lond). 2022;22(1):34‐40.
Broecker V, Mengel M. The significance of histological diagnosis in renal allograft biopsies in 2014. Transpl Int. 2015;28(2):136‐143.
Blydt‐Hansen TD, Sharma A, Gibson IW, Mandal R, Wishart DS. Urinary metabolomics for noninvasive detection of borderline and acute T cell‐mediated rejection in children after kidney transplantation. Am J Transplant. 2014;14(10):2339‐2349.
Blydt‐Hansen TD, Sharma A, Gibson IW, et al. Urinary metabolomics for noninvasive detection of antibody‐mediated rejection in children after kidney transplantation. Transplantation. 2017;101(10):2553‐2561.
Ho J, Sharma A, Mandal R, et al. Detecting renal allograft inflammation using quantitative urine metabolomics and CXCL10. Transplant Direct. 2016;2(6):e78.
Blydt‐Hansen TD, Gibson IW, Gao A, Dufault B, Ho J. Elevated urinary CXCL10‐to‐creatinine ratio is associated with subclinical and clinical rejection in pediatric renal transplantation. Transplantation. 2015;99(4):797‐804.
Foster BJ, Dahhou M, Zhang X, Platt RW, Samuel SM, Hanley JA. Association between age and graft failure rates in young kidney transplant recipients. Transplantation. 2011;92(11):1237‐1243.
Heeger PS, Greenspan NS, Kuhlenschmidt S, et al. Pretransplant frequency of donor‐specific, IFN‐gamma‐producing lymphocytes is a manifestation of immunologic memory and correlates with the risk of posttransplant rejection episodes. J Immunol. 1999;163(4):2267‐2275.
Nickel P, Presber F, Bold G, et al. Enzyme‐linked immunosorbent spot assay for donor‐reactive interferon‐gamma‐producing cells identifies T‐cell presensitization and correlates with graft function at 6 and 12 months in renal‐transplant recipients. Transplantation. 2004;78(11):1640‐1646.
Augustine JJ, Siu DS, Clemente MJ, Schulak JA, Heeger PS, Hricik DE. Pre‐transplant IFN‐gamma ELISPOTs are associated with post‐transplant renal function in African American renal transplant recipients. Am J Transplant. 2005;5(8):1971‐1975.
Ho J, Schaub S, Wiebe C, et al. Urinary CXCL10 chemokine is associated with alloimmune and virus compartment‐specific renal allograft inflammation. Transplantation. 2018;102(3):521‐529.
Blydt‐Hansen TD, Sharma A, Gibson IW, et al. Validity and utility of urinary CXCL10/Cr immune monitoring in pediatric kidney transplant recipients. Am J Transplant. 2021;21(4):1545‐1555.
Ho J, Rush DN, Karpinski M, et al. Validation of urinary CXCL10 as a marker of borderline, subclinical, and clinical tubulitis. Transplantation. 2011;92(8):878‐882.
Handschin J, Hirt‐Minkowski P, Hönger G, et al. Technical considerations and confounders for urine CXCL10 chemokine measurement. Transplant Direct. 2020;6(1):e519.
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(9):1683‐1690.
Hu H, Kwun J, Aizenstein BD, Knechtle SJ. Noninvasive detection of acute and chronic injuries in human renal transplant by elevation of multiple cytokines/chemokines in urine. Transplantation. 2009;87(12):1814‐1820.
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(10):2228‐2234.
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(10):2634‐2644.
Haas M, Sis B, Racusen LC, et al. Banff 2013 meeting report: inclusion of c4d‐negative antibody‐mediated rejection and antibody‐associated arterial lesions [published correction appears in Am J Transplant. 2015;15(10):2784. Rangel, Erika [corrected to Rangel, Erika B]]. Am J Transplant. 2014;14(2):272–283. doi:10.1111/ajt.12590
Solez K, Axelsen RA, Benediktsson H, et al. International standardization of criteria for the histologic diagnosis of renal allograft rejection: the Banff working classification of kidney transplant pathology. Kidney Int. 1993;44(2):411–422. doi:10.1038/ki.1993.259
Ciftci HS, Tefik T, Savran MK, et al. Urinary CXCL9 and CXCL10 levels and acute renal graft rejection. Int J Organ Transplant Med. 2019;10(2):53‐63.
Eikmans M, Gielis EM, Ledeganck KJ, Yang J, Abramowicz D, Claas FFJ. Non‐invasive biomarkers of acute rejection in kidney transplantation: novel targets and strategies. Front Med. 2019;5:5.
Mockler C, Sharma A, Gibson IW, et al. The prognostic value of urinary chemokines at 6 months after pediatric kidney transplantation. Pediatr Transplant. 2018;22(5):e13205.
Mincham CM, Gibson IW, Sharma A, et al. Evolution of renal function and urinary biomarker indicators of inflammation on serial kidney biopsies in pediatric kidney transplant recipients with and without rejection. Pediatr Transplant. 2018;22(5):e13202.
Hirt‐Minkowski P, Handschin J, Stampf S, et al. Randomized trial to assess the clinical utility of renal allograft monitoring by urine CXCL10 chemokine. J Am Soc Nephrol. 2023;34(8):1456‐1469.
Millan O, Budde K, Sommerer C, et al. Urinary miR‐155‐5p and CXCL10 as prognostic and predictive biomarkers of rejection, graft outcome and treatment response in kidney transplantation. Br J Clin Pharmacol. 2017;83(12):2636‐2650.
Cashion AK, Sabek O, Driscoll C, Gaber L, Tolley E, Gaber AO. Serial analysis of biomarkers of acute pancreas allograft rejection. Clin Transpl. 2010;24(6):E214‐E222.
Tinel C, Vermorel A, Picciotto D, et al. Deciphering the prognostic and predictive value of urinary CXCL10 in kidney recipients with BK virus reactivation. Front Immunol. 2020;11:604353.
Coleman DV, Mackenzie EF, Gardner SD, Poulding JM, Amer B, Russell WJ. Human polyomavirus (BK) infection and ureteric stenosis in renal allograft recipients. J Clin Pathol. 1978;31(4):338‐347.
Gane E, Saliba F, Valdecasas GJC, et al. Randomised trial of efficacy and safety of oral ganciclovir in the prevention of cytomegalovirus disease in liver‐transplant recipients. The Oral Ganciclovir International Transplantation Study Group [corrected]. Lancet. 1997;350(9093):1729‐1733.
Singh N. Late‐onset cytomegalovirus disease as a significant complication in solid organ transplant recipients receiving antiviral prophylaxis: a call to heed the mounting evidence. Clin Infect Dis. 2005;40(5):704‐708.
Humar A, Limaye AP, Blumberg EA, et al. Extended valganciclovir prophylaxis in D+/R‐ kidney transplant recipients is associated with long‐term reduction in cytomegalovirus disease: two‐year results of the IMPACT study. Transplantation. 2010;90(12):1427‐1431.
Felt JR, Yurkovich C, Garshott DM, et al. The utility of real‐time quantitative polymerase chain reaction genotype detection in the diagnosis of urinary tract infections in children. Clin Pediatr (Phila). 2017;56(10):912‐919.
Otto G, Burdick M, Strieter R, Godaly G. Chemokine response to febrile urinary tract infection. Kidney Int. 2005;68(1):62‐70.
Alcendor DJ. BK polyomavirus virus glomerular tropism: implications for virus reactivation from latency and amplification during immunosuppression. J Clin Med. 2019;8(9):1477.
Rziha H‐J, Belohradsky BH, Schneider U, Schwenk HU, Bornkamm GW, zur Hausen H. BK virus: II. Serologic studies in children with congenital disease and patients with malignant tumors and immunodeficiencies. Med Microbiol Immunol. 1978;165(2):83‐92.
Kariminik A, Dabiri S, Yaghobi R. Polyomavirus BK induces inflammation via up‐regulation of CXCL10 at translation levels in renal transplant patients with nephropathy. Inflammation. 2016;39(4):1514‐1519.
Ahuja M, Cohen EP, Dayer AM, et al. Polyoma virus infection after renal transplantation. Use of immunostaining as a guide to diagnosis. Transplantation. 2001;71(7):896‐899.
Nickeleit V, Klimkait T, Binet IF, et al. Testing for polyomavirus type BK DNA in plasma to identify renal‐allograft recipients with viral nephropathy. N Engl J Med. 2000;342(18):1309‐1315.
Millán O, Rovira J, Guirado L, et al. Advantages of plasmatic CXCL‐10 as a prognostic and diagnostic biomarker for the risk of rejection and subclinical rejection in kidney transplantation. Clin Immunol. 2021;229:108792.
Tinel C, Devresse A, Vermorel A, et al. Development and validation of an optimized integrative model using urinary chemokines for noninvasive diagnosis of acute allograft rejection. Am J Transplant. 2020;20(12):3462‐3476.
Gama A, Park S, Ellis CL. De‐novo CMV infection manifesting as interstitial nephritis in a high‐risk kidney recipient with concurrent urologic complications: lessons for the clinical nephrologist. J Nephrol. 2022;35(7):1923‐1926.
Morgantetti GF, Balancin ML, de Medeiros GA, Dantas M, Silva GEB. Cytomegalovirus infection in kidney allografts: a review of literature. Transl Androl Urol. 2019;8(Suppl 2):S192‐s197.
Swanson KJ, Djamali A, Jorgenson MR, et al. Cytomegalovirus nephritis in kidney transplant recipients: epidemiology and outcomes of an uncommon diagnosis. Transpl Infect Dis. 2021;23(5):e13702.
Hasanzamani B, Hami M, Zolfaghari V, Torkamani M, Ghorban Sabagh M, Ahmadi Simab S. The effect of cytomegalovirus infection on acute rejection in kidney transplanted patients. J Renal Inj Prev. 2016;5(2):85‐88.
Dall A, Hariharan S. BK virus nephritis after renal transplantation. Clin J Am Soc Nephrol. 2008;3(Suppl 2):S68‐S75.
Higdon LE, Tan JC, Maltzman JS. Infection, rejection, and the connection. Transplantation. 2023;107(3):584‐595.
Audard V, Amor M, Desvaux D, et al. Acute graft pyelonephritis: a potential cause of acute rejection in renal transplant. Transplantation. 2005;80(8):1128‐1130.
Lee JR, Bang H, Dadhania D, et al. Independent risk factors for urinary tract infection and for subsequent bacteremia or acute cellular rejection: a single‐center report of 1166 kidney allograft recipients. Transplantation. 2013;96(8):732‐738.
Maanaoui M, Baes D, Hamroun A, et al. Association between acute graft pyelonephritis and kidney graft survival: a single‐center observational study. Am J Transplant. 2021;21(11):3640‐3648.
Powers HR, Hellinger WC, Cortese C, et al. Histologic acute graft pyelonephritis after kidney transplantation: incidence, clinical characteristics, risk factors, and association with graft loss. Transpl Infect Dis. 2022;24(2):e13801.
Oghumu S, Nori U, Bracewell A, et al. Differential gene expression pattern in biopsies with renal allograft pyelonephritis and allograft rejection. Clin Transpl. 2016;30(9):1115‐1133.
Cartery C, Guilbeau‐Frugier C, Esposito L, et al. Systematic kidney biopsies after acute allograft pyelonephritis. Exp Clin Transplant. 2013;11(3):239‐244.
Haller J, Diebold M, Leuzinger K, et al. Urine CXCL10 to assess BK polyomavirus replication after kidney transplantation. Transplantation. 2023;107(12):2568‐2574.