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Multicenter Study
. 2023 Jul 1;107(7):1630-1641.
doi: 10.1097/TP.0000000000004554. Epub 2023 Jun 20.

Multicenter Validation of a Urine CXCL10 Assay for Noninvasive Monitoring of Renal Transplants

Julie Ho  1   2 , Stefan Schaub  3   4   5 , Annette M Jackson  6 , Robert Balshaw  7 , Robert Carroll  8 , Sylvia Cun  9 , Sacha A De Serres  10 , Daniel Fantus  11 , Joelle Handschin  3 , Gideon Hönger  3   4   5 , Anthony M Jevnikar  12 , Marc Kleiser  5 , Jar-How Lee  13 , Yan Li  6 , Peter Nickerson  1   2   14 , Rui Pei  9 , Denise Pochinco  14 , Remi Shih  13 , Michael Trinh  9 , Jason Wang  9 , Julie Nguyen  9 , Stuart Knechtle  6
Affiliations
Multicenter Study

Multicenter Validation of a Urine CXCL10 Assay for Noninvasive Monitoring of Renal Transplants

Julie Ho et al. Transplantation. .

Abstract

Background: Urine CXCL10 (C-X-C motif chemokine ligand 10, interferon gamma-induced protein 10 [IP10]) outperforms standard-of-care monitoring for detecting subclinical and early clinical T-cell-mediated rejection (TCMR) and may advance TCMR therapy development through biomarker-enriched trials. The goal was to perform an international multicenter validation of a CXCL10 bead-based immunoassay (Luminex) for transplant surveillance and compare with an electrochemiluminescence-based (Meso Scale Discovery [MSD]) assay used in transplant trials.

Methods: Four laboratories participated in the Luminex assay development and evaluation. Urine CXCL10 was measured by Luminex and MSD in 2 independent adult kidney transplant trial cohorts (Basel and TMCT04). In an independent test and validation set, a linear mixed-effects model to predict (log 10 -transformed) MSD CXCL10 from Luminex CXCL10 was developed to determine the conversion between assays. Net reclassification was determined after mathematical conversion.

Results: The Luminex assay was precise, with an intra- and interassay coefficient of variation 8.1% and 9.3%; showed modest agreement between 4 laboratories (R 0.96 to 0.99, P < 0.001); and correlated with known CXCL10 in a single- (n = 100 urines, R 0.94 to 0.98, P < 0.001) and multicenter cohort (n = 468 urines, R 0.92, P < 0.001) but the 2 assays were not equivalent by Passing-Bablok regression. Linear mixed-effects modeling demonstrated an intercept of -0.490 and coefficient of 1.028, showing Luminex CXCL10 are slightly higher than MSD CXCL10, but the agreement is close to 1.0. After conversion of the biopsy thresholds, the decision to biopsy would be changed for only 6% (5/85) patients showing acceptable reclassification.

Conclusions: These data demonstrate this urine CXCL10 Luminex immunoassay is robust, reproducible, and accurate, indicating it can be readily translated into clinical HLA laboratories for serial posttransplant surveillance.

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Conflict of interest statement

S.K. is the founder of Renovar, which licensed its urine chemokine patent to Thermo Fisher. S.C., J.-H.L., J.N., R.P., R.S., M.T., and J.W. work for Thermo Fisher Scientific. A.M.J. is a consultant for Hansa Biopharma and Novartis. R.C. is a consultant for Hansa Biopharma and has an investigator-initiated grant from Bristol Myers-Squibb. P.N. is a consultant for CSL Behring. The other authors declare no conflicts of interest.

References

    1. Ho J, Okoli GN, Rabbani R, et al. Effectiveness of T cell-mediated rejection therapy: a systematic review and meta-analysis. Am J Transplant. 2022;22:772–785.
    1. Rampersad C, Balshaw R, Gibson IW, et al. The negative impact of T cell-mediated rejection on renal allograft survival in the modern era. Am J Transplant. 2022;22:761–771.
    1. Bouatou Y, Viglietti D, Pievani D, et al. Response to treatment and long-term outcomes in kidney transplant recipients with acute T cell-mediated rejection. Am J Transplant. 2019;19:1972–1988.
    1. Wiebe C, Rush DN, Gibson IW, et al. Evidence for the alloimmune basis and prognostic significance of borderline T cell-mediated rejection. Am J Transplant. 2020;20:2499–2508.
    1. Lefaucheur C, Gosset C, Rabant M, et al. T cell-mediated rejection is a major determinant of inflammation in scarred areas in kidney allografts. Am J Transplant. 2018;18:377–390.

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