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. 2022 May 20:35:10135.
doi: 10.3389/ti.2022.10135. eCollection 2022.

Proposed Definitions of T Cell-Mediated Rejection and Tubulointerstitial Inflammation as Clinical Trial Endpoints in Kidney Transplantation

Daniel Seron  1 , Marion Rabant  2 , Jan Ulrich Becker  3 , Candice Roufosse  4 , Maria Irene Bellini  5 , Georg A Böhmig  6 , Klemens Budde  7 , Fritz Diekmann  8 , Denis Glotz  9 , Luuk Hilbrands  10 , Alexandre Loupy  11 , Rainer Oberbauer  12 , Liset Pengel  13 , Stefan Schneeberger  14 , Maarten Naesens  15
Affiliations

Proposed Definitions of T Cell-Mediated Rejection and Tubulointerstitial Inflammation as Clinical Trial Endpoints in Kidney Transplantation

Daniel Seron et al. Transpl Int. .

Abstract

The diagnosis of acute T cell-mediated rejection (aTCMR) after kidney transplantation has considerable relevance for research purposes. Its definition is primarily based on tubulointerstitial inflammation and has changed little over time; aTCMR is therefore a suitable parameter for longitudinal data comparisons. In addition, because aTCMR is managed with antirejection therapies that carry additional risks, anxieties, and costs, it is a clinically meaningful endpoint for studies. This paper reviews the history and classifications of TCMR and characterizes its potential role in clinical trials: a role that largely depends on the nature of the biopsy taken (indication vs protocol), the level of inflammation observed (e.g., borderline changes vs full TCMR), concomitant chronic lesions (chronic active TCMR), and the therapeutic intervention planned. There is ongoing variability-and ambiguity-in clinical monitoring and management of TCMR. More research, to investigate the clinical relevance of borderline changes (especially in protocol biopsies) and effective therapeutic strategies that improve graft survival rates with minimal patient morbidity, is urgently required. The present paper was developed from documentation produced by the European Society for Organ Transplantation (ESOT) as part of a Broad Scientific Advice request that ESOT submitted to the European Medicines Agency for discussion in 2020. This paper proposes to move toward refined definitions of aTCMR and borderline changes to be included as primary endpoints in clinical trials of kidney transplantation.

Keywords: EMA guideline; T cell-mediated rejection; borderline changes; kidney transplantation; outcomes.

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Conflict of interest statement

MR has received lecture fees from Astellas and Chiesi; and research grant support (paid to institution) for investigator-initiated studies from Astellas and Chiesi. JB consults for Sanofi. GB has received honoraria and/or research funding from Astellas, CareDx, CSL Behring, Fresenius, Hansa, Neovii, and Vitaeris. KB has received honoraria and/or research funding from Alexion, Astellas, Bristol Myers Squibb, Chiesi, Fresenius, Hansa, Hexal, Merck, Novartis, Otsuka, Pfizer, Roche, Sandoz, Siemens, and Veloxis. DG reports consultancy agreements and scientific boards for AstraZeneca, BMS, Hansa, and Sanofi. LH reports speaker fees from Astellas, consultancy and research support from Chiesi, consultancy for Novartis, and research support from Sandoz. RO has received grants/research support from Amgen, Astellas, and Chiesi; and speakers’ bureaux/honoraria from Amgen, Astellas, Chiesi, Hansa, Neovii, Novartis, and Teva. SS has received grants/research support from Bridge to Life, Chiesi, Neovii, Novartis, Organ Recovery Systems, and Sandoz; speakers’ bureaux/honoraria from Astellas, BMS, Chiesi, Novartis, OrganOx, and Sanofi; and consulting fees from Astellas, Atara, Merck, NefroHealth, Novartis, Sandoz, and Teva. The remaining authors declare that the work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

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