Does the definition of chronic active T cell–mediated rejection need revisiting?

Naesens, Maarten; Haas, Mark; Loupy, Alexandre; Roufosse, Candice; Mengel, Michael

doi:10.1111/ajt.16419

Cited by 5 publications

(3 citation statements)

References 5 publications

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“…[44][45][46][47][48] Definitions of chronic-active TCMR were revised in Banff 2017 48 to require moderate or severe tubulitis and will be revisited in Banff 2022. 46,47,49 Inflammation in atrophy-fibrosis lesions is a general feature of progressive nephron injury, even in primary renal diseases in native kidneys, and strongly related to future transplant failure. 50,51 Our finding that mean tubulitis scores remain at or near diagnostic levels in late molecular TCMR is reassuring, but it would be useful to identify and validate histologic features indicating TCMR when the atrophy-fibrosis is too extensive for reliable tubulitis assessment.…”

Section: Discussionmentioning

confidence: 99%

Relating Molecular T Cell–mediated Rejection Activity in Kidney Transplant Biopsies to Time and to Histologic Tubulitis and Atrophy-fibrosis

Madill‐Thomsen¹,

Böhmig²,

Bromberg³

et al. 2023

Transplantation

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Background. We studied the variation in molecular T cell–mediated rejection (TCMR) activity in kidney transplant indication biopsies and its relationship with histologic lesions (particularly tubulitis and atrophy-fibrosis) and time posttransplant. Methods. We examined 175 kidney transplant biopsies with molecular TCMR as defined by archetypal analysis in the INTERCOMEX study ( ClinicalTrials.gov #NCT01299168). TCMR activity was defined by a molecular classifier. Results. Archetypal analysis identified 2 TCMR classes, TCMR1 and TCMR2: TCMR1 had higher TCMR activity and more antibody-mediated rejection (“mixed”) activity and arteritis but little hyalinosis, whereas TCMR2 had less TCMR activity but more atrophy-fibrosis. TCMR1 and TCMR2 had similar levels of molecular injury and tubulitis. Both TCMR1 and TCMR2 biopsies were uncommon after 2 y posttransplant and were rare after 10 y, particularly TCMR1. Within late TCMR biopsies, TCMR classifier activity and activity molecules such as IFNG fell progressively with time, but tubulitis and molecular injury were sustained. Atrophy-fibrosis was increased in TCMR biopsies, even in the first year posttransplant, and rose with time posttransplant. TCMR1 and TCMR2 both reduced graft survival, but in random forests, the strongest determinant of survival after biopsies with TCMR was molecular injury, not TCMR activity. Conclusions. TCMR varies in intensity but is always strongly related to molecular injury and atrophy-fibrosis, which ultimately explains its effect on survival. We hypothesize, based on the reciprocal relationship with hyalinosis, that the TCMR1-TCMR2 gradient reflects calcineurin inhibitor drug underexposure, whereas the time-dependent decline in TCMR activity and frequency after the first year reflects T-cell exhaustion.

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Section: Discussionmentioning

confidence: 99%

Relating Molecular T Cell–mediated Rejection Activity in Kidney Transplant Biopsies to Time and to Histologic Tubulitis and Atrophy-fibrosis

Madill‐Thomsen¹,

Böhmig²,

Bromberg³

et al. 2023

Transplantation

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“…Finally, grade II caTCMR (chronic allograft arteriopathy, arterial intimal fibrosis with mononuclear cell inflammation in fibrosis, and formation of neointima) is even less well defined than other rejection subtypes, and may also be a manifestation of caAMR, cAMR, or mixed AMR/TCMR. Taken together, it is anticipated that further refinement of the diagnostic criteria of caTCMR will be important, both for clinical decision-making and before such criteria could be considered for clinical trial endpoints ( 70 ).…”

Section: Borderline Changes or Tcmr In Protocol Biopsiesmentioning

confidence: 99%

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

Serón

Rabant²,

Becker

et al. 2022

Transpl Int

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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.

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“…According to Helgeson et al, the new definition should designate an acute process combined with non-specific chronic changes. Moreover, Loupy et al [ 22 ], based on previously provided research, reported a need of revisiting CA TCMR grade I category as a part of chronic changes but without automatically assuming TCMR as its only possible cause.…”

Section: Characteristic Feature Of Chronic Active T-cell Mediated Rej...mentioning

confidence: 99%

Chronic Active T-Cell Mediated Kidney Rejection as a Clinically Significant Type of Allograft Loss?

et al. 2022

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The purpose of this article is to assess the present knowledge about chronic active (CA) T-cell mediated rejection (TCMR) of a kidney. In the research authors review current Banff diagnostic criteria used in kidney rejection, focus on their possible future evolution, and investigate the role of currently available molecular methods that could be implemented into the diagnostic scheme. Research also points out previously and currently available treatment methods applied to CA TCMR and takes into account possible side effects consequent upon the therapy. Moreover, attention is being paid to the CA TCMR coincidence with other kidney rejection types such as antibody-mediated rejection (ABMR) and its influence on the treatment approach. Authors also mark the possibility of non-HLA antibodies coexistence in patients with CA TCMR and describe its possible resonance on kidney allograft function. Nonetheless, it seems that current knowledge about CA TCMR is not sufficient and requires further investigation.

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Does the definition of chronic active T cell–mediated rejection need revisiting?

Cited by 5 publications

References 5 publications

Relating Molecular T Cell–mediated Rejection Activity in Kidney Transplant Biopsies to Time and to Histologic Tubulitis and Atrophy-fibrosis

Relating Molecular T Cell–mediated Rejection Activity in Kidney Transplant Biopsies to Time and to Histologic Tubulitis and Atrophy-fibrosis

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

Chronic Active T-Cell Mediated Kidney Rejection as a Clinically Significant Type of Allograft Loss?

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