Chronic Antibody-Mediated Rejection in Nonhuman Primate Renal Allografts: Validation of Human Histological and Molecular Phenotypes

Adam, Benjamin; Smith, Rex Neal; Rosales, Ivy A.; Matsunami, Masatoshi; Afzali, B.; Oura, Tetsu; Cosimi, A. Benedict; Kawai, Tatsuo; Colvin, Robert B.; Mengel, Michael

doi:10.1111/ajt.14327

Cited by 33 publications

(42 citation statements)

References 32 publications

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“…This fits in the concept that chronic ABMR is the result of a progressive disease with cumulative injury over time due to continuing antibody activity, rather than a one-hit phenomenon. The finding that prior rejection episodes were present in 70% of cases with transplant glomerulopathy, with most being ABMR (53%), and fewer being mixed (10%) or TCMR (5%) [68], as well as several animal models [69][70][71], corroborates this concept.…”

Section: Transplant Glomerulopathymentioning

confidence: 64%

The time dependency of renal allograft histology

2017

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Much of the complexity of the histological appearance of kidney transplant biopsies depends on the time at which the biopsies are obtained. It is well established that many elementary histological lesions and diagnoses have a time-dependent occurrence. While some "active" inflammatory lesions are noted primarily early after transplantation, other lesions are "chronic" and accumulate over time post-transplant, sometimes closely related to the prior active inflammatory lesions. With time after transplantation, the complexity of histology increases, by the co-occurrence of chronic damage and specific diseases. This leads to difficulties in clinical interpretation of the histological picture. We discuss the time-dependent prevalence of active and chronic lesions in kidney allograft biopsies and their associations with outcome. We also elaborate on the importance of time post-transplant in the interpretation of complex histological lesions or mixed diagnoses and illustrate that further research is necessary to evaluate whether time post-transplant is important for prognostication of graft injury processes. Adding a multidimensional prognostic layer to the current diagnostic Banff classification, including graft functional characteristics and time after transplantation, could become an interesting aid in the interpretation of complex histological lesions and mixed diagnoses, and in therapeutic decision-making.

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Section: Transplant Glomerulopathymentioning

confidence: 64%

The time dependency of renal allograft histology

2017

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“…Recently, more practical technologies based on FFPE biopsy analysis are now available, in particular the NanoString nCounter system (NanoString Technologies, Seattle, WA). Several NanoString publications using FFPE transplant specimens identify similar transcript associations with the molecular and histologic phenotypes as those reported in microarray studies 3,4,13‐18,27‐29,29‐33 . Among the advantages of NanoString are (1) a separate core processed at the time of biopsy is not required; (2) transcripts are assessed in the same sample analyzed by light microscopy; and (3) large retrospective and longitudinal analyses of archived samples can be readily performed in the setting of multicenter studies, which will enable retrospective randomization with long‐term survival end points available (Table 1).…”

Section: Current State Of Molecular Transplant Diagnosticsmentioning

confidence: 80%

Banff 2019 Meeting Report: Molecular diagnostics in solid organ transplantation–Consensus for the Banff Human Organ Transplant (B-HOT) gene panel and open source multicenter validation

Mengel

Loupy

Haas

et al. 2020

American Journal of Transplantation

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140

113

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This meeting report from the XV Banff conference describes the creation of a multiorgan transplant gene panel by the Banff Molecular Diagnostics Working Group (MDWG). This Banff Human Organ Transplant (B‐HOT) panel is the culmination of previous work by the MDWG to identify a broadly useful gene panel based on whole transcriptome technology. A data‐driven process distilled a gene list from peer‐reviewed comprehensive microarray studies that discovered and validated their use in kidney, liver, heart, and lung transplant biopsies. These were supplemented by genes that define relevant cellular pathways and cell types plus 12 reference genes used for normalization. The 770 gene B‐HOT panel includes the most pertinent genes related to rejection, tolerance, viral infections, and innate and adaptive immune responses. This commercially available panel uses the NanoString platform, which can quantitate transcripts from formalin‐fixed paraffin‐embedded samples. The B‐HOT panel will facilitate multicenter collaborative clinical research using archival samples and permit the development of an open source large database of standardized analyses, thereby expediting clinical validation studies. The MDWG believes that a pathogenesis and pathway based molecular approach will be valuable for investigators and promote therapeutic decision‐making and clinical trials.

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“…It should be stressed that for this to be done at any given center, the cut‐off value of such molecular assessment in the diagnosis of ABMR must be independently validated at each center at this point in time. With technologies becoming available to derive the molecular assessment (classifier or gene set) from formalin‐fixed paraffin‐embedded (FFPE) routine biopsy specimens, multicenter validation should become feasible in the near future through collaborative efforts of the ongoing Banff working groups (Table ).…”

Section: Revisions To the Banff Classificationmentioning

confidence: 99%

“…It should be noted that at this point no specific Banff recommendations are given regarding which molecular classifiers/transcript sets should be tested for or the platform(s) used to assess gene expression. This includes the decision whether to perform molecular studies on freshly sampled tissue or FFPE, the latter having the advantage of being done on the same tissue used for routine histology but with possible reduced sensitivity due to RNA degradation during processing. In all cases, molecular analyses need to be validated in any individual laboratory performing such testing, and gene expression thresholds significantly associated with ABMR, TCMR, or other lesions may well be different in different laboratories using the same transcript sets and platforms.…”

Section: Revisions To the Banff Classificationmentioning

confidence: 99%

The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell–mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials

Haas

Loupy

Lefaucheur

et al. 2018

American Journal of Transplantation

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876

997

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The kidney sessions of the 2017 Banff Conference focused on 2 areas: clinical implications of inflammation in areas of interstitial fibrosis and tubular atrophy (i‐IFTA) and its relationship to T cell–mediated rejection (TCMR), and the continued evolution of molecular diagnostics, particularly in the diagnosis of antibody‐mediated rejection (ABMR). In confirmation of previous studies, it was independently demonstrated by 2 groups that i‐IFTA is associated with reduced graft survival. Furthermore, these groups presented that i‐IFTA, particularly when involving >25% of sclerotic cortex in association with tubulitis, is often a sequela of acute TCMR in association with underimmunosuppression. The classification was thus revised to include moderate i‐IFTA plus moderate or severe tubulitis as diagnostic of chronic active TCMR. Other studies demonstrated that certain molecular classifiers improve diagnosis of ABMR beyond what is possible with histology, C4d, and detection of donor‐specific antibodies (DSAs) and that both C4d and validated molecular assays can serve as potential alternatives and/or complements to DSAs in the diagnosis of ABMR. The Banff ABMR criteria are thus updated to include these alternatives. Finally, the present report paves the way for the Banff scheme to be part of an integrative approach for defining surrogate endpoints in next‐generation clinical trials.

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Chronic Antibody-Mediated Rejection in Nonhuman Primate Renal Allografts: Validation of Human Histological and Molecular Phenotypes

Cited by 33 publications

References 32 publications

The time dependency of renal allograft histology

The time dependency of renal allograft histology

Banff 2019 Meeting Report: Molecular diagnostics in solid organ transplantation–Consensus for the Banff Human Organ Transplant (B-HOT) gene panel and open source multicenter validation

The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell–mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials

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