Fundamental Concepts Regarding Graft Injury and Regeneration: Tissue Injury, Tissue Quality, and Recipient Factors

Kreepala, Chatchai; Famulski, Konrad S.; Halloran, Philip F.

doi:10.1002/9781118873434.ch10

Cited by 2 publications

(4 citation statements)

References 207 publications

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“…The i‐ and t‐scores are slightly higher in DSA‐negative mABMR but not close to being diagnostic for TCMR, and combined with the negative TCMR Prob scores suggest the residual effects of AKI in the transplant process. The elevated FICOL transcripts, which are induced by transplant AKI and regress slowly over the first several years, 31,43,44 also support this interpretation.…”

Section: Discussionmentioning

confidence: 83%

“…The i-and t-scores are slightly higher in DSA-negative mABMR but not close to being diagnostic for TCMR, and combined with the negative TCMR Prob scores suggest the residual effects of AKI in the transplant process. The elevated FICOL transcripts, which are induced by transplant AKI and regress slowly over the first several years,31,43,44 also support this interpretation.Alternative explanations for DSA-negative mABMR are not necessarily mutually exclusive because there may be several ways that ABMR can occur without DSA being identified. As listed in the introduction, these include incomplete donor genotyping, complete absorption of DSA by kidney, DSA directed against non-HLA alloantigens, autoantibody such as AT1R,45 and antibody-independent NK cell recognition of missing self.…”

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confidence: 80%

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Molecular diagnosis of ABMR with or without donor-specific antibody in kidney transplant biopsies: Differences in timing and intensity but similar mechanisms and outcomes

Halloran

Madill‐Thomsen

Pon

et al. 2022

American Journal of Transplantation

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We studied the clinical, histologic, and molecular features distinguishing DSA‐negative from DSA‐positive molecularly defined antibody‐mediated rejection (mABMR). We analyzed mABMR biopsies with available DSA assessments from the INTERCOMEX study: 148 DSA‐negative versus 248 DSA‐positive, compared with 864 no rejection (excluding TCMR and Mixed). DSA‐positivity varied with mABMR stage: early‐stage (EABMR) 56%; fully developed (FABMR) 70%; and late‐stage (LABMR) 58%. DSA‐negative patients with mABMR were usually sensitized, 60% being HLA antibody‐positive. Compared with DSA‐positive mABMR, DSA‐negative mABMR was more often C4d‐negative; earlier by 1.5 years (average 2.4 vs. 3.9 years); and had lower ABMR activity and earlier stage in molecular and histology features. However, the top ABMR‐associated transcripts were identical in DSA‐negative versus DSA‐positive mABMR, for example, NK‐associated (e.g., KLRD1 and GZMB) and IFNG‐inducible (e.g., PLA1A). Genome‐wide class comparison between DSA‐negative and DSA‐positive mABMR showed no significant differences in transcript expression except those related to lower intensity and earlier time of DSA‐negative ABMR. Three‐year graft loss in DSA‐negative mABMR was the same as DSA‐positive mABMR, even after adjusting for ABMR stage. Thus, compared with DSA‐positive mABMR, DSA‐negative mABMR is on average earlier, less active, and more often C4d‐negative but has similar graft loss, and genome‐wide analysis suggests that it involves the same mechanisms. Summary Sentence In 398 kidney transplant biopsies with molecular antibody‐mediated rejection, the 150 DSA‐negative cases are earlier, less intense, and mostly C4d‐negative, but use identical molecular mechanisms and have the same risk of graft loss as the 248 DSA‐positive cases.

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Section: Discussionmentioning

confidence: 83%

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confidence: 80%

Molecular diagnosis of ABMR with or without donor-specific antibody in kidney transplant biopsies: Differences in timing and intensity but similar mechanisms and outcomes

Halloran

Madill‐Thomsen

Pon

et al. 2022

American Journal of Transplantation

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“…Many biopsies with atrophy-fibrosis also have increased expression of AKI-related IRRATs and increased risk of failure, reflecting recent or ongoing parenchymal injury (Table 3). 49,136 Note that the IGTs reflect plasma cell infiltrates that accompany atrophy-fibrosis, and do not correlate with AMR activity. The DSA that causes AMR presumably originates in marrow plasma cells.…”

Section: Molecular Features Of Irreversible Atrophy-fibrosismentioning

confidence: 99%

Section: The Genome Canada MMDX Project: Defining Rejection and Injur...mentioning

confidence: 99%

The Molecular Phenotype of Kidney Transplants: Insights From the MMDx Project

2023

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This review outlines the molecular disease states in kidney transplant biopsies as documented in the development of the Molecular Microscope Diagnostic System (MMDx). These states include T cell-mediated rejection (TCMR), antibody-mediated rejection (AMR), recent parenchymal injury, and irreversible atrophy-fibrosis. The MMDx project, initiated through a Genome Canada grant, is a collaboration involving many centers. MMDx uses genome-wide microarrays to measure transcript expression, interprets the results using ensembles of machine learning algorithms, and generates a report. Experimental studies in mouse models and cell lines were extensively used to annotate molecular features and interpret the biopsy results. Over time, MMDx revealed unexpected aspects of the disease states: for example, AMR is usually C4dnegative and often DSA-negative, and subtle "Minor" AMR-like states are frequent. Parenchymal injury correlates with both reduced glomerular filtration rate and increased risk of graft loss. In kidneys with rejection, injury features, not rejection activity, are the strongest predictors of graft survival. Both TCMR and AMR produce injury, but TCMR induces immediate nephron injury and accelerates atrophy-fibrosis, whereas AMR induces microcirculation and glomerular damage that slowly leads to nephron failure and atrophy-fibrosis. Plasma donor-derived cell-free DNA levels correlate strongly with AMR activity, acute kidney injury, and in a complex way with TCMR activity. Thus, the MMDx project has documented the molecular processes that underlie the clinical and histologic states in kidney transplants, and provides a diagnostic tool that can be used to calibrate biomarkers, optimize histology interpretation, and guide clinical trials.

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Fundamental Concepts Regarding Graft Injury and Regeneration: Tissue Injury, Tissue Quality, and Recipient Factors

Cited by 2 publications

References 207 publications

Molecular diagnosis of ABMR with or without donor-specific antibody in kidney transplant biopsies: Differences in timing and intensity but similar mechanisms and outcomes

Molecular diagnosis of ABMR with or without donor-specific antibody in kidney transplant biopsies: Differences in timing and intensity but similar mechanisms and outcomes

The Molecular Phenotype of Kidney Transplants: Insights From the MMDx Project

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