Defining an NK Cell-enriched Rejection-like Phenotype in Liver Transplant Biopsies From the INTERLIVER Study.

Background: Initial analysis of liver transplant biopsies in the INTERLIVER study (ClinicalTrials.gov; unique identifier NCT03193151) using rejection-associated transcripts failed to find an antibody-mediated rejection state (ie, rich in natural killer [NK] cells and with interferon-gamma effects). We recently developed an optimization strategy in lung transplants that isolated an NK cell-enriched rejection-like (NKRL) state that was molecularly distinct from T cell-mediated rejection (TCMR).

Tissue-based Gene Expression Diagnosis of Mild and Moderate T-cell-mediated Rejection to Guide Therapy in Kidney Transplants.

Background: Mild histologic lesions of tubulo-interstitial inflammation could represent a "response-to-wounding" rather than allorecognition. Tissue gene expression may complement histopathology for T-cell-mediated rejection (TCMR) diagnostics.

Methods: We report on the incorporation of tissue gene expression testing using a Molecular Microscope Diagnostic System into the management of kidney transplant biopsies with suspected TCMR.

Transcriptomic Signatures of Antibody-mediated Rejection in Early Biopsies With Negative Histology in HLA-incompatible Kidney Transplantation.

Background: Presensitized patients with circulating donor-specific antibodies (DSAs) before transplantation are at risk for antibody-mediated rejection (AMR). Peritransplant desensitization mitigates but does not eliminate the alloimmune response. We examined the possibility that subthreshold AMR activity undetected by histology could be operating in some early biopsies.

Donor-derived cell-free DNA monitoring for early diagnosis of antibody-mediated rejection after kidney transplantation: a randomized trial.

Background And Hypothesis: Donor-derived cell-free DNA (dd-cfDNA) shows good diagnostic performance for the detection of antibody-mediated rejection (AMR) in kidney transplant recipients (KTR). However, the clinical benefits of dd-cfDNA monitoring need to be established. Early diagnosis of AMR at potentially reversible stages may be increasingly important due to emerging treatment options for AMR.

The Banff 2022 Kidney Meeting Report: Re-Appraisal of Microvascular Inflammation and the Role of Biopsy-Based Transcript Diagnostics.

The XVI-th Banff Meeting for Allograft Pathology was held in Banff, Alberta, Canada, from 19th-23rd September 2022, as a joint meeting with the Canadian Society of Transplantation. To mark the 30 anniversary of the first Banff Classification, pre-meeting discussions were held on the past, present, and future of the Banff Classification. This report is a summary of the meeting highlights that were most important in terms of their effect on the Classification, including discussions around microvascular inflammation and biopsy-based transcript analysis for diagnosis.

Precision diagnostics in transplanted organs using microarray-assessed gene expression: concepts and technical methods of the Molecular Microscope® Diagnostic System (MMDx).

There is a major unmet need for improved accuracy and precision in the assessment of transplant rejection and tissue injury. Diagnoses relying on histologic and visual assessments demonstrate significant variation between expert observers (as represented by low kappa values) and have limited ability to assess many biological processes that produce little histologic changes, for example, acute injury. Consensus rules and guidelines for histologic diagnosis are useful but may have errors.

A Randomized Phase 2 Trial of Felzartamab in Antibody-Mediated Rejection.

Background: Antibody-mediated rejection is a leading cause of kidney-transplant failure. The targeting of CD38 to inhibit graft injury caused by alloantibodies and natural killer (NK) cells may be a therapeutic option.

Methods: In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned patients with antibody-mediated rejection that had occurred at least 180 days after transplantation to receive nine infusions of the CD38 monoclonal antibody felzartamab (at a dose of 16 mg per kilogram of body weight) or placebo for 6 months, followed by a 6-month observation period.

The Clinical Relevance of the Infiltrating Immune Cell Composition in Kidney Transplant Rejection.

Key Points: The estimated composition of immune cells in kidney transplants correlates poorly with the primary rejection categories defined by Banff criteria. Spatial cell distribution could be coupled with a detailed cellular composition to assess causal triggers for allorecognition. Intragraft CD8temra cells showed strong and consistent association with graft failure, regardless of the Banff rejection phenotypes.

Epithelial cell states associated with kidney and allograft injury.

The kidney epithelium, with its intricate arrangement of highly specialized cell types, constitutes the functional core of the organ. Loss of kidney epithelium is linked to the loss of functional nephrons and a subsequent decline in kidney function. In kidney transplantation, epithelial injury signatures observed during post-transplantation surveillance are strong predictors of adverse kidney allograft outcomes.

Comparing Plasma Donor-derived Cell-free DNA to Gene Expression in Endomyocardial Biopsies in the Trifecta-Heart Study.

Background: Plasma donor-derived cell-free DNA (dd-cfDNA) is used to screen for rejection in heart transplants. We launched the Trifecta-Heart study ( ClinicalTrials.gov No.

Redefining the molecular rejection states in 3230 heart transplant biopsies: Relationships to parenchymal injury and graft survival.

The first-generation Molecular Microscope (MMDx) system for heart transplant endomyocardial biopsies used expression of rejection-associated transcripts (RATs) to diagnose not only T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) but also acute injury. However, the ideal system should detect rejection without being influenced by injury, to permit analysis of the relationship between rejection and parenchymal injury. To achieve this, we developed a new rejection classification in an expanded cohort of 3230 biopsies: 1641 from INTERHEART (ClinicalTrials.

Morphologic and Molecular Features of Antibody-Mediated Transplant Rejection: Pivotal Role of Molecular Injury as an Independent Predictor of Renal Allograft Functional Decline.

Current knowledge about the factors correlating with functional decline and subsequent failure of kidney allografts in antibody-mediated rejection (ABMR) is limited. We conducted a cohort study involving 75 renal allograft recipients diagnosed with late ABMR occurring at least 6 months after transplantation. The study aimed to examine the correlation of molecular and histologic features with estimated glomerular filtration rate (eGFR) trajectories and death-censored graft survival.

Distinct Molecular Processes Mediate Donor-derived Cell-free DNA Release From Kidney Transplants in Different Disease States.

Background: Among all biopsies in the Trifecta-Kidney Study ( ClinicalTrials.gov NCT04239703), elevated plasma donor-derived cell-free DNA (dd-cfDNA) correlated most strongly with molecular antibody-mediated rejection (AMR) but was also elevated in other states: T cell-mediated rejection (TCMR), acute kidney injury (AKI), and some apparently normal biopsies. The present study aimed to define the molecular correlates of plasma dd-cfDNA within specific states.

The Banff 2022 Kidney Meeting Report: Reappraisal of microvascular inflammation and the role of biopsy-based transcript diagnostics.

The XVI-th Banff Meeting for Allograft Pathology was held at Banff, Alberta, Canada, from 19th to 23rd September 2022, as a joint meeting with the Canadian Society of Transplantation. To mark the 30th anniversary of the first Banff Classification, premeeting discussions were held on the past, present, and future of the Banff Classification. This report is a summary of the meeting highlights that were most important in terms of their effect on the Classification, including discussions around microvascular inflammation and biopsy-based transcript analysis for diagnosis.

Using Regression Equations to Enhance Interpretation of Histology Lesions of Kidney Transplant Rejection.

Background: The Banff system for histologic diagnosis of rejection in kidney transplant biopsies uses guidelines to assess designated features-lesions, donor-specific antibody (DSA), and C4d staining. We explored whether using regression equations to interpret the features as well as current guidelines could establish the relative importance of each feature and improve histologic interpretation.

Methods: We developed logistic regression equations using the designated features to predict antibody-mediated rejection (AMR/mixed) and T-cell-mediated rejection (TCMR/mixed) in 1679 indication biopsies from the INTERCOMEX study ( ClinicalTrials.

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

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.

On a Long and Winding Road: Alloantibodies in Organ Transplantation.

Today we know that both the humoral and the cellular arm of the immune system are engaged in severe immunological challenges. A close interaction between B and T cells can be observed in most "natural" challenges, including infections, malignancies, and autoimmune diseases. The importance and power of humoral immunity are impressively demonstrated by the current coronavirus disease 2019 pandemic.

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

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).