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Effect of felzartamab anti-CD38 treatment on the molecular phenotype of antibody-mediated rejection in kidney transplant biopsies.

ABSTRACT: A recent randomized controlled trial demonstrated that treatment with CD38 monoclonal antibody felzartamab suppressed antibody-mediated rejection (ABMR) in kidney transplant patients but with recurrence post-treatment in some patients. Felzartamab reduced molecular ABMR activity scores in all 9 patients with baseline ABMR activity, selectively suppressing interferon gamma-inducible and natural killer cell transcripts, with minimal effect on ABMR-induced endothelial transcripts. Suppression was often incomplete when ABMR activity was intense, and molecular recurrence was nearly universal by week 52. However, we also found that felzartamab had parenchymal benefits at week 52, slowing the trajectories of molecular injury scores beyond the treatment period, suggesting that suppression of ABMR activity could potentially slow future progression to kidney failure.

ORGANISM(S): Homo sapiens

PROVIDER: GSE275824 | GEO | 2025/02/24

REPOSITORIES: GEO

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Subthreshold rejection activity in many kidney transplants currently classified as having no rejection.

Project description:Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower eGFR, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR respectively diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems.

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Assessing rejection-related disease in kidney transplant biopsies based on archetypal analysis of molecular phenotypes

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Assessing rejection-related disease in kidney transplant biopsies based on archetypal analysis of molecular phenotypes

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Project description:Background. The Trifecta study (ClinicalTrials.gov #NCT04239703) is a prospective investigator-initiated trial to evaluate the relationship between plasma %dd-cfDNA at the time of indication biopsy and the molecular phenotype of the biopsy. Results. Median time of biopsy post-transplant was 455 days (5 days - 32 years), with case-mix similar to previous studies: 180 (60%) no rejection, 89 (30%) antibody-mediated rejection (ABMR), and 31 (10%) T cell-mediated rejection (TCMR) and mixed. In genome-wide mRNA measurements, all 20 top probesets correlating with %dd-cfDNA were previously annotated for association with ABMR and all rejection, either NK cell-expressed (e.g. GNLY, CCL4, TRDC, and S1PR5) or IFNG-inducible (e.g. PLA1A, IDO1, CXCL11, and WARS). Among gene set and classifier scores, %dd-cfDNA correlated very strongly with ABMR and all rejection, reasonably strongly with active TCMR, and weakly with inactive TCMR, kidney injury and atrophy-fibrosis. %dd-cfDNA was highest in active ABMR, mixed, and active TCMR but lower in late-stage ABMR and less active TCMR. By multivariate random forests and logistic regression, molecular rejection variables predicted %dd-cfDNA better than histologic variables. Conclusions. %dd-cfDNA at time of indication biopsy strongly correlates with active molecular rejection and has potential to reduce unnecessary biopsies.

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MicroRNA Regulation in Blood Cells of Renal Transplanted Patients with Interstitial Fibrosis/Tubular Atrophy and Antibody-Mediated Rejection

Project description:We performed small RNA-Seq and compared expression levels of microRNAs of whole blood cells isolated from patients after kidney transplantation with stable graft function (SGF), antibody-mediated rejection (ABMR) and T cell-mediated rejection (TCMR).

2018-08-20 | GSE115816 | GEO

Transcriptomics of Chronic Active Antibody-Mediated Rejection of Human Kidney Allografts and Identification of Intragraft Overexpression of Natural Kill Cell Cytotoxicity Gene Set

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