Histologic and Molecular Patterns in Responders and Non-responders With Chronic-Active Antibody-Mediated Rejection in Kidney Transplants

Onur Sazpinar; Ariana Gaspert; Daniel Sidler; Markus Rechsteiner; Thomas F Mueller

doi:10.3389/fmed.2022.820085

Histologic and Molecular Patterns in Responders and Non-responders With Chronic-Active Antibody-Mediated Rejection in Kidney Transplants

Front Med (Lausanne). 2022 Apr 29:9:820085. doi: 10.3389/fmed.2022.820085. eCollection 2022.

Authors

Onur Sazpinar¹, Ariana Gaspert², Daniel Sidler³, Markus Rechsteiner², Thomas F Mueller¹

Affiliations

¹ Clinic of Nephrology, Department of Medicine, University Hospital Zürich, Zurich, Switzerland.
² Department of Pathology and Molecular Pathology, University Hospital Zürich, Zurich, Switzerland.
³ Department of Nephrology and Hypertension, University Hospital Bern, Bern, Switzerland.

Abstract

Introduction: There is no proven therapy for chronic-active antibody-mediated rejection (caABMR), the major cause of late kidney allograft failure. Histological and molecular patterns associated with possible therapy responsiveness are not known.

Methods: Based on rigorous selection criteria this single center, retrospective study identified 16 out of 1027 consecutive kidney transplant biopsies taken between 2008 and 2016 with pure, unquestionable caABMR, without other pathologic features. The change in estimated GFR pre- and post-biopsy/treatment were utilized to differentiate subjects into responders and non-responders. Gene sets reflecting active immune processes of caABMR were defined a priori, including endothelial, inflammatory, cellular, interferon gamma (IFNg) and calcineurin inhibitor (CNI) related-genes based on the literature. Transcript measurements were performed in RNA extracted from stored, formalin-fixed, paraffin-embedded (FFPE) samples using NanoString™ technology. Histology and gene expression patterns of responders and non-responders were compared.

Results: A reductionist approach applying very tight criteria to identify caABMR and treatment response excluded the vast majority of clinical ABMR cases. Only 16 out of 139 cases with a written diagnosis of chronic rejection fulfilled the caABMR criteria. Histological associations with therapy response included a lower peritubular capillaritis score (p = 0.028) along with less glomerulitis. In contrast, no single gene discriminated responders from non-responders. Activated genes associated with NK cells and endothelial cells suggested lack of treatment response.

Conclusion: In caABMR active microvascular injury, in particular peritubular capillaritis, differentiates treatment responders from non-responders. Transcriptome changes in NK cell and endothelial cell associated genes may further help to identify treatment response. Future prospective studies will be needed which include more subjects, who receive standardized treatment protocols to identify biomarkers for treatment response.

Clinical trial registration: [ClinicalTrials.gov], identifier [NCT03430414].

Keywords: Banff classification; chronic-active ABMR; eGFR slope; kidney transplantation; therapy response; transcriptome.

Associated data

ClinicalTrials.gov/NCT03430414