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Histologic and Molecular Patterns in Responders and Non-responders With Chronic-Active Antibody-Mediated Rejection in
Onur Sazpinar1, Ariana Gaspert2, Daniel Sidler3
1Clinic of Nephrology, Department of Medicine, University Hospital Zürich, Zurich, Switzerland.
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].
Insights
Identifying effective treatments for chronic-active antibody-mediated rejection (caABMR) is crucial for kidney transplant success. Lower peritubular capillaritis scores indicate better treatment response in caABMR patients.
Area of Science:
- Nephrology
- Transplant Immunology
- Molecular Diagnostics
Background:
- Chronic-active antibody-mediated rejection (caABMR) is a leading cause of kidney transplant failure.
- No established therapies exist for caABMR, and patterns predicting treatment response are unknown.
Purpose of the Study:
- To identify histological and molecular patterns associated with treatment response in kidney transplant recipients with caABMR.
- To differentiate responders from non-responders based on biopsy findings and gene expression.
Main Methods:
- Retrospective analysis of 16 kidney transplant biopsies with pure caABMR (2008-2016).
- Comparison of histological features and gene expression (NanoString™) between treatment responders and non-responders.
- Gene sets included endothelial, inflammatory, interferon gamma (IFNg), and calcineurin inhibitor (CNI) related genes.
Main Results:
- Lower peritubular capillaritis (p=0.028) and glomerulitis scores were associated with treatment response.
- No single gene differentiated responders from non-responders.
- Upregulated genes related to NK cells and endothelial cells indicated a lack of treatment response.
Conclusions:
- Active microvascular injury, specifically peritubular capillaritis, distinguishes caABMR treatment responders.
- NK cell and endothelial cell gene expression may aid in identifying treatment response.
- Prospective studies with larger cohorts and standardized treatments are needed to validate biomarkers.
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