Multiomic profiling of transplant glomerulopathy reveals a novel T-cell dominant subclass

Iacopo Cristoferi; Hilal Varol; Myrthe van Baardwijk; Layla Rahiem; Karishma A Lila; Thierry P P van den Bosch; Carla C Baan; Dennis A Hesselink; Rafael Kramann; Robert C Minnee; Dana A M Mustafa; Marlies E J Reinders; Dave L Roelen; Shazia P Shahzad-Arshad; Rex N Smith; Andrew P Stubbs; Robert B Colvin; Ivy A Rosales; Marian C Clahsen-van Groningen

doi:10.1016/j.kint.2023.11.026

Multiomic profiling of transplant glomerulopathy reveals a novel T-cell dominant subclass

Kidney Int. 2024 Apr;105(4):812-823. doi: 10.1016/j.kint.2023.11.026. Epub 2023 Dec 19.

Authors

Iacopo Cristoferi¹, Hilal Varol², Myrthe van Baardwijk³, Layla Rahiem², Karishma A Lila², Thierry P P van den Bosch², Carla C Baan⁴, Dennis A Hesselink⁴, Rafael Kramann⁵, Robert C Minnee⁶, Dana A M Mustafa⁷, Marlies E J Reinders⁴, Dave L Roelen⁸, Shazia P Shahzad-Arshad², Rex N Smith⁹, Andrew P Stubbs², Robert B Colvin⁹, Ivy A Rosales⁹, Marian C Clahsen-van Groningen¹⁰

Affiliations

¹ Department of Pathology and Clinical Bioinformatics, Erasmus MC Transplant Institute, Rotterdam, the Netherlands; Department of Surgery, Division of HPB & Transplant Surgery, Erasmus MC Transplant Institute, Rotterdam, the Netherlands. Electronic address: i.cristoferi@erasmusmc.nl.
² Department of Pathology and Clinical Bioinformatics, Erasmus MC Transplant Institute, Rotterdam, the Netherlands.
³ Department of Pathology and Clinical Bioinformatics, Erasmus MC Transplant Institute, Rotterdam, the Netherlands; Department of Surgery, Division of HPB & Transplant Surgery, Erasmus MC Transplant Institute, Rotterdam, the Netherlands.
⁴ Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC Transplant Institute, Rotterdam, the Netherlands.
⁵ Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC Transplant Institute, Rotterdam, the Netherlands; Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany; Department of Nephrology and Clinical Immunology, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
⁶ Department of Surgery, Division of HPB & Transplant Surgery, Erasmus MC Transplant Institute, Rotterdam, the Netherlands.
⁷ Department of Pathology and Clinical Bioinformatics, the Tumor Immuno-Pathology Laboratory, Erasmus MC Transplant Institute, Rotterdam, the Netherlands.
⁸ Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands.
⁹ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹⁰ Department of Pathology and Clinical Bioinformatics, Erasmus MC Transplant Institute, Rotterdam, the Netherlands; Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany. Electronic address: m.clahsen-vangroningen@erasmusmc.nl.

PMID: 38128610
DOI: 10.1016/j.kint.2023.11.026

Abstract

Kidney transplant (KTx) biopsies showing transplant glomerulopathy (TG) (glomerular basement membrane double contours (cg) > 0) and microvascular inflammation (MVI) in the absence of C4d staining and donor-specific antibodies (DSAs) do not fulfill the criteria for chronic active antibody-mediated rejection (CA-AMR) diagnosis and do not fit into any other Banff category. To investigate this, we initiated a multicenter intercontinental study encompassing 36 cases, comparing the immunomic and transcriptomic profiles of 14 KTx biopsies classified as cg+MVI DSA^-/C4d^- with 22 classified as CA-AMR DSA⁺/C4d⁺ through novel transcriptomic analysis using the NanoString Banff-Human Organ Transplant (B-HOT) panel and subsequent orthogonal subset analysis using two innovative 5-marker multiplex immunofluorescent panels. Nineteen genes were differentially expressed between the two study groups. Samples diagnosed with CA-AMR DSA⁺/C4d⁺ showed a higher glomerular abundance of natural killer cells and higher transcriptomic cell type scores for macrophages in an environment characterized by increased expression of complement-related genes (i.e., C5AR1) and higher activity of angiogenesis, interstitial fibrosis tubular atrophy, CA-AMR, and DSA-related pathways when compared to samples diagnosed with cg+MVI DSA^-/C4d^-. Samples diagnosed with cg+MVI DSA^-/C4d^- displayed a higher glomerular abundance and activity of T cells (CD3⁺, CD3⁺CD8⁺, and CD3⁺CD8^-). Thus, we show that using novel multiomic techniques, KTx biopsies with cg+MVI DSA^-/C4d^- have a prominent T-cell presence and activity, putting forward the possibility that these represent a more T-cell dominant phenotype.

Keywords: chronic rejection; immunohistochemistry; kidney transplantation; transcriptomics; transplant glomerulopathy.

Publication types

Multicenter Study

MeSH terms

Biopsy
Complement C4b
Graft Rejection
Humans
Inflammation
Isoantibodies
Kidney Diseases*
Kidney Transplantation* / adverse effects
Multiomics
Peptide Fragments
T-Lymphocytes

Substances

Isoantibodies
Peptide Fragments
Complement C4b