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

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.