Seshan, S. V. | bioRxiv Science

bioRxiv2026

First Order Associations Between Banff Acute Lesions in Kidney Allograft Biopsies and a Urinary Cell Three-Gene Diagnostic Signature

Banff acute lesion scores underpin histologic classification of kidney allograft biopsies; however, biomarker studies rely on second-order associations with diagnostic categories that introduce confounding. We quantified the first-order relationships between Banff acute lesion scores and the validated urinary cell three-gene rejection signature. In 354 biopsy-urine pairs, three-gene signature scores computed using a locked regression equation incorporating absolute copy numbers of CD3E mRNA, CXCL10 mRNA, and 18S rRNA in urinary cell RNA-were related to glomerulitis (g), peritubular capillaritis (ptc), interstitial inflammation (i), and tubulitis (t). Signature scores rose monotonically with Banff acute lesion severity, with 1.5 to 1.8-fold higher odds of more severed g, ptc, i, and t (all P<0.0001), and showed good calibration. Associations remained robust for composite microvascular (g+ptc) and tubulointerstitial (i+t) indices and were strongest for severe g and t, supporting this signature as a noninvasive, quantitative readout of acute rejection pathology with immediate diagnostic applicability.

pathology↗

bioRxiv2022

Adaptive Immune Landscape of T-Cell Mediated Rejection of Human Kidney Allografts

The frequently occurring T cell mediated rejection (TCMR) is a risk factor for allograft failure. Immunosuppressive therapy fails to reverse almost 40% of TCMRs occurring in human kidney allografts. A better understanding of the molecular mechanisms of TCMR and precision therapeutics may improve allograft longevity. We investigated adaptive immune landscape of TCMR by genome wide RNA sequencing of 34 prototypic kidney allograft biopsies from 34 adult recipients of human kidney allografts. Sixteen of the 34 biopsies were categorized as Banff TCMR and the remaining 18 as Banff Normal biopsies. Computational analysis identified higher intragraft abundance of the gene sets for key players of adaptive immune system in TCMR. TCMR allografts were characterized by, i) increased antigen processing and presentation and T cell receptor signaling, ii) increased memory T cells, Tregs, Th1, Th2 and Th17 subsets, iii) increased aerobic glycolysis of lymphocytes and reduced metabolic activity of graft parenchymal cells, iv) increased T cell inhibitory receptors and exhaustion markers, v) increased apoptosis and necroptosis, and vi) increased extracellular matrix remodeling, all in comparison to Normal biopsies. Our genome-wide transcriptomics provides an atlas of adaptive immune landscape of TCMR in human kidney allografts, help deduce molecular mechanisms and prioritization of therapeutic targets.

immunology↗