A spatially resolved analysis of chronic active antibody-mediated rejection in kidney transplantation

• Applicant: Friederike Selbach
• Subject Area: Nephrology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 539291308

Kidney transplantation (KTx) is the treatment of choice for patients with end-stage kidney disease, but long-term graft survival remains disappointing. Under modern immunosuppression, chronic active antibody-mediated rejection (CAAMR) is one of the main causes of graft loss, with no effective treatment available. CAAMR pathophysiology is incompletely understood and entails immunologically mediated acute injury and chronic tissue remodeling, with a yet unclear role of donor-specific antibodies. Especially focal pathologies seem to have a major influence on the formation and progression of CAAMR, and for diagnosis the Banff classification also refers to strictly local histopathological abnormalities. While adequately addressing the highly variable degree of injury in different regions of the kidney, we contend that a spatially-resolved analysis of cellular and molecular characteristics of CAAMR using spatial transcriptomics (ST) and proteomics will provide valuable information on local rejection mechanisms. The Cravedi laboratory at Mount Sinai School of Medicine has already successfully applied ST to human kidney biopsies of patients with chronic glomerular diseases and acute T-cell mediated rejection (TCMR) in KTx, discovering significant divergence of gene expression in tubules and glomeruli. Additionally, in TCMR the ST data did not associate with the pathological score of the biopsies, implying potential superiority of ST in detecting early signs of rejection. Based on this experience, we intend to perform a spatially resolved transcriptomic and proteomic profiling of human kidney allograft biopsies of patients with DSA positive and negative CAAMR, DSA positive and negative non-rejecting KTx, and healthy controls. We plan to test the hypothesis, that antibody-dependent and independent endothelial injury leads to complement activation and inflammatory cell recruitment, which results in a graft initiated regenerative program to contrast progressive fibrosis and functional failure. With the acquired data we intend to dissect the focal mechanisms of endothelial injury, complement activation, immune cell recruitment, kidney injury repair, and progressive fibrosis. We will validate newly identified pathways using immunofluorescence in a larger cohort and correlate molecular findings with patients’ outcomes. Deciphering the spatial heterogeneity of inflammatory and regenerative programs in KTx holds the potential to better understand the process of allograft rejection, discover biomarkers, develop hypothesis-driven therapies, and improve long-term renal allograft survival.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Paolo Cravedi