MO215: Intrarenal Single Cell Sequencing of MPO-Anca Associated Glomerulonephritis Patients Reveal Novel Targetable Treatment Options

Abstract

Abstract BACKGROUND AND AIMS The etiopathogenesis underlying myeloperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (MPO-ANCA-GN) remains incompletely understood. Furthermore, there are only limited treatment options and treatment resistance of MPO-ANCA-GN is still a common problem. METHOD To identify new targeted treatment options, intrarenal single-cell RNA sequencing (scRNA-seq) was applied to 11 kidney biopsies from MPO-ANCA-GN patients and 2 health kidney tissues to define the transcriptomic landscape at single-cell resolution. Intrarenal scRNAseq was also applied to a pre-clinical mouse model of MPO-ANCA-GN to show that this model of disease can be used to trial new targeted treatments. RESULTS We found that kidney endothelial cells in MPO-ANCA-GN patients displayed increased expression of several genes, including CD9 and SPARC, which were closely related to parietal epithelial hyperplasia and crescent formation. NF-κB pathway activation was confirmed in a variety of kidney cells in MPO-ANCA-GN patients. Kidney infiltrating immune cells of MPO-ANCA-GN patients were mainly enriched in inflammatory pathways including TNF signalling, IL-17 signalling and NOD-like receptor signalling. These findings were similar in our pre-clinical mouse model of MPO-ANCA-GN. Furthermore, there was an overexpression of inflammasome-related genes (AIM2, IFI16) in MPO-ANCA-GN patients. Treatment resistance was associated with increased infiltration of CD8+ T cells and elevated expression of SPARC, LAMA4, IL33 and CFL1 in mesangial cells when compared with patients who achieved remission after induction therapy. CONCLUSION These results offer new insight into the pathogenesis of MPO-ANCA-GN, treatment resistance and identify new therapeutic targets for MPO-ANCA-GN that can be tested in a pre-clinical model of disease.