Crescentic glomerulonephritis is a devastating autoimmune disease that without early and properly treat-ment may rapidly progress to end-stage renal disease and death. Current immunosuppressive treatment provided limited efficacy and an important burden of adverse events. Epigenetic drugs are a source of novel therapeutic tools. Among them, bromodomain and extraterminal domain (BET) inhibitors (iBETs) block the interaction between bromodomains and acetylated proteins, including histones and transcription factors. iBETs have demonstrated protective effects on malignancy, inflammatory conditions and experi-mental kidney disease. Recently, Gremlin-1 was proposed as a urinary biomarker of disease progression in human anti-neutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis. We have now evaluated whether iBETs regulate Gremlin-1 in experimental anti-glomerular basement membrane nephritis induced by nephrotoxic serum (NTS) in mice, a model of human crescentic glomerulonephritis. In NTS-injected mice, the iBET JQ1 inhibited renal Gremlin-1 overexpression and diminished glomerular damage, including podocyte loss. Chromatin immunoprecipitation assay demonstrated BRD4 enrichment of the Grem-1 gene promoter in injured kidneys, consistent with Gremlin-1 epigenetic regulation. Moreover, JQ1 blocked BRD4 binding and inhibited Grem-1 gene transcription. The beneficial effect of iBETs was also mediated by targeting NOTCH signaling pathway. JQ1 inhibited the gene expression of the NOTCH effec-tors Hes-1 and Hey-1 in NTS-injured kidneys. Our results further support the role for epigenetic drugs, such as iBETs, in the treatment of rapidly progressive crescentic glomerulonephritis.

ANCA-associated vasculitis (AAV) pose a significant risk of kidney failure, kidney biopsy remains a key prognostic tool. Pathology classification of the AAV glomerulonephritis (GN) developed by Berden et al showed correlation between GN classes and kidney outcomes; ANCA Renal Risk Score (ARRS) included tubular atrophy and interstitial fibrosis (TA/IF) as an additional parameter for risk assessment. We aimed to evaluate kidney survival across AAV GN classes and ARRS groups. A single-center retrospective study included 85 adult patients with biopsy-proven AAV kidney disease followed in 2000-2020. Primary outcome was kidney survival at the end of 18 [5; 66] months follow-up, kidney death considered as CKD stage 5. We found significant difference in the kidney survival for sclerotic, mixed, crescentic and focal AAV GN classes: 19%, 76.2%, 91.7% and 100% respectively (p=0.009). Kidney survival was 0%, 75.6% and 100% for the high, median and low risk ARRS groups respectively (p<0.001); TA/IF analysis showed kidney survival 49.6% vs 87.7% for widespread and mild TA/IF respectively (р=0.003). Kidney survival was significantly lower in anti-MPO-ANCA versus anti-PR3-ANCA carriers (50.3% and 78.1% respectively, р=0.045). We conclude that unfavorable AAV kidney outcomes associated with sclerotic GN class by Berden’s classification, ARRS high risk group, and anti-MPO-ANCA subtype.