Work

Fulacimstat Reduces Angiotensin II in Kidney Allografts in a Cross-Sectional Exploratory Study

Year: 2025

Type: article

Abstract: Introduction: The nephroprotective effects of renin-angiotensin system (RAS) blockade after kidney transplantation (KTx) remain ambiguous. It has been shown that chymase and not angiotensin (Ang)-converting enzyme (ACE) is the most efficient Ang II-forming enzyme. Here, we investigated the efficacy of the novel and highly selective chymase inhibitor fulacimstat (BAY 1142524) on Ang II formation in human allograft biopsy tissue. Methods: = 13) with and without therapeutic RAS blockade. Using a mass spectrometry-based approach and using specific enzyme inhibitors, we performed metabolic assays to study enzyme activities of ACE and chymase and their specific contribution to intrarenal Ang II formation. Results: In contrast to healthy kidneys, a distinct shift from ACE toward chymase-dependent Ang II formation was observed in aged (> 2 years) kidney allografts. Irrespective of RAS blockade, we demonstrated high efficacy of fulacimstat (BAY 1142524) to inhibit endogenous chymase-dependent Ang II formation in biopsy tissues of human kidney allografts. Conclusion: Chymase is the key enzyme for Ang II production in aged graft vintage (> 2 years). Selective inhibition of tissue-specific chymase with fulacimstat (BAY 1142524) inhibits Ang II formation in human kidney allografts, indicating potential therapeutic effects.

Source: Kidney International Reports

DOI: 10.1016/j.ekir.2025.103745