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

## TL;DR

A new drug called fulacimstat effectively reduces the formation of a harmful protein in aged kidney transplants, which could help protect these kidneys.

## Contribution

Fulacimstat is shown to selectively inhibit chymase-dependent angiotensin II formation in human kidney allografts.

## Key findings

- Aged kidney allografts show a shift from ACE to chymase-dependent angiotensin II formation.
- Fulacimstat effectively inhibits chymase-dependent angiotensin II formation in kidney allografts.
- Chymase is identified as the key enzyme for angiotensin II production in aged kidney transplants.

## Abstract

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.

In this cross-sectional, exploratory single-center study we analyzed biopsy samples of KTx recipients (n = 55) and healthy kidney donors (n = 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.

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.

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.