REMODELing mechanistic trials for kidney disease: a multimodal, tissue-centered approach to understand the renal mechanism of action of semaglutide.

Chronic kidney disease poses a major global health burden and is one of the most common complications of type 2 diabetes. Drug trials have demonstrated that treatments, including sodium-glucose cotransporter-2 inhibitors, a glucagon-like peptide-1 receptor agonist, and a nonsteroidal mineralocorticoid receptor antagonist, mitigate chronic kidney disease progression, but the underlying nephroprotective mechanisms of action remain incompletely understood, partly ascribed to their pleiotropic actions. New innovative trial designs are needed to tackle simultaneously the hemodynamic and structural effects induced by these drugs. The REMODEL trial (REnal MODE of action of semagLutide in patients with type 2 diabetes and chronic kidney disease; ClinicalTrials.gov identifier: NCT04865770) is designed to explore the mechanisms of action of semaglutide with a novel multiparametric approach, integrating functional magnetic resonance imaging and research kidney biopsies for structural and molecular interrogation and blood and urine biomarker analysis. Better understanding of these mechanisms will help explain semaglutide's beneficial effects on kidney disease outcomes, reported in the FLOW (Evaluate Renal Function with Semaglutide Once Weekly; ClinicalTrials.gov identifier: NCT03819153) trial, and may identify patient subpopulations to optimize treatment strategies. By combining diverse and state-of-the-art methods, REMODEL aims to pave the way to a larger use of mechanism of action trials in the near future. To this purpose, this article describes the REMODEL framework, methods, technical challenges, and lessons learned as a platform for future mechanistic trials of chronic kidney disease therapies and beyond.