Drivers of multi-organ fibrosis

Intro

This session focuses on the mechanisms that drive multi-organ fibrosis, including but not limited to obesity. Obesity-related pathways can influence fibroblast activity with effects seen in the heart, liver, kidney, and possibly cognitive function, while unintended consequences may arise in bone and muscle. These weight-dependent and weight-independent mechanisms highlight how different drivers can shape fibrotic progression across organs.

“It’s the matrix, stupid”: Remodeling the ECM to impact weight loss quality and multimorbidity

Manu Chakravarthy, Senior Vice President and Global Head at Roche-Genentech

Abstract: In this presentation, we provide a translational perspective on the pathogenic drivers of multi-organ morbidity, positing that Cardiovascular-Kidney-Metabolic (CKM) syndrome is not solely a manifestation of metabolic dysfunction, but fundamentally a structural defect driven by an altered ECM. Fibrosis is not merely an inert, end-stage local scar; rather, a highly dynamic endocrine network. Obesity expands fat mass while simultaneously driving pathogenic fibroblasts and adipose progenitor cells to overproduce COL6A3. The C-terminal cleavage of this collagen releases endotrophin that drives coronary artery disease. This matrix-driven interconnectedness dictates that when the liver stiffens, the heart fails, often in tandem with declining kidney function. Consequently, liver fibrosis (assessed by PRO-C3 ADAPT and FIB-4) combined with cardiac stress (measured by NT-proBNP) exerts an additive impact on cardiovascular mortality risk. Therefore, therapeutic interventions aimed at driving weight loss, lowering blood glucose, or decreasing liver fat must actively remodel this altered ECM to ensure end-organ protection. By integrating precision matrix biomarkers with predictive tools like the Kidney Klinrisk Algorithm in drug development as well as in routine clinical care, we can rigorously stratify patient risk, prognosticate outcomes, and track real-time structural healing necessary to determine the true physiological quality of weight loss and multiorgan function.

Title TBD

Dinesh Khanna, Professor at the Department of Internal Medicine, University of Michigan.

Abstract: TBD