Innovative holistic treatment for CKM: what lies ahead?

Cardiovascular-kidney-metabolic (CKM) syndrome, as defined by the American Heart Association, encompasses interrelated metabolic, kidney, and cardiovascular disorders that mutually reinforce one another along a shared risk continuum. Its five-stage model, supported by the PREVENT risk equations, guides stage-specific prevention and treatment. Albuminuria, alongside eGFR, plays a central role not only as a marker of kidney damage but as an independent cardiovascular risk factor. Visceral adiposity and insulin resistance promote cardiovascular and kidney injury through interconnected inflammatory, oxidative, hemodynamic, and neurohormonal pathways. The metabolic dysfunction-associated steatotic liver disease (MASLD) as part of the proposed cardiovascular-kidney-liver-metaolic (CKLM) framework further highlights the role of the liver as another key contributor in this multiorgan disease. Effective management requires coordinated interventions, including lifestyle modification, weight management, renin-angiotensin system inhibitors, SGLT2 inhibitors, GLP-1 receptor agonist, non-steroidal mineralocorticoid receptor antagonists (nsMRAs), as consolidated by the AHA/ACC/ADA/ASN and ESC guidelines. However, fragmented care, limited awereness and socioeconomic inequalities – including a persistent risk treatment paradox - continue to limit implementation. Improved preclinical models and more inclusive clinical studies incorporating multiorgan outcomes may facilitate the translation of mechanistic findings, while multimodal imaging and artificial intelligence may improve risk prediction and diagnostic algorithms. Further validation of disease trajectories and broad implementation of interdisciplinary care are needed to improve outcomes across the CKM continuum.