Cardiorenal Syndrome Reimagined: From Hemodynamic Failure to a Multisystem Cardio-Renal-Metabolic-Inflammatory Network in the SGLT2 Era.

Cardiorenal syndrome (CRS) has traditionally been conceptualized as a hemodynamic disorder characterized by bidirectional dysfunction between the heart and kidneys. However, recent advances have expanded this paradigm into a complex multisystem disorder involving intertwined cardiovascular, renal, metabolic, inflammatory, neurohormonal, and immunologic pathways. The emergence of sodium-glucose cotransporter-2 (SGLT2) inhibitors has accelerated this conceptual transformation by demonstrating profound cardiovascular and renal benefits extending beyond glycemic control. Contemporary evidence suggests that CRS is not solely driven by impaired perfusion and venous congestion but also by maladaptive neurohormonal activation, mitochondrial dysfunction, oxidative stress, endothelial injury, fibrosis, metabolic derangements, gut microbiota dysbiosis, and chronic low-grade inflammation. This evolving framework aligns closely with the newly proposed cardiovascular-kidney-metabolic syndrome model, emphasizing systemic pathophysiological interconnectedness. SGLT2 inhibitors have emerged as disease-modifying therapies capable of targeting multiple mechanistic pathways simultaneously through natriuresis, restoration of tubuloglomerular feedback, reduction of intraglomerular hypertension, attenuation of inflammatory signaling, improvement in myocardial energetics, modulation of sympathetic activity, and mitigation of oxidative stress. Landmark clinical trials have consistently demonstrated reductions in heart failure hospitalization, chronic kidney disease progression, and cardiovascular mortality across diabetic and non-diabetic populations. In this narrative review, we re-examine CRS through a modern multidimensional lens, highlighting evolving molecular mechanisms, novel biomarkers, inflammatory-metabolic interactions, and the transformative therapeutic implications of SGLT2 inhibitors. We further explore future directions, including precision medicine, multi-omics profiling, artificial intelligence-assisted phenotyping, and emerging cardiorenal therapeutics that may redefine CRS management in the coming decade.