Cardiorenal Syndrome: From Hemodynamic and Humoral Pathophysiology to New Frontiers in Modulation and Enabling Therapy-Part 1.

Cardiorenal syndrome (CRS) encompasses a spectrum of disorders in which acute or chronic dysfunction of the heart or the kidney induces dysfunction in the other. Although the five-subtype classification provides a useful conceptual framework, operational definitions remain heterogeneous and management requires an individualized approach. Traditionally attributed to reduced forward arterial perfusion, renal impairment in heart failure is increasingly associated with systemic venous congestion and renal venous hypertension, although most evidence is observational. At the humoral level, chronic activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system sustains a cycle of oxidative stress, inflammation, and fibrosis. In this first part of a narrative review, we summarize these hemodynamic and humoral mechanisms and examine biomarkers that complement serum creatinine, including markers of filtration, tubular injury, and fibro-inflammatory activity, emphasizing that their interpretation depends on baseline renal function and congestion status. PubMed, Scopus, and Web of Science were searched up to September 2026. The available evidence is mainly observational and heterogeneous; these biomarkers appear complementary rather than substitutive, and their incremental clinical value requires prospective validation. Therapeutic strategies will be addressed in Part 2.