The Heart–Kidney Axis in Heart Failure and Chronic Kidney Disease: Mechanisms, Mediators, and Therapeutic Implications

The heart–kidney axis has emerged as a central framework for understanding the bidirectional interactions that drive cardiorenal syndrome and broader cardiovascular–kidney–metabolic (CKM) disease. However, existing interpretations have often emphasized hemodynamic and neurohormonal mechanisms without fully integrating the growing evidence for endocrine, inflammatory, and metabolic mediators that coordinate injury across organs. This Review was therefore undertaken to provide an updated and clinically relevant synthesis of the physiological basis of heart–kidney communication, the mechanisms underlying its disruption, and the therapeutic implications of these insights. To achieve this aim, we performed a systematic narrative review of the literature using PubMed, Embase, Web of Science, and Scopus for studies, supplemented by manual screening of reference lists. Priority was given to original studies, large cohort analyses, randomized controlled trials, meta-analyses, and authoritative reviews. We integrated evidence spanning physiological regulation, maladaptive signaling pathways, emerging mediators, experimental models, and evolving treatment strategies. The reviewed evidence indicates that heart–kidney crosstalk is driven not only by altered perfusion and venous congestion, but also by sustained activation of the renin–angiotensin–aldosterone system (RAAS) and sympathetic nervous system (SNS), inflammation, oxidative stress, mitochondrial dysfunction, anemia, uremic toxins, and disordered mineral metabolism. Among novel mediators, fibroblast growth factor 23 (FGF23) emerges as a major bone-derived, chronic kidney disease (CKD)-associated endocrine mediator linking renal injury to cardiac hypertrophy, fibrosis, calcium mishandling, and diastolic dysfunction, whereas Klotho appears to exert counter-regulatory protective effects. Heart-derived natriuretic peptides, including atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), remain important modulators of renal blood flow, natriuresis, and volume homeostasis. We further highlight the translational relevance of newer biomarkers and therapies, including sodium–glucose cotransporter 2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists), and mineralocorticoid receptor antagonists (MRAs), which may help address cardiac and renal dysfunction in parallel. Overall, this Review supports a revised conceptual model in which the heart–kidney axis is governed by multidirectional hemodynamic, neurohormonal, immune, and endocrine signaling networks. A more integrated understanding of these mechanisms may improve biomarker discovery, refine risk stratification, and promote therapies that target both organs simultaneously.