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

Figures

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  Figure 1. Bidirectional crosstalk between the heart and kidney. CKD drives cardiac injury via anemia, FGF23–Klotho dysregulation, uremic toxins, and neurohormonal activation. HF promotes renal injury through reduced perfusion, venous congestion, and pericyte-to-myofibroblast transition leading to interstitial fibrosis. Systemic integration, metabolic imbalance, inflammation, and circadian disruption further amplify this bidirectional pathological network.

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  Figure 2. Schematic overview of physiological heart–kidney interactions. The figure illustrates the integrated hemodynamic, neurohumoral, metabolic, and endocrine mechanisms that sustain bidirectional crosstalk between the heart and kidney. Hemodynamic coupling links cardiac output and blood pressure to renal perfusion, which is buffered by afferent and efferent arteriolar autoregulation. Neurohumoral regulation is mediated through the RAAS, SNS, and ADH, with renin release triggered by β1−adrenergic stimulation, macula densa signals (NKCC2/PGE2/NO), and intrarenal baroreceptor sensing; Ang II/AT1R signaling downstream activates Gq/PLC/IP3/Ca2+/PKC/MAPK pathways, promoting vasoconstriction, aldosterone release, and sodium retention. Metabolic crosstalk involves proximal tubular glucose handling via SGLT2 and glutamine-dependent acid–base regulation (NH4+, HCO3−), while renal electrolyte and acid–base balance influence myocardial energetics and electrophysiology. Endocrine signaling is mediated by kidney-derived EPO (via EPOR–JAK2/STAT5−PI3K/Akt/eNOS), renin, and Klotho (via FGFR−FGF23 and insulin/IGF−1/NF−κB/NLRP3 pathways), which collectively regulate myocardial oxygen delivery, vascular…

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  Figure 3. Schematic diagram of the mechanisms by which renal anemia and uremic toxins induce myocardial injury.

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  Figure 4. Schematic diagram of the mechanisms by which AHF induces AKI. AHF triggers AKI through three interconnected axes. Forward failure reduces cardiac output and mean arterial pressure, leading to renal hypoperfusion when autoregulatory capacity is exhausted. Backward congestion, driven by elevated central venous pressure, impairs renal venous outflow, increases interstitial hydrostatic pressure, and reduces the transglomerular filtration gradient. Concurrently, RAAS and SNS overactivation initiates a proinflammatory cascade via Ang II–AT1R signaling, which activates NF-κB and upregulates TNF-α, IL-1β, and IL-6; IL-6 further engages JAK/STAT3 to promote leukocyte recruitment and tubular apoptosis. Additional pathways include NOX/ROS-mediated oxidative stress, HIF-1α-driven inflammatory gene expression, TLR4/MyD88-dependent innate immune responses to DAMPs, complement C3a/C5a signaling, and TGF-β1/Smad-mediated extracellular matrix remodeling. These converging insults culminate in tubulointerstitial injury, characterized by M1 macrophage polarization, mitochondrial dysfunction, and multiple cell death modalities (apoptosis, necrosis, pyroptosis), ultimately leading to fibrosis and…

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  Figure 5. Schematic diagram of circadian control in the kidney and heart and the consequences of circadian disruption. The figure illustrates the molecular clock machinery and its tissue-specific outputs. In the kidney, the local tubular clock regulates segment-specific transporters (NHE3 in the proximal tubule, NKCC2 in the thick ascending limb, and ENaC/AQP2 in the collecting duct) through aldosterone–MR and AVP–V2R–cAMP/PKA signaling, thereby controlling natriuresis, urine concentration, and volume/BP homeostasis. In the heart, the cardiomyocyte clock governs BMAL1-dependent glucose metabolism, REV-ERB-dependent fatty acid oxidation, mitochondrial OXPHOS, ATP production, and ion handling (including Ca2+ cycling, SERCA2a, NCX, and Na+/K+ channels), which collectively modulate contractility, conduction, and arrhythmic susceptibility. Clock disruption—triggered by aging, CKD, diabetes, obesity, shift work, sleep disturbance, or light at night—activates SNS, RAAS, Ang II, and vasopressin, while promoting ROS generation and NF-κB/TGF-β-mediated fibrosis. These alterations lead to non-dipping BP, nocturia, sodium retention, cardiac remodeling, and progressive renal injury. Abbreviations:…