Autonomic-vascular dysregulation in CKD-associated hypertension: a narrative review with evidence hierarchy

Figures

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  Figure 1. Autonomic dysregulation (↑sympathetic, ↓parasympathetic) drives hypertension via vasoconstriction and CKD via renal nerve activity. Central mechanisms: RAAS activation (angiotensin II), oxidative stress (↓NO bioavailability), and uremic milieu (↓nephron mass). Feedback loops perpetuate the cycle: hypertension → nephrosclerosis/glomerular damage → CKD → autonomic imbalance. Pathways converge on vascular outcomes (arterial stiffness, capillary rarefaction, endothelial dysfunction). Solid arrows, direct effects; dashed arrows, feedback loops. This figure is adapted and modified from Ameer (2022), Grassi et al. (2015), KenKnight and Verrier (2022) and made with BioRender.com software.

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  Figure 2. Central integration of the arterial baroreflex, cardiac and renal sympathetic innervation. Sinoaortic baroreceptors located in the carotid sinus and aortic arch send afferent signals via cranial nerves IX and X to the nucleus tractus solitarius (NTS) in the dorsal medulla, where information on beat-to-beat arterial pressure is integrated. The NTS projects to the caudal and rostral ventrolateral medulla (CVLM, RVLM), nucleus ambiguus (NA), and hypothalamic nuclei including the paraventricular nucleus (PVN), with modulatory input from the subfornical organ (SFO). Excitatory and inhibitory connections within this network regulate sympathetic premotor neurons in the RVLM, which descend to preganglionic sympathetic neurons in the intermediolateral cell column (IML) of the thoracic spinal cord. From the IML, efferent fibers project via sympathetic ganglia to the heart, resistance vessels, adrenal medulla, and kidney. Parasympathetic efferents arising from the NA travel with the vagus nerve to the heart, whereas renal afferent nerves convey information from the kidney back to the brainstem and hypothalamus, completing a bidirectional brain–heart–kidney axis. CVLM, caudal ventrolateral…

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  Figure 3. Mechanisms of sympathetic overactivity in chronic kidney disease. Renal injury activates afferent sensory nerves (red) projecting to central autonomic nuclei (RVLM, PVN, NTS). Circulating uremic toxins and inflammatory mediators (blue) released from the damaged kidney directly stimulate central nuclei via the humoral pathway. Chemoreflex sensitization from sleep apnea and intermittent hypoxia (yellow) provides additional excitatory input via the carotid body. Increased central sympathetic efferent outflow (green) targets the heart (↑HR, ↑contractility), kidneys (↑RSNA), and vasculature (↑vasoconstriction), perpetuating hypertension and CKD progression. This figure is adapted and modified from Ameer (2022), Grassi et al. (2015), and KenKnight and Verrier (2022) and made with BioRender.com software.

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  Figure 5. Integrated pathophysiology of CKD-associated hypertension. CKD initiates multiple primary mechanisms including sodium/volume overload (↑Na, ↑ECF), RAAS activation (↑Ang II, ↑aldosterone), oxidative stress (↑ROS, ↓NO), inflammation (↑IL-6, ↑TNF-α, ↑CRP), and uremic toxin accumulation (IS, pCS). These converge on autonomic dysregulation characterized by ↑SNS activity (↑MSNA, ↑RSNA), ↓parasympathetic tone (↓vagal tone, ↓HRV), and impaired baroreflex (↓BRS). Autonomic imbalance, along with direct pathways (blue dashed), drives vascular dysfunction: endothelial dysfunction (↓NO, ↑ET-1), structural remodeling (↑IMT, calcification), and arterial stiffness (↑PWV, ↑PP). These culminate in hypertension (↑SVR, ↑BP) and CV events (LVH, HF, stroke, MI). Feedback loops perpetuate CKD progression and cardiorenal syndrome. Ang II, angiotensin II; BP, blood pressure; BRS, baroreflex sensitivity; CKD, chronic kidney disease; CRP, C-reactive protein; CV, cardiovascular; ECF, extracellular fluid; ET-1, endothelin-1; HF, heart failure; HRV, heart rate variability; IL-6, interleukin-6; IMT, intima-media thickness; IS, indoxyl sulfate; LVH, left ventricular hypertrophy; MI, myocardial infarction; MSNA,…

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  Figure 4. Vascular changes in CKD-associated hypertension. (A) Endothelial dysfunction: CKD reduces nitric oxide (NO) bioavailability and increases endothelin-1 (ET-1), reactive oxygen species (ROS), and impairs eNOS activity, leading to impaired vasodilation. (B) Structural changes: arterial remodeling includes intima-media thickening, vascular calcification, medial hypertrophy, and adventitial fibrosis. (C) Functional consequences: increased arterial stiffness elevates pulse wave velocity (PWV) and widens pulse pressure (PP), increasing systolic BP and cardiac afterload. BP, blood pressure; CKD, chronic kidney disease; eNOS, endothelial nitric oxide synthase; ET-1, endothelin-1; NO, nitric oxide; PP, pulse pressure; PWV, pulse wave velocity; ROS, reactive oxygen species. This figure is adapted and modified from Ameer (2022), Grassi et al. (2015), KenKnight and Verrier (2022), Mancia and Grassi (2014), and Roumeliotis et al. (2020) and made with BioRender.com software.