Renal Denervation Improves Uremic Cardiomyopathy in Rats With Chronic Kidney Disease

Abstract

BACKGROUND: Chronic kidney disease (CKD) is an independent cardiovascular risk factor. Patients with CKD develop uremic cardiomyopathy characterized by activation of the sympathetic nervous system, left ventricular hypertrophy, and accumula tion of uremic toxins such as indoxyl sulfate (IS). The aim of this study was to assess the effects of renal denervation (RDN) on uremic cardiomyopathy in a rat model of CKD. METHODS: Sprague–Dawley rats were fed a standard chow (control group, n=6) or a 0.25% adenine-enriched chow (n=16) for 16weeks to induce CKD. After 4weeks, CKD rats with CKD were subjected to bilateral RDN (AD-RDN, n=8) or to sham opera tion (AD, n=8). Blood pressure measurements, echocardiography, and cardiac magnetic resonance imaging were deployed during the experiment. Left ventricular hypertrophy was evaluated histologically. IS was measured using ELISA. In H9C2 car diomyoblasts, the hypertrophic effects of IS were characterized in vitro. RESULTS: In AD rats, left ventricular septal wall thickness (2.37±0.036 versus 1.91±0.014mm in CTRL, P <0.0001), E/A ratio, and cardiomyocyte size were significantly increased. Following RDN, left ventricular wall thickness (P <0.0001 versus AD), E/A ratio (P <0.0001 versus AD), and myocyte hypertrophy were significantly reduced. Plasma IS was increased in AD (0.79±0.07 versus 0.2±0.12μg/mg in the control group, P=0.0044) and reduced in AD-RDN (P=0.0073 versus AD). Urinary IS remained unchanged after RDN, whereas hepatic concentration of IS decreased after RDN (P=0.023). Plasma IS correlated with left ventricular hypertrophy (r=0.779, P <0.0001). Stimulation of H9C2 cardiomyoblasts with IS or serum from AD rats showed an increase in cell size (P=0.0015), whereas AD-RDN serum showed no effect. CONCLUSIONS: In a rat model of CKD, improved cardiac function following RDN was associated with reduced plasma concen trations of IS. To the present, IS remains a persistent clinical concern in patients with CKD due to its inefficient removal by con ventional hemodialysis and its significant role in promoting both kidney and myocardial disease. Thus, RDN may ameliorate uremic cardiomyopathy by reducing IS and potentially represents a treatment option for patients with CKD and cardiovascular disease. Clinical trials are warranted to investigate the effects of RDN on cardiovascular outcomes in patients with CKD.