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Renal Denervation Improves Uremic Cardiomyopathy in Rats With Chronic Kidney Disease
Philipp Markwirth1, Simina-Ramona Selejan2, Mathias Hohl3
1Klinik für Innere Medizin III Universität des Saarlandes Homburg Germany.
Insights
Renal denervation (RDN) improved cardiac function in a rat model of chronic kidney disease (CKD). This was linked to reduced indoxyl sulfate (IS) levels, suggesting RDN may treat uremic cardiomyopathy in CKD patients.
Area of Science:
- Cardiology
- Nephrology
- Medical Devices
Background:
- Chronic kidney disease (CKD) is a significant cardiovascular risk factor.
- CKD patients develop uremic cardiomyopathy, characterized by sympathetic nervous system activation, left ventricular hypertrophy, and uremic toxin accumulation.
- Indoxyl sulfate (IS) is a key uremic toxin implicated in cardiovascular complications.
Purpose of the Study:
- To investigate the therapeutic effects of renal denervation (RDN) on uremic cardiomyopathy in a rat model of CKD.
- To assess the impact of RDN on plasma indoxyl sulfate (IS) levels and cardiac structure and function.
Main Methods:
- CKD was induced in Sprague-Dawley rats using adenine-enriched chow.
- Bilateral renal denervation (RDN) or sham operation was performed on CKD rats.
- Cardiac function and structure were evaluated using echocardiography and MRI; histological analysis assessed left ventricular hypertrophy; plasma and hepatic IS levels were measured.
Main Results:
- CKD rats exhibited significant left ventricular hypertrophy, increased E/A ratio, and elevated plasma IS levels.
- RDN significantly reduced left ventricular hypertrophy, improved cardiac function, and decreased plasma IS concentrations.
- Plasma IS levels correlated strongly with left ventricular hypertrophy, and IS exposure increased cardiomyocyte size in vitro.
Conclusions:
- RDN ameliorates uremic cardiomyopathy in a rat CKD model, associated with reduced plasma IS.
- IS is a critical factor in CKD-related cardiovascular disease, poorly cleared by hemodialysis.
- RDN presents a potential therapeutic strategy for uremic cardiomyopathy and cardiovascular disease in CKD patients, warranting clinical investigation.
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 accumulation 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 16 weeks to induce CKD. After 4 weeks, CKD rats with CKD were subjected to bilateral RDN (AD-RDN, n=8) or to sham operation (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 cardiomyoblasts, 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±0.014 mm 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±0.12 μg/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 concentrations of IS. To the present, IS remains a persistent clinical concern in patients with CKD due to its inefficient removal by conventional 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.
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