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AST-120 to Target Protein-Bound Uremic Toxins Improves Cardiac Output and Kidney Oxygenation in Experimental Chronic
Ebba Sivertsson1, Sara Ceder1, Masaomi Nangaku2
1Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Insights
Reducing uremic toxins with AST-120 improved cardiac output and kidney function in a chronic kidney disease (CKD) rat model. This approach, alongside angiotensin-converting enzyme inhibitors (ACEI), shows promise for treating cardiac and kidney dysfunction in CKD patients.
Area of Science:
- Nephrology
- Cardiology
- Toxicology
Background:
- Chronic kidney disease (CKD) is a growing global health concern linked to cardiac dysfunction.
- Accumulation of uremic toxins and high salt intake exacerbate CKD and kidney disease.
- Investigated the impact of reducing protein-bound uremic toxins in a CKD rat model.
Purpose of the Study:
- To evaluate the efficacy of AST-120 in reducing uremic toxins in CKD rats.
- To compare AST-120's effects with conventional treatment using an angiotensin-converting enzyme inhibitor (ACEI).
- To assess the impact on cardiac function, kidney function, and oxidative stress under high salt conditions.
Main Methods:
- A 5/6 nephrectomy rat model was used to induce CKD.
- Rats were treated with either AST-120 (oral absorbent) or enalapril (ACEI) for 5 weeks.
- Kidney function, cardiac output, and oxidative stress markers were measured, particularly after high salt intake challenge.
Main Results:
- AST-120 decreased indoxyl sulfate levels, improved cardiac output, and reduced urinary oxidative stress.
- ACEI improved glomerular filtration rate under high salt conditions and reduced kidney oxidative stress.
- Both AST-120 and ACEI enhanced intrarenal oxygen availability compared to controls.
Conclusions:
- AST-120 demonstrates potential benefits for cardiac and kidney function by reducing uremic toxins like indoxyl sulfate.
- Simultaneous targeting of uremic toxins and angiotensin II signaling may be an effective strategy for managing CKD-related cardiac and kidney dysfunction.
- Further research could explore combined therapies to slow CKD progression.
Introduction:
Chronic kidney disease (CKD) is a global health problem with increasing incidence which is closely associated with cardiac dysfunction. In CKD, uremic toxins accumulate as kidney function declines. Additionally, high salt intake is a growing health issue worldwide which can exacerbate kidney disease. In this study, we investigated the effect of reducing plasma levels of protein-bound uremic toxins in a rat model of CKD, challenged with high salt intake and compared the effects to those of conventional treatment using an angiotensin-converting enzyme inhibitor (ACEI).
Methods:
In rats, the right kidney and 2/3 of the left kidney were surgically removed (5/6 nephrectomy). Animals were fed a normal-salt diet and randomized to either no treatment (control) or chronic treatment with either the oral absorbent AST-120 to reduce plasma levels of protein-bound uremic toxins or the ACEI enalapril to inhibit angiotensin II signaling for 5 weeks. Following treatment, kidney function was measured before and after a week of high salt intake. Cardiac output and markers of oxidative stress were measured at the end of the study period.
Results:
Treatment with AST-120 resulted in decreased levels of the uremic toxin indoxyl sulfate, improved cardiac output (mL/min: AST-120 44.9 ± 5.4 compared to control 26.6 ± 2.0; p < 0.05), and decreased urinary oxidative stress. ACEI reduced oxidative stress in kidney tissue and improved the glomerular filtration rate in response to high salt intake (mL/min: ACEI 1.5 ± 0.1; compared to control 1.1 ± 0.1; p < 0.05). Both interventions improved intrarenal oxygen availability (mm Hg: AST-120 42.8 ± 0.8; ACEI 43.2 ± 1.9; compared to control 33.4 ± 1.3; p < 0.05).
Conclusion:
AST-120 administered to reduce plasma levels of uremic toxins, such as indoxyl sulfate, has potential beneficial effects on both cardiac and kidney function. Targeting uremic toxins and angiotensin II signaling simultaneously could be an efficient strategy to target both cardiac and kidney dysfunction in CKD, to further slow progression of disease in patients with CKD.
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