Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan.
Kidney Blood Press Res. 2023;48(1):114-123. doi: 10.1159/000529272. Epub 2023 Feb 15.
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).
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.
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).
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.
慢性肾脏病（CKD）是一个全球性的健康问题，发病率不断上升，与心脏功能障碍密切相关。在 CKD 中，随着肾功能下降，尿毒素会蓄积。此外，高盐摄入是全球日益严重的健康问题，可加重肾脏疾病。在这项研究中，我们在高盐摄入的 CKD 大鼠模型中研究了降低血浆蛋白结合尿毒素水平的效果，并将其与使用血管紧张素转换酶抑制剂（ACEI）的常规治疗效果进行了比较。
在大鼠中，通过手术切除右肾和左肾的 2/3（5/6 肾切除术）。动物喂食正常盐饮食，并随机分为无治疗（对照组）或慢性治疗，分别用口服吸附剂 AST-120 降低血浆蛋白结合尿毒素水平或 ACEI 依那普利抑制血管紧张素 II 信号转导 5 周。治疗后，在高盐摄入前和摄入后一周测量肾功能。在研究结束时测量心输出量和氧化应激标志物。
AST-120 治疗可降低尿毒症毒素吲哚硫酸酯的水平，改善心输出量（mL/min：AST-120 44.9 ± 5.4 与对照组 26.6 ± 2.0 相比；p < 0.05），并降低尿氧化应激。ACEI 可降低肾组织氧化应激，并改善肾小球滤过率对高盐摄入的反应（mL/min：ACEI 1.5 ± 0.1；与对照组 1.1 ± 0.1 相比；p < 0.05）。两种干预措施均改善了肾内氧供应（mmHg：AST-120 42.8 ± 0.8；ACEI 43.2 ± 1.9；与对照组 33.4 ± 1.3 相比；p < 0.05）。
AST-120 用于降低血浆尿毒素水平，如吲哚硫酸酯，对心脏和肾功能均有潜在的有益作用。同时靶向尿毒症毒素和血管紧张素 II 信号可能是 CKD 中心脏和肾脏功能障碍的有效策略，可进一步减缓 CKD 患者的疾病进展。
