Ebba Sivertsson, Sara Ceder, Masaomi Nangaku, Peter Hansell, Lina Nordquist, Fredrik Palm
{"title":"以蛋白结合型尿毒症毒素为靶标的 AST-120 可改善实验性慢性肾病患者的心输出量和肾脏氧合。","authors":"Ebba Sivertsson, Sara Ceder, Masaomi Nangaku, Peter Hansell, Lina Nordquist, Fredrik Palm","doi":"10.1159/000529272","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>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).</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":17813,"journal":{"name":"Kidney & blood pressure research","volume":null,"pages":null},"PeriodicalIF":2.3000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"AST-120 to Target Protein-Bound Uremic Toxins Improves Cardiac Output and Kidney Oxygenation in Experimental Chronic Kidney Disease.\",\"authors\":\"Ebba Sivertsson, Sara Ceder, Masaomi Nangaku, Peter Hansell, Lina Nordquist, Fredrik Palm\",\"doi\":\"10.1159/000529272\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>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).</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":17813,\"journal\":{\"name\":\"Kidney & blood pressure research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2023-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Kidney & blood pressure research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1159/000529272\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/2/15 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"PERIPHERAL VASCULAR DISEASE\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Kidney & blood pressure research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1159/000529272","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/2/15 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"PERIPHERAL VASCULAR DISEASE","Score":null,"Total":0}
AST-120 to Target Protein-Bound Uremic Toxins Improves Cardiac Output and Kidney Oxygenation in Experimental Chronic Kidney Disease.
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.
期刊介绍:
This journal comprises both clinical and basic studies at the interface of nephrology, hypertension and cardiovascular research. The topics to be covered include the structural organization and biochemistry of the normal and diseased kidney, the molecular biology of transporters, the physiology and pathophysiology of glomerular filtration and tubular transport, endothelial and vascular smooth muscle cell function and blood pressure control, as well as water, electrolyte and mineral metabolism. Also discussed are the (patho)physiology and (patho) biochemistry of renal hormones, the molecular biology, genetics and clinical course of renal disease and hypertension, the renal elimination, action and clinical use of drugs, as well as dialysis and transplantation. Featuring peer-reviewed original papers, editorials translating basic science into patient-oriented research and disease, in depth reviews, and regular special topic sections, ''Kidney & Blood Pressure Research'' is an important source of information for researchers in nephrology and cardiovascular medicine.