Clinical, Biochemical, and Microbiological Effects of Constipation Treatment in Patients with Chronic Kidney Disease: A Pilot Feasibility Trial

慢性肾病患者便秘治疗的临床、生化和微生物学效果：初步可行性试验

• 批准号: 10639532
• 负责人: Susmita Datta
• 金额: $ 30.88万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-11 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10639532
• 关键词: Acceleration; Albumins; Animals; Benign; Biochemical; Biological; Cardiovascular system; Chronic Kidney Failure; Clinical; Clinical Trials; Constipation; Data; Defecation; Development; Disease Progression; Economic Burden; Effectiveness; Electrolyte Balance; Electrolytes; Equilibrium; Fiber; Fluid Balance; Foundations; Gastrointestinal Diseases; Goals; Homeostasis; Human; Inflammatory; Inflammatory Response; Intake; Intervention; Intestinal Motility; Kidney; Lactulose; Liquid substance; Mediating; Microbe; Modification; Outcome; Patients; Perception; Pharmaceutical Preparations; Phenotype; Phosphorus; Play; Population; Potassium; Production; Quality of life; Randomized; Research Design; Research Project Grants; Role; Serum; Suggestion; Symptoms; Testing; Therapeutic; Toxin; Uremia; Urine; comorbidity; effectiveness testing; experimental study; feasibility testing; feasibility trial; gastrointestinal; gut microbiota; improved; laxative; microbial; microbiota; novel; open label; prognostic; randomized trial; recruit; social; targeted treatment

Constipation is one of the most prevalent gastrointestinal disorders in patients with chronic kidney disease (CKD), due in part to their multiple comorbidities, concomitant medications, low fiber and fluid intake, and altered gut microbiota. Although constipation is usually perceived as a benign condition, recent evidence has challenged this most common perception, demonstrating its independent association with poor clinical outcomes, partly through the altered gut microbiota favoring the production of fecal metabolites. Among patients with CKD whose gut plays an important role in the disposal of uremic toxins and in fluid and electrolyte homeostasis, the presence of constipation can preclude these compensatory mechanisms and may further contribute to their poor clinical outcomes. Importantly, recent experimental studies in uremic animals have shown that constipation treatment with laxatives not only accelerated intestinal motility but also modified the gut microbiota and fecal metabolites, protected the gut barrier, suppressed inflammatory responses, and even ameliorated CKD progression. These findings led to the suggestion that the adequate management of constipation in patients with CKD may provide additional therapeutic and prognostic benefits beyond its conventional defecation control. However, no human studies have yet examined the effects of constipation treatment on clinical outcomes associated with constipation, or on outcome-related biochemical and microbiological parameters in patients with CKD. The central hypothesis of this proposal is that treatment of constipation in patients with CKD not only improves their constipation symptoms but also favorably modifies the relevant biochemical and gut microbial profiles, and ultimately improves clinical outcomes in these patients. As a first step to test this hypothesis, we propose to perform a single-center, open-label, randomized, controlled, parallel-group, pilot feasibility trial of a 4-week intervention of constipation treatment (vs. control) in patients with CKD and constipation, with the following specific aims: 1) Test the feasibility of delivering the proposed interventions and performing the proposed examinations; and 2) Determine the effects of constipation treatment on the changes in constipation-related clinical symptoms, biochemical parameters, and microbial profiles of the gut and circulating microbiota, in a total of 40 patients with CKD stages G3-G5 and constipation, randomized 1:1 to constipation treatment (with lactulose) vs. control (with no treatment except bisacodyl rescue therapy). Consistent with the objectives of the small R01 mechanism, this small, short-term pilot feasibility trial allows us to acquire preliminary data regarding the effects of constipation treatment on various aspects of patients with CKD and feasibility data related to recruitment, retention, and study conduct. Furthermore, the findings of this study will lay the foundation for our long-term goal to test the effectiveness of constipation treatment on several clinical outcomes associated with constipation in CKD in a large-scale clinical trial, along with the determination of underlying pathophysiological mechanisms, potentially leading to the development of novel gut-targeted therapeutic strategies to improve clinical outcomes in CKD.

便秘是慢性肾脏疾病（CKD）患者中最普遍的胃肠道疾病之一， 部分原因是它们多种合并症，伴随药物，低纤维和液体摄入量以及肠道改变 微生物群。尽管便秘通常被视为良性疾病，但最近的证据已挑战 这种最常见的感知表明了其与临床不良结局的独立关联，部分是 通过改变的肠道菌群，有利于产生粪便代谢产物。在CKD患者中 肠道在处置尿毒症毒素以及液体和电解质稳态中起着重要作用，存在 便秘可以排除这些补偿机制，并可能进一步有助于其临床不良 结果。重要的是，最近在尿毒动物的实验研究表明便秘处理 泻药不仅加速了肠道运动，而且还改变了肠道菌群和粪便代谢产物， 保护肠道屏障，抑制炎症反应，甚至改善CKD的进展。这些 调查结果提出了这样的建议，即CKD患者的便秘的适当管理可能会提供 超出其常规排便控制的其他治疗和预后益处。但是，没有人 研究尚未检查便秘处理对便秘相关的临床结果的影响， 或CKD患者的与结果相关的生化和微生物学参数。中心假设 该提议的是，CKD患者的便秘治疗不仅改善了便秘 症状，但也有利地修改了相关的生化和肠道微生物特征，最终 改善这些患者的临床结果。作为检验该假设的第一步，我们建议执行 单中心，开放标签，随机，受控，平行组，可行性试验4周的干预 CKD和便秘患者的便秘处理（与对照），以下特定目的：1） 测试提供拟议的干预措施并进行拟议检查的可行性；和2） 确定便秘处理对便秘相关临床症状变化的影响， 肠道和循环微生物群的生化参数和微生物谱，共有40例患者 CKD阶段的G3-G5和便秘，随机1：1进行便秘处理（带有乳乳糖）与对照 除Bisacodyl救援疗法外，没有治疗）。与小型R01机制的目标一致 小型，短期的飞行员可行性试验使我们能够获取有关便秘影响的初步数据 对CKD患者的各个方面以及与招聘，保留和研究有关的可行性数据进行治疗 执行。此外，这项研究的结果将为我们的长期目标奠定基础 便秘处理对与CKD中便秘相关的几种临床结果的有效性 大规模临床试验，以及基本的病理生理机制的确定 导致开发新颖的肠道靶向治疗策略，以改善CKD的临床结果。