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

便秘是慢性肾脏病(CKD)患者最常见的胃肠道疾病之一， 部分原因是他们的多种合并症，伴随的药物，纤维和液体的摄入量低，以及肠道改变 微生物区系。尽管便秘通常被认为是一种良性疾病，但最近的证据对此提出了挑战 这种最常见的看法表明，它与糟糕的临床结果独立相关，部分原因是 通过改变的肠道微生物区系有利于粪便代谢物的产生。在CKD患者中，其 肠道在尿毒症毒素的处理以及液体和电解质的动态平衡中起着重要的作用。 便秘可以阻止这些代偿机制，并可能进一步导致其临床不良 结果。重要的是，最近对尿毒症动物的实验研究表明，便秘的治疗 泻药不仅加速了肠道运动，还改变了肠道微生物区系和粪便代谢物， 保护肠道屏障，抑制炎症反应，甚至改善慢性肾脏病的进展。这些 研究结果表明，对慢性肾脏病患者的便秘进行适当的治疗可能会提供 在其常规排便控制之外的其他治疗和预后益处。然而，没有人类 已有研究考察了便秘治疗对便秘相关临床结果的影响， 也不影响慢性肾脏病患者的预后相关生化和微生物参数。中心假说 这项建议的目的是治疗慢性肾脏病患者的便秘，不仅改善他们的便秘 症状，也有利于改变相关的生化和肠道微生物图谱，并最终 改善这些患者的临床结果。作为检验这一假设的第一步，我们建议执行 为期4周的单中心、开放标签、随机、对照、平行分组、试点可行性试验 慢性肾脏病合并便秘患者的便秘治疗(与对照组相比)，具体目标如下：1) 测试提供拟议干预措施和实施拟议检查的可行性；以及2) 确定便秘治疗对便秘相关临床症状变化的影响， 共40例慢性支气管炎患者的肠道和循环微生物区系的生化参数和微生物谱 CKD G3-G5期和便秘，随机1：1便秘治疗(乳果糖治疗)与对照组(乳果糖治疗 除双沙可定抢救疗法外，无其他治疗方法)。与小型R01机制的目标一致，这 小型、短期的试点可行性试验使我们能够获得有关便秘影响的初步数据 慢性肾脏病患者不同方面的治疗以及与招募、保留和研究相关的可行性数据 品行。此外，这项研究的结果将为我们测试 便秘治疗对慢性肾脏病患者便秘相关的几种临床结局的影响 大规模临床试验，以及潜在的病理生理机制的确定 导致了新的肠道靶向治疗策略的发展，以改善慢性肾脏病的临床结果。

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.