Evaluating the Association of Dietary Acid Load and Patterns with Cardiovascular Risk and Graft Histology in Kidney Transplant Recipients (KTRs) Across Race/Ethnicity

评估不同种族/民族的肾移植受者 (KTR) 的饮食酸负荷和模式与心血管风险和移植物组织学的关系

• 批准号: 10531768
• 负责人: Jessica B Kendrick
• 金额: $ 3.67万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-18 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10531768
• 关键词: Acids; Alkalies; Alternative Complement Pathway; Atrophic; Bicarbonates; Calcineurin inhibitor; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cessation of life; Chronic Kidney Failure; Collagen; Complement; Complement Activation; Data; Deposition; Development; Diet; Dietary Practices; Double-Blind Method; Endothelium; Ethnic Origin; Event; Feasibility Studies; Fibrosis; General Population; Histology; Inflammation; Inflammatory; Intervention Trial; Kidney; Kidney Diseases; Kidney Transplantation; Laboratories; Measures; Mediating; Nephrons; Outcome; Patients; Pattern; Pharmaceutical Preparations; Physiologic pulse; Placebo Control; Placebos; Plasma; Play; Race; Randomized; Risk; Serum; Sodium Bicarbonate; Surrogate Markers; Time; Tissues; Transplant Recipients; Tubular formation; Urine; Vascular Diseases; Vascular Endothelium; Vascular Graft; arterial stiffness; base; brachial artery; cardiovascular risk factor; cardiovascular transplantation; clinical practice; dietary; experience; graft failure; graft function; improved; interstitial; kidney biopsy; modifiable risk; mortality; novel; post-transplant; safety study; soluble complement C5b-9; trend

PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in kidney transplant recipients (KTRs) and death from CVD is the leading cause of graft loss. KTRs demonstrate abnormal endothelium-dependent dilation (EDD) and large artery stiffness, key pathophysiological antecedents to the development of CVD. Acid retention is a common feature of patients who have received a kidney transplant. KTRs have a single kidney and a decreased number of nephrons leading to an inability to excrete the daily dietary acid load. Additionally, KTRs receive several medications that can result in acid retention including calcineurin inhibitors. Acid retention results in increased ammoniagenesis leading to activation of the alternative complement pathway. Activation of the alternative complement pathway increases inflammatory factors, collagen deposition and endothelial inflammation contributing to tubulointerstitial damage and vascular dysfunction. We show that complement activation fragments are increased in KTRs compared to healthy controls and are inversely correlated with eGFR and EDD. Lower serum bicarbonate levels, even within the normal laboratory range, in KTRs are associated with an increased risk of graft loss, cardiovascular events and mortality. Small interventional trials have shown that treatment with alkali therapy slows progression of kidney disease, even in patients with normal serum bicarbonate levels. In our preliminary data, alkali therapy improved vascular endothelial function in 20 patients with chronic kidney disease stage 3-4. Because acid retention is common in KTRs, it is plausible that alkali therapy in KTRs may also result in improved vascular and graft function. In our preliminary data, we show in a randomized, double-blind, placebo-controlled crossover safety and feasibility study that sodium bicarbonate therapy is safe and feasible in KTRs and there is a trend towards improved EDD. We are proposing a randomized, double-blinded, placebo-controlled, 12 month study in 120 KTRs to examine the effect of sodium bicarbonate therapy on surrogate markers of CVD and graft function. Our overall hypothesis is that treatment with bicarbonate will improve indicators of vascular and graft function in KTRs by decreasing complement activation. In Aim 1, we will compare changes over time in brachial artery flow- mediated dilation and arterial stiffness, measured by aortic pulse wave velocity, before and after 12 months of sodium bicarbonate therapy or placebo. In Aim 2, we will compare changes over time in tubular atrophy and interstitial fibrosis in kidney biopsies before and after 12 months of sodium bicarbonate therapy or placebo. In Aim 3, we will examine changes in plasma and urine complement activation fragments (Ba and sC5b-9) and complement deposition in kidney tissue before and after 12 months of sodium bicarbonate therapy or placebo. The results of this novel study have the potential to inform clinical practice by providing the necessary evidence to establish sodium bicarbonate therapy as an inexpensive and easy to administer option for the treatment of vascular dysfunction and graft function in KTRs.

项目摘要/摘要 心血管疾病（CVD）是肾脏移植接受者（KTR）和死亡的主要原因 来自CVD是移植物损失的主要原因。 KTR表现出异常的内皮依赖性扩张 （EDD）和大动脉刚度，CVD发展的关键病理生理前因。酸 保留是接受肾脏移植的患者的共同特征。 KTR有一个肾脏 肾单位数量减少，导致无法排除每日饮食酸负荷。此外， KTR可以接受几种可能导致酸保留率在内的药物，包括钙调蛋白抑制剂。酸 保留导致氨基发电增加导致替代补体途径的激活。 替代补体途径的激活增加了炎症因子，胶原蛋白沉积和 内皮炎症导致肾小管间质损伤和血管功能障碍。我们表明 与健康对照相比，KTR中的补体激活片段增加了 与EGFR和EDD相关。降低血清碳酸氢盐水平，即使在正常实验室范围内， KTRS与移植损失，心血管事件和死亡率的风险增加有关。小的 介入试验表明，使用碱疗法的治疗减慢了肾脏疾病的进展，即使 血清碳酸氢盐水平正常的患者。在我们的初步数据中，碱疗法改善了血管 20例慢性肾脏疾病患者的内皮功能3-4。因为抗酸是常见的 KTRS，KTR中的碱疗法也可能导致血管和移植功能改善，这是合理的。在我们的 初步数据，我们以随机，双盲，安慰剂控制的跨界安全性和可行性显示 研究碳酸氢钠疗法在KTR中是安全且可行的，并且有一种改善的趋势 埃德我们提出了一个随机，双盲的，安慰剂对照，12个月的研究，以120 ktrs进行 检查碳酸氢钠治疗对CVD和移植功能的替代标记物的影响。我们的整体 假设是，用碳酸氢盐治疗将改善KTR中血管和移植功能的指标 减少补体激活。在AIM 1中，我们将比较臂动脉流中随时间的变化 - 在12个月之前和之后，通过主动脉脉冲波速度测量的介导的扩张和动脉刚度 碳酸氢钠治疗或安慰剂。在AIM 2中，我们将比较肾小管萎缩和 碳酸氢钠治疗或安慰剂12个月之前和之后的肾脏活检中的间质纤维化。在 AIM 3，我们将检查血浆和尿液补体激活片段（BA和SC5B-9）的变化， 碳酸氢钠治疗或安慰剂12个月前后的肾脏组织中补体沉积。 这项新研究的结果有可能通过提供必要的证据来为临床实践提供信息 建立碳酸氢钠疗法作为便宜且易于管理的选择 KTR中的血管功能障碍和移植功能。