Effect of Alkali Therapy on Vascular and Graft Function in Kidney Transplant Recipients

碱疗法对肾移植受者血管和移植物功能的影响

基本信息

批准号：
10620221
负责人：
Jessica B Kendrick
金额：
$ 53.3万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/10620221
关键词：
Acids Alkalies Allografting Alternative Complement Pathway Ammonium Aorta Arteries Atrophic Bicarbonates Blood Vessels Calcineurin inhibitor Cardiovascular Diseases Cardiovascular system Cause of Death Cessation of life Chronic Kidney Failure Clinical Trials Collagen Complement Complement Activation Controlled Clinical Trials Data Deposition Development Double-Blind Method Elasticity Endothelium Equilibrium Event Excretory function Feasibility Studies Fibrosis General Population Glomerular Filtration Rate Health Histology Inflammation Inflammatory Intervention Trial Kidney Kidney Diseases Kidney Transplantation Laboratories Measures Mediating Metabolic acidosis Nephrons Observational Study Oral Patients Pharmaceutical Preparations Physicians Physiologic pulse Placebo Control Placebos Plasma Proteinuria Randomized Recommendation Renal tubular acidosis Reporting Research Risk Serum Sodium Bicarbonate Surrogate Markers Testing Time Tissues Transplant Recipients Transplantation Tubular formation Urine Vascular Diseases Vascular Endothelium Vascular Graft arterial stiffness base brachial artery cardiovascular risk factor cardiovascular transplantation clinical practice comparison control dietary endothelial dysfunction experience graft function improved interstitial kidney allograft kidney biopsy mortality novel novel therapeutics preservation prospective randomized trial safety and feasibility soluble complement C5b-9 trend urinary

项目摘要

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.

项目概要/摘要心血管疾病 (CVD) 是肾移植受者 (KTR) 死亡和死亡的主要原因 CVD 是移植物丢失的主要原因。 KTRs 表现出异常的内皮依赖性扩张 (EDD) 和大动脉僵硬度是 CVD 发展的关键病理生理学前因。酸滞留是接受肾移植的患者的一个共同特征。 KTR 有一个肾脏肾单位数量减少导致无法排出每日膳食酸负荷。此外， KTR 接受多种可能导致酸潴留的药物，包括钙调神经磷酸酶抑制剂。酸滞留导致氨生成增加，从而激活替代补体途径。替代补体途径的激活会增加炎症因子、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，并且呈反比与 eGFR 和 EDD 相关。较低的血清碳酸氢盐水平，即使在正常实验室范围内， KTR 与移植物丢失、心血管事件和死亡率风险增加相关。小的介入试验表明，碱疗法可以减缓肾脏疾病的进展，即使在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 名慢性肾脏病 3-4 期患者的内皮功能。因为酸潴留是常见的 KTRs，KTRs 中的碱治疗也可能改善血管和移植物功能，这似乎是合理的。在我们的初步数据，我们以随机、双盲、安慰剂对照的方式展示交叉的安全性和可行性研究表明碳酸氢钠治疗 KTR 是安全可行的，并且有改善的趋势预付款。我们提议对 120 个 KTR 进行一项为期 12 个月的随机、双盲、安慰剂对照研究，以检查碳酸氢钠治疗对 CVD 和移植物功能替代标志物的影响。我们的整体假设碳酸氢盐治疗将通过以下方式改善 KTR 中的血管和移植物功能指标：减少补体激活。在目标 1 中，我们将比较肱动脉流量随时间的变化 - 介导的扩张和动脉僵硬度，通过主动脉脉搏波速度测量，在 12 个月之前和之后碳酸氢钠疗法或安慰剂。在目标 2 中，我们将比较肾小管萎缩和肾小管萎缩随时间的变化碳酸氢钠治疗或安慰剂治疗前后 12 个月肾活检显示间质纤维化。在目标 3，我们将检查血浆和尿液补体激活片段（Ba 和 sC5b-9）的变化以及碳酸氢钠治疗或安慰剂治疗前后12个月肾组织中的补体沉积。这项新颖的研究结果有可能通过提供必要的证据来指导临床实践建立碳酸氢钠疗法作为治疗以下疾病的廉价且易于管理的选择 KTR 中的血管功能障碍和移植物功能。