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

项目概要/摘要 心血管疾病（CVD）是肾移植受者（KTR）死亡的主要原因， 是移植物丢失的主要原因。KTR显示异常内皮依赖性舒张 (EDD)和大动脉僵硬，CVD发展的关键病理生理学前因。酸 尿潴留是接受肾移植的病人的常见特征。KTR只有一个肾脏 以及肾单位数量减少，导致不能排泄每日膳食酸负荷。此外，本发明还 KTR接受几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。 补体旁路途径的激活增加了炎症因子、胶原沉积和炎症反应。 导致肾小管间质损伤和血管功能障碍的内皮炎症。我们证明了 与健康对照相比，KTR中的补体激活片段增加， 与eGFR和EDD相关。血清碳酸氢盐水平较低，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的风险增加相关。小 介入性试验表明，即使在肾脏疾病中，碱疗法也能减缓肾脏疾病的进展。 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例慢性肾病3-4期患者的内皮功能。因为酸潴留是常见的 KTRs，这是合理的，碱治疗KTRs也可能导致改善血管和移植物功能。在我们 初步数据，我们在一个随机，双盲，安慰剂对照交叉安全性和可行性 研究碳酸氢钠治疗KTRs是安全可行的，并有改善的趋势 EDD。我们建议在120名KTR中进行一项随机、双盲、安慰剂对照、为期12个月的研究， 检查碳酸氢钠治疗对CVD和移植物功能的替代标志物的影响。我们的整体 假设用碳酸氢盐治疗将通过以下方式改善KTR中血管和移植物功能的指标： 减少补体激活。在目标1中，我们将比较肱动脉血流随时间的变化- 介导的扩张和动脉硬度，通过主动脉脉搏波速度测量，在12个月之前和之后， 碳酸氢钠治疗或安慰剂。在目标2中，我们将比较肾小管萎缩随时间的变化， 碳酸氢钠治疗或安慰剂治疗12个月前后肾活检中的间质纤维化。在 目的3，我们将检测血浆和尿液中补体激活片段（Ba和sC 5 b-9）的变化， 在碳酸氢钠治疗或安慰剂治疗12个月之前和之后肾组织中的补体沉积。 这项新研究的结果有可能通过提供必要的证据来告知临床实践 建立碳酸氢钠治疗作为一种廉价和易于管理的选择，用于治疗 KTR的血管功能障碍和移植物功能。

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.