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

项目摘要/摘要 心血管疾病是肾移植受者死亡和死亡的主要原因。 心血管疾病是移植物丢失的主要原因。KTRS显示内皮依赖性异常扩张 (EDD)和大动脉僵硬是CVD发生的关键病理生理因素。酸 肾内滞留是接受肾移植的患者的常见特征。KTRS只有一个肾 肾单位的数量减少，导致无法排泄每日饮食中的酸负荷。另外， KTRS接受几种可能导致胃酸滞留的药物，包括钙调神经磷酸酶抑制剂。酸 滞留导致氨化作用的增加，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。我们证明了 与健康对照组相比，KTRS患者补体激活片段增加，而补体激活片段增加 与EGFR、EDD呈正相关。较低的血清碳酸氢盐水平，即使在正常的实验室范围内， KTRS与移植物丢失、心血管事件和死亡率的风险增加相关。小的 介入试验表明，碱疗法可以延缓肾脏疾病的进展，即使是在 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例慢性肾脏病3~4期患者血管内皮功能的研究因为酸滞留在 KTRS，碱疗法在KTRS中也可能导致血管和移植物功能的改善。在我们的 初步数据显示，我们在随机、双盲、安慰剂对照的交叉试验中显示出安全性和可行性 碳酸氢钠治疗KTRs安全可行并有改善趋势的研究 EDD。我们提出了一项随机、双盲、安慰剂对照、为期12个月的研究，研究对象为120名KDR 检查碳酸氢钠治疗对心血管疾病替代标志物和移植物功能的影响。我们的整体 假设碳酸氢盐治疗将通过以下方式改善KTRs的血管和移植物功能指标 降低补体激活。在目标1中，我们将比较臂动脉血流随时间的变化- 12个月前和12个月后，用主动脉脉搏波速度测量介导性扩张和动脉僵硬 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12个月前后肾活检中的间质纤维化。在……里面 目的3，我们将检测血浆和尿补体激活片段(BA和sC5b-9)和 碳酸氢钠治疗或安慰剂治疗12个月前后肾组织中补体沉积。 通过提供必要的证据，这项新研究的结果有可能为临床实践提供信息。 将碳酸氢钠疗法确立为一种廉价且易于实施的治疗方法 KDR患者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.