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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.

项目总结/文摘