Phosphate Lowering to Treat Vascular Dysfunction in Chronic Kidney Disease

描述（由申请人提供）：慢性肾脏疾病（CKD）是普通人群和退伍军人人群的主要健康问题。事实上，CKD在大量退伍军人人群中的患病率为20%。心血管疾病（CVD）在CKD中显著增加，并且是发病率和死亡率的重要原因。多达80%的CVD与血管功能障碍相关，特别是通过肱动脉血流介导的舒张（FMDBA）测量的内皮依赖性舒张（EDD）受损，以及通过主动脉脉搏波速度（aPWV）测量的大弹性动脉硬化。毫不奇怪，CKD患者表现出这些功能障碍的血管表型。即使在CKD的早期阶段，氧化应激也会增加，导致结构和功能性血管变化，这反过来又会导致血管功能障碍（EDD受损和大弹性动脉硬化）。在CKD中，磷保持在正常范围内（2.5-4.5 mg/dL），直到疾病晚期。然而，血清磷升高，即使在正常范围内，也与CKD患者的不良CVD结局相关。血清磷的升高与EDD受损和动脉僵硬度的间接测量相关。降低CKD患者的血清磷是否会改善EDD和动脉僵硬度尚不清楚。此外，对CKD中的磷平衡知之甚少。没有研究评价非钙基磷结合剂对CKD受试者磷平衡的影响，也没有其他研究检查改变磷平衡对血管功能的影响。对于这个职业发展奖-2（CDA-2），建议进行一项碳酸镧（一种非钙基磷结合剂）治疗血管功能障碍和检查CKD中磷平衡的随机对照试验。目的1将评估磷酸盐结合碳酸镧治疗基线血清磷3.5-5.5 mg/dL的IIIb或IV期CKD（估计肾小球滤过率15-45 mL/min/1.73 m2）患者的血管内皮功能障碍和大弹性动脉僵硬的疗效。目的2将确定碳酸镧降低血清磷是否也能降低氧化应激的循环和内皮细胞标志物。目标3将确定IIIb期和IV期CKD受试者接受碳酸镧或安慰剂治疗12周后的磷平衡及其对FMDBA变化的影响。这些研究可以通过建立一种新的治疗方法来降低不需要长期血液透析的CKD患者的CVD风险，从而改变临床实践指南。随着成为一名独立的VA临床研究者的长期职业目标，这个指导CDA-2将提供主要研究者，安娜Jovanovich博士，有机会建立在她的知识和技能的流行病学，生物统计学和研究设计。她还将在进行随机对照试验的各个方面获得重要经验，包括患者招募，进行干预以及数据收集和分析。此外，她将 学习和发展测量血管功能的技术，这是一个重要的CVD中间终点。沿着她的多学科指导团队的指导，这CDA-2将使她成功地过渡到一个独立的VA调查员。

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is a major health concern both in the general and Veteran populations. Indeed, the prevalence of CKD in a large Veteran population is 20%. Cardiovascular disease (CVD) is significantly increased in CKD and is an important cause of morbidity and mortality. As much as 80% of all CVD is associated with vascular dysfunction, particularly impaired endothelium-dependent dilation (EDD), measured by brachial artery flow-mediated dilation (FMDBA), and stiffening of the large elastic arteries, measured by aortic pulse-wave velocity (aPWV). Not surprisingly, patients with CKD demonstrate these dysfunctional vascular phenotypes. Even in early stages of CKD, there is an increase in oxidative stress resulting in structural and functional vascular changes, which, in turn, contributes to vascular dysfunction (impaired EDD and large elastic artery stiffening). In CKD, phosphorus remains within the normal range (2.5-4.5 mg/dL) until late in the disease. However, elevated serum phosphorus, even within the normal range, is associated with adverse CVD outcomes in CKD. Elevations in serum phosphorus have been associated with impaired EDD and with indirect measures of arterial stiffness. Whether lowering serum phosphorus in patients with CKD will improve EDD and arterial stiffness is unknown. Furthermore, little is known about phosphorus balance in CKD. There are no studies evaluating the effect of non-calcium based phosphate binders on phosphorus balance in subjects with CKD nor other studies examining the effects of changing phosphorus balance on vascular function. For this Career Development Award-2 (CDA-2), a randomized-controlled trial of lanthanum carbonate, a non-calcium based phosphate binder, to treat vascular dysfunction and examine phosphorus balance in CKD is proposed. Aim 1 will assess the efficacy of phosphate binding with lanthanum carbonate for treating vascular endothelial dysfunction and large elastic artery stiffness in patients with stage IIIb or IV CKD (estimated glomerular filtration rate 15-45 mL/min/1.73 m2) with baseline serum phosphorus of 3.5-5.5 mg/dL. Aim 2 will determine if lowering serum phosphorus with lanthanum carbonate also reduces circulating and endothelial cell markers of oxidative stress. Aim 3 will determine phosphorus balance in subjects with stage IIIb and IV CKD after 12 weeks of treatment with lanthanum carbonate or placebo and its effects on changes in FMDBA. These studies could shift clinical practice guidelines by establishing a novel therapy for reducing CVD risk in CKD patients not requiring chronic hemodialysis. With a long-term career goal of becoming an independent VA clinical investigator, this mentored CDA-2 will provide the principal investigator, Dr. Anna Jovanovich, with the opportunity to build on her knowledge of and skills in epidemiology, biostatistics, and study design. She will also gain important experience in all aspects of conducting a randomized-controlled trial, including patient recruitment, carrying out an intervention, and data collection and analysis. Additionally, she will learn and develop techniques to measure vascular function, an important CVD intermediate end-point. Along with the guidance of her multidisciplinary mentoring team, this CDA-2 will allow her to successfully transition to an independent VA investigator.