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在大量退伍军人中的患病率为20%。心血管疾病（CVD）在CKD中显著增加，是发病率和死亡率的重要原因。多达80%的CVD与血管功能障碍有关，特别是内皮依赖性扩张（EDD）受损，通过肱动脉血流介导的扩张（FMDBA）测量，以及大弹性动脉的硬化，通过主动脉脉冲波速度（aPWV）测量。毫不奇怪，CKD患者表现出这些功能失调的血管表型。即使在CKD的早期阶段，氧化应激的增加也会导致血管的结构和功能改变，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的不良CVD结局相关。血清磷升高与EDD受损和动脉硬度的间接测量有关。降低CKD患者的血清磷是否会改善EDD和动脉硬度尚不清楚。此外，对慢性肾病的磷平衡知之甚少。目前还没有研究评估非钙基磷酸盐结合剂对CKD患者磷平衡的影响，也没有其他研究检查改变磷平衡对血管功能的影响。在本次职业发展奖2 （CDA-2）中，提出了一项随机对照试验，即碳酸镧（一种非钙基磷酸盐粘合剂）治疗CKD的血管功能障碍和检查磷平衡。目的1将评估磷酸盐结合碳酸镧治疗IIIb或IV期CKD患者血管内皮功能障碍和大弹性动脉僵硬的疗效（估计肾小球滤过率15- 45ml /min/1.73 m2），基线血清磷为3.5-5.5 mg/dL。目的2将确定用碳酸镧降低血清磷是否也会降低循环和内皮细胞氧化应激标志物。目的3将确定在接受碳酸镧或安慰剂治疗12周后，IIIb期和IV期CKD患者的磷平衡及其对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慢性血液透析的CKD患者的CVD风险，从而改变临床实践指南。长期的职业目标是成为一名独立的VA临床研究者，这名受指导的CDA-2将为首席研究员Anna Jovanovich博士提供机会，以建立她在流行病学，生物统计学和研究设计方面的知识和技能。她还将在开展随机对照试验的各个方面获得重要经验，包括患者招募、实施干预以及数据收集和分析。此外，她将

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.