Phosphate Lowering to Treat Vascular Dysfunction in Chronic Kidney Disease

描述(申请人提供)：慢性肾脏疾病(CKD)是一个主要的健康问题，在普通和退伍军人群体。事实上，CKD在一个庞大的退伍军人群体中的患病率为20%。心血管疾病(CVD)在慢性肾脏病(CKD)中显著增加，是发病率和死亡率的重要原因。高达80%的CVD与血管功能障碍有关，尤其是内皮依赖性扩张(EDD)受损(以肱动脉血流介导性扩张(FMDBA)衡量)，以及大弹性动脉硬化(以主动脉脉搏波速度(APWV)衡量)。毫不奇怪，慢性肾脏病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，导致结构和功能上的血管改变，进而导致血管功能障碍(EDD受损和大的弹性动脉硬化)。在慢性肾脏病中，磷一直保持在正常范围(2.5-4.5毫克/分升)，直到疾病晚期。然而，血清磷升高，即使在正常范围内，也与CKD的不利CVD结局有关。血磷升高与EDD受损和间接测量动脉僵硬有关。降低CKD患者的血磷是否会改善EDD和动脉僵硬尚不清楚。此外，对慢性肾脏病中的磷平衡知之甚少。没有研究评估非钙基磷酸盐结合剂对慢性肾脏病患者磷平衡的影响，也没有其他研究探讨改变磷平衡对血管功能的影响。对于这项职业发展奖-2(CDA-2)，建议进行一项随机对照试验，使用碳酸镧(一种非钙基磷酸盐粘结剂)治疗血管功能障碍，并检查CKD患者的磷平衡。目的1评价磷酸盐结合碳酸镧治疗基础血磷为3.5~5.5 mg/dL的IIIb期或IV期慢性肾功能不全(肾小球滤过率15~45mL/min/1.73m2)患者血管内皮功能障碍和大弹性动脉硬化的疗效。目标2将确定使用碳酸镧降低血清磷是否也能减少循环和内皮细胞氧化应激的标记物。目的3将在使用碳酸镧或安慰剂治疗12周后，测定IIIb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改变临床实践指南，以降低不需要长期血液透析的CKD患者的心血管疾病风险。作为一名独立的退伍军人事务部临床调查员，这项有指导的CDA-2考试将为首席调查员Anna Jovanovich博士提供一个机会，让她在流行病学、生物统计学和研究设计方面的知识和技能的基础上再接再厉。她还将在进行随机对照试验的各个方面获得重要经验，包括招募患者、进行干预以及数据收集和分析。此外，她还将 学习和开发测量血管功能的技术，这是心血管疾病的重要中间终点。在她的多学科指导团队的指导下，这份CDA-2将使她成功地过渡到一名独立的退伍军人管理局调查员。

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.