Impact of phosphate and FGF23 reduction on intermediate end points in CKD

描述(申请人提供)：矿物质代谢紊乱是慢性肾脏疾病(CKD)的一种几乎普遍的并发症，与心血管疾病(CVD)、CKD进展、骨折和死亡的风险密切相关。磷酸盐过量导致动脉钙化，这是CKD中CVD的一个重要表型。CKD患者成纤维细胞生长因子23(FGF23)升高使血磷维持在正常范围内，但FGF23过高是导致左室肥厚(LVH)的机械性因素。总而言之，过量的磷酸盐和FGF23对心血管系统的有害影响会导致心血管事件和死亡。饮食中的磷吸收是磷酸盐和FGF23水平的一个可修改的决定因素。在动物中，高磷饮食会促进肾衰竭，在我们的初步数据中，它 升高磷酸盐和FGF23水平，并诱导左心室肥厚。相比之下，在CKD 3-4期患者的试点研究中，使用磷酸盐结合剂、低磷饮食或烟酰胺前体烟酸(降低胃肠道NPT2b表达)来减少饮食中的磷酸盐吸收，可以降低磷酸盐和FGF23水平。因此，靶向磷酸盐和FGF23过量可能代表了一种新的治疗模式，以改善CKD的临床结果。然而，推进这一方法的一个关键障碍是缺乏关于磷酸盐和FGF23减少对慢性肾脏病中间终点的影响的证据。NIDDK U01支持的联合研究为填补这一空白提供了一个独特的机会。在这项对200名CKD 3-4期患者进行的为期18个月的随机、双盲、平行分组研究中，由U01资助的母体研究将检验烟酰胺和碳酸镧联合使用将降低血磷和FGF23水平的假设。这项对时间敏感的辅助建议的目的是通过增加对骨和矿物质代谢的纵向评估以及在基线和随机后9个月和18个月时心血管疾病和肾脏风险的替代测量来丰富母研究。在目标1中，通过对骨转换标志物和矿物质代谢物的一系列评估，我们将检验这一假设，即与安慰剂相比，积极治疗将减缓甲状旁腺素上升的斜率，减缓骨化三醇和高铁水平的下降，并改善骨转换标志物。在目标2中，我们将使用心脏MRI和心血管生物标志物的一系列测量来检验这一假设，即与安慰剂相比，积极治疗可以减少或钝化左室重量的增加，减轻左室舒张功能障碍，降低心血管生物标志物的水平。在目标3中，我们将使用系列血清学检测和无Gd血氧水平依赖的MRI和弥散加权MRI来监测肾内氧合和纤维化的变化，验证与安慰剂相比，积极治疗将减缓GFR下降的斜率和蛋白尿和炎症标志物的上升，改善肾内氧合，稳定或减缓肾纤维化的进展。这项U01批准的辅助研究提案的结果将产生新的机械性见解，并提供为未来针对慢性肾脏病中磷酸盐和FGF23过量的最终第三阶段结果试验选择终点所需的关键数据。

DESCRIPTION (provided by applicant): Disordered mineral metabolism is a near-universal complication of chronic kidney disease (CKD) that is strongly linked to risks of cardiovascular disease (CVD), CKD progression, fractures, and death. Phosphate excess induces arterial calcification, which is an important phenotype of CVD in CKD. Elevated fibroblast growth factor 23 (FGF23) maintains serum phosphate in the normal range in CKD, but FGF23 excess contributes mechanistically to left ventricular hypertrophy (LVH). Together, the deleterious effects of phosphate and FGF23 excess on the cardiovascular system promote CVD events and death. Dietary phosphate absorption is a modifiable determinant of phosphate and FGF23 levels. In animals, a high phosphate diet promoted kidney failure, and, in our preliminary data, it raised phosphate and FGF23 levels and induced LVH. In contrast, reducing dietary phosphate absorption with phosphate binders, low phosphate diets or the nicotinamide precursor, niacin, which reduces gastrointestinal NPT2b expression, lowered phosphate and FGF23 levels in pilot studies of CKD stage 3-4 patients. Thus, targeting phosphate and FGF23 excess may represent a novel therapeutic paradigm to improve clinical outcomes in CKD. However, a key road block to advancing this approach is the lack of evidence on the effects of phosphate and FGF23 reduction on intermediate end points in CKD. The NIDDK U01-supported COMBINE Study provides a unique opportunity to fill this gap. In this randomized, double-blinded, 18-month, parallel-group study in 200 CKD stage 3-4 patients, the U01-funded parent study will test the hypothesis that combining nicotinamide and lanthanum carbonate will lower serum phosphate and FGF23 levels. The purpose of this time-sensitive ancillary proposal is to enrich the parent study by adding longitudinal assessments of bone and mineral metabolism and surrogate measures of CVD and renal risks at baseline and at 9 and 18 months post-randomization. In Aim 1, by obtaining serial assessments of bone turnover markers and mineral metabolites, we will test the hypothesis that compared with placebo, active therapy will blunt the slope of PTH rise, attenuate the decline of calcitriol and klotho levels, and improve bone turnover markers. In Aim 2, we will use serial measures of cardiac MRI and CVD biomarkers to test the hypothesis that compared with placebo, active therapy will reduce or blunt the increase in LV mass; attenuate LV diastolic dysfunction and reduce levels of CVD biomarkers. In Aim 3, using serial serologic testing and gadolinium-free blood oxygenation level dependent MRI and diffusion-weighted MRI to monitor changes in intra-renal oxygenation and fibrosis, we will test the hypothesis that compared with placebo, active therapy will blunt the slope of decline in GFR and the rise in proteinuria and inflammatory markers, improve intra-renal oxygenation and stabilize or reduce progression of renal fibrosis. The results of this U01-approved ancillary study proposal will yield novel mechanistic insights and provide critical data needed to select the endpoints for the future definitive phase-III outcomes trial targeting phosphate and FGF23 excess in CKD.