Effects of Dietary Phosphorus Restriction on Whole-Body Calcium and Phosphorus Balance and Kinetics in Patients with Moderate Chronic Kidney Disease

项目总结/摘要 钙磷代谢异常是慢性肾脏病发生发展的中心环节 疾病-矿物质骨骼疾病（CKD-MBD），会导致心血管和骨骼疾病，从而导致 心血管事件、骨折和死亡风险增加。各种饮食和药物 CKD-MBD的治疗影响钙和磷代谢，但关于这些代谢如何影响钙和磷代谢存在重大知识空白。 治疗影响两种离子的全身生理学。对钙磷代谢的认识不足， CKD-MBD进展阻碍了有效疗法的开发。这个项目的目标是生产 关于通常规定的膳食磷限制对全身钙和 CKD患者的P平衡和动力学，以支持未来更大规模的临床研究。具体目标是 确定1）肠钙和磷吸收分数和2）钙和磷平衡和全动力学，效应大小和 CKD患者低钙饮食加高磷饮食与饮食磷限制的方差估计。中 采用随机交叉设计，对4例中度CKD成人患者进行对照饮食研究 典型的美国人饮食中钙摄入量低，磷摄入量高，或者 钙摄入量与饮食中的磷限制通常规定。筛选确定合格性后，入组 患者将在门诊接受随机分配的控制饮食1周，然后入住 临床研究中心的48小时吸收测试协议，将利用口服和静脉注射剂量的 稳定的Ca-44和放射性P-33同位素。将在48小时住院期间进行连续抽血， 沿着定时排尿和完整的粪便收集。钙和磷的肠道吸收分数将 通过口服和静脉内给药后同位素的血清和尿液测量的动力学建模来确定 剂量。两名患者将作为住院患者继续进行为期12天的对照研究 饮食与抽血和定时，完整的尿液和粪便收集，以确定全身钙和磷平衡 以及通过对血清、尿液和粪便同位素数据建模获得的完整Ca和P动力学， 这将给出Ca和P转移到和从各种身体池（例如，到和从骨骼）的速率。在1- 在一周的洗脱期内，患者将交叉研究其他饮食条件。预计这项研究 将产生必要的影响大小和方差估计的影响，膳食磷限制钙和磷 吸收、平衡和动力学，以充分支持未来的临床研究。这项研究的长期目标是 是确定各种当前和新的饮食和药物干预对全身的影响 钙和磷生理学，目的是改善CKD-MBD的治疗。这关系到联合国难民事务高级专员办事处的使命， NIDDK支持旨在改善肾病患者健康和生活质量的研究。

PROJECT SUMMARY/ABSTRACT Abnormal calcium (Ca) and phosphorus (P) metabolism are central to the development of chronic kidney disease-mineral bone disorder (CKD-MBD), which causes cardiovascular and bone disease leading to cardiovascular events, bone fractures, and increased risk of death. The various dietary and pharmaceutical treatments for CKD-MBD affect both Ca and P metabolism, yet major knowledge gaps exist on how these treatments affect whole-body physiology of both ions. The lack of understanding on Ca and P metabolism in CKD-MBD progression precludes the development of effective therapies. The goal of this project is to produce preliminary data on the effects of the commonly prescribed dietary phosphorus restriction on whole-body Ca and P balance and kinetics in patients with CKD, to support a larger future clinical study. The specific aims are to determine 1) intestinal Ca and P fractional absorption and 2) Ca and P balance and full kinetics, effect sizes and variance estimates in patients with CKD on a low Ca diet with high P diet versus dietary P restriction. In a randomized cross-over design, four adult patients with moderate-stage CKD will be studied on a controlled diet of either low dietary Ca intake and high dietary P intake, representative of a typical American diet, or a low dietary Ca intake with a dietary P restriction as commonly prescribed. After screening to determine eligibility, enrolled patients will be given the randomly assigned controlled diet for 1 week as outpatients, and then admitted to the clinical research center for a 48-hour absorption testing protocol that will utilize oral and intravenous doses of stable Ca-44 and radioactive P-33 isotopes. Serial blood draws will be taken over the 48-hour inpatient period, along with timed urine and complete fecal collections. Fractional Ca and P intestinal absorption will be determined by kinetic modeling of serum and urine measurements of the isotopes after oral and intravenous dosing. Two patients will be studied for an additional 12-days as inpatient continuing on the controlled research diet with blood draws and timed, complete urine and fecal collections to determine whole-body Ca and P balance over 2-weeks, as well as full Ca and P kinetics obtained by modeling the serum, urine, and fecal isotopic data, which will give rates of Ca and P transfer to and from various body pools (e.g. to and from bone). Following a 1- week washout, patients will crossover to be studied on the other dietary condition. It is expected that this study will produce the necessary effect size and variance estimates on the effect of dietary P restriction on Ca and P absorption, balance, and kinetics to adequately power a future clinical study. The long-term goal of this research is to determine effects of a variety of current and novel dietary and pharmaceutical interventions on whole-body Ca and P physiology with the goal of improving treatments for CKD-MBD. This relates to the mission of the NIDDK to support research aimed at improving the health and quality of life of patients with kidney disease.