Fractures and bone disease in living kidney donors

项目总结 自1988年以来，美国有154,944名在世个人捐赠了肾脏。仅在2018年，就有6446名在世捐赠者 在美国，共有16,313例肾移植手术。做出明智的决定 关于肾脏捐赠，在世的捐赠者必须意识到与器官捐赠相关的潜在风险。这个 肾脏捐赠对骨骼健康的影响还没有明确的定义。活着的肾脏捐赠者可能会有 由于肾质量和肾小球滤过率(GFR)减少而增加的骨折风险 血清1，25-二羟基维生素D(1，25(OH)2D)浓度与甲状旁腺继发性升高 激素(PTH)和骨转换。我们应用程序的科学前提是基于对 在前瞻性研究中，我们证明了捐献后6个月和36个月，肾脏捐赠者有 血清(S)完整甲状旁腺激素和成纤维细胞生长因子-23浓度显著升高，而降低 与健康对照组比较，S1，25(OH)2D，磷酸盐(PI)浓度和管状PI重吸收。更高 骨吸收和骨形成标志物的浓度在供者中观察到，与健康人相比。 控制。罗切斯特流行病学项目的初步数据显示，骨折的风险是普通人的2-3倍 与对照组相比，接受肾切除的患者患骨质疏松症的风险增加了3倍。 研究表明，肾脏捐赠者的骨骼质量可能受到损害，容易发生骨折。我们 假设捐献肾脏后肾质量和GFR的减少会导致 S1，25(OH)2D以及sPTH和sFGF23浓度的增加，这反过来又有助于增加骨骼 周转、骨密度和强度的降低以及骨折的风险。为了检验我们的假设，我们提出了两个 目标。在目标1中，我们将比较3000名活体肾脏捐赠者的骨折风险和骨折风险。 在一组年龄、性别、种族和合并症匹配的受试者中，他们本来有资格捐献，但 没有捐献肾脏。在目标2中，我们将评估200名肾捐赠者在10年后接受≥的骨骼健康状况。 肾捐赠和≥50岁通过测量腰椎和髋部的面积骨密度 和前臂；骨骼结构和力量通过外周高分辨率微型计算机断层扫描和 有限元分析；以及血清矿物质和骨生物标志物。为了进行比较，我们将检查200岁-， 性别、种族和合并症匹配的对照组，没有捐赠肾脏，但本可以是健康的 足够捐献了。我们的研究将提供重要的、以前无法获得的信息，关于 在一大批肾脏捐赠者中发现骨折，并将确定骨骼并发症的机制 发生。观察到的肾脏捐赠者中骨折的增加将改变医疗实践，因为 对献血者矿物质代谢和骨骼完整性异常的评估。精神障碍的治疗 矿物质代谢的1α-羟基化维生素D类似物将被提示。相反，演示 捐赠者中没有增加骨折的情况将使肾脏捐赠者放心，捐赠是安全的。

PROJECT SUMMARY Since 1988, 154,944 living individuals in the US have donated a kidney. In 2018 alone, 6,446 living donor kidney transplants were performed in the US from a total of 16,313 transplants. To make informed decisions about kidney donation, living donors must be aware of potential risks associated with organ donation. The effects of kidney donation upon skeletal health are not well-defined. Living kidney donors may potentially have an increased risk of fractures due to reductions in renal mass and glomerular filtration rate (GFR) and concentrations of serum 1,25-dihydroxyvitamin D (1,25(OH)2D), and secondary increases in parathyroid hormone (PTH) and bone turnover. The scientific premise of our application is based on observations from a prospective study, in which we demonstrated that 6 and 36 months after donation, kidney donors had significantly higher serum (s) intact PTH and fibroblast growth factor-23 (FGF-23) concentrations, and reduced s1,25(OH)2D, phosphate (Pi) concentrations, and tubular Pi reabsorption compared to healthy controls. Higher concentrations of bone resorption and formation markers were observed in donors compared to healthy controls. Preliminary data from the Rochester Epidemiology Project show a 2-3-fold excess risk of fractures and a 3-fold excess risk of osteoporosis in individuals who had a nephrectomy compared to control subjects. The studies suggest that bone quality may be impaired in kidney donors predisposing them to fractures. We hypothesize that reductions in renal mass and GFR following kidney donation result in a decrease in s1,25(OH)2D and an increase in sPTH and sFGF-23 concentrations, which in turn contribute to increased bone turnover, reductions in bone density and strength and risk of fractures. To test our hypothesis, we propose two aims. In AIM 1, we will compare the risk of fractures among 3000 living kidney donors with the risk of fractures in a group of age-, sex-, race-, and comorbidity-matched subjects who would have been eligible to donate but did not donate a kidney. In AIM 2 we will assess skeletal health in 200 kidney donors who are ≥10 years after kidney donation and are ≥50 years of age by measuring areal bone mineral density at the lumbar spine, hip and forearm; skeletal architecture and strength by peripheral high-resolution micro-computed tomography and finite element analysis; and serum mineral and bone biomarkers. For comparison, we will examine 200 age-, sex-, race- and comorbidity-matched controls that have not donated a kidney, but would have been healthy enough to donate. Our studies will provide important, previously unavailable information, regarding the risk of fractures in a large cohort of kidney donors, and will identify mechanisms by which skeletal complications occur. An observed increase in fractures amongst kidney donors will change medical practice by supporting evaluation of abnormalities in mineral metabolism and skeletal integrity in donors. Therapy of disordered mineral metabolism with 1α-hydroxylated vitamin D analogs would be indicated. Conversely, demonstration of an absence of increased fractures amongst donors will reassure kidney donors of the safety of donation.