Fractures and bone disease in living kidney donors

活体肾捐献者的骨折和骨病

• 批准号: 10413030
• 负责人: RAJIV KUMAR
• 金额: $ 67.11万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-09 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413030
• 关键词: Age; Age-Years; American; Architecture; Awareness; Biological Markers; Bone Density; Bone Diseases; Bone Resorption; Calcitriol; Clinical; Data; Dihydroxycholecalciferols; Disease; Donor person; End stage renal failure; Ensure; Epidemiology; Evaluation; Finite Element Analysis; Forearm; Fracture; Future; Glomerular Filtration Rate; Health; Hip region structure; Impairment; Incidence; Individual; Kidney; Kidney Diseases; Kidney Transplantation; Knowledge; Living Donors; Measures; Medical; Metabolism; Minerals; Nephrectomy; Organ Donations; Osteogenesis; Osteoporosis; PTH gene; Peripheral; Persons; Prospective Studies; Race; Renal Mass; Resolution; Risk; Safety; Secondary Hyperparathyroidism; Serum; Testing; Therapeutic Intervention; Time; Transplantation; Tubular formation; Vertebral column; Vitamin D Analog; X-Ray Computed Tomography; age group; base; bone; bone health; bone quality; bone strength; bone turnover; cohort; comorbidity; cortical bone; evidence base; fibroblast growth factor 23; fracture risk; inorganic phosphate; living kidney donor; microCT; prevent; programs; screening; sex; skeletal; substantia spongiosa

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.

项目摘要 自1988年以来，美国有154，944名在世的人捐献了肾脏。仅在2018年，就有6，446名活体捐赠者 在美国进行的肾移植手术共有16，313例。作出知情决定 关于肾脏捐赠，在生捐赠者必须注意捐赠器官的潜在风险。的 肾脏捐赠对骨骼健康的影响尚未明确。活体肾脏捐赠者可能有 由于肾质量和肾小球滤过率（GFR）降低而导致骨折风险增加， 血清1，25-二羟维生素D（1，25（OH）2D）浓度和继发性甲状旁腺激素升高 激素（PTH）和骨转换。我们申请的科学前提是基于一个 一项前瞻性研究表明，在捐献后6个月和36个月，肾脏捐献者 血清完整PTH和成纤维细胞生长因子-23（FGF-23）浓度显著升高， s1，25（OH）2D，磷酸盐（Pi）浓度和肾小管Pi重吸收与健康对照组相比。更高 与健康人相比，在供体中观察到骨吸收和骨形成标志物的浓度。 对照来自罗切斯特流行病学项目的初步数据显示， 与对照组相比，肾切除术患者患骨质疏松症的风险高3倍。 研究表明，肾脏捐赠者的骨质可能受损，使他们容易骨折。我们 假设肾脏捐赠后肾质量和GFR的降低导致 s1，25（OH）2D以及sPTH和sFGF-23浓度的增加，这反过来又有助于增加骨 骨密度和骨强度的降低以及骨折的风险。为了验证我们的假设，我们提出两个 目标。在AIM 1中，我们将比较3000例活体供肾者的骨折风险， 在一组年龄、性别、种族和合并症相匹配的受试者中， 没有捐肾在AIM 2中，我们将评估200名肾脏捐献者的骨骼健康状况，这些捐献者在移植后≥10年， 肾脏捐献者，年龄≥50岁，通过测量腰椎、髋关节和股骨的区域骨密度 和前臂;通过外周高分辨率微型计算机断层扫描和 有限元分析和血清矿物质和骨生物标志物。为了比较，我们将检查200岁， 性别、种族和共病匹配的对照组，没有捐献肾脏，但会很健康 足以捐赠。我们的研究将提供重要的，以前无法获得的信息，关于风险， 骨折的一个大队列的肾脏捐赠者，并将确定机制，骨骼并发症 发生.肾脏捐赠者中观察到的骨折增加将改变医疗实践， 评估供体矿物质代谢和骨骼完整性的异常。疾病的治疗 1α-羟基化维生素D类似物的矿物质代谢将被指示。相反， 捐肾者骨折的个案没有增加，可令捐肾者对捐肾的安全放心。

项目成果

Fracture Risk Among Living Kidney Donors 25 Years After Donation.

• DOI: 10.1001/jamanetworkopen.2023.53005
• 发表时间: 2024-01-02
• 期刊: JAMA network open
• 影响因子: 13.8
• 作者: Maradit Kremers H;Grossardt BR;Miller AR;Kasiske BL;Matas AJ;Khosla S;Kremers WK;Amer H;Kumar R
• 通讯作者: Kumar R

Short carboxyl terminal parathyroid hormone peptides modulate human parathyroid hormone signaling in mouse osteoblasts.

• DOI: 10.1016/j.bbrc.2021.07.085
• 发表时间: 2021-10-01
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Kritmetapak K;Singh RJ;Craig TA;Hines JM;Kumar R
• 通讯作者: Kumar R

Chemical Characterization and Quantification of Circulating Intact PTH and PTH Fragments by High-Resolution Mass Spectrometry in Chronic Renal Failure.

• DOI: 10.1093/clinchem/hvab013
• 发表时间: 2021-06-01
• 期刊: Clinical chemistry
• 影响因子: 9.3
• 作者: Kritmetapak K;Losbanos LA;Hines JM;O'Grady KL;Ulmer CZ;Vesper HW;Enders FT;Singh RJ;Kumar R
• 通讯作者: Kumar R