Renal Senescence and Transplantation

肾衰老与移植

• 批准号: 6916268
• 负责人: BRYAN David MYERS
• 金额: $ 40.91万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6916268
• 关键词: aging; angiography; biopsy; clinical research; cytology; gene expression; glomerular filtration rate; glomerulonephritis; homologous transplantation; human subject; kidney cell; kidney disorder; kidney transplantation; longitudinal human study; magnetic resonance imaging; mathematical model; morphometry; patient oriented research; polymerase chain reaction; postmortem; renal glomerulus; renal ischemia /hypoxia; renal tubule; reperfusion; tissue donors; urine

DESCRIPTION (provided by applicant): Elderly cadaveric donors >60 years old are reluctantly used tbr kidney transplantation (Tx), because an aged renal allograft has been shown to be associated with a short half-life. We now propose to elucidate the relationship between renal senescence and acceleration of chronic allograft nephropathy (CAN) in recipients of aged cadaveric transplants. We have developed sensitive methods for evaluating injury to the human kidney, which we now propose to combine with novel techniques of urine cytology and glomerular gene expression. We will use this approach serially to quantify the extent and course of the CAN that complicates senescence in aged recipient-donor pairs (>60 yr; group 1, N=25). Youthful Tx recipient-donor pairs (<40 yr; group 2, N=25) will serve as controls. We will also make the same evaluation on a single occasion in recipients of long-standing (48-72 mo) dual (both) kidney Tx from aged, cadaveric donors (>60 yr; Group 3, N-19), who will serve as a comparison group for group 1. We wish to test four hypotheses in groups 1 and 2, and a fifth hypothesis in group 3. Hypothesis #1 is that a combination of renal senescence and CAN leads to progressive, incremental glomerulopenia in allografts from aged donors. We will use physiologic and morphometric techniques serially, along with mathematical modeling and MRangiography, to determine filtration capacity (Kf) and glomerular number longitudinally for 48 months in groups 1 and 2. Hypothesis #2 is that limited reversibility in the elderly of postischemic/reperfusion tubular injury (delayed graft function) results in formation of atubular, and hence non-functional glomeruli. Serial biopsies will be used to relate initial tubular injury to the incidence of atubular glomeruli at 48 months. Hypothesis #3 is that loss from aged Tx kidneys of podocytes, a cell type that does not replicate in vivo, leads to podocytopenia and glomerulosclerosis. We will determine podocyte number per glomerulus in serial biopsies. We will then quantify podocyturia in an effort to account for any incremental podocytopenia over 48 months. We will also explore altered expression of podocyte-related genes in glomeruli obtained by biopsy using RT-PCR. Hypothesis #4 is that analysis at harvesting and at Tx of aged, donor kidney function, structure and expression of senescence- and podocyte-related genes will permit prediction of 48- month graft function and survival, thereby permitting optimal selection prospectively of aged donors in the future. Hypothesis #5 is that the 2-fold complement of glomeruli grafted during a dual Tx, in group 3, will prevent a "remnant kidney" phenomenon, thereby preserving glomerular filtration capacity and number at >2x group 1 values.

描述(由申请人提供)：60岁的老年身体供者不情愿地使用TBR肾移植(TX)，因为老年同种异体肾移植被证明与较短的半衰期有关。我们现在建议阐明肾脏衰老与老年身体移植受者慢性移植物肾病(CAN)加速的关系。我们已经开发了评估人类肾脏损伤的敏感方法，现在我们建议将其与尿细胞学和肾小球基因表达的新技术相结合。我们将连续使用这种方法来量化在老年受者-供者对中使衰老复杂化的CAN的程度和进程(60岁；第1组，N=25)。年轻的TX受体-供体对(40岁；第二组，N=25)将作为对照。我们还将对来自老年身体供者的长期(48-72个月)双(双)肾移植的受者(&gt；60岁；第3组，N-19)进行一次相同的评估，他们将作为第1组的对照组。我们希望检验第1组和第2组中的4个假说，以及第3组中的第5个假说。假说1是肾脏衰老的组合，可导致老年供者移植肾的进行性、渐进性肾小球减少。我们将连续使用生理学和形态计量学技术，结合数学建模和磁共振血管成像，在组1和组2中纵向测定滤过能力(KF)和肾小球数量。假说2是老年人缺血/再灌流后肾小管损伤(移植肾功能延迟)的有限可逆性导致肾小管形成，从而导致无功能肾小球的形成。连续活检将被用来将最初的肾小管损伤与48个月后无管性肾小球的发生率联系起来。假设3是衰老的TX肾脏失去了足细胞，这是一种在体内不能复制的细胞类型，导致足细胞减少和肾小球硬化。我们将在连续活检中确定每个肾小球的足细胞数量。然后，我们将对足细胞尿进行量化，以解决48个月内足细胞减少的情况。我们还将利用RT-PCR研究肾小球活检获得的足细胞相关基因表达的变化。假设4：对老年供者的肾功能、结构和衰老及足细胞相关基因的表达进行分析，可以预测48个月的移植肾功能和存活率，从而使将来对老年供者的最佳选择成为可能。假设5在第3组中，在双肾移植期间移植2倍的肾小球将防止“残肾”现象，从而保持肾小球滤过能力和数量为第1组的2倍。