RENAL SENESCENCE AND TRANSPLANTATION

肾脏衰老和移植

• 批准号: 7375243
• 负责人: BRYAN David MYERS
• 金额: $ 1.91万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7375243
• 关键词: RENAL; SENESCENCE; TRANSPLANTATION

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Elderly cadaveric donors >60 yrs old are reluctantly used for 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 cadaver transplants. We will use sensitive methods for evaluating injury to human kidney in combination with novel techniques in urine cytology and gene expression. We will use this approach serially to quantify the extent and course of CAN that complicates senescence in aged recipient-donor pairs. Youthful Tx recipient-donor pairs will serve as controls. There will be two types of studies: A prospective longitudinal study and a single retrospective study. These are described below. PROSPECTIVE STUDY We will test four hypotheses. Hypothesis 1: A combination of renal senescence and CAN leads to progressive and incremental glomerulopenia in allografts from aged donors. We will use physiologic and morphometric techniques serially, along with mathematical modeling and MRA to determine filtration capacity and glomerular number longitudinally for 48 months in the aged and youthful groups. Hypothesis 2: Limited reversibility in the elderly of post-schemic/reperfusion tubular injury (delayed graft function) results in formation of atubular, and hence non-functioning glomeruli. Serial biopsies will be used to relate initial tubular injury to the incidence of atubular glomeruli at 48 months. Hypothesis 3: Loss from aged Tx kidneys of podocytes, a cell type that does not replicate in vivo, leads to 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: 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. RETROSPECTIVE STUDY We will bring back subjects who have undergone kidney Tx at our institution from 1995-1999. During this period, subjects underwent Tx with a single youthful kidney, a single aged kidney, or two aged kidneys. Subjects whose Tx kidneys are still functioning, will be asked to participate in this study. Hypothesis 5: The two-fold complement of glomeruli grafted during a dual Tx will prevent a "remnant kidney" phenomenon, thereby preserving glomerular filtration capacity and number at >2x that of the single aged Txs.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。60岁的老年身体供者不情愿地用于肾移植(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。我们将结合尿细胞学和基因表达的新技术，使用敏感的方法来评估人类肾脏的损伤。我们将连续使用这种方法来量化老年受者-供者对中使衰老复杂化的CAN的程度和进程。年轻的德克萨斯州受赠者-捐赠者对将作为对照。将有两种类型的研究：前瞻性的纵向研究和单一的回顾研究。下面将对这些内容进行说明。前瞻性研究我们将检验四个假设。假设1：肾脏衰老和肾小球减少可导致老年供者移植肾中进行性和渐进性肾小球减少。我们将连续使用生理和形态测量技术，以及数学建模和MRA来纵向测定老年组和青年组48个月的滤过能力和肾小球数量。假设2：老年人缺血/再灌注后肾小管损伤(移植肾功能延迟)的可逆性有限，导致肾小管闭锁，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：衰老的TX肾失去足细胞，这是一种在体内不能复制的细胞类型，导致肾小球硬化。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个月的移植物功能和存活率，从而使将来对老年供者进行最佳选择成为可能。回顾研究我们将带回1995-1999年间在我们机构接受过肾移植的受试者。在此期间，受试者接受了TX，其中有一个年轻的肾脏、一个老化的肾脏或两个老化的肾脏。TX肾功能正常的受试者将被要求参加这项研究。假设5：双肾移植期间移植的双倍肾小球将防止“残肾”现象，从而保持肾小球滤过能力和数量是单发老年肾移植的2倍。