Renal Senescence and Transplantation

肾衰老与移植

• 批准号: 7092016
• 负责人: BRYAN David MYERS
• 金额: $ 47.82万
• 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/7092016
• 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岁的老年尸体供体不愿意用于肾移植（Tx），因为已显示老年肾同种异体移植物与短半衰期相关。我们现拟阐明老年尸体肾移植受者肾脏衰老与慢性移植物肾病（CAN）加速之间的关系。我们已经开发了敏感的方法来评估人类肾脏的损伤，我们现在建议联合收割机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CAN的程度和过程，CAN使老年志愿者-供体对（>60岁;第1组，N=25）的衰老复杂化。年轻的Tx受试者-供体对（<40岁;组2，N=25）将用作对照。我们还将对来自老年尸体供体（>60岁;第3组，N-19）的长期（48-72个月）双（双）肾Tx接受者进行单次相同的评价，他们将作为第1组的对照组。我们希望在第1组和第2组中检验四个假设，在第3组中检验第五个假设。假设#1是肾脏衰老和CAN的组合导致来自老年供体的同种异体移植物中进行性、增量肾小球肾炎。我们将连续使用生理和形态测量技术，沿着数学建模和磁共振血管造影，以确定第1组和第2组48个月的纵向滤过能力（Kf）和肾小球数量。假设#2是老年人缺血后/再灌注肾小管损伤（移植物功能延迟）的有限可逆性导致无小管形成，因此形成无功能的肾小球。将使用连续活检将初始肾小管损伤与48个月时无小管肾小球的发生率联系起来。假设#3是来自老化Tx肾的足细胞（一种不能在体内复制的细胞类型）的损失导致足细胞减少症和肾小球硬化症。我们将在连续活检中确定每个肾小球的足细胞数量。然后，我们将量化足细胞尿，以解释48个月内任何增量足细胞减少症。我们还将探讨用RT-PCR活检获得的肾小球中足细胞相关基因表达的改变。假设#4是在收获时和在Tx时分析老年供体肾功能、衰老和足细胞相关基因的结构和表达将允许预测48个月移植物功能和存活，从而允许将来前瞻性地最佳选择老年供体。假设#5是在组3中，在双重Tx期间移植的肾小球的2倍补体将防止“残余肾”现象，从而将肾小球滤过能力和数量保持在> 2倍组1值。