Renal Senescence and Transplantation

肾衰老与移植

• 批准号: 6670378
• 负责人: BRYAN David MYERS
• 金额: $ 39.93万
• 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/6670378
• 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）：老年尸体捐赠者> 60岁以下是不情愿使用的TBR肾脏移植（TX），因为已显示出老化的肾同种异体移植物与短半衰期有关。现在，我们建议阐明在老年尸体移植者接受者中肾脏衰老与加速度的肾脏加速度之间的关系。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液细胞学和肾小球基因表达的新技术结合使用。我们将在串行上使用这种方法来量化罐头的程度和过程，这使老年受体donor对中的衰老变得复杂（> 60年；第1组，n = 25）。年轻的TX接受者唐诺对（<40年；第2组，n = 25）将用作对照。我们还将在一次接收者中进行一次同样的评估（48-72 mo）双（两个）双（两个）肾脏TX，来自老年人，尸体供体（> 60岁> 60年；第3，N-19组），他们将作为第1组的比较组，我们希望在第1组和第2组中进行四个假设，以及在第1组中进行四个假设，以及一个可以在3个中进行的假设。老年供体的同种异体移植物中的渐进性肾小球减少症。 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肾小球。连续活检将用于将初始管状损伤与48个月时肾小球肾小球的发生率相关联。假设＃3是，老年TX肾脏的损失是一种不在体内复制的细胞类型，导致足细胞减少症和肾小球硬化症。我们将确定连续活检中每个肾小球的足细胞数。然后，我们将量化足细胞尿素，以便在48个月内占任何增量足细胞减少症。我们还将探索使用RT-PCR活检获得的肾小球中足细胞相关基因的表达改变。假设＃4是，在收获和TX的分析中，供体肾脏功能，衰老和足细胞相关基因的结构和表达将允许预测48个月的移植物功能和生存，从而允许未来对老年捐助者进行最佳选择。假设＃5是在第3组中，在双Tx期间移植的肾小球的2倍补体将防止“残留肾脏”现象，从而保留glomerular滤过能力和数量> 2x组1值的肾小球过滤能力。