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.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。老年尸体供体> 60岁以上，不情愿地用于肾脏移植（TX），因为已显示出老年肾脏同种异体移植物与短半衰期相关。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衰老与加速度之间的关系。我们将使用敏感方法与尿液细胞学和基因表达的新技术相结合评估对人肾脏的损伤。我们将在串行上使用这种方法来量化对老年受体donor对衰老的范围和过程的范围和过程。年轻的TX接收者唐诺对将充当控制。 将有两种类型的研究：一项前瞻性纵向研究和一项回顾性研究。这些如下所述。 前瞻性研究我们将检验四个假设。假设1：肾脏衰老的结合，可以导致老年供体的同种异体移植物中进行性和渐进性肾小球减少症。我们将在年龄和年轻的群体中纵向使用生理和形态计量技术以及数学建模和MRA纵向确定48个月的过滤能力和肾小球数。 假设2：术后/再灌注管状损伤的老年人的可逆性有限（延迟移植功能）导致形成atubular的形成，从而导致无功能的肾小球。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：未在体内复制的细胞类型的足细胞的老化TX肾脏会导致肾小球硬化。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：在收获和Tx的分析年龄，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。 回顾性研究，我们将带回1995 - 1999年在我们机构中接受过肾脏TX的受试者。在此期间，受试者接受了一个年轻的肾脏，一个年龄的肾脏或两个老年肾脏。 TX肾脏仍在起作用的受试者将被要求参加这项研究。 假设5：双重TX期间移植的肾小球的两倍补体将防止“残留肾脏”现象，从而保留单个老年TXS的肾小球过滤能力和> 2x的数字。