RENAL SENESCENCE AND TRANSPLANTATION

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 >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。 我们将使用敏感的方法，结合尿细胞学和基因表达的新技术来评估人类肾脏的损伤。 我们将连续使用这种方法来量化CAN的程度和过程，使老年人的衰老变得复杂。 年轻的Tx受试者-供体对将作为对照。 将有两类研究：前瞻性纵向研究和单一回顾性研究。 下文对此作了说明。 前瞻性研究 我们将测试四个假设。 假设1：肾脏衰老和CAN的结合导致老年供体同种异体移植物中进行性和增加性肾小球肾炎。 我们将连续使用生理和形态测量技术，沿着数学建模和MRA，以确定老年组和青年组48个月的纵向滤过能力和肾小球数量。 假设二：老年人缺血/再灌注后肾小管损伤（移植物功能延迟）的可逆性有限，导致形成无小管，因此形成无功能肾小球。 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：足细胞（一种不能在体内复制的细胞类型）从老化的Tx肾脏中丢失，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：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，从而允许在未来前瞻性地选择老年供体。 回顾性研究 我们将带回1995-1999年在我们机构接受肾脏Tx的受试者。 在此期间，受试者接受Tx与一个年轻的肾脏，一个老化的肾脏，或两个老化的肾脏。 将要求Tx肾脏仍在发挥功能的受试者参加本研究。 假设5：在双重Tx期间移植的肾小球的两倍补体将防止“残余肾”现象，从而将肾小球过滤能力和数量保持为单次老化Tx的> 2倍。

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.