RENAL SENESCENCE AND TRANSPLANTATION

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 >60 岁的老年尸体捐献者不情愿地用于肾移植 (Tx)，因为老化的同种异体肾移植物已被证明与半衰期短有关。 我们现在建议阐明老年尸体移植受者肾脏衰老与慢性同种异体移植肾病（CAN）加速之间的关系。 我们将使用敏感的方法结合尿液细胞学和基因表达的新技术来评估对人体肾脏的损伤。 我们将连续使用这种方法来量化 CAN 的程度和过程，CAN 使老年受体-供体对的衰老变得复杂。 年轻的德克萨斯州接受者-捐赠者对将作为对照。 将有两种类型的研究：前瞻性纵向研究和单一回顾性研究。 这些将在下面描述。 前瞻性研究 我们将检验四个假设。 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量性肾小球减少症。 我们将连续使用生理学和形态测量技术，以及数学模型和 MRA 来纵向确定老年组和青年组的滤过能力和肾小球数量，为期 48 个月。 假设2：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，导致肾小管形成，从而导致肾小球无功能。 连续活检将用于将初始肾小管损伤与 48 个月时管状肾小球的发生率联系起来。 假设 3：老化的 Tx 肾中足细胞（一种在体内不能复制的细胞类型）的损失会导致肾小球硬化症。 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 个月内任何增量的足细胞减少症。 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变化。 假设 4：在收获时和 Tx 时对老年供体肾功能、衰老和足细胞相关基因的结构和表达进行分析将允许预测 48 个月的移植物功能和存活率，从而允许未来对老年供体进行最佳选择。 回顾性研究 我们将带回 1995 年至 1999 年在我们机构接受过肾脏 Tx 的受试者。 在此期间，受试者使用单个年轻肾脏、单个老年肾脏或两个老年肾脏进行 Tx。 Tx 肾脏仍具有功能的受试者将被要求参加本研究。 假设 5：在双 Tx 期间移植的两倍肾小球将防止“残余肾”现象，从而保持肾小球滤过能力和数量 > 2 倍于单一老年 Tx。

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.