Renal Senescence and Transplantation

描述（由申请人提供）：60岁以上的老年尸体供体被不情愿地用于肾移植（Tx），因为年老的同种异体肾移植已被证明与半衰期短有关。我们现在建议阐明肾脏衰老与老年尸体移植接受者慢性同种异体肾病（CAN）加速之间的关系。我们已经开发了评估人体肾脏损伤的敏感方法，我们现在建议将其与尿细胞学和肾小球基因表达的新技术相结合。我们将使用这种方法来量化老年受体-供体对（60岁，1组，N=25）中CAN的程度和进程。年轻的Tx受体-供体配对（<40岁，第二组，N=25）作为对照。我们还将对长期（48-72个月）接受老年尸体供体（60 - 60岁，第3组，N-19）双（双）肾Tx的受者进行一次相同的评估，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：肾脏衰老和CAN的结合导致老年供体异体移植物进行性、渐进性肾小球减少。我们将连续使用生理和形态测量技术，以及数学建模和磁共振血管造影，来测定第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：老年人缺血/再灌注后小管损伤（移植物功能延迟）的可逆性有限，导致小管肾小球的形成，从而导致无功能肾小球的形成。连续活检将用于48个月时初始小管损伤与非小管肾小球发生率的关系。假设3是老年Tx肾足细胞（一种不能在体内复制的细胞类型）的损失导致足细胞减少和肾小球硬化。我们将在连续活检中确定每个肾小球的足细胞数量。然后，我们将量化足细胞减少，以解释超过48个月的任何增量足细胞减少。我们还将利用RT-PCR技术探讨活检获得的肾小球中足细胞相关基因表达的改变。假设4：在采集和移植时分析老年人、供者的肾脏功能、衰老和足细胞相关基因的结构和表达，可以预测48个月的移植物功能和存活，从而可以在未来对老年供者进行最佳选择。假设5：在第3组中，双Tx期间移植的2倍补体肾小球将防止“残肾”现象，从而使肾小球滤过能力和数量保持在第1组的>倍。

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.