RENAL SENESCENCE AND TRANSPLANTATION

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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.