Renal Senescence and Transplantation

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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.