Molecular events in kidney ageing.

PURPOSE OF REVIEW: Ageing of the kidney is a problem of clinical and basic interest. The problem of renal dysfunction and end-stage renal disease is a major burden on the health system, and old donor age is a major limitation on the use of donor organs and on survival of transplanted kidneys. Moreover, stresses linked to nephropathies, postoperative stress, inflammation and allograft rejection can lead to premature senescence of renal cells thus accelerating organ atrophy. Age-related and disease or stress-related nephron loss could reflect both the limited ability of epithelial cells to repair and replicate in the face of environmental stresses, and limitations on the number of cell replications caused by telomere shortening. Therefore, elucidating cellular senescence mechanisms is relevant to kidney diseases and kidney transplantation. RECENT FINDINGS: Recent findings suggest additive effects of replicative and environmental stress-induced senescence in cellular and organ ageing. In particular, ATM/p53/p21 and Ras/p38/p16 pathways have been shown to co-contribute to the overall cellular senescence, which is caused by extrinsic and intrinsic stimuli. Moreover, the role of epigenetic factors, including protein acylation/deacetylation, chromatin remodeling or caloric restriction, is the focus of recent studies on ageing and senescence. SUMMARY: Despite significant progress, cellular senescence is still better understood in vitro than in vivo. So far, p16 remains the best marker of chronological age in the kidney, and can be considered as an indicator of premature senescence caused by stresses or disease. The beneficial effects of caloric restriction on organ ageing and the role of histone acetylation in pathologic states in rodents are of considerable interest, and deserve future studies.

A prospective 3-yr evaluation of tacrolimus-based immunosuppressive therapy in immunological high risk renal allograft recipients.

BACKGROUND: There have been no published data on use of the the newer immunosuppressants tacrolimus and mycophenolate mofetil (MMF) in high immunological risk renal transplantation. We therefore undertook a prospective study to systematically assess outcomes using these agents as part of an aggressive immunosuppressive regimen. METHODS: Fifty-nine high-risk renal allograft recipients were enrolled at 10 Canadian sites and given a regimen of: a biological induction agent, tacrolimus, MMF, and corticosteroids. Patients included 10 (17%) who had lost a previous graft to rejection <1 yr, 31 (53%) with a current panel reactive antibody (PRA) >30%, 47 (80%) with a historic PRA >50%, four (7%) who had a positive historical T-cell crossmatch with the current donor, and six (10%) with a current positive B-cell crossmatch. The mean peak PRA was 76 +/- 33%. RESULTS: The estimated 3-yr Kaplan-Meier patient and graft survival estimates were 89% and 75%, respectively. There were nine graft losses other than deaths with a functioning graft, of which six were preceded by delayed graft function (p = 0.01, chi2). Sixteen (27%) recipients experienced at least one episode of biopsy-confirmed acute rejection. Infections included cytomegalovirus in 16 patients, eight of whom had tissue-invasive disease. Only one malignancy occurred. CONCLUSIONS: The immunosuppressive strategy investigated is effective and displays a satisfactory safety profile in high immunological risk renal allograft recipients.