Untitled - Roche Trasplantes

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EARLY DIAGNOSIS OF CHRONIC ALLOGRAFT NEPHROPATHY BY MEANS OF PROTOCOL BIOPSIES prevalence was correlated with prior acute rejection episodes, acute nephrotoxicity and with donor age. The Westmead series showed what was to some a remarkably high prevalence of CAN, with almost all grafts affected by CAN grade I by two years, and around 50% with CAN grade III by ten years (7) (Figure 3). Figure 3. Prevalence of chronic allograft nephropathy diagnosed on protocol biopsy by the Banff criteria in 120 simultaneous kidney pancreas transplant recipients. Steroid avoidance and use of either sirolimus or mycophenolate mofetil with tacrolimus lead to 20% grade II and III CAN at only 12 months in both African Americans and non- African Americans, similar to the Westmead data using predominantly cyclosporine therapy (49). Moreso et al. showed an even higher prevalence of CAN with 175 of 435 (40%) of grafts affected by six months (29). The precise estimate of CAN grade after at different times after transplantation varies with the study and to a certain extent also with the histologist, but the important and common theme is that the level of pathological impact is substantially underestimated by the serum creatinine and other functional measures in all studies. It is thus our contention that it is necessary to intervene early if one is to reduce the level of histological chronic allograft nephropathy. Utility of diagnosing and detecting CAN early One could legitimately ask the question: is it worth making the diagnosis of CAN? Is there a therapeutic utility to making the diagnosis? Is it possible to either reverse or prevent deterioration in the histology once the diagnosis has been made? These questions are all predicated on therapeutic nihilism which dictates that once the damage has been done it cannot be undone. There is some justice in this approach, since sclerosed glomeruli will not spring back to life and atrophic tubules will not regenerate to normal morphology and function. The only conclusion that one can make is that therapy designed to halt the 23
BIOPSIA DE PROTOCOLO EN EL TRASPLANTE RENAL progression of disease and therapy designed to remove the aetiological agents would have to be effective to justify the intervention. The options available for prevention of graft damage are: treatment of subclinical rejection; reversal of and prevention of further CNI nephrotoxicity, especially arteriolar hyalinosis; prevention of ischaemia and selection of a younger donor. The latter strategies will not help after the transplant but there is evidence that treatment of subclinical rejection and switch from CNI based immunosuppression can make a difference. Treatment of subclinical rejection The diagnosis of subclinical rejection and the repeated and reliable demonstration of a correlation between subclinical cellular infiltrates and subsequent graft fibrosis, does not prove that it is possible to treat subclinical rejection with benefit. It was thus important to see proof of this hypothesis in a single centre study from Canada (26). In this study Rush and his colleagues randomised half of the patients to protocol biopsy and treatment of subclinical rejection and the other half to treatment based upon clinical indices only. Interstitial fibrosis and tubular atrophy scores on biopsy at six months and serum creatinine at 24 months were statistically significantly superior in the protocol biopsy group, thus proving the hypothesis. In our own series, published recently, it was demonstrated that treatment of subclinical rejection diagnosed on one month protocol biopsy, eliminated differences in chronic fibrosis and tubular atrophy at three months, between those with and without subclinical rejection at one month (50). While this cohort study again does not constitute formal proof of the utility of treating subclinical rejection, it is encouraging that this therapy did seem to eliminate chronic damage which we have otherwise seen consistently for the past 15 or more years. A more recent formal trial by the Canadian group with a number of other North American centres has been reported in abstract form in 2006, but failed to demonstrate an impact because of the low incidence of subclinical rejection when using immunosuppression based upon tacrolimus and mycophenloate mofetil (27). Interestingly there was a higher than expected level of interstitial fibrosis in that study –perhaps exchanging subclinical rejection for CNI nephrotoxicity. In conclusion, the weight of evidence favours the diagnosis and treatment of subclinical rejection, especially when using lower intensity immunosuppressive regimens, as a strategy for reducing chronic allograft nephropathy. Avoidance of CNI nephrotoxicity One strategy for avoidance of nephrotoxicity is to avoid these agents entirely and a number of studies have attempted to do that by using combinations of sirolimus or everolimus with mycophenolate mofetil and steroids with induction using a monoclonal 24
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