Balancing Efficacy and Toxicity of Kidney Transplant Immunosuppression
ABSTRACT Late renal allograft loss is mainly the result of progressive histological damage. Both underimmunosuppression (rejection phenomena) and overimmunosuppression (calcineurin inhibitor nephrotoxicity) contribute to the progression of chronic histological damage. The current study was performed to elucidate the complementary impact of immune and nonimmune phenomena on renal allograft histology and function. By performing protocol biopsies, it was demonstrated that clinical and subclinical acute cellular rejection phenomena continue to play important roles, despite the use of the powerful combination of tacrolimus, mycophenolate mofetil, and steroids. Next to immune phenomena, the importance of nonimmune factors in renal allograft histological evolution was shown in protocol biopsy studies. Both in adult and in pediatric renal allograft recipients, the characteristics of the donor kidney (donor age, size discrepancy) appeared to be major determinants of the histological and functional evolution. This impact of donor characteristics was not only important in the immediate peritransplantation period, it was also shown that higher donor age increased the risk for progressive posttransplant histological injury and calcineurin inhibitor nephrotoxicity. Systemic levels of tacrolimus, if kept within a relatively narrow target window, were not associated with a risk for calcineurin inhibitor nephrotoxicity. However, we observed a significant association between renal allograft histology and P-glycoprotein (ABCB1) gene polymorphisms and expression, suggesting a role of this protein in the individual susceptibility to calcineurin inhibitor nephrotoxicity. Finally, the interplay between immune and nonimmune phenomena was demonstrated by the association between donor origin (deceased versus living) and local renal complement gene expression, by using whole-genome expression microarrays.
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ABSTRACT: De calcineurineremmers ciclosporine en tacrolimus hebben zonder twijfel een belangrijke bijdrage geleverd aan de verbetering van de kortetermijnresultaten na niertransplantatie. Het percentage acute afstoting is door deze middelen gedaald, en de 1-jaars transplantaatoverleving is verbeterd. Echter, op transplantaatverlies op de langere termijn hebben de calcineurineremmers een veel minder gunstig effect.06/2008; 46(6):90-91. DOI:10.1007/BF03077015
- NÃ©phrologie & ThÃ©rapeutique 08/2008; 4(4):295-9. DOI:10.1016/j.nephro.2008.01.006
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ABSTRACT: Mammalian target of rapamycin (mTOR) is an important nutrient sensor that plays a critical role in cellular metabolism, growth, proliferation and apoptosis and in the cellular response to oxidative stress. In addition, mTOR-raptor complex, also called mammalian target of rapamycin complex 1 (mTORC1), generates an inhibitory feedback loop on insulin receptor substrate proteins. It was suggested that nutrient overload leads to insulin/insulin-like growth factor 1 resistance in peripheral insulin-responsive tissues and in the beta-cells through sustained activation of mTORC1. In this review, we summarize the literature on the regulation and function of mTOR, its role in the organism's response to nutrients and its potential impact on lifespan, insulin resistance and the metabolic adaptation to hyperglycaemia in type 2 diabetes. We also propose a hypothesis based on data in the literature as well as data generated in our laboratory, which assigns a central positive role to mTOR in the maintenance of beta-cell function and mass in the diabetic environment.Diabetes Obesity and Metabolism 11/2008; 10 Suppl 4:157-69. DOI:10.1111/j.1463-1326.2008.00952.x