title: Chronic allograft dysfunction: can we use mammalian target of rapamycin inhibitors to replace calcineurin inhibitors to preserve graft function?
abstract: OBJECTIVE
  Graft loss after first year of transplantation can be due to composite of factors that may include immunological and nonimmunological factors. Among the nonimmunological factors, toxicity of immunosuppression drugs, especially calcineurin inhibitor (CNI) toxicity is perhaps the leading cause of graft dysfunction. The most common phenotype associated with progressive graft dysfunction is the development of interstitial fibrosis and tubular atrophy not otherwise specified, a hallmark finding of chronic allograft nephropathy as well as CNI toxicity. Protocol biopsies have demonstrated that histological lesions of CNI toxicity can develop as early as 3 months posttransplantation.
  
  
  RESULTS
  Early detection of interstitial fibrosis and tubular atrophy offers the opportunity for replacement of the CNI with mammalian target of rapamycin inhibitors. Early detection of CNI-associated graft damage even before the onset of graft dysfunction is critical to prevent progressive nephron loss. Furthermore, the conversion to sirolimus in patients with advanced graft dysfunction may not be beneficial.
  
  
  CONCLUSIONS
  Until the day transcriptomic assays and high-density microarrays are available routinely to detect the incipient graft injury, early allograft biopsy, preferably during the first 3-6 months of transplantation can detect the presence of interstitial fibrosis and tubular atrophy not otherwise specified before the onset of graft dysfunction and replacement of CNI with sirolimus could prevent the progressive nephron loss.
authors.affiliation: Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Ravinder K
authors.initials: RK
authors.lastname: Wali
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Weir
mesh_terms: D000818:Animals; D001284:Atrophy; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002908:Chronic Disease; D005355:Fibrosis; D006084:Graft Rejection / Q000378:metabolism / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism*; D016032:Randomized Controlled Trials as Topic; D058570:TOR Serine-Threonine Kinases; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D019703:Calcineurin