Interstitial Fibrosis and Tubular Atrophy in Renal Allograft Protocol Biopsies as a Surrogate of Graft Survival

Interstitial fibrosis and tubular atrophy (IF/TA) evaluated in protocol renal allograft biopsies are associated with decreased graft survival, especially when associated with transplant vasculopathy, subclinical rejection, or transplant glomerulopathy. IF/TA evaluated in protocol biopsies has been used as a secondary efficacy variable in clinical trials, some of which have shown that the prevalence of IF/TA depends on the type of immunosuppressive treatment. These observations suggest that IF/TA may be considered a surrogate of graft survival. However, there is an important difference between a predictive and a surrogate variable. A predictive variable is associated only with the main outcome variable, whereas in case of a surrogate variable, an additional condition must be accomplished; that is, modifications of the predictive variable as a result of treatment imply changes in the main outcome variable. In a trial of cyclosporine withdrawal from a cyclosporine-sirolimus-prednisone regimen, cyclosporine discontinuation was associated with less severe chronic lesions in protocol biopsies at 3 years and also with improved graft survival at 4 years. This observation suggest that IF/TA may be a surrogate of survival. This conclusion must be confirmed in other trials before accepting IF/TA as a real surrogate of graft outcome.