Molecular Diagnosis of Renal-Allograft Rejection: Correlation with Histopathologic Evaluation and Antirejection-Therapy Resistance

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Abstract
Because histopathologic criteria cannot always predict the pathogenesis and response to curative antirejection therapy, new hope derives from the molecular analysis of intragraft immunologic markers. We studied whether the cutoff of intragraft expression level of T-cell activation markers may define subgroups of acute rejection differing either in type of rejection or clinical outcome. Forty-three human renal-allograft biopsies were quantified for mRNA expression of granzyme B, Fas ligand, interferon (IFN)γ, interleukin (IL)-4, and IL-6 with a reverse-transcriptase real-time quantitative polymerase chain reaction (RT-PCR) method. Expression levels were correlated with the histopathologic rejection type according to the Banff 1997 classification criteria, and with the sensitivity to the antirejection immunosuppressive therapy, by means of receiver operating-characteristic (ROC) curves. Granzyme B and Fas ligand mRNA expression up-regulation correlated with all allograft rejection types (P<0.01 for all). Moreover, granzyme B showed the highest sensitivity (90%) and specificity (78%) for the potential detection of histologic borderline changes that will require immunosuppressive therapy (area under the curve [AUC]=0.856, P<0.01). Curative antirejection-therapy resistance of overt, acute-rejection episode was significantly associated with higher Fas ligand gene expression (AUC=0.764, P<0.01, sensitivity [71%], specificity [99.5%]). Real-time RT-PCR quantification of the over-expression of the granzyme B gene in kidney-graft biopsies has proved to be as reliable in detecting acute rejection as histologic assessment. Furthermore, we demonstrate that the simultaneous measurement of the mRNA up-regulation of Fas ligand might represent an efficient new tool for the prediction of pejorative outcome of acute rejection.