Serial Peripheral Blood Interleukin-18 and Perforin Gene Expression Measurements for Prediction of Acute Kidney Graft Rejection

BACKGROUND: We and others have shown that expression of the cytotoxic T-lymphocyte effector gene perforin in the peripheral blood is a strong predictor of acute rejection in the early posttransplant period. In the present study we investigated whether interleukin (IL)-18, an immunostimulatory gene that up-regulates perforin-dependent cytotoxicity and promotes tissue damage through other noncytotoxic T-lymphocyte mechanisms alone or in combination with perforin gene expression, may serve as a better predictor of renal allograft rejection in the first weeks after transplantation. METHODS: Peripheral blood was collected twice weekly, and gene expression was measured using real-time polymerase chain reaction. RESULTS: Recipients with acute rejection (n = 17) showed higher levels of perforin and IL-18 transcript on days 5 to 7, 8 to 10, and 11 to 13, compared with patients without rejection (n = 37, P < 0.01 in all cases). Rejection diagnosis using gene expression criteria was possible 1 to 32 days before traditional diagnosis (median 11 days). High specificity was associated with IL-18 expression (72%-93%), and high sensitivity was associated with perforin expression (63%-90%). Positive predictive value was optimized (78%-100%) by using combined up-regulation in both genes as a diagnostic criterion (double-positive). Using high expression in "either or both" genes as a diagnostic criterion yielded high sensitivity (82%-91%) and negative predictive value (91%-96%). CONCLUSIONS: Our data indicate that combined perforin and IL-18 gene expression measurements are useful tools for the recognition of graft rejection in its earliest stages. Serial measurements could be implemented as a monitoring system to identify patients at higher risk of rejection, making them candidates for biopsy or prophylactic increases in immunosuppression.