SERIAL PERIPHERAL BLOOD IL-18 AND PERFORIN GENE EXPRESSION MEASUREMENTS FOR PREDICTION OF ACUTE KIDNEY GRAFT REJECTION

Abstract

O205* Aims: We and others have previously shown that expression of cytotoxic T lymphocyte (CTL) effector gene perforin in the peripheral blood is a strong predictor of acute rejection in the early post-transplant period. In the present study we investigated whether IL-18, an immunostimulatory gene which upregulates perforin-dependent cytotoxicity and promotes tissue damage through other non-CTL mechanisms, alone or in combination with perforin gene expression, may serve as a better predictor of renal allograft rejection in the first weeks following transplantation. Methods: Peripheral blood was collected twice weekly and gene expression was measured using real-time PCR. Results: Recipients with acute rejection (n=17) had higher levels of perforin and IL-18 transcript on days 5-7, 8-10, and 11-13, as compared to 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 with perforin expression (63-90%). Positive predictive value was optimized (78-100%) by using combined upregulation 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 high 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.