SEQUENTIAL DETERMINATIONS OF SERUM INTERLEUKIN-6 LEVELS AS AN IMMUNODIAGNOSTIC TOOL TO DIFFERENTIATE REJECTION FROM NEPHROTOXICITY IN RENAL-ALLOGRAFT RECIPIENTS

Serum interleukin 6 (IL-6) levels were utilized as an immunologic marker of activation of T cells and macrophages in renal allograft recipients treated with a cyclosporine and prednisone immunosuppressive regimen. IL-6 concentrations were estimated in serum samples selected to correspond to similar timepoints in the clinical courses of renal transplant recipients suffering four types of events: group I, quiescent patients without rejection or infectious disease (n = 16, 147 samples); group II, patients with only rejection episodes (n = 26, 291 samples); group III, patients with only infectious episodes (n = 10, 87 samples); and group IV, patients with CsA-induced nephrotoxicity (n = 15, 117 samples). Serum IL-6 activity measured using an IL-6-dependent cell line (MH60.BSF-2) was specific for this lymphokine based upon the capacity of monoclonal anti-IL-6 antibodies to block target cell proliferation. The control group displayed uniformly elevated IL-6 levels during the first posttransplant day (mean 20.1+/-4.1 U/ml range 6.4-64 U/ml), thereafter decreasing by 10-14 days to a mean level of 3.4+/-0.9 U/ml (range 1.0-4.2 U/ml). The rejection group showed increased IL-6 levels ranging from 5.3+/-0.4 U/ml (range 1.0-64 U/ml) to 56.2+/-13.3 U/ml (range 10-300 U/ml, P < 0.01), occurring at a mean of 2 days (range 0-10 days) before the diagnosis of rejection was established by clinical criteria. Interestingly, all three recipients treated with OKT3 and 5/11 treated with antilymphocyte globulin displayed further significant increases in serum IL-6 levels (OKT3: 46.0+/-12.9 U/ml; ALG: 34.6+/-7.8 U/ml) one day after inception of treatment. Five of 10 recipients displaying septic events showed elevated serum IL-6 activity-namely, 5.0+/-1.2 U/ml to 47.5+/-16.2 U/ml, beginning at a mean of 1.2 days before diagnosis. Contrariwise, recipients afflicted with CsA-induced nephrotoxicity displayed reduced IL-6 levels (mean = 1.4+/-0.18 U/ml). The ratio (IL-6 activity/CsA trough level) proved to be even more useful than the serum IL-6 level itself to discriminate acute rejection from nephrotoxicity-namely, 0.53 versus 0.006, respectively (P < 0.01).