Corticosteroid inhibition of the OKT3‐induced febrile and nephrotoxic responses during treatment of renal allograft rejection

Abstract

The anti‐CD3 monoclonal antibody OKT3, highly effective at treating renal allograft rejection, is associated with a severe first‐dose reaction (FDR), two components of which are high fever and nephrotoxicity. This FDR is thought to be caused by lymphokines (LK) released following administration of OKT3. High‐dose corticosteroids (HDS) block LK release when used as part of a renal transplant OKT3 induction protocol. The effect of HDS on the febrile response and renal function of established transplants has not been well studied. We sought to lest the hypothesis that HDS would also block the FDR when OKT3 was used for the treatment of biopsy proven, acute cellular, renal allograft rejection. Forty‐two renal transplant recipients were retrospectively analyzed. Background immunosuppression consisted of prednisone, azathioprine (AZA), and cyclosporine (CyA). At the time of rejection, the oral prednisone dose was increased to 1–2 mg/kg/d. and both CyA and AZA doses were maintained at pre‐rcjection levels. HDS (>5 mg/kg. mean 24.9±6. n = 29) and low‐dose (LDS) (<5 mg/kg. mean 0.8±0.4, n = 13) groups were defined by the dose of intravenous steroids given at the time of OKT3 treatment. Premedication also included diphenhydramine and acetaminophen. Maximum temperature (Tmax) on days 1 and 2 after OKT3, total days febrile, the serum Creatinine (Cr) on days 0, 1.2, 3, 7, 14, and 28, and the frequency of anli‐OKT3 antibody formation and infections were compared using ANOVA or Chi Square. HDS decreased Tmax on day 1 (37.5 C vs. 38.3°C. p = 0.03) but not on day 2 (38.2 ± 1 vs. 38.6 ±0.7. p = 0.18). There was no effect on the number of days febrile (2.7 vs. 2.8. p = 0.8). The optimal steroid dose for complete suppression was about 25 mg/kg. The degree of suppression decreased with time over the interval of 0.5 to 5.75 hours indicating an optimal time of 1 hour or less. The protective effect of HDS on renal function was seen as a significantly reduced increase in Cr on day 2 after OKT3 (0.2±0.4 mg/dl vs. 0.8±0.9. p = 0.008) in the HDS group. The nephrotoxicity was not completely inhibited even at the highest doses of steroids. The rate of OKT3Ab formation was substantially less in the HDS group (10% vs. 38%, p=0.03). The incidence of infections requiring hospitalization was similar (38% vs. 46%, p = 0.62). No post‐OKT3 lymphomas occurred to date in this cohort. In conclusion. HDS at the time of OKT3 dulled the initial febrile response, decreased the nephrotoxicity, and protected against OKT3Ab formation. These advantages of HDS were achieved without a short term increase in the rate of infections or the appearance of lymphomas. The lack of complete suppression of the nephrotoxicity, even at dose of steroids that completely suppressed the febrile response, suggests that its mechanism might be different from that of the febrile response.