Increased morbidity and high variability of cyclosporine levels in pediatric heart transplant recipients

Objectives: This study analyzed the relationship of variability in routine trough cyclosporine (CSA) levels to morbidity after pediatric cardiac trans plantation. Background: Due to high interindividual variation between dosage and blood concentrations, trough surveillance CSA levels are routinely performed afte r cardiac transplantation to adjust dosages. In addition, trough CSA levels have been used as a measure of patient compliance in transplant recipients . Recent investigations have demonstrated a relationship between late rejec tion and mistimed CSA dosing intervals, which could also lead to CSA levels that are incorrectly presumed to be trough levels. Methods: Trough surveillance whole-blood CSA levels were retrospectively re viewed in 49 pediatric heart transplant recipients who had a median follow- up of 42 months (range 6 to 138 months). All patients received the same imm unosuppression regimen (CSA, azathioprine, and steroids), the same CSA-leve l surveillance protocol, and the same stabilization of CSA dose and level i n the therapeutic range (150 to 300 ng/ml) prior to hospital discharge. CSA levels drawn because of coexisting phenomena (drug interaction, gastroente ritis) that could cause CSA-level fluctuation were excluded from analysis. Cyclosporine variability was measured as the percentage of CSA levels that were considered sub-therapeutic (less than or equal to 100 ng/ml), toxic (g reater than or equal to 450 ng/ml), or both. Cyclosporine-level variability was then analyzed in respect to demographic and outcome variables. Results: For the group, the median percentage of sub-therapeutic levels was 3% (range, 0% to 16%); the median percentage of toxic levels was 5% (range , 0% to 36%); and the median of the combination of sub-therapeutic and toxi c levels was 10% (0% to 38%), Eight of the 49 patients (16%) had a high (> 20%) percentage of subtherapeutic + toxic levels or high CSA variability. H igh CSA variability was significantly associated with recipients > 12 month s of age (p = 0.05), black recipients (p = 0.009), recipients from single-p arent households (p = 0.028), and recipients with a history of non-complian ce (p < 0.001). Patients with high CSA variability had a significantly high er median number of hospitalized days per year of follow-up (p = 0.036), hi gher rate of recurrent rejection (greater than or equal to 2 episodes; p = 0.0003), and higher death rate more than 6 months after transplant (p = 0.0 1). Conclusion: Although this study could not determine cause, high variability in trough CSA levels was a marker for pediatric heart transplant recipient s at greater risk for recurrent rejection and hospitalization after transpl antation.