Aminophylline improves urine output but not renal function when used in combination with furosemide during tacrolemus-induced renal insufficiency in pediatric transplant recipients

Introduction: Tacrolimus (TAC), a widely used immunosuppressant, causes dose-dependent but reversible renal vasoconstriction. Resulting oliguria complicates the post-operative management of the pediatric transplant recipient. Theophylline, an adenosine antagonist, prevents and reverses renal injury under various conditions and is an effective adjuvant diuretic in pediatric ECMO patients. This study was undertaken to determine if the addition of aminophylline to the post-transplant diuretic regimen enhances urine output during TAC-induced nephrotoxicity. Methods: Records of patients who received aminophylline (single dose 3-5 mg/kg IV) during TAC-induced nephrotoxicity, defined as a whole blood TAC concentration ≥ 15 ng/mL and a 25% increase in baseline creatinine (CR), were retrospectively reviewed. Data (mean ± SEM) were analyzed by paired Student's t test (pre vs post aminophylline)and Pearson's correlation coefficient. Results: N=19 episodes (12 patients, ages 4-160 months, 1 heart, 4 liver and 7 liver/small bowel recipients). Mean whole blood TAC concentration was 37±5 ng/mL,and serum CR increased 85±13% over baseline (p<0.01). Both 6-hr and 1-hr urine output increased from 1.9±0.3 to 4.3±0.6 mL/kg/hr (p<0.001) and from 2.0±0.5 to 8.1±3.0 ml/kg (p=0.01) respectively. Diuretic use was equivalent in the 6-hr study periods both pre and post aminophylline. One-hr study data supports a true diuretic effect of aminophylline rather than a response to decreasing TAC concentrations. Net 24 hr fluid balance pre and post aminophylline improved from positive 25±9 mL/kg to negative 18±13 mL/kg(p<0.01). Mean arterial pressure,central venous pressure, TAC clearance and serum CR were not altered by aminophylline administration. There was no correlation between whole blood TAC or serum CR concentration and response to aminophylline. Conclusions: The addition of aminophylline to loop diuretics improves urine output during TAC toxicity, but does not affect serum CR. This finding suggests that acute TAC-induced nephrotoxicity is mediated in part by adenosine.