Background. Acute tacrolimus toxicity is manifest by oliguria and elevated serum creatinine. Various vasoregulatory molecules have been implicated in calcineurin inhibitor-mediated nephrotoxicity, including calcium, adenosine and endothelin. Theophylline (THEO), a non-specific adenosine-receptor antagonist prevents renal dysfunction from various nephrotoxins which mediate vasoconstriction. In the setting of acute tacrolimus toxicity, we demonstrated that administration of THEO along with a loop diuretic (LD) enhanced diuresis. This randomized, controlled trial was undertaken to confirm these earlier findings under more rigorous conditions. Methods. Children with non-renal visceral transplant(s) and evidence of tacrolimus nephrotoxicity oliguria with a 25% increase in serum creatinine concentration from baseline, a whole blood tacrolimus concentration >20 ng/dl and oliguria resistant to therapy with a LD were randomized to receive either THEO (n = 10) or normal saline placebo (n = 8). Using pre and post (6 h) timed urine collections and coincident plasma concentrations the following were measured or calculated: urine flow rate, net fluid balance, creatinine clearance, fractional excretion of chloride, free water clearance and distal delivery of chloride. Results. These patients had markedly impaired creatinine clearance at the onset of tacrolimus toxicity. Urine flow increased in the LD + THEO group by 110% over baseline, but was unchanged in the LD + NS group. An increase in creatinine clearance did not reach statistical significance (P = 0.09). Fractional excretion of chloride and distal solute delivery increased after THEO treatment. Conclusions. THEO induced a solute diuresis during furosemide-resistant oliguric tacrolimus toxicity in paediatric patients with a trend towards improved renal function.
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