McLaughlin Gwenn E, Abitbol Carolyn L
Department of Pediatrics, University of Miami School of Medicine/Holtz Children's Hospital, Miami, FL 33130, USA.
Nephrol Dial Transplant. 2005 Jul;20(7):1471-5. doi: 10.1093/ndt/gfh785. Epub 2005 Apr 19.
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.
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.
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.
THEO induced a solute diuresis during furosemide-resistant oliguric tacrolimus toxicity in paediatric patients with a trend towards improved renal function.
急性他克莫司毒性表现为少尿和血清肌酐升高。多种血管调节分子与钙调神经磷酸酶抑制剂介导的肾毒性有关，包括钙、腺苷和内皮素。茶碱（THEO）是一种非特异性腺苷受体拮抗剂，可预防由介导血管收缩的各种肾毒素引起的肾功能障碍。在急性他克莫司毒性的情况下，我们证明给予THEO联合襻利尿剂（LD）可增强利尿作用。这项随机对照试验旨在在更严格的条件下证实这些早期发现。
患有非肾内脏移植且有他克莫司肾毒性少尿证据（血清肌酐浓度较基线升高25%、全血他克莫司浓度>20 ng/dl且对LD治疗耐药的少尿）的儿童被随机分为接受THEO（n = 10）或生理盐水安慰剂（n = 8）。通过收集给药前和给药后（6小时）的定时尿液以及同时测定的血浆浓度，测量或计算以下指标：尿流率、净液体平衡、肌酐清除率、氯的分数排泄、自由水清除率和氯的远端输送。
这些患者在他克莫司毒性发作时肌酐清除率明显受损。LD + THEO组的尿流率比基线增加了110%，但LD + NS组未发生变化。肌酐清除率的增加未达到统计学显著性（P = 0.09）。THEO治疗后氯的分数排泄和远端溶质输送增加。
在对速尿耐药的少尿性他克莫司毒性期间，THEO在儿科患者中诱导了溶质利尿，肾功能有改善趋势。
