Diltiazem used as a tacrolimus-sparing agent for treatment of pediatric patients with refractory nephrotic syndrome: a case report and retrospective analysis
【摘要】：The 2012 Kidney Disease Improving Global Outcomes(KDIGO) guidelines recommended calcineurin inhibitor tacrolimus to be used to treat several types of nephrotic syndrome(NS) in children and adults, such as steroid-resistant nephrotic syndrome(SRNS), steroid-dependent NS and frequently relapsing idiopathic membranous nephropathy. Owing to its narrow therapeutic window and chronic nephrotoxicity,tacrolimus drug level should be closely therapeutically monitored. Furthermore,due to immunosuppressant-associated toxicities aggravate immune-mediated nephron injury and side effects, low dosing strategies have been increasingly adopted. Based on its metabolic elimination pathway, CYP3A5 genotype and drug-drug interaction will profoundly impact the systemic exposure to tacrolimus after medication. We report here the case of a Chineseboy, aged 5 years, who was diagnosed with refractory nephrotic syndrome(RNS) and was given tacrolimus. The tacrolimus dose was tailored according to the therapeutic concentration window, CYP3A5 genotype, and minimal dosage strategy. More importantly, in combination with corticosteroids and tacrolimus, diltiazem was used as a tacrolimus-sparing agent for the treatment.We also retrospectively reviewed the coadministered therapy records from 2016 to 2018 at our hospital to evaluate the spring effect of diltiazem. Diltiazem induced an average increase of tacrolimus trough concentration(C_0) by 86.5%, irrespective of the CYP3A5 genotype. Tacrolimus maintenance dose ranged from 0.058 to 0.091 mg/kg/d, and the monitored mean C_0 reached to 4.6 μg/L. Serum albumin, total cholesterol, triglyceride, and urine protein of the pediatric patients were within the normal ranges after treatment, and nonephrotoxicity was observed. Additionally,regular dose of diltiazem was well tolerated.Conclusion: CYP3A5 genotype screening is informative to tailor the tacrolimus dosage. Diltiazem was proved to be an effective tacrolimus-sparing agent for pediatric RNS treatment. Long-term sparing effect and safety profiling of diltiazem would benefit from more clinical applications.