Grenda Ryszard, Prokurat Sylwester, Ciechanowicz Andrzej, Piatosa Barbara, Kaliciński Piotr
Department of Nephrology, Kidney Transplantation and Hypertension Children's Memorial Health Institute, Warsaw, Poland.
Ann Transplant. 2009 Jul-Sep;14(3):18-24.
Immunosuppressant toxicity is a limiting factor for the efficacy and safety of long-term therapy. Whether it stems solely from drug exposure, remains unclear.
MATERIAL/METHODS: Overall, 207 children and adolescents at the mean age of 11+/-4.4, with primary renal allograft were analyzed. Immunosuppression regimens included CsA or TAC, combined with AZA or MMF and steroids. Drug-specific toxicities were diagnosed by renal biopsy and/or clinical criteria. Genotyping for MDR1, CYP3A5, IL1B, IL1RN, IL-6, IL-10, MCP-1, TGFB1, CCR5, VEGF and TNF-alpha gene polymorphisms was performed with the use of PCR and PCR-RFLP techniques.
Nephrotoxicity was seen in 38.5% of patients treated with CsA and 29.5% - with TAC, while gingival hypertrophy was observed in 28% of CsA patients. Myelotoxicity was found in 3% of AZA-treated and 6.4% of MMF-treated patients. No significant correlation was seen between the patient's age, gender, type of pre-transplantation dialysis, donor age, graft origin or cold ischemia time, and the occurrence of drug-related toxicity. For CNIs, the drug exposure and the duration of treatment did not prove of significance either. TAC associated nephrotoxicity correlated with the CCR5 gene polymorphism, as the wt/32 genotype was found in 21% of patients with no detected toxicity (p<0.041) and in none of the nephrotoxicity cases. The presence of this genotype was also associated with significantly better graft function at 1 year post-transplant (GFR 115.104+/-28.40 vs 86.434+/-29.96; p=0.022). An association was seen between the MMF-induced myelotoxicity and the TNF-alpha G(-308)A polymorphism (p<0.005), but the MMF exposure was higher in patients who developed toxicity.
Genetic background should be regarded one of the risk factors for immunosuppressant related toxicity in renal transplantation.
免疫抑制剂毒性是长期治疗疗效和安全性的限制因素。其是否仅源于药物暴露尚不清楚。
材料/方法：共分析了207例平均年龄为11±4.4岁的原发性肾移植儿童和青少年。免疫抑制方案包括环孢素A（CsA）或他克莫司（TAC），联合硫唑嘌呤（AZA）或霉酚酸酯（MMF）及类固醇。通过肾活检和/或临床标准诊断药物特异性毒性。使用聚合酶链反应（PCR）和聚合酶链反应-限制性片段长度多态性（PCR-RFLP）技术对多药耐药蛋白1（MDR1）、细胞色素P450 3A5（CYP3A5）、白细胞介素1β（IL1B）、白细胞介素1受体拮抗剂（IL1RN）、白细胞介素6（IL-6）、白细胞介素10（IL-10）、单核细胞趋化蛋白1（MCP-1）、转化生长因子β1（TGFB1）、C-C趋化因子受体5（CCR5）、血管内皮生长因子（VEGF）和肿瘤坏死因子α（TNF-α）基因多态性进行基因分型。
接受CsA治疗的患者中38.5%出现肾毒性，接受TAC治疗的患者中29.5%出现肾毒性，而接受CsA治疗的患者中有28%出现牙龈增生。接受AZA治疗的患者中有3%、接受MMF治疗的患者中有6.4%出现骨髓毒性。患者的年龄、性别、移植前透析类型、供体年龄、移植物来源或冷缺血时间与药物相关毒性的发生之间未发现显著相关性。对于钙调神经磷酸酶抑制剂（CNIs），药物暴露和治疗持续时间也无显著意义。TAC相关肾毒性与CCR5基因多态性相关，因为在21%未检测到毒性的患者中发现了野生型/32基因型（p<0.041），而在肾毒性病例中均未发现。该基因型的存在还与移植后1年时显著更好的移植物功能相关（肾小球滤过率[GFR]为115.104±28.40 vs 86.434±29.96；p=0.022）。MMF诱导的骨髓毒性与TNF-α G(-308)A多态性之间存在关联（p<0.005），但出现毒性的患者中MMF暴露更高。
遗传背景应被视为肾移植中免疫抑制剂相关毒性的危险因素之一。
