Tacrolimus Improves the Proteinuria Remission in Patients with Refractory IgA Nephropathy
Tacrolimus Improves the Proteinuria Remission in Patients with Refractory IgA Nephropathy
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他克莫司可改善难治性 IgA 肾病患者的蛋白尿缓解
DOI：
10.1159/000337175
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发表时间：
2012-01-01
影响因子：
4.2
通讯作者：
Wang, Hai-yan
中科院分区：
文献类型：
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作者：
Zhang, Qingxian;Shi, Su-fang;Wang, Hai-yan
背景资料：据报道，他克莫司可有效治疗难治性肾病综合征，如局灶节段性肾小球硬化和膜性肾病。部分伊加肾病（IgAN）患者在接受以肾素-血管紧张素系统阻断剂为基础的支持治疗后，对类固醇和/或细胞毒免疫抑制剂产生耐药性。他克莫司治疗难治性IgA肾病的疗效和安全性尚不明确，其改善蛋白尿缓解的机制有待进一步研究。方法：14例难治性IgA肾病患者入选。患者接受他克莫司（0.05-0.1 mg/kg/d）和泼尼松（0.5 mg/kg/d）治疗至少6个月。再次活检患者肾组织中检测突触足蛋白和钙调神经磷酸酶的表达。应用嘌呤霉素氨基糖苷（PAN）诱导的人足细胞损伤模型，研究他克莫司在蛋白尿缓解中的可能作用。结果：在入组的14例患者中，3例因血清肌酐升高超过基线值的30%而退出研究。在11例接受他克莫司治疗超过6个月的患者中，9例显示完全或部分缓解，7例在1个月内达到缓解。在肾组织中，钙调神经磷酸酶的表达增加，而突触足蛋白减少，并在他克莫司治疗后部分恢复。在一项体外研究中，PAN刺激后，人足细胞中的F-肌动蛋白被破坏，而钙调磷酸酶增加，突触足蛋白减少。与他克莫司共同治疗后，F-肌动蛋白的重组和钙调神经磷酸酶和突触足蛋白的表达恢复。结论：他克莫司对难治性IgA肾病患者的蛋白尿有快速缓解作用。他克莫司缓解蛋白尿的机制可能是通过抑制钙调神经磷酸酶的表达来稳定足细胞骨架。
Background: Tacrolimus has been reported to be effective in refractory nephrotic syndrome, such as focal segmental glomerulosclerosis and membranous nephropathy. Some IgA nephropathy (IgAN) patients with massive proteinuria showed resistance to steroids and/or cytotoxic immunosuppressants based on the supportive therapy with renin- angiotensin system blockade. The efficacy and safety of tacrolimus in such refractory IgAN patients are extremely ambiguous, and the mechanism of tacrolimus improving proteinuria remission needs to be investigated. Methods: 14 refractory IgAN patients were enrolled. The patients received tacrolimus (0.05–0.1 mg/kg/day) and prednisone (0.5 mg/kg/day) for at least 6 months. Synaptopodin and calcineurin expression were detected in renal tissues of patients who received re-biopsy. A puromycin aminonucleoside (PAN)-induced human podocyte injury model was applied to investigate the possible role of tacrolimus in proteinuria remission. Results: Of the 14 patients enrolled, 3 were withdrawn because serum creatinine increased over 30% baseline. In 11 patients treated with tacrolimus over 6 months, 9 showed complete or partial remission and 7 achieved remission within 1 month. In renal tissues, the expression of calcineurin increased while synaptopodin decreased and recovered partially after tacrolimus therapy. In an in vitro study, F-actin disrupted in human podocytes after stimulation of PAN, while calcineurin increased and synaptopodin decreased. After co-treatment with tacrolimus the reorganization of F-actin and the expression of calcineurin and synaptopodin recovered. Conclusions: Tacrolimus showed a rapid proteinuria remission in refractory IgAN patients. The possible mechanism of tacrolimus to proteinuria remission might be podocyte cytoskeleton stabilization through inhibition of calcineurin expression.