Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, PR China.
Am J Nephrol. 2012;35(4):312-20. doi: 10.1159/000337175. Epub 2012 Mar 23.
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.
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.
Of the 14 patients enrolled, 3 were withdrawn because serum creatinine increased over 30% baseline.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.
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.
他克莫司已被报道对难治性肾病综合征（如局灶节段性肾小球硬化症和膜性肾病）有效。一些表现为大量蛋白尿的 IgA 肾病（IgAN）患者对基于肾素-血管紧张素系统阻断的支持治疗的类固醇和/或细胞毒性免疫抑制剂产生抵抗。他克莫司在这些难治性 IgAN 患者中的疗效和安全性极不明确，需要研究他克莫司改善蛋白尿缓解的机制。
共纳入 14 例难治性 IgAN 患者。患者接受他克莫司（0.05-0.1mg/kg/天）和泼尼松（0.5mg/kg/天）治疗至少 6 个月。对接受再次肾活检的患者的肾组织进行突触蛋白和钙调神经磷酸酶的表达检测。应用嘌呤霉素氨基核苷（PAN）诱导的人足细胞损伤模型来研究他克莫司在蛋白尿缓解中的可能作用。
14 例患者中，3 例因血清肌酐较基线升高超过 30%而退出。在接受他克莫司治疗 6 个月以上的 11 例患者中，9 例完全或部分缓解，7 例在 1 个月内缓解。在肾组织中，钙调神经磷酸酶的表达增加，而突触蛋白的表达减少，在他克莫司治疗后部分恢复。在体外研究中，PAN 刺激后人类足细胞中的 F-肌动蛋白被破坏，而钙调神经磷酸酶增加，突触蛋白减少。与他克莫司共同处理后，F-肌动蛋白的重组以及钙调神经磷酸酶和突触蛋白的表达恢复。
他克莫司在难治性 IgAN 患者中迅速表现出蛋白尿缓解。他克莫司治疗蛋白尿缓解的可能机制是通过抑制钙调神经磷酸酶的表达稳定足细胞细胞骨架。
