Yin Dong, Huang Jie, Feng Lei, Liao Zhong-kai, Feng Guang-xun, Wang Wei, Song Yun-hu, Hu Sheng-shou
Department of Cardiology, Chinese Academy of Medical Sciences, Beijing, China.
Zhonghua Xin Xue Guan Bing Za Zhi. 2012 Feb;40(2):136-40.
To observe the effect of sirolimus-based immunosuppression administered on heart transplant recipients with chronic renal dysfunction.
From June 2004 to December 2008, standard calcineurin inhibitors (CNI)-based immunosuppressive regimen was changed to reduced-dose CNI plus sirolimus due to CNI-related chronic renal dysfunction in 20 out of 138 cardiac transplant recipients at Fuwai Hospital. The standard immunosuppressive regimen included steroid, CNI (cyclosporine or tacrolimus), and mycophenolate mofetil or azathioprine. Sirolimus was started at 0.75 - 1.50 mg/d with titration to achieve levels of 5 - 15 µg/L, and CNI dose was reduced gradually to 1/2-2/3 of the baseline level. Patients were followed for changes in renal function, lipid level and clinical side effects related to immunosuppressive therapy. Endomyocardial biopsy (EMB) was performed routinely at 3 weeks, 3, 6 and 12 months after transplantation. EMB was also performed at 3 months after regimen change within 1 year post-transplantation or when rejections were suspected in patients beyond 1 year post-transplantation. Echocardiography was performed for monitoring purpose.
The mean follow-up after regimen change was (7.9 ± 6.3) months. Final sirolimus dose was (0.89 ± 0.22) mg/d and blood drug level was (7.6 ± 3.8)µg/L. Cyclosporine dose was reduced from (191.7 ± 60.0) mg/d to (123.6 ± 34.8) mg/d, with blood drug concentration reduced from (175.5 ± 58.0) µg/L to (111.9 ± 56.0) µg/L in 18 patients (P < 0.01). Tacrolimus average dose was reduced from 4.25 mg/d to 3.00 mg/d, with blood drug concentration reduced from 13.5 µg/L to 10.5 µg/L in 2 patients. Serum creatinine level fell from (160.4 ± 25.5) µmol/L to (134.4 ± 26.8) µmol/L (P < 0.01) and urea nitrogen fell from (13.8 ± 4.7) µmol/L to (10.4 ± 3.0) µmol/L (P < 0.01) at one month after regimen change. Twenty two EMBs were performed in 11 patients within 1 year post-transplant, there were 4 episodes of acute rejected (ISHLT grade 2). Twenty patients are all alive and cardiac function was normal. The most common side effect was hyperlipidemia, and triglycerides, total cholesterol and low density lipoprotein levels were significantly increased at 1 month post regimen change (P < 0.05 or P < 0.01). Leukocyte, hemoglobin and platelet as well as liver function remained unchanged at 1 month post regimen change (all P > 0.05).
Our results show that change from CNI-based immunosuppressive regimen to reduced-dose CNI plus sirolimus is an effective and safe approach for the management of patients with CNI-related chronic renal dysfunction, leading to an improvement in renal function without compromise in anti-rejection efficacy and with tolerable side effects.
观察西罗莫司为基础的免疫抑制方案应用于慢性肾功能不全心脏移植受者的效果。
2004年6月至2008年12月，阜外医院138例心脏移植受者中，20例因钙调神经磷酸酶抑制剂（CNI）相关的慢性肾功能不全，将标准的基于CNI的免疫抑制方案改为低剂量CNI加西罗莫司。标准免疫抑制方案包括类固醇、CNI（环孢素或他克莫司）以及霉酚酸酯或硫唑嘌呤。西罗莫司起始剂量为0.75 - 1.50mg/d，滴定至血药浓度达5 - 15μg/L，CNI剂量逐渐减至基线水平的1/2 - 2/3。随访患者肾功能、血脂水平及免疫抑制治疗相关的临床副作用变化。移植后3周、3个月、6个月及12个月常规行心内膜心肌活检（EMB）。移植后1年内方案改变后3个月或移植后1年以上怀疑有排斥反应时也进行EMB。进行超声心动图监测。
方案改变后的平均随访时间为（7.9±6.3）个月。最终西罗莫司剂量为（0.89±0.22）mg/d，血药浓度为（7.6±3.8）μg/L。18例患者环孢素剂量从（191.7±60.0）mg/d降至（123.6±34.8）mg/d，血药浓度从（175.5±58.0）μg/L降至（111.9±56.0）μg/L（P < 0.01）。2例患者他克莫司平均剂量从4.25mg/d降至3.00mg/d，血药浓度从13.5μg/L降至10.5μg/L。方案改变后1个月时，血清肌酐水平从（160.4±25.5）μmol/L降至（134.4±26.8）μmol/L（P < 0.01），尿素氮从（13.8±4.7）μmol/L降至（10.4±3.0）μmol/L（P < 0.01）。11例患者在移植后1年内进行了22次EMB，有4次急性排斥发作（国际心脏和肺移植学会2级）。20例患者均存活，心功能正常。最常见的副作用是高脂血症，方案改变后1个月时甘油三酯、总胆固醇和低密度脂蛋白水平显著升高（P < 0.05或P < 0.01）。方案改变后1个月时白细胞、血红蛋白、血小板以及肝功能均无变化（均P > 0.05）。
我们的结果表明，将基于CNI的免疫抑制方案改为低剂量CNI加西罗莫司是治疗CNI相关慢性肾功能不全患者的一种有效且安全的方法，可改善肾功能，不影响抗排斥疗效，且副作用可耐受。
