罗格列酮对环孢素A早期肾损伤保护作用的临床研究

Protective effect of rosiglitazone on early renal interstitial damage induced by CsA

目的探讨罗格列酮对环孢素A（Cyclosporine，CsA）早期肾损伤的保护作用。方法选择2013年1月至2014年5月在郑州大学第一附属医院和南阳市中心医院经肾活检确诊的膜性。肾病患者61例，采用随机数字表法分为对照组和罗格列酮干预组（干预组）。对照组30例，服用常规量激素泼尼松1mg·kg-1·d-1，环孢素胶囊2～3mg·kg-1·d-1；干预组31例，在对照组基础上服用罗格列酮片4mg／d。分别在服用罗格列酮前、服用后第3、6个月时检测患者动脉压、组织型金属蛋白酶抑制剂1（tissue inhibitor of metallo-proteinase-1，TIMP-1）、尿82微球白蛋白（β2-microspheres，β2-MG）、禁水12h尿渗透压数值。结果与治疗前比较，对照组和干预组治疗后第3个月的血清TIMP-1分别为（248．1±48．6）ng／ml和（179．4±38．2）ng／ml，尿胆-MG分别为（253．2±39．7）μg／L和（190．8±35．4）μg／L，动脉压分别为（115．8±10．3）mmHg和（101．5±8．7）mmHg，2组均较治疗前升高（P〈0．05）；治疗后第3个月时，对照组和干预组禁水12h尿渗透压分别为（542．6±79．3）mosm／L和（615．4±68．7）mosm／L，2组均较治疗前下降（P〈0．05）。治疗后第6个月时，对照组和干预组血清TIMP-1分别为（401．3±52．1）ng／ml和（212．7±43．6）ng／ml，尿β2-MG分别为（382．7±41．2）μg／L和（221．3±36．7）μg／L，2组均高于治疗后第3个月（P〈0．05），呈时间依赖性。治疗后第6个月时，对照组和干预组动脉压分别为（128．6±8．9）mmHg和（114．4±12．6）mmHg，均高于治疗后第3个月（P〈0．05）；治疗后第6个月时，对照组和干预组禁水12h尿渗透压分别为（461．3±62．7）mosm／L和（531．2±72．6）mosm／L，均低于治疗后第3个月（P〈0．05）。干预组与同时间段的对照组比较，血清TIMP-1、尿β2-MG和动脉压均低于对照组（P〈0．05），禁水12h尿渗透压高于对照组（P〈0．05）。结论CsA能够上调肾病综合征患者血清TIMP-1和尿β2-MG表达，使患者动脉压升高，禁水12h尿渗透压下降。罗格列酮可以明显降低CsA诱导的血清TIMP-1和尿β2-MG的表达，改善CsA导致的动脉压升高和尿渗透压下降，减少CsA导致的患者高血压和肾脏间质小管纤维化的风险。

Objective To investigate the protective effects of rosiglitazone on the blood pressure, TIMP-1, urine β2-MG and urine osmolality in patients with nephrotic syndrome given cyclosporine, and discuss renal protective effect of rosiglitazone on renal toxicity of cyclosporine A. Methods Patients enrolled in this study had been diagnosed with membranous nephropathy by percutaneous biopsy diagnosis between January 2013 and May 2014 at the First Affiliated Hospital of Zhengzhou Uni- versity and Nanyang Central Hospital. Sixty-one patients were randomly assigned to control group （n= 30） and rosiglitazone group （n = 31） after 4 weeks of run-in period of cyclosporine A treatment. The patients in control group were treated with cyclosporine A （2-3 mg·kg-1 ·d -1 ） and prednisone （1 mg· kg- 1· d- 1 ）. The patients in rosiglitazone group were treated with cyclosporine A （2-3 mg· kg- 1· d- 1 ）, prednisone （ 1 mg· kg- 1 · d- 1 ） and rosiglitazone （4 mg/d）. Arterial pressure, serum TIMP-1, urinary β-MG and no water 12 h urine osmotic pressure were detected before and 3 and months after rosiglitazone administration. Results After treatment for 3 months, serum TIMP-1, urinary 132-MG and arterial pressure in control group were respectively （248. 1± 48. 6） ng/ml, （253.2 ± 39. 7） lag/L and （115.8 ± 10. 3） mm Hg, which were significantly higher than before treatment （P〈0. 05）. The above indexes in treatment group were respectively （179.4 ± 38. 2） ng/ml, （190. 8± 35.4） μg/L, and （101.5 ± 8. 7） mmHg, which were significantly higher than before treatment too （P〈0. 05）. After treatment for 3 months, the urine osmotic pressure in control group was （542. 6 ± 79. 3） mosm/L, and （615.4 ± 68. 7） mosm/L in treatment group, which was significantly lower than before treatment （P 〈0. 05）. After treatment for 6 months, serum TIMP-1 and urinary β2-MG in control group were respectively （401.3 ± 52. 1） ng/ml and （382. 7 ± 41.2） ug/L, and （212. 7 ±43.6） ng/ml and （221.3 ± 36. 7） ug/L in treatment group. The above indexes were respectively higher than those after treatment for 3 months （P〈0. 05）. After treatment for 6 months, arterial pressure was （128. 6 ±8. 9） mm Hg in control group, and （114. 4 ± 12. 6） mm Hg in treatment group, significantly higher than that after treatment for 3 months （P〈0. 05）. After treatment for 6 months, the urinary osmotic pressure in control group was （461.3 ± 62. 7） mosm/L, and （531.2 ± 72. 6） mosm/L in treatment group, significant- ly lower than that after treatment for 3 months （P〈0. 05）. Serum TIMP-1, urinary β2-MG and arterial pressure were lower （P〈0. 05）,and urine osmotic pressure was higher in treatment group than in control group at the same time point （P〈0. 05）. Conclusions Cyclosporine A can increase the expression of serum TIMP-1 and urinary β-MG in patients with nephrotic syndrome, can elevate the arterial pressure, and decrease the blood pressure. The treatment with cyclosporine A, prednisone and rosiglitazone can reduce the blood pressure, TIMP-1 and urinary β-MG, and improve the urine osmolality of patients with nephrotic syndrome.