环磷酰胺静脉冲击联合糖皮质激素治疗特发性膜性肾病的疗效及安全性研究

Efficacy and safety of high-dose cyclophosphamide intravenous boost combined with glucocorticoid in treatment of idiopathic membranous nephropathy

目的评价环磷酰胺(cyclophosphamide, CTX)静脉冲击联合糖皮质激素在治疗特发性膜性肾病(idiopathic membranous nephropathy, IMN)治疗中的有效性和安全性。方法回顾性分析78例临床表现为肾病综合征(nephrotic syndrome, NS)的IMN患者临床资料。治疗组:静脉滴注CTX联合糖皮质激素组39例[ICTX组:每月静脉滴注CTX 0.50~0.75 g/m^(2)+口服泼尼松0.5 mg/(kg·d)];对照组:口服CTX联合糖皮质激素组39例[OCTX组:第1、3、5月静脉滴注甲强龙0.50 g qd×3 d+口服泼尼松0.5 mg/(kg·d)×27 d;第2、4、6月口服CTX 2.5 mg/(kg·d)+泼尼松10 mg/d]。比较两组患者治疗前及治疗后3、6、12个月的蛋白尿缓解、血清白蛋白、估算肾小球滤过率(estimated glomerular filtration rate, eGFR)变化、复发率及不良反应发生情况。结果 ICTX组在3、6、12个月的蛋白尿总缓解率高于OCTX组,分别为50.0%vs 46.4%,59.4%vs 50.0%,88.9%vs 75%,但差异无统计学意义。两组患者在治疗3、6、12个月后血清白蛋白(sALB)、eGFR较基线值均明显升高,治疗3个月时,ICTX组sALB升高更显著(6.2 vs 4.8 g/L,P=0.013)。两组治疗后24 h尿蛋白(24 h UP)、血清肌酐(Scr)基线值均明显下降(P<0.05)。在完全缓解(complete remission, CR)或部分缓解(partial remission, PR)后,ICTX组和OCTX组复发率分别为8.3%和13%,但差异无统计学意义。治疗3个月时,ICTX组血WBC较OCTX组高[(10.76±2.89)×10^(9)/L vs(8.85±3.02)×10^(9)/L,P=0.013]。ICTX组共发生9例(23.1%)不良反应,而OCTX组为10例(25.6%)。结论 ICTX组方案可显著降低临床表现为NS的IMN患者尿蛋白,提高蛋白尿缓解率,且治疗结束后复发率低,同时可更快速升高血清白蛋白,耐受性好,不良反应无明显增加。

Objective To evaluate the efficacy and safety of high-dose cyclophosphamide(CTX) intravenous injection combined with glucocorticoid in the treatment of idiopathic membranous nephropathy(IMN). Methods Clinical data of 78 IMN patients with manifestation of nephrotic syndrome(NS) admitted in Guangdong Provincial People’s Hospital from January 2007 to June 2019 were collected and retrospectively analyzed. The patients were assigned into either intravenous CTX combined with glucocorticoid group(ICTX group, n=39), or oral CTX combined with glucocorticoid group(OCTX group, n=39). The subjects of ICTX group were treated with monthly intravenous CTX administration 0.50~0.75 g/m^(2)+oral prednisone 0.5 mg/(kg·d) for 6 months. By contrast, those in OCTX group were given intravenous methylprednisolone 0.5 g qd×3 d+oral prednisone 0.5 mg/(kg·d)×27 d in the first, third and fifth month, respectively, and given oral CTX 2.5 mg/(kg·d)+ oral prednisone 10 mg/d in the second, fourth and sixth month, respectively. Comparison was made between the 2 groups about the remission of proteinuria, serum albumin(sALB), estimated glomerular filtration rate(eGFR), recurrence rate and incidence of adverse reactions(ADR) before and 3, 6 and 12 months after the treatment. Results The total remission rate of proteinuria in ICTX group was higher than that in OCTX group at 3, 6, 12 months(50.0% vs 46.4%;59.4% vs 50.0%;88.9% vs 75.0%, respectively), though showed no significant differences. sALB and eGFR in both groups were significantly increased from baseline, while 24 h urinary protein(24 hUP) and serum creatinine(Scr) were decreased in 3, 6, 12 months after the treatment(P<0.05);and sALB had a more significant rise in ICTX group than OCTX group at 3 months(6.2 vs 4.8 g/L, P=0.013). After complete remission(CR) or partial remission(PR), the recurrence rates of ICTX and OCTX groups represented 8.3% and 13.0%, respectively, with no significant differences. In addition, the WBC count in the ICTX group was higher than that in the OCTX group [(10.76±2.89)×10^(9)/L vs(8.85±3.02)×10^(9)/L, P=0.013] at 3 months. Finally, a total of 9 cases of ADR occurred in the ICTX group(23.1%) and 10 cases in the OCTX group(25.6%). Conclusion The ICTX regimen significantly reduces proteinuria of IMN patients with clinical manifestation of NS, improving the remission rate of proteinuria, increasing serum albumin rapidly, and showing a low recurrence rate, good tolerance, as well as no significant increase in adverse reactions.