利妥昔单抗在特发性膜性肾病中的治疗

doi:10.24920/21803

摘要/Abstract

摘要： 目的利妥昔单抗（rituximab, RTX）在表现为肾病综合征（nephrotic syndrome, NS）的特发性膜性肾病（idiopathic membranous nephropathy, IMN）中应用的有效性和安全性仍存在争议,尚缺乏大样本研究证实。方法从PubMed, Embase, Cochrane Library 和 Clinical Trials (2016年12月)检索RTX治疗成人IMN的相关研究,共7项研究（总样本量120人）纳入该系统综述和meta分析。完全缓解和部分缓解为治疗有效,统计累积治疗有效率。结果该7项研究均为前瞻性观察性队列研究或配对-队列研究,主要来自2个中心,此外其中1项为多中心研究（来自意大利北部4个肾脏中心）。纳入患者为肾活检诊断IMN、肌酐清除率>20ml/min/1.73m2、前期治疗（44人（36.7%）既往接受过免疫抑制治疗）后仍持续尿蛋白>3.5g/d至少6个月,RTX作为一线或二线治疗。研究结果表明,RTX在IMN中的治疗有效,12和24个月时分别有56% (95% CI, 0.47-0.65) 和68% (95% CI, 0.41-0.87)的患者可以达到缓解,完全缓解率为15% (95% CI, 0.09-0.23) 和 20% (95% CI, 0.12-0.32)。治疗过程中,尿蛋白下降明显,伴血清白蛋白升高和胆固醇水平下降,肾功能稳定。24个月内复发率为8%左右。相关不良反应少且轻,主要为输液相关治疗反应。结论 RTX对IMN治疗有效且安全,超过60%的患者可在24个月内达到部分缓解或完全缓解。

关键词: rituximab, idiopathic membranous nephropathy, nephrotic syndrome, meta analysis, 利妥昔单抗, 特发性膜性肾病, 肾病综合征

Abstract: Objective To investigate the efficacy and safety of rituximab (RTX) in the treatment of idiopathic membranous nephropathy (IMN) with nephrotic syndrome with a systematic review and meta-analysis.Methods PubMed, Embase, Cochrane Library and Clinical Trials (December 2016) were searched to identify researches investigating the treatment of RTX in adult patients with biopsy-proven IMN. Complete remission (CR) or partial remission was regarded as effective therapy, and the cumulated remission rate was calculated.ResultsSeven studies involved 120 patients (73% were men) were included in our systematic review and meta-analysis. All were prospective observation cohort studies or matched-cohort studies, mainly came from two medical centers, and one study was multi-centric (four nephrology units in northern Italy). The creatinine clearance was more than 20 ml/(min·1.73 m²) and persistent proteinuria higher than 3.5 g/d for at least 6 months. All patients received treatment previously [44 (36.7%) had immunosuppressive treatment]. In 12- and 24-month, 56% (95%CI, 0.47-0.65) and 68% (95%CI, 0.41-0.87) patients could reach remission, while 15% (95%CI, 0.09-0.23) and 20% (95%CI, 0.12-0.32) patients could reach CR. The reduction in proteinuria was gradual and obvious, paralleled with upward trend of serum albumin level and decreasing serum cholesterol level. Renal functions were stable. Relapses happened in 24 months were around 8%. RTX related adverse events were mild and were mostly infusion-related reactions.Conclusions RTX treatment in IMN was efficient, well tolerated and safe. More than 60% patients can reach partial remission or CR in 24 months, and relapse is rare. Adverse events of RTX are mostly infusion-related reactions and generally mild.

Zou Peimei,Li Hang,Cai Jianfang,Chen Zhenjie,Li Chao,Li Xuewang. Therapy of Rituximab in Idiopathic Membranous Nephropathy with Nephrotic Syndrome: A Systematic Review and Meta-analysis[J].Chinese Medical Sciences Journal, 2018, 33(1): 9-19.

图/表 8

Figure 1.

Table 1

Baseline characteristics of the included studies§"

Study	Country	Study design	Patient (n)	Sex (M/F, n)	Age (yrs)	Disease duration (mon)	Treatment before RTX	RTX administration	Follow-up time (mon)	Proteinuria prior to RTX (g/d)	Renal function prior to RTX	Quality score
Ruggenenti et al^[20]	Italy	Prospective cohort study	8	3/5	52.8±19.6	29.7±13.5	Full-dose ACEi	4*375 mg/m²	12	8.6±4.2	1.5±0.9	8
Ruggenenti et al^[21]	Italy	Retrospective and prospective cohort study	14 9 (TI score<1.7)	8/6 4/5	60.2±18.2 51.2±13.2	31.5±18 Not mentioned	Full-dose ACEi Full-dose ACEi	4375 mg/m² 4375 mg/m²	12 12	9.2±3.9 8.9±5.3	1.7±0.7 1.0±0.3	9
Cravedi et al^[15]	Italy	Matched-cohort study	12 (B cell-driven protocol) 24 (four-dose protocol)	8/4 16/8	57±13 55±15	Not mentioned Not mentioned	Full-dose ACEi Full-dose ACEi	1375 mg/m² (n=11) and 2 375 mg/m²(n=1) 4*375 mg/m²	12 12	10.3±8.9 9.1±3.8	1.4±0.5 1.5±0.7	8
Fervenza et al^[18]	Canada	Prospective cohort study	15	13/2	47±8	13.1±13.6	Prednisone, CTX, CsA, MMF (n=7); ACEi/ARB (n=8)	21 g (n=5), 21 g and a second course at 6-month (n=10)	12	13.0±5.7	1.4±0.5	9
Fervenza et al^[17]	Canada	Prospective cohort study	20	17/3	48±13	29.7±39.7	Prednisone, CsA, CTX, MMF, tacrolimus (n=11); ACEi/ARB (n=9)	4*375 mg/m² and a second course at 6-month	24	11.9±4.9	1.5±0.5	9
Cravedi et al^[16]	Italy	Matched-cohort study	11 (second-line therapy) 11 (first-line therapy)	10/1 10/1	48.6±13.9 50.1±12.3	51 (25.6-55.2) 9 (6.0-17.0)	Prednisone, CTX, CsA, immunoglobulin G Full-dose ACEi/ARB	4*375 mg/m²(n=10) and B cell-driven protocol (n=12)	24 24	10.9 (6.6-18.6) 10.3 (5.8-13.8)	1.3±0.5 1.1±0.4	9
Moroni et al^[19]	Italy	Multi-centric prospective study	34	23/11	47.5 (22-77)	16.3 (0.2-176.4)	Methylprednisolone, MMF, CsA, and other immunosuppressive agents (n=15); not mentioned (n=19)	1375 mg/m²(n=18), 2375 mg/m²(n=16)	24	11.9±8.2	1.3±0.6	9

Table 1

Table 2

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Figure 3.

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Figure 5.

Figure 6.

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Items	Ruggenenti et al20	Ruggenenti et al21	Cravedi et al15	Fervenza et al18	Fervenza et al17	Cravedi et al16	Moroni et al19
Selection
Representativeness of the exposed cohort	1	1	1	1	1	1	1
Selection of the non-exposed cohort	1	1	1	1	1	1	1
Ascertainment of exposure	1	1	1	1	1	1	1
Demonstration that outcome of interest was not present at Start of study	1	1	1	1	1	1	1
Comparability	1	2	1	2	2	2	2
Outcome
Assessment of outcome	1	1	1	1	1	1	1
Was follow-up long enough for outcomes to occur?	1	1	1	1	1	1	1
Adequacy of follow-up of cohort	1	1	1	1	1	1	1
Total score	8	9	8	9	9	9	9

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