免疫抑制治疗和利妥昔单抗靶向治疗在特发性膜性肾病中有效性及安全性比较

Comparison of efficacy and safety of immunosuppressive therapy and rituximab targeting therapy in idiopathic membranous nephropathy

目的评价中风险及以上特发性膜性肾病(IMN)3种治疗方案[利妥昔单抗(RTX)靶向B细胞疗法、钙调磷酸酶抑制剂(CNI)联合小剂量糖皮质激素、足量激素联合环磷酰胺(CTX)]的有效性及安全性,同时分析影响IMN缓解率的因素。方法采用回顾性队列研究的方法分析我院肾病科经肾穿刺活检诊断为IMN的患者,其中中风险及以上的患者共148例。按以上治疗方案分组,RTX组60例,CNI组42例,CTX组46例。记录随访开始患者基线24 h尿蛋白定量(24 h UTP)、血清白蛋白、血肌酐、尿酸、估算的肾小球滤过率(eGFR)、抗血清磷脂酶A2受体(PLA2R)抗体水平;比较3组患者治疗6、12、18个月后,24 h UTP、eGFR变化以及患者的缓解率、不良事件发生情况,并利用COX回归分析影响IMN缓解率的因素。结果随访开始时,患者基线性别、年龄、24 h UTP、血清白蛋白、血肌酐、尿酸、eGFR、血清抗PLA2R抗体水平、体质量指数(BMI)、收缩压无明显差别,具有可比性。随访6个月时,3组24 h UTP与eGFR无明显变化;RTX组与CTX组缓解率均低于CNI组。随访12个月时,RTX组24 h UTP显著低于CNI组,3组患者总缓解率差异不明显。随访18个月时,RTX组24 h UTP显著低于CNI组,eGFR水平显著高于CNI组,CTX组24 h UTP低于CNI组,RTX组与CTX组缓解率均高于CNI组。RTX主要不良反应是输液反应和感染;CNI主要不良反应是代谢综合征和血肌酐升高;CTX组主要不良反应为肝功能不全。多因素COX回归分析结果显示,基线抗PLA2R抗体与IMN缓解率存在关联(HR=1.162,95%CI:1.078~1.249)。结论RTX治疗IMN起效慢,在18个月诱导疾病缓解率高于CNI,等同于CTX,且维持缓解时间较长;CNI起效快,但易导致患者肾功能进展;高滴度血清抗PLA2R抗体水平是影响IMN缓解的独立危险因素。

Objective To assess the efficacy and safety of three treatment modalities(rituximab targeted B-cell therapy,calcium-phosphate inhibitor in conjunction with low-dose corticosteroids,and full-dose corticosteroids combined with cyclophosphamide)for patients at intermediate or high risk of idiopathic membranous nephropathy(IMN)and to analyze the factors impacting the remission rates of IMN.Methods A retrospective cohort study was conducted to analyze patients diagnosed with IMN in our nephrology department via renal biopsy,identifying a total of 148 patients at intermediate or high risk.These patients were categorized into three treatment groups:a RTX group with 60 patients receiving rituximab,a CNI group with 42 patients receiving calcineurin inhibitors,and a CTX group with 46 patients received cyclophosphamide.Baseline measurements of 24-hour urine protein,serum albumin,blood creatinine,uric acid,estimated glomerular filtration rate(eGFR),and serum anti-phospholipase A2 receptor antibody levels were recorded at the onset of the follow-up.Subsequently,changes in 24-hour urine protein,eGFR,remission rates,and occurrence of adverse events among the three patient groups were compared at 6,12,and 18 months post-treatment.Moreover,COX regression analysis was employed to ascertain factors influencing the remission rate of IMN.Results At the outset of the follow-up period,no significant difference existed in baseline characteristics such as gender,age,24-hour urine protein quantification,serum albumin,serum creatinine,uric acid,eGFR,serum anti-PLA2R antibody levels,body mass index(BMI),and systolic blood pressure among the patients,indicating the comparability of three groups.After 6 months,there were no notable changes in 24-hour urine protein quantification and eGFR among the three groups;however,remission rates in the RTX and CTX groups were lower than those in the CNI group.By the 12-month mark,24-hour urine protein quantification in the RTX group significantly decreased compared to the CTX group,with overall remission rates showing no significant differences among the three groups.By the 18-month milestone,24-hour urine protein quantification in the RTX group remained notably lower than that in the CTX group,with significantly higher eGFR levels.Additionally,the CTX group exhibited lower 24-hour urine protein quantification compared to the CNI group,with both RTX and CTX groups displaying higher remission rates than the CNI group.Predominant adverse reactions in the RTX group included infusion reactions and infections,whereas the CNI group were associated with metabolic syndrome and elevated serum creatinine,and the CTX group primarily experienced hepatic dysfunction.Multifactorial COX regression analysis revealed an association between baseline anti-PLA2R antibodies and remission rates of IMN(HR=1.162,95%CI 1.078-1.249).Conclusion RTX therapy for IMN exhibits a gradual onset of action,boasting a superior disease remission rate at 18 months in comparison to CNI.It demonstrates a similarity to CTX in this aspect and offers prolonged maintenance of remission.Conversely,CNI demonstrates a rapid onset of action but poses a risk of exacerbating renal impairment in patients.Notably,elevated levels of serum anti-PLA2R antibodies emerge as an independent risk factor influencing remission in IMN.