Supplementary Material for: Long-term safety, clinical and immunological outcomes in Primary Membranous Nephropathy with Severe Renal Impairment treated with cyclophosphamide and steroid-based regimen

Introduction and Aims Therapy of Primary Membranous nephropathy (PMN) with progressive advanced kidney dysfunction is challenging with limited literature and no clear therapeutic strategies. This is due to the scant evidence of effectiveness and uncertainty around the risk-benefit profile of immunosuppression (ImS) when eGFR is less than 30 ml/min. We aimed to determine long term clinical outcomes in patients with PMN and severe renal impairment treated with combined cyclophosphamide and steroids. Methods The study is a single-centre retrospective longitudinal cohort study. All patients (between 2004-2019) with biopsy confirmed PMN who initiated combination therapy with steroids and cyclophosphamide and had an eGFR of ≤30ml/min/1.73m2 at the time of initiation of therapy were included for analysis. Clinical and laboratory parameters including Anti-PLA2R-Ab were monitored as per standard clinical guidance. Primary outcome was achievement of partial remission. Secondary outcomes included immunological remission, need for renal replacement therapy, and adverse effects. Results Eighteen patients with median age of 68 (IQR 58-73) years and 5:1 M:F ratio received the combination therapy when eGFR was ≤30ml/min/1.73m2 (CKD-EPI). At time of immunosuppression, median eGFR and uPCR were 23 (IQR 18-27) ml/min/1.73m2 and 1000 (IQR 838-1285) mg/mmol respectively. Median follow-up was for 67 (IQR 27-80) months. 16 patients (89%) achieved partial Remission and 7 (39%) achieved complete remission. eGFR increased by 7ml/min/1.73m2 (27%) after one year of starting immunosuppression treatment and 12ml/min/1.73m2 at end of follow-up. Two patients (11%) developed end stage renal disease needing renal replacement therapy. 67% achieved both immunological and clinical remission. Two (11%) patients required hospitalization secondary to infections, 4 (22%) patients developed cancer and 4 patients died (22%). Conclusion Combination therapy with cyclophosphamide and steroids is effective in achieving partial remission and improving renal function in PMN with advanced renal dysfunction. Prospective controlled studies are required to provide further evidence and improve outcomes in such patients.

引言与研究目的：伴进行性晚期肾功能不全的原发性膜性肾病（Primary Membranous nephropathy, PMN）治疗颇具挑战，相关文献匮乏且无明确治疗策略。这是由于当估算肾小球滤过率（estimated glomerular filtration rate, eGFR）低于30 ml/min时，免疫抑制治疗（immunosuppression, ImS）的有效性证据稀缺，且其风险-获益比存在不确定性。本研究旨在探讨联合环磷酰胺与糖皮质激素治疗原发性膜性肾病伴重度肾功能不全患者的长期临床结局。

方法：本研究为单中心回顾性纵向队列研究。纳入2004-2019年间经肾活检确诊为原发性膜性肾病、启动糖皮质激素联合环磷酰胺治疗，且治疗启动时估算肾小球滤过率≤30ml/min/1.73m²的所有患者进行分析。按照标准临床指南监测患者的临床与实验室参数，包括抗磷脂酶A2受体抗体（Anti-PLA2R-Ab）。主要结局为达到部分缓解，次要结局包括免疫学缓解、肾脏替代治疗需求及不良反应。

结果：共纳入18例患者，中位年龄68岁（四分位距IQR 58~73），男女比例为5:1，均在估算肾小球滤过率≤30ml/min/1.73m²（采用CKD-EPI公式计算）时接受联合治疗。免疫抑制治疗启动时，患者的中位eGFR为23（IQR 18~27）ml/min/1.73m²，中位尿蛋白肌酐比（urinary protein creatinine ratio, uPCR）为1000（IQR 838~1285）mg/mmol。中位随访时长为67（IQR 27~80）个月。16例患者（89%）达到部分缓解，7例（39%）达到完全缓解。启动免疫抑制治疗1年后，患者的eGFR较基线提升7ml/min/1.73m²（增幅27%），随访结束时较基线提升12ml/min/1.73m²。2例患者（11%）进展为终末期肾病，需接受肾脏替代治疗。67%的患者同时达到免疫学与临床缓解。2例患者（11%）因感染需住院治疗，4例患者（22%）罹患肿瘤，4例患者（22%）死亡。

结论：联合环磷酰胺与糖皮质激素治疗可有效实现伴晚期肾功能不全的原发性膜性肾病患者的部分缓解，并改善其肾功能。未来需开展前瞻性对照研究以提供更多证据，优化此类患者的治疗结局。