MO262: Intravenous Cyclophosphamide for High-Risk Primary PLA2R-Positive Membranous Nephropathy
Authors: Stefan Gabriel , Stancu Simona , Dorin Zugravu Adrian , Petre Nicoleta , Mircescu Gabriel 
Published: May 2022

Abstract

BACKGROUND AND AIMS
The mainstay of treatment for high-risk primary membranous nephropathy (MN) is the cyclic steroid-oral cyclophosphamide (CYC) regimen (modified Ponticelli regimen). However, there has been increasing awareness of serious treatment-related toxicity. Intravenous CYC offers the potential benefit of lower cumulative dose and a lower rate of adverse events. Therefore, we aimed to evaluate the efficacy and safety of intravenous CYC in high-risk primary PLA2R-positive MN.

METHOD
We retrospectively examined the renal outcome on 1 August 2020 of 40 adult patients [age 57 (interquartile range (IQR) 48–69] years, 70% male, serum creatinine 1.1 (IQR 0.9–1.3) mg/dL) who were diagnosed with MN by kidney biopsy and had positive serum anti-PLA2R ab at diagnosis [median titer 257.3 (IQR 86.4–603.0) RU/mL] during 2016–2019.
We included only patients with first episode MN at high risk according to 2021 KDIGO guideline, and who were followed for at least 6 months.
All patients received CYC at a dose of 600 mg/m2 every 4 weeks for up to 6 months in conjunction with prednisone at a dose of 0.75 mg/kg daily (up to 60 mg/day) with gradual tapering to 0.5 mg/kg/day by 3 months and 0.1 mg/kg/day by 6 months.
The outcomes were as follows: kidney survival defined as kidney replacement therapy (KRT) initiation; partial (proteinuria 0.5–3.5 g/24 h) or complete remission (proteinuria &lt; 0.5 g/24 h and serum albumin ≥ 3.5 g/dL)—whichever came first.

RESULTS
Patients were followed for a median of 26 (95% CI 19.2–32.7) months, and 27 (67%) patients reached a form of remission with complete remission observed in 15 patients (37%) and partial remission in 12 (30%).
Cumulative remission rates were 24% after 6 months, 57% after 12 months and 77% after 24 months. Median time to cumulative remission was 11.0 (95%CI 6.6–15.3) months.
Absence of response was observed in 13 patients (33%), three (8%) of whom started KRT after a mean follow-up of 4.2 (95% CI 3.9–4.5) years.
Patients who did not respond to immunosuppression had more severe nephrotic syndrome [24 h proteinuria 12.5 (IQR 7.9–15.0) versus 6.1 (IQR 4.0–8.7) g/24 h, P = .002; serum albumin 2.1 (IQR 2.0–2.3) versus 2.4 (IQR 2.0–2.8) g/dL, P = .04] at diagnosis, but similar titer of PLA2R ab [417 (IQR 258–690) versus 185.7 (IQR 85–439) RU/mL, P = .2].
In the Cox proportional hazard model, only lower serum albumin [HR 3.9 (95% CI 1.2–12.3), P = .01] was retained as a risk factor for absence of remission, while 24 h proteinuria [HR 1.0 (95% CI 0.9–1.0), P = .6], baseline PLA2R ab titer [HR 1.0 (95% CI 0.9–1.0), P = .7] and kidney biopsy chronicity index [HR 1.0 (95% CI 0.8–1.2), P = .5] were not.
Clinical relapse occurred in 3 of 27 (11%) patients at a mean of 11 months after treatment discontinuation.
During the follow-up period five (13%) patients died. Cardiovascular disease (three patients) and infections (two patients) were the main causes of death; apparently not related to CYC treatment.
Median cumulative dose of CYC was 7.2g. None of the patients required blood transfusions or granulocyte–colony-stimulating factor for the management of myelosuppression. Two patient developed community-acquired pneumonia after the first CYC dose and required hospital admission. When the infection resolved, immunosuppressive treatment was successfully completed.

CONCLUSION
Monthly intravenous CYC pulses in patients with high-risk primary PLA2R-positive MN seems to be an effective and safe alternative for treatment. Also, in these patients, lower serum albumin at diagnosis is an early marker for lack of remission.