Combination Therapy With Rituximab and Low-Dose Cyclophosphamide and Prednisone in Membranous Nephropathy

Abstract

Introduction: Standard treatment with cyclophosphamide (CP) or rituximab (RTX) is suboptimal. We adapted and used the low-dose regimen used in vasculitis (RTX 2 × 1000 mg, CP 1.5 mg/kg/d × 8 weeks, and prednisone [i.v. 2 × 1 g + 3 weeks oral starting at 1 mg/kg]).

Methods: High-risk, anti-PLA2R antibodies (PLA2Rab)-positive patients with membranous nephropathy (MN) were included in this single-arm prospective cohort study. PLA2Rab levels were regularly measured. We report the PLA2Rab kinetics and overall immunological and clinical remission (CR) rate.

Results: We analyzed 26 patients (15 males, aged 57 ± 14 years, PLA2Rab titer 176 [115-460] RU/ml, serum creatinine 128 [102-136] μmol/l, serum albumin 18 [14-21] g/l, and urinary protein-to-creatinine ratio [uPCR] 7.1 [5.7-10] g/10 mmol). Within 8 weeks immunological remission (IR) (enzyme-linked immunosorbent assay < 14 RU/ml) was 88 %. Proteinuria remission after initial therapy developed in 21 patients. Seven patients received renewed therapy, which resulted in proteinuria remission in all. IR and CR were associated with baseline PLA2Rab tertile. Five of 7 patients in need of additional therapy were identified at 4 weeks after start of therapy by PLA2Rab half-life (T_1/2) > 7 days. Serious adverse events occurred in 4 patients. Adverse events were mild; leukopenia was most frequent.

Conclusion: Low-dose triple therapy induced a rapid IR and CR in most patients. Patients with insufficient clinical response were characterized by high baseline PLA2Rab levels and longer PLA2Rab T_1/2. Assessment of PLA2Rab levels within 2 to 4 weeks after start of therapy may enable to identify patients who need more intensive therapy.

Keywords: anti-PLA2R antibodies; immunosuppression; membranous nephropathy.

Graphical abstract

Figure 1

Flowchart of patient inclusion. ∗Some patients were not eligible because of inability to consent (dementia and old age) or comorbidity (malignancy, systemic disease, diabetes). CP, cyclophosphamide; MN, membranous nephropathy; Pred, prednisone; RTX, rituximab.

Figure 2

Percentage decrease of PLA2Rab during treatment (baseline titer is plotted as 100%). Patients in the highest tertile of PLA2Rab are depicted in red. PLA2Rab half-life is more than 7 days in 5 of 9 patients in the highest tertile (identifiable by PLA2Rab levels > 25% after 2 weeks or > 6.25% after 4 weeks, respectively).

Figure 3

Course of absolute PLA2Rab levels during treatment. PLA2Rab half-life is more than 7 days in 5 of 9 patients with a baseline titer in the highest tertile.

Figure 4

Percentage decrease of PLA2Rab versus percentage increase of serum albumin 12 weeks after start of treatment. Calculation: percentage change = (C12 − C0)/ (Cn − C0), where C12 = concentration at week 12, C0 is concentration at week 0, and Cn = normal concentration (for PLA2Rab = 0 RU/ml; for Salb = 40 g/l).