Treatment Options for Idiopathic Membranous Nephropathy with Seronegative Anti-PLA2R Antibody

There are nearly 20-30% of idiopathic membranous nephropathy (IMN) patients showing the negative of serum antibodies against the M-type phospholipase A2 receptor (PLA2R). The therapeutic options and efficacy of the three treatment regimens recommended by KDIGO for IMN with seronegative anti-PLA2R antibody remains unclear.

This multicenter retrospective study involved adult IMN patients who were serum-negative for anti-PLA2R antibodies but were diagnosed with biopsy-proven stage II or stage III from four research centers in China. Any secondary cause of MN (hepatitis B and C, systemic lupus erythematosus, medications, tumors) or patients who were pregnant or nursing or had active infection or life-threatening complications, such as heart failure or active gastrointestinal bleeding, were excluded. Based on the treatment regimens, patients were assigned to the tacrolimus (TAC plus glucocorticoids) group, rituximab (RTX) group, and the cyclophosphamide (CYC plus glucocorticoids) group. The complete remission (CR) was defined as urinary protein (UP) ≤ 0.3 g/24 h with stable estimate glomerular filtration rate (eGFR), and overall remission (OR) was CR plus partial remission, with partial remission was defined as a 50% reduction in the UP to a proteinuria level < 3.5 g/d.

103 IMN with anti-PLA2R antibodies-negative patients were retrospectively collected. Of these patients, 42 (40.78%) patients were assigned to the TAC group and received TAC and GC therapies, the mean UP was 5.16 ± 2.34 g/d. 29 (28.15%) patients who received RTX were assigned to the RTX group, with the mean UP was 6.05 ± 3.39 g/d. The remaining 32 (31.07%) patients were assigned to the CYC group who received cyclic regimen, with the mean UP was 6.18 ± 3.08 g/d. Furthermore, patients were divided into stage II (n = 74) group and stage III (n = 29) group according to the pathological data. Additionally, risk stratification categorized them into non-high-risk (n = 49) and high-risk (n = 54) groups (Table 1).

The CR and OR rates in the 103 anti-PLA2R antibodies-negative IMN patients were 43.69% and 78.64%, respectively at 12 months. Kaplan-Meier survival curve results showed that the incidence of CR and OR were significantly greater in the TAC group than in the RTX and CYC groups at 12 months (P = 0.046, P = 0.031, respectively, Figure 1A and 1B). After adjustment for baseline proteinuria, eGFR, age, sex, and serum albumin, multivariate Cox regression analysis of CR and OR revealed that TAC being more likely to achieve remission than RTX (hazard ratio: 0.29, 95% confidence interval [CI] 0.11-0.77, P = 0.01; hazard ratio: 0.54, 95% CI 0.31-0.96, P = 0.03, respectively; Figure 2).

In the stage II subgroup, 19/33 patients in the TAC group, 5/23 in the RTX, and 7/18 in the CYC group achieved CR at 12 months (P = 0.027). In the non-high-risk subgroup, the TAC group maintained the highest OR rate (P = 0.024). Kaplan-Meier curves were used to illustrate differences in remission rates between the groups (Figure 1C-F). There were no statistically differences in remission rates between treatment groups in the stage III and in the high-risk subgroups.

 For seronegative anti-PLA2R antibodies patients, particularly those at non-high-risk, TAC plus glucocorticoids may provide greater clinical benefits.