Clinicopathological Characteristics and Outcomes of PLA2R-Associated Membranous Nephropathy in Seropositive Patients Without PLA2R Staining on Kidney Biopsy

Rationale & Objective Phospholipase A2 receptor (PLA2R)–associated membranous nephropathy (MN) with circulating serum autoantibodies to PLA2R (SAb+) but no deposits of PLA2R antigen in glomerular tissue by immunofluorescence (GAg−) has been reported. However, little is known about the clinicopathological characteristics or prognosis of this subtype of MN. Study Design Retrospective cohort study. Setting & Participants 130 SAb+ patients in China with biopsy-proven MN who had follow-up data and received immunosuppressive therapy. The median follow-up was 16 (IQR, 9-25) months. Predictor PLA2R antigen detection by immunofluorescence staining of kidney biopsy specimens. Outcomes Complete remission (CR) was defined as proteinuria levels <0.3 g/d and a >50% decrease compared with a previously established baseline. Partial remission (PR) was defined as proteinuria levels <3.5 g/d and a >50% decrease compared with a previously established baseline. The kidney function outcome was defined as a >40% decrease in estimated glomerular filtration rate (eGFR) at the end of the study compared with baseline. Analytical Approach Kaplan-Meier analysis of PR and CR comparing SAb+/GAg+ and SAb+/GAg− patients. Cox proportional hazards models to examine these associations were adjusted for confounders. Results Among 130 SAb+ patients with PLA2R-associated MN, 18 were GAg−. Compared with SAb+/GAg+ patients, those who were SAb+/GAg− presented with more severe kidney injury as evidenced by higher SAb titer, greater proteinuria, lower serum albumin concentrations, lower eGFR (all P < 0.05), and more severe disease with higher chronicity scores (P < 0.001) on kidney biopsies. SAb+/GAg− patients exhibited a significantly lower probability of PR (P < 0.001) and CR (P = 0.03) and were more likely to experience a >40% decrease in eGFR (P = 0.008) than patients who were SAb+/GAg+. After adjusting for clinical and pathologic variables available at the time of biopsy, compared with SAb+/GAg+ patients, SAb+/GAg− patients had a lower rate of experiencing remission (hazard ratio, 0.32 [95% CI, 0.15-0.68]; P = 0.003) and a higher rate of the >40% eGFR decrease outcome (hazard ratio, 7.66 [95% CI, 1.54-38.08]; P = 0.01). Limitations Retrospective study, small sample size, and lack of a uniform approach to treatment. Conclusions Seropositive PLA2R-associated MN without PLA2R staining on kidney biopsy may represent a distinct clinical subtype with more severe disease and a worse prognosis. GAg− is independently associated with poor response to treatment and >40% eGFR decrease in seropositive PLA2R-associated MN. Phospholipase A2 receptor (PLA2R)–associated membranous nephropathy (MN) with circulating serum autoantibodies to PLA2R (SAb+) but no deposits of PLA2R antigen in glomerular tissue by immunofluorescence (GAg−) has been reported. However, little is known about the clinicopathological characteristics or prognosis of this subtype of MN. Retrospective cohort study. 130 SAb+ patients in China with biopsy-proven MN who had follow-up data and received immunosuppressive therapy. The median follow-up was 16 (IQR, 9-25) months. PLA2R antigen detection by immunofluorescence staining of kidney biopsy specimens. Complete remission (CR) was defined as proteinuria levels <0.3 g/d and a >50% decrease compared with a previously established baseline. Partial remission (PR) was defined as proteinuria levels <3.5 g/d and a >50% decrease compared with a previously established baseline. The kidney function outcome was defined as a >40% decrease in estimated glomerular filtration rate (eGFR) at the end of the study compared with baseline. Kaplan-Meier analysis of PR and CR comparing SAb+/GAg+ and SAb+/GAg− patients. Cox proportional hazards models to examine these associations were adjusted for confounders. Among 130 SAb+ patients with PLA2R-associated MN, 18 were GAg−. Compared with SAb+/GAg+ patients, those who were SAb+/GAg− presented with more severe kidney injury as evidenced by higher SAb titer, greater proteinuria, lower serum albumin concentrations, lower eGFR (all P < 0.05), and more severe disease with higher chronicity scores (P < 0.001) on kidney biopsies. SAb+/GAg− patients exhibited a significantly lower probability of PR (P < 0.001) and CR (P = 0.03) and were more likely to experience a >40% decrease in eGFR (P = 0.008) than patients who were SAb+/GAg+. After adjusting for clinical and pathologic variables available at the time of biopsy, compared with SAb+/GAg+ patients, SAb+/GAg− patients had a lower rate of experiencing remission (hazard ratio, 0.32 [95% CI, 0.15-0.68]; P = 0.003) and a higher rate of the >40% eGFR decrease outcome (hazard ratio, 7.66 [95% CI, 1.54-38.08]; P = 0.01). Retrospective study, small sample size, and lack of a uniform approach to treatment. Seropositive PLA2R-associated MN without PLA2R staining on kidney biopsy may represent a distinct clinical subtype with more severe disease and a worse prognosis. GAg− is independently associated with poor response to treatment and >40% eGFR decrease in seropositive PLA2R-associated MN.