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

Abstract

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.

Keywords: PLA(2)R antigen staining; PLA(2)R-associated MN; Phospholipase A(2) receptor (PLA(2)R); anti-PLA(2)R autoantibodies; glomerular deposits; idiopathic MN; immunofluorescence; kidney biopsy; membranous nephropathy (MN); prognosis; remission; renal function.