Detection of PLA2R Autoantibodies before the Diagnosis of Membranous Nephropathy

Significance Statement Primary membranous nephropathy (MN) is an autoimmune glomerular disease associated with nephrotic syndrome and poor kidney prognosis. Autoantibodies against the M-type phospholipase A2 receptor (PLA2R-AB) are present at diagnosis in about 70% of cases. However, when PLA2R-AB first appear and their trajectory are unknown. The authors used the Department of Defense Serum Repository to describe the prediagnostic evolution of PLA2R-AB over time. In most patients who tested positive for the antibodies, PLA2R-AB appeared and rose rapidly before biopsy-proven MN and before the earliest preclinical evidence of disease, including non-nephrotic range proteinuria and hypoalbuminemia. Our data provides the strongest evidence to date of direct PLA2R-AB pathogenicity in humans and suggests that earlier screening of patients with unexplained NNRP may be warranted. Background Circulating serum autoantibodies against the M-type phospholipase A2 receptor (PLA2R-AB) are a key biomarker in the diagnosis and monitoring of primary membranous nephropathy (MN). However, little is known about the appearance and trajectory of PLA2R-AB before the clinical diagnosis of MN. Methods Using the Department of Defense Serum Repository, we analyzed PLA2R-AB in multiple, 1054 longitudinal serum samples collected before diagnosis of MN from 134 individuals with primary MN, 35 individuals with secondary MN, and 134 healthy volunteers. We evaluated the presence and timing of non-nephrotic range proteinuria (NNRP) and serum albumin measurements in relation to PLA2R-AB status. Results Analysis of PLA2R-AB in longitudinal serum samples revealed seropositivity in 44% (59 out of 134) of primary MN cases, 3% (one out of 35) of secondary MN cases, and in 0% of healthy controls. Among patients with MN, PLA2R-AB were detectable at a median of 274 days before renal biopsy diagnosis (interquartile range, 71–821 days). Approximately one third of the participants became seropositive within 3 months of MN diagnosis. Of the 21 individuals with documented prediagnostic NNRP, 43% (nine out of 21) were seropositive before NNRP was first documented and 28.5% (six out of 21) were seropositive at the same time as NNRP; 66% (39 out of 59) of those seropositive for PLA2R-AB had hypoalbuminemia present at the time antibody was initially detected. Twelve participants (20%) were seropositive before hypoalbuminemia became apparent, and eight participants (14%) were seropositive after hypoalbuminemia became apparent. Conclusions Circulating PLA2R-AB are detectable months to years before documented NNRP and biopsy-proven diagnosis in patients with MN.