Detection of PLA2R Autoantibodies before the Diagnosis of Membranous Nephropathy

Abstract

BackgroundCirculating 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.MethodsUsing 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.ResultsAnalysis 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.ConclusionsCirculating PLA2R-AB are detectable months to years before documented NNRP and biopsy-proven diagnosis in patients with MN.

Development of a Standardized Chemiluminescence Immunoassay for the Detection of Autoantibodies Against Human M-Type Phospholipase A2 Receptor in Primary Membranous Nephropathy

“…The clinical sensitivity of the ChLIA exceeded that of ELISA and RC-IFA by 10.4% and 0.7%, respectively, at similar specificities (>99%). The anti-PLA2R-positive rates detected by ChLIA (83.9%), ELISA (73.5%), and RC-IFA (83.2%) were equal to or higher than the prevalence data determined among non-preselected patients with pMN by different methods, such as Western blot (53.0%-81.7%), 10,11 RC-IFA (48.0-82.3%), 12,13 ELISA (50.0-71.8%), 14,15 addressable laser bead immunoassay (51.5-66.9%), 16,17 luciferase immunoprecipitation systems assay (53.3%), 18 and time-resolved fluoroimmunoassay (71.0-89.7%). 19,20 These variations may be due to differences in assay techniques (e.g., epitope exposure, cutoff values, detected Ig subclass) and cohort characteristics (e.g., ethnicity, immunosuppressive treatment).…”

“…19,20 These variations may be due to differences in assay techniques (e.g., epitope exposure, cutoff values, detected Ig subclass) and cohort characteristics (e.g., ethnicity, immunosuppressive treatment). Recently, Burbelo et al 18 reported a quantitative PLA2R-NanoLuc luciferase immunoprecipitation system assay that provides high diagnostic performance (receiver operating characteristics area under the curve ¼ 1.0) and is, just like the novel ChLIA, more sensitive in detecting anti-PLA2R seropositivity than the ELISA. In the respective pMN panels, luciferase immunoprecipitation system found 1 and ChLIA found 16 additional anti-PLA2Rpositive samples compared with ELISA.…”

Personalized Medicine for PLA2R1-Related Membranous Nephropathy: A Multicenter Randomized Control Trial

“…. ) might then induce intramolecular epitope spreading in PLA2R1 toward the C-terminal end (CTLD1, CTLD7 and/or CTLD8 domains) leading to more active disease, which may happen even before the clinical onset of MN (35,36).…”

“…These findings led us to hypothesize that PLA2R1-Ab may be initially raised against the N-terminal CysR domain with pauci-symptomatic iMN disease: patients in the CysR group are younger, probably at the beginning of the disease. A second immune challenge (allergy, infection …) might then induce intramolecular epitope spreading in PLA2R1 toward the C-terminal end (CTLD1, CTLD7 and/or CTLD8 domains) leading to more active disease, which may happen even before the clinical onset of MN ( 35 , 36 ).…”

Fumarate modulates phospholipase A2 receptor autoimmunity-induced podocyte injury in membranous nephropathy

“…11 Metabolomics might be a valid method for elucidating the pathogenic mechanisms of PLA2R-associated MN, as this condition shows highly variable clinical manifestations, despite the definite pathogenic role of anti-PLA2R autoantibody. 12,13 In the present study, we aimed to characterize the urinary metabolomic profiles of PLA2Rassociated MN, assess the prognostic value of metabolites that could reflect disease activity, and investigate the role of these metabolites in podocyte biology via in vitro experiments mimicking the PLA2R-associated MN milieu.…”