Phospholipase A2 Receptor Autoantibodies and Clinical Outcome in Patients with Primary Membranous Nephropathy

Abstract

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults, with an uncertain clinical outcome. The characterization of the phospholipase A 2 receptor (PLA 2 R) as the major target antigen in primary MN and the detection of circulating autoantibodies in these patients is a major advance in understanding this disease. To test whether PLA 2 R antibody levels reflect disease activity or clinical outcome, we performed a prospective multicenter study of 133 adult patients with primary MN and detectable serum PLA 2 R antibodies who had not received immunosuppressive therapy. Patients were followed #24 months. PLA 2 R antibody levels associated with clinical disease activity (proteinuria) in patients with immunosuppressive therapy (n=101) or supportive care (n=32). Within 3 months, immunosuppressive therapy led to a sustained 81% reduction in PLA 2 R antibody levels paralleled by a 39% reduction in proteinuria. Patients who experienced remission of proteinuria after 12 months had significantly lower PLA 2 R antibody levels at the time of study inclusion compared with patients with no remission. Patients with high PLA 2 R antibody levels achieved remission of proteinuria significantly later than patients with low PLA 2 R antibody levels. PLA 2 R antibody levels fell over time in patients with spontaneous remission but remained elevated in patients who did not show a reduction in proteinuria. Multivariable Cox regression analysis confirmed PLA 2 R antibody level as an independent risk factor for not achieving remission of proteinuria. We conclude that a decrease in PLA 2 R antibody level is associated with a decrease of proteinuria in patients with primary MN.

Antiphospholipase A2 Receptor Autoantibody Guided Diagnosis and Treatment of Membranous Nephropathy

“…As in other studies, the authors confirmed that the aPLA2R levels decline before the development of remissions of proteinuria and that such remissions can develop weeks or months after the discontinuation of treatment (7)(8)(9). Perhaps most important, the level of aPLA2R at the end of treatment predicted the long-term outcomes.…”

Identification of a Major Epitope Recognized by PLA2R Autoantibodies in Primary Membranous Nephropathy

“…2 Genetic evidence of the involvement of PLA2R in IMN came from the genome-wide association study identifying PLA2R and DQA1 as genes accountable for the genetic susceptibility to IMN. 3 Clinical confirmation that anti-PLA2R antibodies are relevant in MN is evident from studies showing an association between high levels of anti-PLA2R and active disease, 4,5 poor clinical outcome at 5 years, 5,6 and less chance of spontaneous remission. 7 Failure to render patients anti-PLA2R seronegative by immunosuppression therapy is associated with high risk of relapse.…”

Epitope Spreading of Autoantibody Response to PLA2R Associates with Poor Prognosis in Membranous Nephropathy

“…10 Furthermore, high anti-PLA2R1 antibody titers at presentation appear to correlate with subsequent poor renal outcome in most cases, but some patients with high autoantibody titers at onset exhibit a sharp decrease of anti-PLA2R1 activity and disease remission. 11,12 The treatment of iMN is controversial. 13,14 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend a supportive symptomatic treatment with blockers of the RAS and diuretics in all patients with iMN, and immunosuppressive therapy only in the case of renal function deterioration or persistent nephrotic syndrome.…”