Correspondence

Research Letter

Antibodies to M-Type Phospholipase A2 Receptor (PLA2R) and Membranous Lupus Nephritis

To describe the clinical and pathological phenotype of membranous nephropathy (MN) associated with M-type-phospholipase–A₂-receptor (PLA₂R), thrombospondin-type-1-domain-containing-7A (THSD7A), semaphorin 3B (SEMA3B), neural-epidermal-growth-factor-like-1-protein (NELL-1), protocadherin 7 (PCDH7), exostosin 1/exostosin 2 (EXT1/EXT2) and neural cell adhesion molecule 1 (NCAM-1) as target antigens.

A retrospective cohort of 270 adult patients with biopsy-proven MN diagnosed between January 2015 and April 2020 was classified as PLA₂R-, THSD7A-, SEMA3B-, NELL-1–, PCDH7-, EXT1/EXT2-, NCAM-1–associated or septuple-negative MN using serologic tests, immunostaining, and/or mass spectrometry. Clinical, biochemical, pathologic, and follow-up data were systematically abstracted from the medical records, including disease activity of conditions traditionally associated with MN and occurring within 5 years of MN diagnosis.

Patients with PLA₂R-associated MN were predominantly middle-aged white men without associated disease. The presence of associated disease did not affect the clinical and pathologic characteristics of PLA₂R-associated MN, suggesting that they were coincidental rather than causally linked. THSD7A-, NELL-1–, PCDH7-, and NCAM-1–associated MN were rare and SEMA3B-associated MN was not discovered in our cohort. EXT1/EXT2-associated MN was primarily diagnosed in younger women with active systemic autoimmunity. A significant proportion of septuple-negative patients had associated malignancy or systemic autoimmunity.

The widely used distinction between primary and secondary MN has limitations. We propose a refined terminology that combines the target antigen and associated disease to better classify MN and guide clinical decision making.

Membranous lupus nephritis (MLN) (Class V lupus nephritis [LN]) is a distinct form of LN defined by the presence of subepithelial immune complex deposits seen on kidney biopsy. MLN is often associated with the nephrotic syndrome. The histology of MLN closely resembles that of idiopathic (primary) membranous nephropathy (pMN). However, MLN typically has abundant mesangial deposits that are absent in primary membranous nephropathy. The clinical presentation, management, and prognosis of MLN differ from that of the proliferative forms of LN (Class III, IV, or Mixed III/IV + V). Although immunosuppressive therapy is often warranted in MLN, the optimal treatment regimen remains unclear. Here we describe the clinical presentation, histologic features, and natural history of MLN. We also review the role of supportive treatment and discuss when to deploy immunosuppressive management in MLN.

La glomérulonéphrite extramembraneuse est la première cause de syndrome néphrotique de l’adulte. Son évolution est très variable d’un patient à l’autre : environ un tiers des patients rentrent spontanément en rémission sous traitement symptomatique par blocage du système rénine–angiotensine, un tiers développent un syndrome néphrotique persistant et un tiers évoluent vers une insuffisance rénale chronique terminale avec 30 à 40 % de récidive sur le greffon. Le traitement des glomérulonéphrites extramembraneuses reste controversé. Le recours à un traitement immunosuppresseur est recommandé en cas de dégradation de la fonction rénale ou de syndrome néphrotique persistant 6 mois après l’instauration du traitement symptomatique. Ce délai d’observation peut induire des lésions irréversibles. Jusqu’à récemment aucun marqueur ne pouvait prédire l’évolution d’un patient. La découverte du récepteur de type M des phospholipases A2 (PLA2R1) et de la thrombospondine de type 1 domaine 7A (THSD7A) comme les deux cibles antigéniques impliqués dans respectivement 70 et 5 % des glomérulonéphrites extramembraneuses idiopathiques ont permis d’identifier de nouveaux marqueurs prédictifs de l’évolution de la fonction rénale. Le transfert passif d’anticorps humain anti-THSD7A à la souris induit l’apparition d’une protéinurie secondaire à une glomérulonéphrite extramembraneuse. Un taux élevé d’anticorps anti-PLA2R1 au moment du diagnostic est associé à un pronostic défavorable. Les anticorps anti-PLA2R1 sont dirigés contre au moins trois domaines différents de PLA2R1. Les patients immunisés contre un seul domaine de PLA2R1 rentrent plus souvent en rémission spontanée, alors que les patients immunisés contre plusieurs domaines de PLA2R1 ont une évolution défavorable avec un plus fort risque d’évolution vers une insuffisance rénale chronique terminale. Ces nouveaux outils devraient nous permettre de proposer à chaque patient une prise en charge personnalisée.

Membranous nephropathy is a major cause of nephrotic syndrome in adults, with various etiologies and outcomes. One third of patients enter spontaneous remission with blockade of the renin–angiotensin system, one third develop a persistent nephrotic syndrome, while another third of patients develop end-stage kidney disease and 40% of them relapse after kidney transplantation. Treatment of membranous nephropathy remains controversial. Immunosuppressive therapy is only recommended in case of renal function deterioration or persistent nephrotic syndrome after 6 months of renin–angiotensin system blockade. Therefore, delayed immunosuppressive treatments may lead to significant and potentially irreversible complications. For long, no biological markers could predict clinical outcome and guide therapy. The discovery of autoantibodies to the phospholipase A2 receptor (PLA2R1) in 2009, and to the thrombospondin type 1 domain containing 7A (THSD7A) in 2014 in respectively 70 and 5% of patients with membranous nephropathy were major breakthroughs. The passive infusion of human anti-THSD7A antibodies in mouse induces proteinuria and membranous nephropathy. The identification of these antigens has allowed developing diagnostic and prognostic tests. High anti-PLA2R1 titers at time of diagnosis predict a poor renal outcome. Anti-PLA2R1 antibodies can bind at least three different domains of PLA2R1. Epitope spreading with binding of two or three of these antigenic domains is associated with active membranous nephropathy and poor renal survival. These new tools could help us to monitor disease severity and to predict renal prognosis for a better selection of patients that should benefit of early immunosuppressive therapy.

Membranous lupus nephritis (MLN) has a favorable prognosis compared to proliferative lupus nephritis (PLN) or combined MLN/PLN, although a significant proportion of cases will progress to end-stage kidney disease. There is considerable morbidity associated with thrombotic complications and treatment. Nondirected care includes renin-angiotensin-aldosterone system blockade, cardiovascular risk management, and antimalarial agents. There may be a role for corticosteroid monotherapy in some patients, but this requires further investigation. Clinical trials and observational reports have led to different immunosuppression regimens for MLN, although high-grade evidence favoring a particular agent remains elusive. Established medications used in the treatment of PLN, such as mycophenolate, cyclophosphamide, and azathioprine, may also be efficacious in MLN, or at least steroid sparing. The calcineurin inhibitors appear promising as an alternative treatment in MLN, particularly with emerging experimental data supporting their nonimmunologic antiproteinuric effects. There is also emerging evidence for “multitargeted therapy” in combined MLN/PLN, although the long-term efficacy is still unproved.

Membranous nephropathy (MN) accounts for most cases of the nephrotic syndrome in adults. Recently, studies on the underlying pathomechanisms led to the identification of the podocyte M-type receptor for secretory phospholipase A2 (PLA₂R1) as a target antigen of circulating autoantibodies.

Autoantibodies to PLA₂R1 may not only play a role in the development of primary MN, but also serve as a marker for diagnosis, disease activity and therapy monitoring. Antibody detection is crucial to discriminate between patients with primary MN and those with a secondary form of the disease, as both forms require different diagnostic approaches and treatment strategies. Standardized test systems based on recombinant PLA₂R1 allow for the sensitive and specific analysis of anti-PLA₂R1 autoantibodies. Further research into pathogenic mechanisms and other disease markers can pave the way for improved patient care.