Thread by @ERAkidney

💥Membranous Nephropathy (MN); New antigens, new disease?
#tweetorialERA #membranous #nephtwitter #FOAMed #tweetorial

MN occurs due to immune complex deposition in the subepithelial GBM. @SethiRenalPath reckons classification of MN should be made based on the antigen, much like the nomenclature of complement activated GN following better understanding of the role of complement dysregulation.

☄️Hot off the press review suggesting we should consider MN as a pattern of injury. @SethiRenalPath @CKJsocial

🔍Let's take a look at the discovery of antigens in MN.

academic.oup.com/ckj/advance-ar…

The recognition that an antigen trigger is involved was first shown in an animal model in 1959. In 2020, a rare case of an infant born with severe MN due to anti-neutral endopeptidase antibodies from the mother; pioneering other antigen detection.

journals.sagepub.com/doi/abs/10.318…

💥The discovery of M-type phospholipase A2 receptor 1 'PLA2R' in 2009, the first antigen identified in adult MN revolutionised how we classify MN. PLA2R occurs in 80% of primary MN; measured in serum and staining on kidney biopsy specimen.

💥2014 brought along thrombospondin type 1 domain-containing 7A' THSD7A', which occurs in <5% of primary MN

In 2018, @SethiRenalPath et al. @MayoClinic @MayoClinicNeph using laser microdissection and mass spectrometry (MS/MS), detected novel proteins in PLA2R negative MN.

pubmed.ncbi.nlm.nih.gov/3106113

⚡️Exostosin 1/exostosin 2 (EXT1/EXT2) was the first novel protein, most common among the unique proteins present in secondary (autoimmune) MN.

Unlike with primary MN, patients with EXT1/2 positive MN are younger (35 years), 81% 🚺, 71% have signs of autoimmunity.

Strictly speaking, the term antigen cannot be used as yet as circulating anti-EXT1/EXT2 antibodies have not been detected thus far. Because of the specificity for lupus, EXT1/EXT2 staining prompts a subcategory of young female lupus patients with a diagnosis of "primary" MN.

⚡️Neural EGF-like-1 protein (NELL-1) is the 2nd most common after PLAR2 associated GN. Patients are older (63 years), and coexisting malignancy (30%) may be present. Antibodies to NELL1 are detected in NELL1-associated MN.

⚡️Neural cell adhesion molecule 1 (NCAM1); patients are younger (34years), more common in 🚺. 90% have SLE; 40% of patients have neuropsychiatric disease.

⚡️Semaphorin 3B (Sema3B); Sema3B-associated MN is rare and accounts for 1–3% of all MN. Commoner in children, representing ~16%. May be genetic as found in siblings. Potentially easily misdiagnosed as steroid-resistant nephrotic syndrome in cases without kidney biopsy.

⚡️Lastly, protocadherin 7 (PCDH7) detected in 2020. PCDH7 is primarily present in older adults. Complement activation is minimal, and seems patients undergo spontaneous remission without immunotherapy. Could this subgroup of patients do without immunotherapy and better outcomes?

These antigens provide an exciting development in MN, insight to pathogenesis, treatment and outcomes of these specific subgroups.

⬇️📌Summary table #TweetorialERA #tweetorial