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February 8, 2019

Disease Week: Membranous Glomerulopathy


History of MG

Timeline of major discoveries in membranous glomerulopathy.

Timeline of major discoveries in membranous glomerulopathy

Heymann nephritis was unique as a model of membranous glomerulopathy when it was reported in 1959 because it was the first to produce renal disease through autosensitization.

Heymann nephritis

The antigenic target of Heymann nephritis (megalin) is largely absent from human podocytes but does have a role in human autoimmune disease as the antigenic target of anti-brush border antibody disease (LRP2-assoc nephropathy).

tubular basement membrane staining, Membranous glomerulopathy, renal biopsy

The case report of placental transfer of maternal antibodies directed against the neutral endopeptidase protein in fetal glomeruli was the first description of a podocyte antigen as the etiology of MG in humans.

Tweet text: PLA2R was described as the major autoantigen of primary MG in 2009, approximately 50 years after the initial description of this form of glomerulonephritis.

PLA2R renal biopsy



Monitoring for serum anti-PLA2R antibodies is useful to determine the prognosis at time of diagnosis, monitoring response to treatment, and predicting disease recurrence.

Membranous glomerulopathy chart

PLA2R epitope spreading: CysR only= “nonspreader” CysR + other (CTLD1, 5, 7, or 8) = “spreader”.

PLA2R chart, arkana laboratories, renal pathology

After PLA2R, the next antigen identified in membranous was THSD7A, representing approximately 2.5% of primary MG cases.


THSD7A staining of glom, kidney pathology, Membranous glomerulopathy



Additional Antigens

We have seen an antigen explosion in membranous glomerulopathy over the past few years! A quick summary thread of each.

EXT1/2 as putative autoantigens in ~30% of patients with membranous lupus nephritis. EXT1 and EXT2 are always both present in cases of EXT-associated membranous.

EXT colocal

NELL1-associated MG commonly shows segmental to incomplete global granular capillary loop IgG staining. In one report, approximately 1/3 patients with NELL1-associated MN have a history of malignancy.

NELL1-associated MG

SEMA3B-associated membranous is more common in pediatric patients.


NCAM1 represents about 6% of cases of membranous lupus nephritis and in 2% of primary membranous.


HTRA1 is the antigen in approximately 4% of patients with primary MN.

Membranous Glomerulopathy

Approximately 2% of primary MG are PCDH7-associated.

CNTN1 antibodies lead to a simultaneous autoimmune neuropathy and membranous glomerulopathy.

Approximately 6% of MLN biopsies are TGFBR3 positive.

Membranous Glomerulopathy


Unusual membranous variants

20% of MG patients with light chain restriction have a lymphoproliferative disorder. Features worrisome for presence of underlying lymphoproliferative disorder on biopsy: absence of PLA2R, staining for single IgG subclass, presence of focal proliferation.

Membranous glomerulopathy with light chain-restricted deposits

Membranous-like glomerulopathy with masked IgG Kappa deposits is a recently described form of glomerulonephritis that primarily affects young females.


Membranous-like glomerulopathy with masked IgG Kappa deposits

Antibodies to BSA can cause a rare form of MG in young children that is important to detect as eliminating it from the diet could be beneficial. Could other food antigens be involved in the development of membranous nephropathy?

Antibodies to BSA


Membranous glomerulopathy

Membranous glomerulopathy is an immune complex-mediated glomerulopathy in which the immune deposits are predominantly subepithelial and IgG is the principal immunoglobulin. Traditionally, this disease has been divided into “primary” and “secondary”. Secondary associations are a broad and diverse group that includes drugs, malignancy, infection, and autoimmune disease, among others.1  The discovery of PLA2R as the major autoantigen in primary membranous glomerulopathy ushered in a new era of diagnosis for this disease.2 This discovery was rapidly applied to clinical practice through serologic monitoring as it became clear that this biomarker was useful for classifying disease, assessing disease activity, and prognostication.3-5 The discovery of THSD7A followed shortly thereafter, though it’s impact has not been as large in classifying disease due to the rarity of this  type of membranous glomerulopathy.6

More recently, through applying advances in mass spectrometry techniques to discovery in membranous, the number of known antigens has exploded to also include EXT1/2, NELL1, SEMA3B, NCAM1, HTRA1, PCDH7, CNTN1, and TGFBR3. However, many more are sure to be described since the antigens in approximately 20% of “primary” and the majority of membranous lupus nephritis remain unknown.  This understanding of membranous glomerulopathy on an antigenic level has revolutionized the way we think about this disease. There is now hope for a future where all patients with membranous glomerulopathy will be diagnosed, monitored, and treated based on the true driver of their disease. We live in exciting times for discovery in medicine. The tools available today are so powerful that the molecular pathogenic mechanisms of disease are being worked out at a dizzying pace, and membranous glomerulopathy is no exception!  

  1. Glassock RJ. The pathogenesis of membranous nephropathy: evolution and revolution. Curr Opin Nephrol Hypertens 2012; 21: 235-242.
  2. Beck LH, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009; 361: 11-21.
  3. Dahan K, Debiec H, Plaisier E, et al. Rituximab for Severe Membranous Nephropathy: A 6-Month Trial with Extended Follow-Up. J Am Soc Nephrol 2016; 28: 348-358.
  4. Ruggenenti P, Debiec H, Ruggiero B, et al. Anti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy. J Am Soc Nephrol 2015; 26: 2545-2458.
  5. Larsen CP, Messias NC, Silva FG, et al. Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor staining in renal biopsies. Mod Pathol 2013; 26: 709-715.
  6. Tomas NM, Beck LH, Jr., Meyer-Schwesinger C, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med 2014; 371: 2277-2287.