Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults, which is characterized by the accumulation of immune complexes along the glomerular basement membrane (GBM). In most primary MN cases, phospholipase A2 receptor (PLA2R) has been identified as the primary target antigen. However, in the absence of PLA2R, the target antigens have remained unknown – a mystery that stands to be unfolded. Identifying these antigens can lead to better understanding, diagnoses, and treatment pathways for patients with MN. A recent study published in the Journal of the American Society of Nephrology (JASN) has shed light on this topic by identifying the glycoproteins exostosin 1 (EXT1) and exostosin 2 (EXT2) as potential contributors to MN where PLA2R is not present. This article delves into the study, its implications, and the future of MN diagnosis and treatment.

In the June 2019 issue of JASN, Sethi et al. conducted a research study to uncover new antigens associated with MN cases that tested negative for PLA2R. The study, funded partly by National Cancer Institute’s NIH Grant (P30 CA015083), was instrumental in identifying new biomarkers related to MN.


The study examined 224 cases of biopsy-proven PLA2R-negative MN, along with 102 controls that included 47 cases of PLA2R-associated MN, which formed the pilot and discovery cohorts. A subsequent validation cohort assessed 48 cases of PLA2R-negative presumed primary MN and lupus MN to verify the findings. Through employing laser microdissection and mass spectrometry, the researchers identified EXT1 and EXT2 in a subset of the PLA2R-negative MN cases.

The mass spectrometry findings were corroborated by immunohistochemistry, which displayed bright granular staining for EXT1 and EXT2 along the GBM. The clinical and biopsy results of the study suggested a significant association between the presence of EXT1/EXT2 and autoimmune diseases, including lupus, with a striking rate of 80.7% among the identified cases of EXT1/EXT2-associated MN. Notably, none of the patients with EXT1/EXT2-associated MN had circulating anti-exostosin antibodies, indicating the need for further research into the body’s immune response mechanisms in these cases.

The Findings

The detailed results showed that in the 26 cases out of the discovery cohort with EXT1/EXT2-associated MN, granular GBM staining was a consistent finding. In the validation cohort, EXT1/EXT2 staining was observed in 8 of 18 patients with pure class 5 lupus nephritis and 3 of 16 with presumed primary MN with autoimmune indications, providing further evidence of the association between EXT1/EXT2 expression and autoimmune dispositions.

The Implications

The discovery of EXT1 and EXT2 in the context of MN has significant implications. The study points to a subset of MN that is associated with the accumulation of these proteins within the GBM. Given the autoimmune features commonly observed in these patients, this discovery opens a discussion on MN’s link with broader immune system dysfunctions.

Autoimmune disease is prominently common in EXT1/EXT2-associated MN patients, suggesting that these proteins might have a facilitative role in the manifestation or progression of MN within the context of autoimmune diseases. The absence of circulating anti-exostosin antibodies also poses a question about the pathogenesis of MN and whether the immune system’s attack on renal tissue is strictly an extracellular phenomenon or involves more complex intracellular interactions.

The research by Sethi et al. serves as a harbinger of new diagnostic and therapeutic strategies. The research suggests that protein markers such as EXT1 and EXT2 could serve as biomarkers for MN, particularly in PLA2R-negative patients, meaning that, with further research and development, new testing methods could become available to identify MN more accurately and earlier in the disease progression. This could lead to more targeted therapeutic approaches, individualized patient care, and better outcomes for those affected by MN.

Future Research

While this discovery is a leap forward in nephrology, it signals the commencement of extensive research that is to follow. Future studies are needed to explore the mechanism by which EXT1 and EXT2 influence glomerular pathology and to determine the precise role these antigens play in the broader context of MN and related autoimmune diseases.


The findings presented by Sethi and colleagues represent a milestone in the understanding of membranous nephropathy’s pathogenesis, especially for cases that test negative for PLA2R. This research illuminates the diverse etiologies of MN and emphasizes the importance of personalized medicine in treating renal diseases.

As the investigation into the role of EXT1 and EXT2 genes in MN continues, the medical community anticipates significant advancements in nephrology. This study’s DOI number is 10.1681/ASN.2018080852. Do note, the full implications of these findings are yet to be fully realized clinically.


1. Sethi S et al. Exostosin 1/Exostosin 2-Associated Membranous Nephropathy. J Am Soc Nephrol. 30:1123-1136, 2019.
DOI: 10.1681/ASN.2018080852
2. De Vriese AS, et al. A proposal for a serology-based approach to membranous nephropathy. J Am Soc Nephrol. 2017;28:421-430.
3. Beck LH Jr., et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361:11-21.
4. Tomas NM, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med. 2014;371:2277-2287.
5. Ronco P, Debiec H. Pathogenesis of membranous nephropathy: Recent advances and future challenges. Nat Rev Nephrol. 2012;8:203-213.


1. Membranous Nephropathy
2. Exostosin 1
3. Exostosin 2
4. PLA2R-Negative MN
5. Nephrotic Syndrome

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Last Update: February 22, 2024