Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy

Sethi, Sanjeev; Dębiec, Hanna; Madden, Benjamin J.; Charlesworth, M. Cristine; Morelle, Johann; Gross, Lou Ann; Ravindran, Aishwarya; Buob, David; Jadoul, Michel; Fervenza, Fernando C.; Ronco, Pierre

doi:10.1016/j.kint.2019.09.014

Cited by 254 publications

(285 citation statements)

References 26 publications

(31 reference statements)

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“…[4] The target antigen has been identified as the Mtype phospholipase A2 receptor 1 (PLA2R) in 70-80%, the thrombospondin type-1 domain containing 7A (THSD7A) in 1-5% and the recently described neural epidermal growth factor-like 1 protein (NELL-1) in 5-10% of cases). [5][6][7] In approximately 20% of patients, MN is secondary to infections (hepatitis B), systemic autoimmune diseases (SLE), drugs (NSAIDs) or malignancy. [8] Traditionally, the gold standard for diagnosis of MN has been a kidney biopsy.…”

Section: Gabriel Richetmentioning

confidence: 99%

Kidney Biopsy Is Required for Nephrotic Syndrome with PLA2R+ and Normal Kidney Function: The Con View

Bobart

Fervenza

2020

Kidney360

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Section: Gabriel Richetmentioning

confidence: 99%

Kidney Biopsy Is Required for Nephrotic Syndrome with PLA2R+ and Normal Kidney Function: The Con View

Bobart

Fervenza

2020

Kidney360

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“…[1][2][3] Target antigens for primary MN, which account for 75% to 80% of cases, are PLA2R (60%-70%), thrombospondin type-1 domain-containing 7A (1%-5%), and the recently described neural epidermal growth factor-like 1 protein (w5%-10%). [2][3][4][5][6][7] Secondary MN, which accounts for 20% to 25% of MN, is associated with autoimmune diseases, malignancies, infections, and drugs. 1 EXT1 and EXT2 have been recently identified as putative antigens in 30% to 40% of secondary autoimmune MN.…”

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Proteomic Analysis of Complement Proteins in Membranous Nephropathy

Ravindran

Madden

Charlesworth

et al. 2020

Kidney International Reports

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Introduction: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in Caucasian adults. Phospholipase A2 receptor (PLA2R)-and exostosin 1 (EXT1)/exostosin 2 (EXT2)associated MN represent the most common primary and secondary forms of MN. The complement profile using a proteomics approach has not been studied in these 2 common forms of MN.Methods: We used laser microdissection and mass spectrometry (MS/MS) to dissect glomeruli and identify glomerular complement proteins in PLA2R-associated (n ¼ 7), EXT1/EXT2-associated MN (n ¼ 21), and 11 control cases (time 0 transplant biopsies).Results: MS/MS identified high total spectral counts for PLA2R and EXT1/EXT2 in corresponding cases of PLA2R-and EXT1/EXT2-positive MN. Both PLA2R-and EXT1/EXT2-associated MN had high spectral counts of complement proteins C3, C4, C5, C6, C7, C8, and C9. Complement protein C1 was present in low spectral counts in EXT1/EXT2-associated MN. Regulators of complement activation that were detected in MN included higher spectral counts of FH, FHR-1, FHR-5, clusterin, vitronectin and lower spectral counts of FHR-3, FHR-4, and CD59. Low spectral counts of FB and properdin, key components of the alternative pathway, also were detected. IgG4 and IgG1 were the most abundant IgG subclasses in PLA2R-and EXT1/ EXT2-associated MN. Lower spectral counts for C3, C4, and C5 were detected in control cases when compared with MN.Conclusion: Significant complement activation is present in MN as evidenced by large spectral counts of complement proteins from C3-and C4-based pathways, including regulatory proteins of complement pathways. These data suggest that anticomplement drugs may be effective in treatment for MN.Kidney Int Rep (2020) 5, 618-626; https://doi.

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“…Primary MN patients who are negative for both PLA2R and THSD7A would be ideal candidates for further testing in view of the newly discovered autoantibodies in MN. 7,8…”

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Profile of Indian Patients With Membranous Nephropathy

Subramanian

Kumar

Tiwari

et al. 2020

Kidney International Reports

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Introduction: The majority of primary membranous nephropathy (MN) cases are no longer considered idiopathic with the discovery of the podocytic autoantigens: phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain-containing 7A (THSD7A). Limited data on PLA2R-related MN in Indians exist in literature, and THSD7A-related MN remains undocumented in this population. We aimed to characterize the baseline PLA2R and THSD7A profile of adult and pediatric membranous nephropathy (MN) in a large Indian single-institution cohort. Methods: A retrospective analysis of all cases of MN (primary and secondary) between 2014 and 2017 was performed with PLA2R direct immunofluorescence and THSD7A immunohistochemistry on the biopsies and anti-PLA2R enzyme-linked immunosorbent assay (ELISA) on baseline sera. Results: MN constituted 10% of kidney biopsies received in the study period. A total of 216 cases with adequate tissue underwent PLA2R direct immunofluorescence, and 110 of them had available sera for PLA2R ELISA. Combining both testing methods, the prevalence of PLA2R-related primary MN was 72.8%, with moderate concordance between the 2 methods (kappa 0.61). PLA2R was also detected in 16.7% cases of secondary MN, most commonly lupus MN. THSD7A immunohistochemistry performed on 176 cases showed a prevalence of 3.4% in primary MN. One case of lupus MN was also positive for THSD7A. Dual positivity (PLA2R and THSD7A) was noted in 2 cases. The large pediatric cohort tested showed a prevalence of 44% of PLA2R based on tissue testing, whereas 1 case demonstrated THSD7A positivity. Conclusion: This study in a large cohort of Indian patients demonstrates prevalence rates of PLA2R-and THSD7A-related MN similar to world literature, including the substantial cohort of pediatric MN. It also confirms variation in MN in the form of outliers within PLA2R (related to tissue and serum testing), dual positivity for PLA2R and THSD7A, and PLA2R/THSD7A-positive secondary MN.

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Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy

Abstract: We initially selected 35 cases (pilot cohort) of PLA2R-negative MN on kidney biopsy for analysis by tandem mass spectrometry (MS/MS), and detected the unique protein, NELL-1,

Cited by 254 publications

References 26 publications

Kidney Biopsy Is Required for Nephrotic Syndrome with PLA2R+ and Normal Kidney Function: The Con View

Kidney Biopsy Is Required for Nephrotic Syndrome with PLA2R+ and Normal Kidney Function: The Con View

Proteomic Analysis of Complement Proteins in Membranous Nephropathy

Profile of Indian Patients With Membranous Nephropathy

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