Semaphorin 3B–associated membranous nephropathy is a distinct type of disease predominantly present in pediatric patients

Sethi, Sanjeev; Dębiec, Hanna; Madden, Benjamin J.; Vivarelli, Marina; Charlesworth, M. Cristine; Ravindran, Aishwarya; Gross, Lou Ann; Ulinski, Tim; Buob, David; Tran, Cheryl L.; Emma, Francesco; Diomedi-Camassei, Francesca; Fervenza, Fernando C.; Ronco, Pierre

doi:10.1016/j.kint.2020.05.030

Cited by 151 publications

(145 citation statements)

References 15 publications

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“…Indeed 1 of our 20 PLA2R negative patients had a positive glomerular immune deposit staining for THSD7A, an antigenic target that was identified 6 years after PLA2R. Other novel proteins including neural epidermal growth factor-like 1 protein (NELL-1) [24] and Semaphorin 3B [25] have recently been identified to be associated with membranous nephropathy. NELL-1 was present in 23% [29/126] of European PLA2R and THSD7A negative PMN patients while Semaphorin 3B was predominantly present in paediatric patients with MGN.…”

Section: Comparison Of Pla2r Positive Pmn and Class V Lnmentioning

confidence: 88%

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Diagnostic performance of glomerular PLA2R and THSD7A antibodies in biopsy confirmed primary membranous nephropathy in South Africans

Lwezaula

Ameh²,

Ekrikpo

et al. 2021

BMC Nephrol

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Background: Serum and tissue-based tests using phospholipase A2 receptor 1 (PLA2R) and thrombospondin type-1 domain containing 7A (THSD7A) are established immune biomarkers for the diagnosis of primary membranous nephropathy (PMN). This study assessed the diagnostic performance of these biomarkers in the diagnosis of PMN in South Africans. Methods This was a cross-sectional analysis from a single centre in Cape Town, South Africa. Relevant biodata was collected from all patients. Histology, including slides for PLA2R and THSD7A were processed and assessed by typical microscopic and immunohistochemical features. Biopsy tissues of patients with membranous lupus nephritis (LN-V) and diabetic nephropathy (DN) were used as controls. The diagnostic accuracy for diagnosis of PMN using positive PLA2R and THSD7A were evaluated. Results Of the 88 patients included, 41 had PMN with a mean age of 44.5 ± 17.5 years and 61.0% were female. Histologically, PLA2R and THSD7A were only positive in the PMN group (51.2% and 4.9%, respectively) but negative in both control groups. The sensitivity of PLA2R and THSD7A for identifying PMN was 51.2% and 4.9%, respectively. The sensitivity of both tests together was 53.7% while the specificity and positive predictive values (PPV) for any of the tests (alone or in combination) was 100%. There was no difference in the sensitivity and specificity when using PLA2R alone compared to combining the two tests (p=0.32). Conclusion Glomerular staining of PLA2R and THSD7A could have potential diagnostic values in South Africans. This has implications on how immunotherapies can be initiated and used in these settings.

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Section: Comparison Of Pla2r Positive Pmn and Class V Lnmentioning

confidence: 88%

“…NELL-1 was present in 23% [29/126] of European PLA2R and THSD7A negative PMN patients while Semaphorin 3B was predominantly present in paediatric patients with MGN. [24,25].…”

Section: Comparison Of Pla2r Positive Pmn and Class V Lnmentioning

confidence: 99%

Diagnostic performance of glomerular PLA2R and THSD7A antibodies in biopsy confirmed primary membranous nephropathy in South Africans

Lwezaula

Ameh²,

Ekrikpo

et al. 2021

BMC Nephrol

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“…In a previous study, DKD was reported as the leading cause of death in patients with ESRD, followed by MN, with a 40% contribution to ESRD-related mortality [ 4 , 5 ]. Moreover, the limitation of proteinuria in the early diagnosis of DKD [ 6 , 7 ] and the lack of options for PLA2R-negative MN identification need to be addressed further [ 11 ]. Undoubtedly, the analysis of the intestinal-microbiota in this study provides new insight into the identification and classification of DKD and MN.…”

Section: Discussionmentioning

confidence: 99%

The gut microbiome in differential diagnosis of diabetic kidney disease and membranous nephropathy

Shang

Guo

et al. 2020

Renal Failure

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Background Diabetic kidney disease (DKD) and membranous nephropathy (MN) are the two major causes of end-stage renal disease (ESRD). Increasing evidence has shown that intestinal dysbiosis is associated with many diseases. The aim of this study was to explore the composition of the gut microbiome in DKD and MN patients. Methods 16S rRNA gene sequencing was performed on 271 fecal samples (DKD = 129 and MN = 142), and taxonomic annotation of microbial composition and function was completed. Results We observed distinct microbial communities between the two groups, with MN samples exhibiting more severe dysbiosis than DKD samples. Relative increases in genera producing short-chain fatty acids (SCFAs) in DKD and a higher proportion of potential pathogens in MN were the main contributors to the microbiome alterations in the two groups. Five-fold cross-validation was performed on a random forest model, and four operational taxonomic unit (OTU)-based microbial markers were selected to distinguish DKD from MN. The results showed 92.42% accuracy in the training set and 94.52% accuracy in the testing set, indicating high potential for these microbiome-based markers in separating MN from DKD. Overexpression of several amino acid metabolic pathways, carbohydrate metabolism and lipid metabolism was found in DKD, while interconversion of pentose/glucoronate and membrane transport in relation to ABC transporters and the phosphotransferase system were increased in MN. Conclusion The composition of the gut microbiome appears to differ considerably between patients with DKD and those with MN. Thus, microbiome-based markers could be used as an alternative tool to distinguish DKD and MN.

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“…7 The third novel antigen, not common but unique, was semaphorin 3B (Sema3B). 8 Lastly, protocadherin 7 (PCDH7), another novel antigen that was recently detected in PLA2Rnegative MN, 9 is the third most common novel protein, after EXT1/EXT2 and NELL1, in our MS/MS cohort of PLA2R-negative MN. Further studies are required to confirm the prevalence of these novel proteins and putative antigens in MN.…”

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confidence: 89%

New ‘Antigens’ in Membranous Nephropathy

Sethi

2020

JASN

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128

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Membranous nephropathy (MN) occurs due to deposition of immune complexes along the subepithelial region of glomerular basement membrane. Two previously identified target antigens for the immune complexes, PLA2R (identified in 2009) and THSD7A (in 2014), account for approximately 60% of all MN, both primary and secondary. In the remaining MN, target antigens were unknown. Use of laser microdissection and mass spectrometry enabled identification of new “antigens.” This approach led to the identification of four novel types of MN: exotosin 1 (EXT1)– and exotosin 2 (EXT2)–associated MN, NELL1-associated MN, Sema3B-associated MN, and PCDH7-associated MN. Each of these represents a distinct disease entity, with different clinical and pathologic findings. In this review, the structure of the proteins and the clinical and pathologic findings of the new types of MN are discussed. The role of mass spectrometry for accurate diagnosis of MN cannot be overemphasized. Finally, any classification of MN should be made on the basis of the antigens that are detected. Further studies are required to understand the pathophysiology, response to treatment, and outcomes of these new MNs.

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Semaphorin 3B–associated membranous nephropathy is a distinct type of disease predominantly present in pediatric patients

Cited by 151 publications

References 15 publications

Diagnostic performance of glomerular PLA2R and THSD7A antibodies in biopsy confirmed primary membranous nephropathy in South Africans

Diagnostic performance of glomerular PLA2R and THSD7A antibodies in biopsy confirmed primary membranous nephropathy in South Africans

The gut microbiome in differential diagnosis of diabetic kidney disease and membranous nephropathy

New ‘Antigens’ in Membranous Nephropathy

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