Prevalence of neural epidermal growth factor-like 1- and exostosin 1/exostosin 2-associated membranous nephropathy: a single-center retrospective study in Japan

Abstract

Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. We previously reported that the prevalence of phospholipase A2 receptor (PLA2R)- and thrombospondin type 1 domain containing 7A (THSD7A)-associated MN patients in Japan is 52.7% and 9.1%, respectively. In addition to PLA2R and THSD7A, we assessed the presence of newly discovered target antigens, neural epidermal growth factor-like 1 (NELL-1), semaphorin 3B (SEMA3B), and exostosin 1/exostosin 2 (Ext1/Ext2), in renal specimens from patients with primary and secondary MN by immunohistochemistry. We found enhanced glomerular staining of PLA2R, THSD7A, NELL-1, and Ext1/Ext2 in 53.6%, 8.7%, 1.5%, and 13.0% of the renal samples, respectively, in patients with primary MN. None of the patient specimens showed enhanced staining of SEMA3B. Enhanced glomerular staining of PLA2R, NELL-1, and Ext1/Ext2 was detected in 5.7%, 8.6%, and 22.9% of the patients with secondary MN, respectively. Based on our findings, we recommend the assessment of PLA2R, THSD7A and NELL-1 in addition to clinical information and IgG4 staining to differentiate between primary and secondary MN. This would aid in distinguishing secondary MN patients from primary MN patients who coincidentally have some secondary characteristics.

Analysis of the Expression of Exostosins and Clinicopathological Features in Membranous Lupus Nephritis in a Chinese Cohort

“…Recently, the deposition of EXT1/EXT2 in LMN glomeruli have been validated in a few studies [2][3][4][5][6] . We confirmed that a subset of LMN patients was positive for EXT1/EXT2 in a Chinese cohort and the ratios of EXT-positive among combined and pure LMN were similar to studies by Ravindran et al and Saïdi et al 2,4 .…”

The Many Faces of NELL1 MN

“…NELL1 in primary MN: Most cases of NELL1 MN do not have an underlying associated disease [ 8 , 15 , 16 ]. In these cases, the kidney biopsy does not show any secondary features (although IgG1 might be the dominant IgG subtype), but importantly, there is no underlying disease association.…”

Bucillamine use for rheumatoid arthritis and type 2 diabetes mellitus are associated with neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy

“…The frequency of PLA2R-associated MN among primary MN cases in Japan was reported to be about 53%, which is considerably less frequent than in Europe, US, or China 16,17 . The frequency of PLA2R-associated MN in our MN cohort was slightly lower than the previously reported frequency of PLA2R-associated MN in primary MN cases in Japan.…”

“…To our knowledge, no association between rheumatic diseases or BUC use and NELL1-associated MN has been reported, which led us to plan the next RA-MN cohort. It should be added that there was a recent report from Japan that 2 out of 4 patients with NELL1-associated MN were RA patients 17 .…”