Clinical InvestigationFumarate modulates phospholipase A2 receptor autoimmunity-induced podocyte injury in membranous nephropathy
Graphical abstract
Section snippets
Baseline characteristics
The baseline characteristics of the study subjects at the time of kidney biopsy are presented in Table 1. No subjects received immunosuppressants at baseline. The median age of the PLA2R-associated MN group was 57 years, and 66.1% of the patients were male. The median anti-PLA2R titer was 126 RU/ml (interquartile range [IQR]: 21–221), and the median follow-up duration was 1067 days (IQR: 522–1659 days) in the PLA2R-associated MN group.
Differentially expressed metabolites in urine samples at the time of kidney biopsy
Each nuclear magnetic resonance (NMR) peak of 71 metabolites
Discussion
The pathologic mechanism that leads to podocyte injury downstream of PLA2R autoimmunity is clinically important because it may be a potential therapeutic target for MN, given that a significant proportion of patients do not respond to immunosuppressive treatment.17,18 We demonstrated that urinary, but not serum, levels of fumarate were differentially expressed in PLA2R-associated MN. This finding remained consistent even after exclusion of the diabetes patients, which was shown to be associated
Study subjects and specimens
This study was conducted according to the Declaration of Helsinki and was approved by the institutional review board of Seoul National University Hospital, Seoul, Korea (H-1601-076-734). The human biospecimens of the study subjects were provided by the National Biobank of Korea.34
The diagnostic algorithm of MN is described in Supplementary Figure S10. PLA2R-associated MN was defined as having positive serum anti-PLA2R antibodies or glomerular PLA2R antigens.35 The serum anti-PLA2R level was
Disclosure
All the authors declared no competing interests.
Acknowledgments
This work was supported by the Industrial Strategic Technology Development Program - Development of bio-core technology (10077474, Development of early diagnosis technology for acute/chronic renal failure) funded by the Ministry of Trade, Industry & Energy (MOTIE, Korea) and the Korea Basic Science Institute (C060200).
Author Contributions
DKK and GSH designed the study. DKK, GSH, HAJ, JSH, and SHY participated in the conception of the study. HAJ, SHY, CWJ, CK, YK, HL, JPL, KWJ, YSK, and DKK participated in the
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2022, Autoimmunity ReviewsCitation Excerpt :In vitro studies have shown that anti-PLA2R1 IgG4 can activate the complement lectin pathway in a glycosylation-dependent manner, leading to podocyte injury [29]. Anti-PLA2R1 IgG4 also reduces the level of fumarate hydrase, leading to the accumulation of fumarate and thus damaging podocytes [30]. Moreover, serum from MN patients with anti-PLA2R1 IgG directly interferes with cell adhesion to type IV collagen in a complement-independent manner [31].
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HAJ, JSH, and SHY contributed equally to this work.