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Abstract: TH-PO1008

The Role of Fumarate on the Outcomes of Membranous Nephropathy: Urine Metabolomics Analysis and Its Experimental Validation

Session Information

Category: Glomerular Diseases

  • 1203 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

  • Jo, Hyung Ah, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Korea (the Republic of)
  • Hyeon, Jin Seong, Korea Basic Science Intsitute, Seoul, Korea (the Republic of)
  • Jung, Youngae, Korea Basic Science Intsitute, Seoul, Korea (the Republic of)
  • Park, Minkyoung, Kidney Research Institute, Seoul National University, Seoul, Korea (the Republic of)
  • Yang, Seung Hee, Kidney Research Institute, Seoul National University, Seoul, Korea (the Republic of)
  • Kim, Dong Ki, Seoul National University Hospital, Jong ro Gu, SEOUL, Korea (the Republic of)
  • Hwang, Geum-Sook, Korea Basic Science Intsitute, Seoul, Korea (the Republic of)
Background

Anti-PLA2R antibody (PLA2R Ab) is a useful biomarker in membranous nephropathy (MN), however, the levels of PLA2R Ab do not always predict the prognosis or treatment response. There are need to seek additional biomarker to predict both of immunosuppressive agent response and renal prognosis. Also, it is not yet known how PLA2R Ab-antigen reaction causes the changes in podocytes and become a pathogenicity of MN. We aimed to figure out biomarkers predicting the prognosis and treatment response using metabolomics analysis of urine samples.

Methods

The nuclear magnetic resonance-based method was used to examine the urine samples at the time of kidney biopsy from patients with PLA2R-associated MN and minimal change disease (MCD). The negative control was urine samples from healthy controls.

Results

Metabolites significantly higher in PLA2R-associated MN than healthy controls were fumarate, choline, mannitol, isoleucine, glucose, valine, leucine, tyrosine, and betaine. Fumarate was the only differential metabolite in PLA2R-associated MN compared with MCD. PLA2R-associated MN patients with high urine fumarate levels had a greater risk of composite renal outcome and lower likelihood of having treatment response and achieving remission. The in-vitro validation study was performed using primary cultured human podocytes treated with IgG purified from a patient with PLA2R-associated MN (MN IgG). PLA2R Ab-antigen interaction in MN IgG stimulated podocytes was confirmed and further identified increased the expression of both fibronectin and Snail, despite decreased fumarate hydratase, WT-1, and ZO-1 expression. Lentivirus-mediated fumarate hydratase activation showed improvement of fumarate hydratase, WT-1 and ZO-1, and attenuation of expression in fibronectin and Snail. Albumin permeability test confirmed that absorbance of albumin was increased in podocytes after activation of MN IgG. The fluorescence intensity of ZO-1 was decreased in podocytes by stimulation of MN IgG. Albumin absorbance and fluorescence intensity of ZO-1 in podocytes were reversed by activation of fumarate hydratase.

Conclusion

These findings suggest that fumarate might play an important role in the progression and disease activity of PLA2R-associated MN via the regulation of podocyte integrity and renal fibrosis.