Fumarate in membranous nephropathy: more questions than answers

A recent metabolomics study of urine in membranous nephropathy (MN) reports significant changes in 14 of 71 metabolites quantified by nuclear magnetic resonance, including 2-fold higher urinary fumarate in phospholipase A2 receptor–associated MN versus healthy controls. 1 Jo H.A. Hyeon J.S. Yang S.H. et al. Fumarate modulates phospholipase A2 receptor autoimmunity-induced podocyte injury in membranous nephropathy. Kidney Int. 2021; 99: 443-455 Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar This increase in urinary fumarate is attributed to the downregulation in podocytes of fumarate hydrase—the enzyme converting fumarate to malate—followed by a buildup in fumarate levels. However, alternative interpretations are possible. Supporting evidence from patients is limited to decreased fumarate hydrase staining in glomeruli from phospholipase A2 receptor–associated MN. However, net changes in fumarate levels also depend on other reactions producing or consuming this metabolite, not investigated in this study. Fumarate reacts with cysteine residues via Michael addition, forming a covalent adduct, 2-succinocysteine, that can be detected immunohistochemically. Aberrant protein succination provides a robust biomarker for high fumarate levels in fumarate hydrase deficiency. 2 Bardella C. El-Bahrawy M. Frizzell N. et al. Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status. J Pathol. 2011; 225: 4-11 Crossref PubMed Scopus (189) Google Scholar Immunostaining for 2-succinocysteine, which could have probed for high fumarate levels in podocytes from MN patients, was not performed. Fumarate modulates phospholipase A2 receptor autoimmunity-induced podocyte injury in membranous nephropathyKidney InternationalVol. 99Issue 2PreviewDownstream mechanisms that lead to podocyte injury following phospholipase A2 receptor (PLA2R) autoimmunity remain elusive. To help define this we compared urinary metabolomic profiles of patients with PLA2R-associated membranous nephropathy (MN) at the time of kidney biopsy with those of patients with minimal change disease (MCD) and to healthy individuals. Among the metabolites differentially expressed in patients with PLA2R-associated MN compared to healthy individuals, fumarate was the only significant differentially expressed metabolite in PLA2R-associated MN compared to MCD [fold-difference vs. Full-Text PDF The authors replyKidney InternationalVol. 100Issue 3PreviewWe appreciate the thoughtful letter from Dr. Borza.1 We agree with the critique that 2-succinocysteine staining would be informative to identify the source of the increased urinary fumarate in patients with phospholipase A2 receptor (PLA2R)–associated membranous nephropathy (MN). We also speculate that this increase might not entirely originate from the podocytes. However, we showed that the fumarate hydratase (FH) expression in the podocytes of patients with PLA2R-associated MN was attenuated compared with that of healthy and disease controls. Full-Text PDF