A study of pediatric patients with lupus nephritis found that abnormal sugar attachments on immunoglobulin G antibodies may disrupt kidney cell metabolism, leading to cell damage and reduced energy production.
These sugar modifications, known as glycosylation, differed in pediatric patients with active renal involvement compared with those who had systemic lupus erythematosus (SLE) without renal disease.
Researchers analyzed blood samples from 40 pediatric patients with SLE, including those with and without renal involvement. Using mass spectrometry, they found that the patients with lupus nephritis had distinct immunoglobulin G (IgG) glycan patterns.
To assess the impact of these antibodies, the team exposed podocytes—kidney cells essential for filtration—to IgG from three groups: patients with lupus nephritis, those with nonrenal lupus, and healthy controls. Podocytes treated with lupus nephritis IgG showed lower glycolytic activity, reduced adenosine triphosphate production, disrupted cytoskeletal structure, and decreased levels of nephrin, a key filtration protein.
Removing the abnormal sugars from the IgG reversed many of these effects. Podocytes exposed to deglycosylated IgG restored normal energy metabolism and structure. The researchers also found that lupus nephritis IgG increased intracellular calcium levels, which may contribute to further injury.
Metabolomics analysis identified five key glycolytic intermediates—pyruvate, phosphoenolpyruvate, 2-phosphoglycerate, 3-phosphoglycerate, and fructose 1,6-bisphosphate—that were altered in podocytes exposed to lupus nephritis IgG. Changes in these metabolites clustered around pyruvate kinase, a key enzyme in glycolysis. Consistent with these findings, patients with lupus nephritis had higher urinary levels of pyruvic acid and pyruvate kinase mRNA, suggesting potential biomarkers of renal involvement.
The study also evaluated IgG glycosylation prior to and following immunosuppressive treatment in 10 pediatric patients with lupus nephritis. Treatment reduced sialylated glycan levels and increased galactosylated glycans, particularly in patients who responded to therapy. One glycan chain, G9, remained elevated in nonresponders but decreased in responders.
The researchers concluded that IgG glycosylation may help differentiate patients with SLE and kidney disease from those without renal involvement and could serve as a tool to monitor treatment response or identify patients at risk for nephritis.
The research team used digital polymerase chain reaction, Seahorse metabolic analysis, and cell imaging to track the effects of IgG glycosylation on podocyte function. Their findings supported further studies on glycosylation as both a biomarker and a possible therapeutic target in lupus nephritis.
Full disclosures are available in the published study.
Source: Arthritis & Rheumatology
