Assistant Professor Donald and Barbara Zucker School of Medicine at Hofstra/Northwell New Hyde Park, New York, United States
Background: Focal segmental glomerulosclerosis (FSGS) accounts for approximately 20% of cases of pediatric nephrotic syndrome and is the leading cause of end-stage renal disease among glomerular disorders in the US. Primary FSGS is thought to be caused by a circulating factor which causes podocyte, glomerular and endothelial injury, and presumably immune dysregulation. There is growing evidence that the JAK/STAT pathway is involved in various kidney diseases, however, its role in FSGS has not been thoroughly studied. We recently identified JAK1 gain-of-function mutation in a pediatric patient with membranous nephropathy and multisystem immune dysregulation, which was successfully treated with a JAK inhibitor. Objective: We hypothesized that JAK/STAT pathway hyperactivity may play a role in the pathogenesis of pediatric primary FSGS, and may be suppressed by ex vivo JAK inhibition. Design/Methods: We recruited eleven individuals age 2-18yr with primary FSGS and ten age- and sex-matched healthy controls. Mass cytometry (CyTOF) with antibodies against STAT proteins was performed on heparinized whole blood samples to characterize JAK/STAT pathway activity in immune cell subsets. Multiplex immunoassay was performed on plasma samples to quantify circulating cytokine levels. Plasma from patients were added to healthy control peripheral blood mononuclear cells (PBMCs) and treated with or without tofacitinib for 4 hours, followed by CyTOF. Results: The JAK/STAT pathway is overactive in 60% patients despite immunosuppression, predominantly showing increased phosphorylated STAT3 (pSTAT3) activity in T cell subsets. The level of STAT3 phosphorylation in T cells predicts lower kidney function, lower serum albumin, and increased proteinuria 1 year later. IL6 and IL17 which stimulate STAT3 phosphorylation are increased in patient plasma. Tofacitinib treatment of healthy control PBMCs incubated with patient plasma leads to reduction in pSTAT3 activity in T cell subsets, particularly in CD4+ T cells.
Conclusion(s): JAK/STAT pathway overactivity is present in pediatric patients with primary FSGS and predicts future severity of disease. JAK/STAT hyperactivity is likely driven by cytokine signaling and may be targeted by JAK inhibition.
