Cytokine-Driven Janus Kinase Signal Transducer and Activator of Transcription (JAK/STAT) Pathway Hyperactivity Predicts Disease Severity in Pediatric Focal Segmental Glomerulosclerosis

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Background: Focal segmental glomerulosclerosis (FSGS) accounts for approximately 20% of cases of pediatric nephrotic syndrome and is the leading cause of end-stage kidney 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 immune dysregulation. There is growing evidence that the Janus kinase signal transducer and activator of transcription (JAK/STAT) immunoregulatory 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. We hypothesized that JAK/STAT pathway hyperactivity may play a role in the pathogenesis of pediatric primary FSGS, and may correlate with worse clinical outcomes.

Methods: We recruited eleven individuals aged 2-18 years 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. Unsupervised clustering by machine learning algorithms and statistical analyses were performed to determine clinically relevant patterns.

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. Various cytokines upstream of STAT3 phosphorylation are increased in patient plasma.

Conclusions: JAK/STAT pathway overactivity is present in pediatric patients with primary FSGS and predicts severity of disease. JAK/STAT hyperactivity is likely driven by cytokine signaling and may be targeted by JAK inhibition.