Association of Glomerular JAK/STAT Activity with APOL1 Expression, Kidney Function, and Outcomes in Patients from NEPTUNE

Background: The JAK/STAT pathway was previously reported as elevated in kidneys of patients with FSGS and IgA nephropathy (Tao, et al., 2018, Tao et al, 2020). The pathway is implicated in the regulation of APOL1 which is a risk factor for kidney diseases, especially FSGS. We examined the association of a gene expression-based JAK/STAT activity score with baseline kidney function, outcome, the effects of APOL1 high risk, and N264K variant status on the score. Methods: A 16-gene JAK-STAT activity score was computed using mean z-scores of the network genes in patients with glomerular gene expression data. The scores were correlated with log2eGFR (CKD-Epi) and urine protein to creatine ratio (log2UPCR) by Pearson correlation. A median value was used to stratify patients into high JAK/STAT activity and low JAK/STAT activity for the survival analysis with both complete remission and composite endpoint (ESRD or 40% loss of eGFR). Results: The glomerular JAK/STAT score is significantly correlated with log2 eGFR at baseline and (r = -0.25, p = 6.5 x 10-5) was associated with complete remission (p = 0.019). It is also strongly correlated with APOL1 mRNA abundance (r = 0.63, p = 2.2 x 10-16). The correlation with APOL1 becomes stronger in FSGS patients (r = 0.69, p = 1.3 x 10-14) and in patients with APOL1 high risk status (r = 0.74, p = 5.4 x 10-5). Conclusion: The JAK/STAT activity score was strongly correlated with APOL1 mRNA abundance across NEPTUNE and within patients with FSGS and its association with a longer time to complete remission across the cohort underlies its importance in glomerular disease, and in FSGS and APOL1-mediated kidney disease in particular. More investigation is needed to understand the effects of APOL1 high risk and N264K variants on this pathway. Funding: NIDDK Support