Enhanced T Cell STAT3 Activity Drives Disease Severity in APOL1-Associated FSGS and Minimal Change Disease

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Background: Proteinuric glomerulopathies such as focal segmental glomeruloserosis (FSGS) and minimal change disease (MCD) are major causes of end-stage kidney disease (ESKD), yet lack targeted treatments due to limited understanding of immune mechanisms. Interest is growing in the JAK/STAT immune pathway, particularly its activation in APOL1 high-risk (HR) FSGS. Baricitinib, a JAK1/2 inhibitor, is in clinical trials for APOL1 HR FSGS. Despite evidence of JAK/STAT dysregulation, no targeted therapies are approved. Clarifying the role of this pathway and its link to APOL1 could enable targeted treatments in FSGS and MCD. Methods: We included adults and children with FSGS and MCD (n=221) from the NEPTUNE cohort with available tissue RNAseq data. A STAT3 activation score was derived from known T-cell target genes and compared across glomerular (GM) and tubulointerstitium (TI) compartments in FSGS, MCD, and healthy donors. Linear regression adjusted for APOL1 HR (i.e. presence of 2 HR alleles), age, sex and diagnosis and assessed associations with baseline eGFR and urine protein/creatinine ratio (UPCR). Log-rank tests and adjusted Cox models evaluated the impact of STAT3 activation on time to progression to ESKD/40% eGFR decline. Results: STAT3 scores did not differ among participants with FSGS, MCD and healthy controls. However, scores were significantly higher in the TI of participants with APOL1 HR (Z=0.26 [95% CI 0.09–0.45]) compared to non-HR APOL1 (Z=-0.14 [-0.20 to -0.07]) and controls (Z=-0.14 [-0.27 to -0.01]), with no difference in GM. Adjusted STAT3 scores correlated with lower baseline eGFR in GM and TI (p=0.027, p<0.001) and higher baseline UPCR in TI only (p=0.049). Individuals with higher STAT3 scores in TI had faster progression to ESKD/40% eGFR decline (p=0.011) with an adjusted hazard ratio of 2.45 [95% CI 1.14-5.23], whereas stratifying by APOL1 HR reduced the effect (p=0.054). Conclusion: In FSGS and MCD, T-cell STAT3 activation particularly in TI is linked to the APOL1 HR genotype and correlates with lower eGFR, higher UPCR, and faster progression to ESKD or eGFR decline. Further research is needed to explore the STAT3–APOL1 interaction in proteinuric glomerulopathies. Funding: Private Foundation Support

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