507 - Enhanced CD4+ T Cell STAT3 Activity Drives Disease Severity in Focal Segmental Glomerulosclerosis and Minimal Change Disease: A NEPTUNE Study

Publication Number: 2493.507

Carol L. Shen, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, NY, United States; Kashish Kumar, Columbia University, New York, NY, United States; Sean Eddy, University of Michigan Medical School, Ann Arbor, MI, United States; Meghana Karan, Cohen Children's Medical Center, New Hyde Park, NY, United States; Matthew Schuchman, Cohen Children's Medical Center, New Hyde Park, NY, United States; John Hartman, University of Michigan, Ann Arbor, MI, United States; Felix Eichinger, University of Michigan Medical School, Ann Arbor, MI, United States; Mahie Abdullah, Cohen Children's Medical Center, New Hyde Park, NY, United States; Suzanne Vento, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, NY, United States; Abby M. Basalely, Cohen Children's Medical Center, NEW HYDE PARK, NY, United States; Laura Castellanos, Cohen Children's Medical Center, New Hyde Park, NY, United States; Pamela Singer, Cohen Children's Medical Center, Cedarhurst, NY, United States; Christine Sethna, Cohen Children's Medical Center, New Hyde Park, NY, United States; Jennifer Yee, University of Michigan, Ann Arbor, MI, United States

Background: Proteinuric glomerulopathies such as focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) are major causes of end stage kidney disease (ESKD), yet lack targeted therapies. The JAK/STAT pathway is involved in inflammation and autoimmunity and may play a role in progressive kidney diseases. Prior transcriptomic studies revealed STAT1 overactivation linked to APOL1 expression in FSGS, while our group described increased T-cell STAT3 activation in children with FSGS with severe disease. Thus, dysregulated JAK/STAT3 immune regulation may directly impact kidney tissue and contribute to poor outcomes in certain individuals with FSGS and MCD.

Objective: We aim to determine the impact of JAK/STAT3 pathway activity on long-term kidney outcomes, to investigate the contribution of APOL1 to the JAK/STAT3 pathway, and to identify urinary biomarkers of JAK/STAT3 pathway in FSGS and MCD.

Design/Methods: Patients with FSGS and MCD (n=180) with kidney biopsy tissue RNASeq data in the NEPTUNE study were included. We derived a CD4⁺ T cell–specific STAT3 target gene set to calculate a STAT3 transcriptional score from kidney biopsy RNA-seq data. STAT3 scores were compared between patients vs controls and stratified by number of APOL1 risk alleles. Linear regression assessed associations between STAT3 score, baseline eGFR and urine protein/creatinine ratio (UPCR), while Cox regression evaluated its relation to time to 40% eGFR decline or ESKD. Urine biomarkers were quantified by Somascan proteomic assay, and unsupervised clustering identified the biomarkers correlating with the STAT3 score.

Results: STAT3 scores were similar across FSGS, MCD, and controls but significantly higher in the tubulointerstitial (TI) compartment of APOL1 high-risk (HR) patients (p < 0.01 vs low-risk; p< 0.01 vs controls). Both glomerular and TI STAT3 scores correlated with lower baseline eGFR and higher UPCR (adjusted for APOL1 status), and higher TI STAT3 scores predicted shorter time to ESKD or 40% eGFR decline (adjusted HR 2.4 [1.1–5.2], log rank p=0.01). Urine TIMP1 correlated with higher TI STAT3 score, lower BL eGFR, and higher UPCR (all p< 0.01), adjusting for APOL1 status.

Conclusion(s): In FSGS and MCD, CD4⁺ T-cell and renal STAT3 activation correlate with the APOL1 high-risk genotype. Independent of APOL1 status, STAT3 activation is also linked to worse kidney outcomes, with TIMP1 as a potential urinary biomarker. The JAK/STAT3 pathway is a potential target for treatment in at-risk individuals with FSGS and MCD.