Abstract: TH-OR076
Kidney and Immune STAT3 Targets Drive Severity in FSGS and Minimal Change Disease: A NEPTUNE/CureGN Study
Session Information
- Glomerular Diseases: Novel Mechanisms of Injury
October 22, 2026 | Location: Room 401, Convention Center
Abstract Time: 05:00 PM - 05:10 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Shen, Carol L., Cohen Children's Medical Center, New York, New York, United States
- Kumar, Kashish, Columbia University, New York, New York, United States
- Eddy, Sean, University of Michigan, Ann Arbor, Michigan, United States
- Karan, Meghana, Cohen Children's Medical Center, New York, New York, United States
- Schuchman, Matthew, University of Michigan, Ann Arbor, Michigan, United States
- Hartman, John R., University of Michigan, Ann Arbor, Michigan, United States
- Fermin, Damian, University of Michigan, Ann Arbor, Michigan, United States
- Eichinger, Felix H., University of Michigan, Ann Arbor, Michigan, United States
- Basalely, Abby Miriam, Cohen Children's Medical Center, New York, New York, United States
- Castellanos, Laura J., Cohen Children's Medical Center, New York, New York, United States
- Sethna, Christine B., Cohen Children's Medical Center, New York, New York, United States
- Lai Yee, Jennifer, University of Michigan, Ann Arbor, Michigan, United States
Background
There are no targeted therapies for focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD). In vivo, tubular and podocyte STAT3 promotes interstitial fibrosis. We found hyperactive peripheral T-cell STAT3 in severe FSGS. STAT3's role in immuno-pathogenesis of FSGS/MCD is poorly understood. We aim to determine the impact of kidney and humoral STAT3 on FSGS/MCD outcomes, dissect cell-type specific STAT3 functions, and identify STAT3 biomarkers.
Methods
Patients with FSGS or MCD with glomerular (glom) and tubulointerstitial (TI) biopsy RNASeq (NEPTUNE n=173) and whole blood RNASeq (CureGN n=1012) were included. STAT3 score was calculated from mean Z-score (mZ) of 13 known target genes. Robust Linear Model (RLM) associated mZ with clinical variables. Cox regression associated mZ with 40% eGFR decline/ESKD adjusting for age, sex and APOL1. MuSiC deconvolution inferred cell-type specific expression. Urine and plasma SOMAscan biomarkers correlated with mZ by adjusted RLM.
Results
In kidney, glom and TI mZ were higher in FSGS vs MCD and in APOL1 high-risk (HR) vs low-risk (LR)(Table 1). Elevated TI mZ independently predicted higher risk of ESKD/40% eGFR decline (aHR 2.7[1.17–6.32])(Fig 1). Deconvolution of RNASeq revealed enriched Glom and TI mZ in fibroblast, myeloid, mesangial and endothelial cells. Conversely, high blood mZ was enriched in B, T cells and neutrophils and predicted lower risk of ESKD/40% eGFR decline (aHR 0.86[0.76-0.98]). Urine TIMP1 and plasma IL9 positively correlated with TI STAT3 mZ (p<0.05).
Conclusion
Kidney STAT3 mZ correlated with fibrosis and ESKD risk in FSGS and MCD, whereas immune-driven STAT3 activity correlated with more favorable prognosis. Plasma IL9 and urine TIMP1 are candidate biomarkers. JAK/STAT3 is a potential therapeutic target in FSGS/MCD.
Acknowledgment
This project is supported by the NephCure/PNRC Pediatric Glomerular Disease Accelerator Grant Project (NKI-PNRC 2024-03-A/B) CureGN Funding: U24DK100845, U01DK100846, U01DK100866 and U01DK100867 from the NIDDK. The Nephrotic Syndrome Study Network (NEPTUNE) is part of the Rare Diseases Clinical Research Network (RDCRN) and funded by the National Center for Advancing Translational Sciences (NCATS) and the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) (U54DK083912).
| mZ | FSGS | MCD | p-value |
| Glom | 0.13 | -0.12 | <0.01 |
| TI | 0.06 | -0.21 | <0.01 |
| APOL1 High-Risk | APOL1 Low-Risk | ||
| Glom | 0.14 | -0.07 | <0.01 |
| TI | 0.27 | -0.14 | 0.01 |
Funding
- NIDDK Support