Abstract: FR-PO0695
Circulating Lipid Metabolites Exacerbate Progression via Podocyte Injury in FSGS
Session Information
- Pediatric Nephrology: CKD, ESKD, and Glomerular Diseases
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pediatric Nephrology
- 1900 Pediatric Nephrology
Authors
- Humphrey, Jacob A., Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
- Wilson, Landon Shay, University of Alabama at Birmingham Health System, Birmingham, Alabama, United States
- Krallman, Kelli A., Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
- Moritz, Michael L., Akron Children's Hospital, Akron, Ohio, United States
- Zaritsky, Joshua, Phoenix Children's Hospital, Phoenix, Arizona, United States
- Erkan, Elif, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
Background
Focal Segmental Glomerulosclerosis (FSGS) is one of the most challenging diseases in nephrology because of its resistance to treatment and rapid progression to end stage kidney disease. We hypothesize that circulating lipid products augment cardiovascular morbidity and progression in FSGS.
Methods
Patients undergoing LDL-pheresis for primary or recurrent FSGS after kidney transplantation were enrolled to the study. Atherogenic lipid metabolites Lp-PLA2 and ox LDL were collected pre and post-treatment. Effluent collected with LDL-pheresis treatments were processed by untargeted lipidomics in collaboration with University of Alabama metabolomics laboratory.
Immortalized human podocytes were incubated with effluent for 24 hours. Nephrin expression and cytoskeletal changes were examined with western blotting and immunofluorescence staining under confocal microscopy.
Results
Patients with FSGS had high oxLDLlevels at baseline. Serum OxLDL level reduced from 94.7 ±15.3 u/L to 78.6 ±11.4 u/L (p = 0.019) post treatment. Lp-PLA2 showed a trend towards reduction from 173.6 ±36.8 ng/mL to 117.9 ±15.7 ng/mL (p = 0.07). LDL pheresis lead to an improvement in urine protein concentration from 10.3 ±2.5 mg/mg to 5.7 ±1.8 mg/mg (p = 0.005). 4/10 patients achieved either remission or partial remission.
Lipidomic analysis of LDL-pheresis effluents revealed high concentrations of hexosylceramide(HexCer), sphingomyelin (SM), phosphotidylcholine (PC)and phosphotidylethanolamine(PE) levels in patients with primary FSGS where as patients with recurrence of FSGS had elevated levels of saturated free fatty acids (FFA 18:0,16:0 and 12:0). Furthermore exposure of podocytes to effluent resulted in decreased nephrin expression and cytoskeletal derangements.
Conclusion
Patients with primary and post transplant FSGS recurrence have significant dysregulation of lipid metabolism resulting in elevated serum levels of atherogenic lipid metabolites. Analysis of LDL-pheresis effluent revealed an unconventional lipid metabolite profile that sheds light to mechanism of progression in FSGS. We propose that increased serum levels of hexCer, SM, PC and PE can perpetuate podocyte injury, proteinuria and progression by causing mitochondria, ER stress and subsequent apoptosis. Increased effluent concentration of saturated FFA can potentiate cardiovascular morbidities.
Funding
- NIDDK Support