Abstract: FR-PO0800
Glomerular Hyposialylation in Kidney Biopsies: Potential Biomarker for Assessing Innovative Therapies in Proteinuric Kidney Diseases
Session Information
- Glomerular Diseases: Cell Homeostasis and Novel Injury Mechanisms
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Ganguli, Anirban, National Institute of Diabetes and Digestive and Kidney Diseases Division of Intramural Research, Bethesda, Maryland, United States
- Leoyklang, Petcharat, National Human Genome Research Institute Undiagnosed Diseases Program, Bethesda, Maryland, United States
- Bolanos, Jonathan Alexis, National Institute of Diabetes and Digestive and Kidney Diseases Division of Intramural Research, Bethesda, Maryland, United States
- Malicdan, May Christine, National Human Genome Research Institute Undiagnosed Diseases Program, Bethesda, Maryland, United States
- Gahl, William, National Human Genome Research Institute Undiagnosed Diseases Program, Bethesda, Maryland, United States
- Huizing, Marjan, National Human Genome Research Institute, Bethesda, Maryland, United States
Background
Terminal sialic acid (SA) residues on podocyte proteins like nephrin and podocalyxin help preserve podocyte foot-process architecture and the charge-selective glomerular filtration barrier. Loss of SA can lead to podocytopathy, as shown in genetic models (e.g., GNE-deficient mice) or via neuraminidase and toxins (adriamycin, streptozotocin, puromycin aminonucleoside). Oral N-acetylmannosamine (ManNAc), an SA precursor, reversed these effects. Detecting hyposialylation in human glomerular disease may enable safer, targeted therapeutic strategies.
Methods
Glomerular sialylation was assessed by lectin histochemistry, using the sialylation-defining lectins Sambucus Nigra Agglutinin (SNA; binds sialylated proteins) and Helix Pomatia Agglutinin (HPA; binds de-sialylated proteins) and confocal imaging in kidney biopsies of 111 well-phenotyped subjects supplied by the Nephrotic Syndrome Study Network (NEPTUNE), including minimal change disease (MCD; 29 subjects), focal segmental glomerulosclerosis (FSGS; 59 subjects), and/or membranous nephropathy (MN; 23 subjects).
Results
Glomerular hyposialylation was detected in 63% of renal biopsies across all three disease entities, indicating that this condition may occur frequently, remains greatly unexplored and, importantly, may be treatable. These findings prompted the initiation of a first-in-class, Phase-1 clinical trial (NCT02639260), evaluating oral ManNAc in the treatment of podocytopathies. In this trial, 1.5 g of ManNAc given twice daily to 6 patients was found to be safe, well tolerated, and resulted in increased plasma sialic acid, with 5 patients showing 26-54% urine protein-creatinine ratio (UPCR) reduction correlated with extent of hyposialylation, noted on pre-treatment kidney biopsies. We are currently performing an open-label Phase 2 clinical trial (NCT06664814) to evaluate the effect of 12-weeks of oral ManNAc on proteinuria, kidney function, safety, and tolerability in FSGS patients.
Conclusion
Collectively, lectin histochemistry reveals that glomerular hyposialylation is quite common in primary glomerular diseases. This lends support to the potential use of tissue re-sialylation therapies like ManNAc, in restoring podocyte integrity and, thereby, mitigating proteinuria associated kidney disease.
Funding
- Other NIH Support