Abstract: PUB202
Correlating FSGS Recurrence with Disease-Induced Alterations in Albumin Structure and Factor Binding
Session Information
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Giusti, Sixto G., University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, United States
- Rodriguez, Ivan E, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, United States
- Dougherty, Julie, Nationwide Children's Hospital, Columbus, Ohio, United States
- Hashemi Haeri, Haleh, Martin Luther University Halle-Wittenberg, Halle, Germany
- Racke, Caroline A, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, United States
- Hoyer, Peter F., University Hospital Essen, Essen, Germany
- Kaplan, Bruce, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, United States
- Hinderberger, Dariush, Martin Luther University Halle-Wittenberg, Halle, Germany
- Smoyer, William E., Nationwide Children's Hospital, Columbus, Ohio, United States
Background
Primary FSGS (pFSGS) is a major cause of ESKD. Unknown circulating factors (CF) are thought to cause disease progression as well as recurrence after kidney transplant (KT). Given its morbidity and poorly understood pathogenesis, FSGS and its recurrence (rFSGS) represent a significant clinical and economic burden in need of more effective treatments. We previously reported profound changes in the functional structure and dynamics of albumin in nephrotic syndrome. We hypothesized that the albumin molecule, modified by either bound factors or changes in its shape, charge, or binding properties, may represent the CF of rFSGS.
Methods
6 patients (median 34 y) with pFSGS and at least 1 recurrence had sera samples analyzed (Pre-KT, 1-month and 3-months Post-KT) with healthy adult sera as controls. Labeled fatty acid (FA) probes were used alongside dynamic and electrophoretic light scattering to inspect albumin’s size and effective surface charge, and electron paramagnetic resonance spectroscopy to characterize its binding behavior.
Results
All rFSGS pre-KT albumin analyses revealed notable deviations in FA binding vs. controls and compared among each other, indicating that rFSGS patients have a differential albumin conformation and/or FA binding behavior, potentially indicating an albumin-bound CF or posttranslational modification of albumin itself. Post-KT, the FA binding behavior is more homogeneous and more closely resembles native albumin behavior, and further changes with time post-KT are observed.
Conclusion
This proof-of-concept study suggests that albumin-bound CF or physical changes in albumin structure, shape, or charge play a role in the pathogenesis of rFSGS, potentially making the albumin molecule “toxic”. Moreover, by binding albumin, physically or chemically, CF may elude standard proteomic assays which discard highly abundant proteins prior to analysis. Pre and post-KT albumin seems strongly different in their functional structure. Further confirmation of rFSGS-induced alterations in albumin structure, charge, shape, or CF-binding may enable “detoxifying” the albumin molecule itself via reversal of these modifications or removal of CFs to treat rFSGS.