TNFα pathway blockade ameliorates toxic effects of FSGS plasma on podocyte cytoskeleton and β3 integrin activation.

Abstract

BACKGROUND:

In the absence of mutant genes encoding components of the podocyte slit diaphragm, about 30-50 % of children with primary glucocorticoid-resistant focal segmental glomerulosclerosis (FSGS) develop recurrent proteinuria and slowly progressive FSGS lesions following renal transplantation. Recurrence of FSGS in the allograft strongly suggests a circulating factor that disturbs normal podocyte biology. To date, the nature of the circulating factor is unclear, and there is no cure for the recurrent form of FSGS (R-FSGS).

METHODS:

Cultured differentiated human podocytes were exposed to the plasmapheresis effluent or blood plasma samples from pediatric patients with recurrent or primary FSGS; in some cases, podocytes were pre-incubated with specific antibodies to block the tumor necrosis factor-alpha (TNFα) signaling pathway. Integrity of focal adhesion complexes and actin cytoskeleton were investigated by immunofluorescent microscopy.

RESULTS:

Plasmapheresis effluent from an R-FSGS child or fresh plasma from two children with primary FSGS rapidly disturbed the cytoskeleton of normal human podocytes in vitro. Plasma from a child with R-FSGS also activated β3 integrin and dispersed focal adhesion complexes. The effects were reversed by pre-incubation with antibodies against TNFα or either of the two TNFα receptors. When our patient with R-FSGS became resistant to plasmapheresis, we initiated treatment with twice weekly etanercept injections and then infliximab. Within 3 weeks of regular anti-TNFα therapy, the patient achieved sustained partial remission of proteinuria, allowing us to wean her off plasmapheresis completely.

CONCLUSIONS:

We suggest that in some FSGS patients, disruption of the podocyte cytoskeleton and β3 integrin-mediated podocyte attachment are driven by the TNFα pathway.

• Authors: Martin Bitzan, Sima Babayeva, Anil Vasudevan, Paul Goodyer, Elena Torban
• Journal: Pediatric nephrology (Berlin, Germany) (Pediatr Nephrol) Vol. 27 Issue 12 Pg. 2217-26 (Dec 2012) ISSN: 1432-198X [Electronic] Germany
• PMID: 22538781 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Immunoglobulin G
• Integrin beta3
• Receptors, Tumor Necrosis Factor
• Tumor Necrosis Factor-alpha
• Infliximab
• Etanercept

Topics

• Adolescent
• Antibodies, Monoclonal (therapeutic use)
• Cells, Cultured
• Child
• Cytoskeleton (pathology)
• Etanercept
• Female
• Glomerulosclerosis, Focal Segmental (blood, pathology, therapy)
• Humans
• Immunoglobulin G (therapeutic use)
• Infliximab
• Integrin beta3 (metabolism)
• Kidney Transplantation
• Microscopy, Fluorescence
• Plasma
• Plasmapheresis
• Podocytes (metabolism, pathology)
• Receptors, Tumor Necrosis Factor (therapeutic use)
• Tumor Necrosis Factor-alpha (metabolism)