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

Pediatr Nephrol. 2012 Dec;27(12):2217-26. doi: 10.1007/s00467-012-2163-3. Epub 2012 Apr 27.

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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