Intrinsic tumor necrosis factor-α pathway is activated in a subset of patients with focal segmental glomerulosclerosis

Chen Fang Chung, Thomas Kitzler, Nadezda Kachurina, Katarina Pessina, Sima Babayeva, Martin Bitzan, Frederic Kaskel, Ines Colmegna, Nada Alachkar, Paul Goodyer, Andrey V. Cybulsky, Elena Torban

Research output: Contribution to journalArticle

Abstract

Focal segmental glomerulosclerosis (FSGS) is frequently found in biopsies of patients with steroid resistant nephrotic syndrome (SRNS). The pathogenesis of SRNS/FSGS is often unknown and the disease will recur in up to 50% of patients post-transplant, indicating the presence of circulating podocyte-toxic factor(s). Several studies have reported clinical improvement after anti-TNFα therapy. However, prediction of the clinical outcome in SRNS/ FSGS is difficult, and novel predictive biomarkers are needed. An image-based assay, which measures disassembly of focal adhesion complexes in cultured podocytes, was used to ascertain the presence of podocyte toxic activity in SRNS/FSGS sera. Expression of TNFα pathway genes was analysed in the Nephroseq FSGS cohort and in cultured podocytes treated with SRNS/FSGS sera. Podocyte toxic activity was detected in 48/96 SRNS/ FSGS patients. It did not correlate with serum TNFα levels, age, sex, ethnicity or glomerular filtration rate. In ~25% of the toxic samples, the toxicity was strongly inhibited by blockade of TNFα signaling. Transcriptional profiling of human FSGS biopsies and podocytes treated with FSGS sera revealed significant increases in expression of TNFα pathway genes. We identified patients with serum podocyte toxic activity who may be at risk for FSGS recurrence, and those patients in whom serum podocyte toxicity may be reversed by TNFα blockade. Activation of TNFα pathway genes occurs in podocytes of FSGS patients suggesting a causative effect of this pathway in response to circulating factor(s). In vitro analyses of patient sera may stratify patients according to prognostic outcomes and potential responses to specific clinical interventions.

Original languageEnglish (US)
Article numbere0216426
JournalPloS one
Volume14
Issue number5
DOIs
StatePublished - May 1 2019

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Focal Segmental Glomerulosclerosis
tumor necrosis factors
nephrotic syndrome
Podocytes
Poisons
Tumor Necrosis Factor-alpha
Steroids
steroids
Nephrotic Syndrome
Biopsy
Genes
Serum
Toxicity
biopsy
Transplants
Biomarkers
toxicity
glomerular filtration rate
genes
Assays

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Chung, C. F., Kitzler, T., Kachurina, N., Pessina, K., Babayeva, S., Bitzan, M., ... Torban, E. (2019). Intrinsic tumor necrosis factor-α pathway is activated in a subset of patients with focal segmental glomerulosclerosis. PloS one, 14(5), [e0216426]. https://doi.org/10.1371/journal.pone.0216426

Intrinsic tumor necrosis factor-α pathway is activated in a subset of patients with focal segmental glomerulosclerosis. / Chung, Chen Fang; Kitzler, Thomas; Kachurina, Nadezda; Pessina, Katarina; Babayeva, Sima; Bitzan, Martin; Kaskel, Frederic; Colmegna, Ines; Alachkar, Nada; Goodyer, Paul; Cybulsky, Andrey V.; Torban, Elena.

In: PloS one, Vol. 14, No. 5, e0216426, 01.05.2019.

Research output: Contribution to journalArticle

Chung, CF, Kitzler, T, Kachurina, N, Pessina, K, Babayeva, S, Bitzan, M, Kaskel, F, Colmegna, I, Alachkar, N, Goodyer, P, Cybulsky, AV & Torban, E 2019, 'Intrinsic tumor necrosis factor-α pathway is activated in a subset of patients with focal segmental glomerulosclerosis', PloS one, vol. 14, no. 5, e0216426. https://doi.org/10.1371/journal.pone.0216426
Chung, Chen Fang ; Kitzler, Thomas ; Kachurina, Nadezda ; Pessina, Katarina ; Babayeva, Sima ; Bitzan, Martin ; Kaskel, Frederic ; Colmegna, Ines ; Alachkar, Nada ; Goodyer, Paul ; Cybulsky, Andrey V. ; Torban, Elena. / Intrinsic tumor necrosis factor-α pathway is activated in a subset of patients with focal segmental glomerulosclerosis. In: PloS one. 2019 ; Vol. 14, No. 5.
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AU - Babayeva, Sima

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AU - Kaskel, Frederic

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