A zebrafish model for uremic toxicity: Role of the complement pathway

Nathaniel Berman, Melisa Lectura, Joshua M. Thurman, James Reinecke, Amanda C. Raff, Michal L. Melamed, Zhe Quan, Todd Evans, Timothy W. Meyer, Thomas H. Hostetter

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Many organic solutes accumulate in end-stage renal disease (ESRD) and some are poorly removed with urea-based prescriptions for hemodialysis. However, their toxicities have been difficult to assess. We have employed an animal model, the zebrafish embryo, to test the toxicity of uremic serum compared to control. Serum was obtained from stable ESRD patients predialysis or from normal subjects. Zebrafish embryos 24 h postfertilization were exposed to experimental media at a water:human serum ratio of 3:1. Those exposed to serum from uremic subjects had significantly reduced survival at 8 h (19 ± 18 vs. 94 ± 6%, p < 0.05, uremic serum vs. control, respectively). Embryos exposed to serum from ESRD subjects fractionated at 50 kDa showed significantly greater toxicity with the larger molecular weight fraction (83 ± 11 vs. 7 ± 17% survival, p < 0.05, <50 vs. >50 kDa, respectively). Heating serum abrogated its toxicity. EDTA, a potent inhibitor of complement by virtue of calcium chelation, reduced the toxicity of uremic serum compared to untreated uremic serum (96 ± 5 vs. 28 ± 20% survival, p < 0.016, chelated vs. nonchelated serum, respectively). Anti-factor B, a specific inhibitor of the alternative complement pathway, reduced the toxicity of uremic serum, compared to untreated uremic serum (98 ± 6 vs. 3 ± 9% survival, p < 0.016, anti-factor B treated vs. nontreated, respectively). Uremic serum is thus more toxic to zebrafish embryos than normal serum. Furthermore, this toxicity is associated with a fraction of large size, is inactivated by heat, and is reduced by both specific and nonspecific inhibitors of complement activation. Together these data lend support to the hypothesis that at least some uremic toxicities may be mediated by complement.

Original languageEnglish (US)
Pages (from-to)265-269
Number of pages5
JournalBlood Purification
Volume35
Issue number4
DOIs
Publication statusPublished - Aug 1 2013

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Keywords

  • End-stage renal disease
  • Uremic toxicity
  • Zebrafish model

ASJC Scopus subject areas

  • Hematology
  • Nephrology

Cite this

Berman, N., Lectura, M., Thurman, J. M., Reinecke, J., Raff, A. C., Melamed, M. L., ... Hostetter, T. H. (2013). A zebrafish model for uremic toxicity: Role of the complement pathway. Blood Purification, 35(4), 265-269. https://doi.org/10.1159/000348456