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A Zebrafish Model for Uremic Toxicity: Role of the Complement Pathway #MMPMID23689420
Blood Purif 2013[]; 35 (4): 265-9 PMID23689420show ga
Many organic solutes accumulate in ESRD and some are poorly removed 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 pre-dialysis or from normal subjects. Zebrafish embryos 24 hours post fertilization were exposed to experimental media at a ratio of 3:1 water:human serum. Those exposed to serum from uremic subjects had significantly reduced survival at 8 hours (19% +/? 18% vs. 94% +/? 6%; p < 0.05, uremic serum vs control, respectively). Embryos exposed to serum from ESRD subjects fractionated at 50kD showed significantly greater toxicity with the larger molecular weight fraction (83% +/? 11% vs 7% +/?17% survival, p < 0.05, <50kD vs >50 kD, 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 non chelated 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 non treated, 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 non-specific inhibitors of complement activation. Together these data lend support to the hypothesis that at least some uremic toxicities may be mediated by complement.