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Animal Models for Studying Protein-Bound Uremic Toxin Removal-A Systematic Review
Sabbir Ahmed1, Joost C de Vries2, Jingyi Lu1
1Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
Abstract:
Protein-bound uremic toxins (PBUTs) are associated with the progression of chronic kidney disease (CKD) and its associated morbidity and mortality. The conventional dialysis techniques are unable to efficiently remove PBUTs due to their plasma protein binding. Therefore, novel approaches are being developed, but these require validation in animals before clinical trials can begin. We conducted a systematic review to document PBUT concentrations in various models and species. The search strategy returned 1163 results for which abstracts were screened, resulting in 65 full-text papers for data extraction (rats (n = 41), mice (n = 17), dogs (n = 3), cats (n = 4), goats (n = 1), and pigs (n = 1)). We performed descriptive and comparative analyses on indoxyl sulfate (IS) concentrations in rats and mice. The data on large animals and on other PBUTs were too heterogeneous for pooled analysis. Most rodent studies reported mean uremic concentrations of plasma IS close to or within the range of those during kidney failure in humans, with the highest in tubular injury models in rats. Compared to nephron loss models in rats, a greater rise in plasma IS compared to creatinine was found in tubular injury models, suggesting tubular secretion was more affected than glomerular filtration. In summary, tubular injury rat models may be most relevant for the in vivo validation of novel PBUT-lowering strategies for kidney failure in humans.
Insights
Protein-bound uremic toxins (PBUTs) contribute to chronic kidney disease (CKD) progression. Tubular injury rat models best mimic human kidney failure for testing new PBUT-lowering therapies.
Area of Science:
- Nephrology
- Toxicology
- Pharmacology
Background:
- Protein-bound uremic toxins (PBUTs) are key drivers of chronic kidney disease (CKD) progression, morbidity, and mortality.
- Conventional dialysis is ineffective at removing PBUTs due to their strong plasma protein binding.
- Novel therapeutic strategies targeting PBUTs require robust preclinical validation in relevant animal models.
Approach:
- A systematic review was conducted to document PBUT concentrations across diverse animal models and species.
- 1163 studies were screened, with data extracted from 65 full-text papers (rats, mice, dogs, cats, goats, pigs).
- Descriptive and comparative analyses focused on indoxyl sulfate (IS) concentrations in rats and mice.
Key Points:
- Rodent studies frequently reported plasma IS concentrations mirroring human kidney failure levels.
- Tubular injury models in rats exhibited the highest IS concentrations.
- Compared to nephron loss models, tubular injury models showed a disproportionately greater increase in plasma IS relative to creatinine, indicating impaired tubular secretion.
Conclusions:
- Data for large animals and other PBUTs were too heterogeneous for pooled analysis.
- Tubular injury rat models appear most relevant for in vivo validation of novel PBUT-lowering interventions.
- These findings guide the selection of appropriate preclinical models for advancing CKD therapies.
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