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Animal models of naturally occurring stone disease

Abstract

The prevalence of urolithiasis in humans is increasing worldwide; however, non-surgical treatment and prevention options remain limited despite decades of investigation. Most existing laboratory animal models for urolithiasis rely on highly artificial methods of stone induction and, as a result, might not be fully applicable to the study of natural stone initiation and growth. Animal models that naturally and spontaneously form uroliths are an underused resource in the study of human stone disease and offer many potential opportunities for improving insight into stone pathogenesis. These models include domestic dogs and cats, as well as a variety of other captive and wild species, such as otters, dolphins and ferrets, that form calcium oxalate, struvite, uric acid, cystine and other stone types. Improved collaboration between urologists, basic scientists and veterinarians is warranted to further our understanding of how stones form and to consider possible new preventive and therapeutic treatment options.

Key points

  • Common and rare human urolith types also occur naturally in companion and captive animal species, offering diverse opportunities for research.

  • Calcium oxalate uroliths are common in dogs, cats and Asian small-clawed otters; these models are uniquely suited for research on genetic risk factors, Randall’s plaques and dietary hyperoxaluria, respectively.

  • Infection-induced struvite uroliths are common in dogs, whereas sterile struvite uroliths occur frequently in cats and ferrets; these models could be used to investigate medical dissolution therapy.

  • Natural animal models of uric acid uroliths are best suited to the discovery of genetic modifiers (dogs), study of dietary hyperuricaemia (dolphins) and treatment (dogs, cats, dolphins).

  • Other human urolith types occurring in domestic animals include those that form secondary to rare hereditary disorders (cystine, xanthine and 2,8-dihydroxyadenine) or mineral and toxin ingestion (silica and melamine).

  • Companion animal models of urolithiasis are also useful for discovering environmental and lifestyle risk factors and for testing novel devices or therapeutics, which might simultaneously advance veterinary and human medicine.

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Fig. 1: Similar morphological appearance of naturally occurring calcium oxalate uroliths from four different species.
Fig. 2: X-ray images of naturally occurring calcium oxalate nephrolithiasis in four different species.
Fig. 3: MicroCT scan of naturally occurring calcium oxalate nephroliths.
Fig. 4: Strengths and limitations of naturally occurring animal models for major stone types.

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Acknowledgements

Partial support for E.F. was provided by the Office of the Director, National Institutes of Health (NIH) under award number K01-OD019912.

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A.A., E.F., J.L. and M.B. researched data for the article and made substantial contributions to the discussion of content. A.A. and E.F. wrote the manuscript. All authors reviewed and edited the manuscript before submission.

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Correspondence to Ashley Alford.

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Nature Reviews Urology thanks M. Bultitude, S. Howles and H. Syme for their contribution to the peer review of this work.

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Alford, A., Furrow, E., Borofsky, M. et al. Animal models of naturally occurring stone disease. Nat Rev Urol 17, 691–705 (2020). https://doi.org/10.1038/s41585-020-00387-4

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