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Studies using a porcine model: what insights into human calcium oxalate stone formation mechanisms has this model facilitated?

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Abstract

Animal models are useful in the study of many human diseases. Our current understanding of the biological, physiological, and biochemical aspects of hyperoxaluria and calcium oxalate urolithiasis has been greatly informed by studies using animals. Recently, limitations in the extrapolation to humans of research results derived from laboratory rodents have been identified. The use in biomedical research of a variety of organisms, including large animals, is increasingly encouraged. The purpose of this article is to review the use of pigs in biomedical and stone research, to provide a rationale for using pigs in metabolic stone research, and to describe our 8-year experience in developing a porcine platform for studying hyperoxaluria and calcium oxalate urolithiasis. In this article, we share and review some of the highlights of our findings. We also report results from a recent feeding swine study that demonstrated oxalate-induced renal nephropathy. Finally, we offer ideas for future directions in urolithiasis research using swine.

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References

  1. Holmes RP, Goodman HO, Assimos DG (2009) Contribution of dietary oxalate to urinary oxalate excretion. Kidney Int 59:270–276

    Article  Google Scholar 

  2. Khan SR, Glenton PA, Byer KJ (2006) Modeling of hyperoxaluric calcium oxalate nephrolithiasis: experimental induction of hyperoxaluria by hydroxy-l-proline. Kidney Int 70:914–923

    Article  CAS  PubMed  Google Scholar 

  3. Cohen BJ, Loew FM (1984) Laboratory animal medicine: historical perspectives in laboratory animal medicine. Academic Press Inc, Orlando

    Google Scholar 

  4. Cottingham J (1978) A brute to the brutes-Descartes’ treatment of animals. Philosophy 53:551–559

    Article  Google Scholar 

  5. Franco NH (2013) Animal experiments in biomedical research: a historical perspective. Animals (Basel) 3:238–273

    Article  Google Scholar 

  6. Hedrich HJ (2000) The history and development of the rat as a laboratory animal model. In: Krinke G (ed) The laboratory rat. Academic, Waltham, MA, pp 3–16

    Chapter  Google Scholar 

  7. Lindsey JR, Baker HJ (2006) Historical foundations. In: Suckow MA, Weisbroth SH, Franklin CL (eds) The laboratory rat. Elsevier, Amsterdam, the Netherlands, pp 1–52

  8. Lai M, Chandrasekera PC, Barnard ND (2014) You are what you eat, or are you? The challenges of translating high-fat-fed rodents to human obesity and diabetes. Nutr Diabetes 4:e135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shanks N, Greek R, Greek J (2009) Are animal models predictive for humans? Philos Ethics Humanit Med 4:2

    Article  PubMed  PubMed Central  Google Scholar 

  10. Roth JA, Tuggle CK (2015) Livestock models in translational medicine. ILAR J 56:1–6

    Article  CAS  PubMed  Google Scholar 

  11. Reynolds LP, Ireland JJ, Caton JS, Bauman DE, Davis TA (2009) Commentary on domestic animals in agricultural and biomedical research: an endangered enterprise. J Nutr 139:427–428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. NIH announcement (2016) PAR-13-204, Dual purpose with dual benefit: research in biomedicine and agriculture using agriculturally important domestic animal species (R01). http://grants.nih.gov/grants/guide/pa-files/PAR-13-204.html. Accessed on 28 September 2016

  13. Schachtschneider KM, Madsen O, Park C, Rund LA, Groenen MA, Schook LB (2015) Adult porcine genome-wide DNA methylation patterns support pigs as a biomedical model. BMC Genom 16:743

    Article  Google Scholar 

  14. Reardon S (2015) New life for pig-to-human transplants. Nature 527:152–154

    Article  CAS  PubMed  Google Scholar 

  15. Gonzalez LM, Moeser AJ, Blikslager AT (2015) Porcine models of digestive disease: the future of large animal translational research. Transl Res 166(1):12–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cooper DK, Ekser B, Tector AJ (2015) A brief history of clinical xenotransplantation. Int J Surg 23:205–210

    Article  PubMed  PubMed Central  Google Scholar 

  17. Swindle MM, Makin A, Herron AJ, Clubb FJ Jr, Frazier KS (2012) Swine as models in biomedical research and toxicology testing. Vet Pathol 49:344–356

    Article  CAS  PubMed  Google Scholar 

  18. Ganpule A, Chhabra JS, Desai M (2015) Chicken and porcine models for training in laparoscopy and robotics. Curr Opin Urol 25:158–162

    Article  PubMed  Google Scholar 

  19. Bagetti Filho HJ, Pereira-Sampaio MA, Favorito LA, Sampaio FJ (2008) Pig kidney: anatomical relationships between the renal venous arrangement and the kidney collecting system. J Urol 179:1627–1630

    Article  PubMed  Google Scholar 

  20. Giraud S, Favreau F, Chatauret N, Thuillier R, Maiga S, Hauet T (2011) Contribution of large pig for renal ischemia-reperfusion and transplantation studies: the preclinical model. J Biomed Biotechnol 2011:532127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhang Q, Widmer G, Tzipori S (2013) A pig model of the human gastrointestinal tract. Gut Microbes 4:193–200

    Article  PubMed  PubMed Central  Google Scholar 

  22. Baker DH (2008) Animal models in nutrition research. J Nutr 138:391–396

    CAS  PubMed  Google Scholar 

  23. Gandarillas M, Bas F (2009) The domestic pig (Sus scrofa domestica) as a model for evaluating nutritional and metabolic consequences of bariatric surgery practiced on morbid obese humans. Cienc Inv Agr 36:163–176

    Article  Google Scholar 

  24. Heinritz SN, Mosenthin R, Weiss E (2013) Use of pigs as a potential model for research into dietary modulation of the human gut microbiota. Nutr Res Rev 26:191–209

    Article  PubMed  Google Scholar 

  25. Gutierrez K, Dicks N, Glanzner WG, Agellon LB, Bordignon V (2015) Efficacy of the porcine species in biomedical research. Front Genet 6:293

    Article  PubMed  PubMed Central  Google Scholar 

  26. Mandel NS, Henderson JD Jr, Hung LY, Wille DF, Wiessner JH (2004) A porcine model of calcium oxalate kidney stone disease. J Urol 171:1301–1303

    Article  CAS  PubMed  Google Scholar 

  27. Drouin G, Godin JR, Pagé B (2011) The genetics of vitamin C loss in vertebrates. Curr Genomics 12:371–378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Looft T, Allen HK, Cantarel BL, Levine UY, Bayles DO, Alt DP, Henrissat B, Stanton TB (2014) Bacteria, phages and pigs: the effects of in-feed antibiotics on the microbiome at different gut locations. ISME J 8:1566–1576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gonzalez-Vega JC, Stein HH (2014) Invited review: calcium digestibility and metabolism in pigs. Asian-Australas J Anim Sci 27:1–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Djurickovic SM, Gandhi D, Brown K, Yoon S (1973) Urolithiasis in baby pigs. Vet Med Small Anim Clin 68:1151–1153

    CAS  PubMed  Google Scholar 

  31. Edwards BL (1977) Urolithiasis in pigs. Vet Rec 101:432–433

    Article  CAS  PubMed  Google Scholar 

  32. Manning RA, Blaney BJ (1986) Identification of uroliths by infrared spectroscopy. Aust Vet J 63:393–396

    Article  CAS  PubMed  Google Scholar 

  33. Smyth JA, Rice DA, Kavanagh NT, Collins DS (1986) Urolithiasis in weaned pigs. Vet Rec 119:158–159

    Article  CAS  PubMed  Google Scholar 

  34. Palmer JL, Dykes NL, Love K, Fubini SL (1998) Contrast radiography of the lower urinary tract in the management of obstructive urolithiasis in small ruminants and swine. Vet Radiol Ultrasound 39:175–180

    Article  CAS  PubMed  Google Scholar 

  35. Maes DG, Vrielinck J, Millet S, Janssens GP, Deprez P (2004) Urolithiasis in finishing pigs. Vet J 168:317–322

    CAS  PubMed  Google Scholar 

  36. Chigerwe M, Shiraki R, Olstad EC, Angelos JA, Ruby AL, Westropp JL (2013) Mineral composition of urinary calculi from potbellied pigs with urolithiasis: 50 cases (1982–2012). J Am Vet Med Assoc 243:389–393

    Article  PubMed  Google Scholar 

  37. Stine CB, Reimschuessel R, Gieseker CM, Evans ER, Mayer TD, Hasbrouck NR, Tall E, Boehmer J, Gamboa da Costa G, Ward JL (2011) A no observable adverse effects level (NOAEL) for pigs fed melamine and cyanuric acid. Regul Toxicol Pharmacol 60:363–372

    Article  CAS  PubMed  Google Scholar 

  38. Kakino J, Sato R, Naito Y (1998) Purine metabolism of uric acid nephrolithiasis induced in newborn piglets. J Vet Med Sci 60:203–206

    Article  CAS  PubMed  Google Scholar 

  39. Sun W-D, Zhang K-C, Wang J-Y, Wang X-L (2009) Sulfamonomethoxine-induced urinary calculi in pigs. Int J Biol Biomol Agri Food Biotechnol Eng 3:462–464

    Google Scholar 

  40. Trojan B, Trojan S, Underwood L, Staches B, Navetta A, Filleur S, Nelius T (2014) Assessment of induction of calcium oxalate nephrolithiasis in a novel porcine stone forming model—pilot study. J Urol 191:e268–e269

    Article  Google Scholar 

  41. Grujic D, Brettman L, Langman C, Fedkiv O, Goncharaova K, Kardas M, Pierzinowski S (2016) ALLN-177 reduces hyperoxaluria in a porcine model of secondary hyperoxaluria (2°HO) induced by a human-like oxalate rich diet. J Urol 195:e721

    Article  Google Scholar 

  42. Langman CB, Grujic D, Pease RM, Easter L, Nezzer J, Margolin A, Brettman L (2016) A double-blind, placebo controlled, randomized phase 1 cross-over study with ALLN-177, an orally administered oxalate degrading enzyme. Am J Nephrol 44:150–158

    Article  CAS  PubMed  Google Scholar 

  43. Strasburger JF (2009) Meeting the research infrastructure needs of micropolitan and rural communities. WMJ 108:133–138

    PubMed  Google Scholar 

  44. National Research Council (U.S.) (2012) Nutrient requirements of swine. Natl Acad Press, Washington DC

    Google Scholar 

  45. Kaplon DM, Penniston KL, Darriet C, Crenshaw TD, Nakada SY (2010) Hydroxyproline-induced hyperoxaluria using acidified and traditional diets in the porcine model. J Endourol 24:355–359

    Article  PubMed  Google Scholar 

  46. Knight J, Jiang J, Assimos DG, Holmes RP (2006) Hydroxyproline ingestion and urinary oxalate and glycolate excretion. Kidney Int 70:1929–1934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Patel SR, Penniston KL, Iwicki L, Saeed I, Crenshaw TD, Nakada SY (2012) Dietary induction of long-term hyperoxaluria in the porcine model. J Endourol 26:433–438

    Article  PubMed  Google Scholar 

  48. Patel SR, Penniston KL, Crenshaw TD, Nakada SY (2011) Dietary hydroxyproline induces nephrolithiasis in the adult porcine model. J Endourol 25:A5–A6

    Google Scholar 

  49. Sivalingam S, Nakada SY, Sehgal PD, Crenshaw TD, Penniston KL (2013) Dietary hydroxyproline induced calcium oxalate lithiasis and associated renal injury in the porcine model. J Endourol 27:1493–1498

    Article  PubMed  Google Scholar 

  50. Ogawa Y, Yamaguchi K, Morozumi M (1990) Effects of magnesium salts in preventing experimental oxalate urolithiasis in rats. J Urol 144:385–389

    CAS  PubMed  Google Scholar 

  51. Khan SR, Johnson JM, Peck AB et al (2002) Expression of osteopontin in rat kidneys: induction during ethylene glycol induced calcium oxalate nephrolithiasis. J Urol 168:1173–1181

    Article  CAS  PubMed  Google Scholar 

  52. Bushinsky DA, Asplin JR, Grynpas MD et al (2002) Calcium oxalate stone formation in genetic hypercalciuric stone forming rats. Kidney Int 61:975–987

    Article  CAS  PubMed  Google Scholar 

  53. Khan SR, Glenton PA, Byer KJ (2006) Modeling of hyperoxaluric calcium oxalate nephrolithiasis: Experimental induction of hyperoxaluria by hydroxyl-L-proline. Kidney Int 70:914–923

    Article  CAS  PubMed  Google Scholar 

  54. Canales BK, Ellen J, Khan SR, Hatch M (2013) Steatorrhea and hyperoxaluria occur after gastric bypass surgery in obese rats regardless of dietary fat or oxalate. J Urol 190:1102–1109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mandel NS, Henderson JR, Hung LY et al (2004) A porcine model of calcium oxalate kidney stone disease. J Urol 171:1301–1303

    Article  CAS  PubMed  Google Scholar 

  56. Kaplon DM, Penniston KL, Darriet C et al (2010) Hydroxyproline-induced hyperoxaluria using acidified and traditional diets in the porcine model. J Endourol 3:355–359

    Article  Google Scholar 

  57. Patel SR, Penniston KL, Iwicki L et al (2011) Dietary induction of long-term hyperoxaluria in the porcine model. J Endourol 26:433–438

    Article  PubMed  Google Scholar 

  58. Sivalingam S, Nakada SY, Sehgal PD, Crenshaw TD, Penniston KL (2013) Dietary hydroxyproline induced calcium oxalate lithiasis and associated renal injury in the porcine model. J Endourol 27:1493–1498

    Article  PubMed  Google Scholar 

  59. Knight J, Jiang J, Assimos DG et al (2006) Hydroxyproline ingestion and urinary oxalate and glycolate excretion. Kidney Int 70:1929–1934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank the following undergraduates for their enthusiastic commitment and able laboratory assistance: Sarah Johnson, Leema John, David Bennett, and Elizabeth Zars; and the laboratory and chromatography expertise of Dr. Ibrahim Saeed. The authors also thank Dr. James Williams (Indiana University), Dr. John Knight (University of Alabama at Birmingham), and Dr. John Asplin (LithoLink Corporation) for their analytical consultation and advice. Finally, the efforts described herein would not have been possible without the knowledge, guidance, and collaboration of Dr. Tom Crenshaw, director of the Swine Research and Teaching Center, and the efforts of his staff.

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Authors and Affiliations

  1. Department of Urology, University of Wisconsin School of Medicine and Public Health, 1685 Highland Avenue, Medical Foundation Centennial Building, Madison, WI, 53705-2281, USA

    Kristina L. Penniston, Sutchin R. Patel & Stephen Y. Nakada

  2. Research Animal Resources Center, University of Wisconsin-Madison, Madison, WI, USA

    Denise J. Schwahn

  3. Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Stephen Y. Nakada

Authors
  1. Kristina L. Penniston
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  2. Sutchin R. Patel
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  3. Denise J. Schwahn
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  4. Stephen Y. Nakada
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Correspondence to Kristina L. Penniston.

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The authors have nothing to disclose.

Funding

The projects described were supported in part by the Clinical and Translational Science Award (CTSA) program through the NIH National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000427 (awarded to KL Penniston) and also by research funds of the Department of Urology at the University of Wisconsin School of Medicine and Public Health (Madison, WI, USA).

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Penniston, K.L., Patel, S.R., Schwahn, D.J. et al. Studies using a porcine model: what insights into human calcium oxalate stone formation mechanisms has this model facilitated?. Urolithiasis 45, 109–125 (2017). https://doi.org/10.1007/s00240-016-0947-9

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  • DOI: https://doi.org/10.1007/s00240-016-0947-9

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