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Urolithiasis

pp 1–12 | Cite as

Development of a two-stage model system to investigate the mineralization mechanisms involved in idiopathic stone formation: stage 2 in vivo studies of stone growth on biomimetic Randall’s plaque

  • Allison L. O’Kell
  • Archana C. Lovett
  • Benjamin K. Canales
  • Laurie B. Gower
  • Saeed R. Khan
Original Paper
  • 72 Downloads

Abstract

Idiopathic stone formers often form calcium oxalate (CaOx) stones that are attached to calcium phosphate (CaP) deposits in the renal tissue, known as Randall’s plaques (RP). Plaques are suggested to originate in the renal tubular basement membrane and spread into the interstitial regions where collagen fibrils and vesicles become mineralized; if the epithelium is breached, the RP becomes overgrown with CaOx upon exposure to urine. We have developed a two-stage model system of CaP–CaOx composite stones, consisting of Stage (1) CaP mineralized plaque, followed by Stage (2) CaOx overgrowth into a stone. In our first paper in this series (Stage 1), osteopontin (and polyaspartate) were found to induce a non-classical mineralization of porcine kidney tissues, producing features that resemble RP. For the Stage 2 studies presented here, biomimetic RPs from Stage 1 were implanted into the bladders of rats. Hyperoxaluria was induced with ethylene glycol for comparison to controls (water). After 4 weeks, rats were sacrificed and the implants were analyzed using electron microscopy and X-ray microanalyses. Differences in crystal phase and morphologies based upon the macromolecules present in the biomimetic plaques suggest that the plaques have the capacity to modulate the crystallization reactions. As expected, mineral overgrowths on the implants switched from CaP (water) to CaOx (hyperoxaluric). The CaOx crystals were aggregated and mixed with organic material from the biomimetic RP, along with some amorphous and spherulitic CaOx near the “stone” surfaces, which seemed to have become compact and organized towards the periphery. This system was successful at inducing “stones” more similar to human idiopathic kidney stones than other published models.

Keywords

Urolithiasis Randall’s plaque Nephrolithiasis Kidney stones Biomimetic model system PILP 

Notes

Acknowledgements

Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number R01DK092311. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We also thank our collaborators who provided the decellularized porcine kidney tissues, Drs. Brad Willenberg and Edward Ross (College of Medicine, University of Central Florida), and Dr. Christopher Batich (Department of Materials Science and Engineering, University of Florida). Data was also gathered from EM core in the College of Medicine, as well as the Research Service Centers within the Herbert Wertheim College of Engineering, so we thank the staff for their training and guidance on these instruments as well.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest in this work.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.

Supplementary material

240_2018_1079_MOESM1_ESM.pdf (4.7 mb)
Supplementary material 1 (PDF 4848 KB)

References

  1. 1.
    Scales CD, Smith AC, Hanley JM, Saigal CS, Project UDiA (2012) Prevalence of kidney stones in the United States. Eur Urol 62:160–165CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Lieske JC, Rule AD, Krambeck AE et al (2014) Stone composition as a function of age and sex. Clin J Am Soc Nephrol 9:2141–2146CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Worcester EM, Coe FL (2010) Clinical practice. Calcium kidney stones. N Engl J Med 363:954–963CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Khan SR, Pearle MS, Robertson WG et al (2016) Kidney stones. Nat Rev Dis Prim 2:16008CrossRefPubMedGoogle Scholar
  5. 5.
    Singh P, Enders FT, Vaughan LE et al (2015) Stone composition among first-time symptomatic kidney stone formers in the community. Mayo Clin Proc 90:1356–1365CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Evan AP, Worcester EM, Coe FL, Williams J, Lingeman JE (2015) Mechanisms of human kidney stone formation. Urolithiasis 43(Suppl 1):19–32CrossRefPubMedGoogle Scholar
  7. 7.
    Evan AP, Lingeman JE, Coe FL et al (2003) Randall’s plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle. J Clin Investig 111:607–616CrossRefPubMedGoogle Scholar
  8. 8.
    Stoller ML, Meng MV, Abrahams HM, Kane JP (2004) The primary stone event: a new hypothesis involving a vascular etiology. J Urol 171:1920–1924CrossRefPubMedGoogle Scholar
  9. 9.
    Bird VY, Khan SR (2017) How do stones form? Is unification of theories on stone formation possible? Arch Esp Urol 70:12–27PubMedPubMedCentralGoogle Scholar
  10. 10.
    Hsi RS, Ramaswamy K, Ho SP, Stoller ML (2017) The origins of urinary stone disease: upstream mineral formations initiate downstream Randall’s plaque. BJU Int 119:177–184CrossRefPubMedGoogle Scholar
  11. 11.
    Mo L, Liaw L, Evan AP, Sommer AJ, Lieske JC, Wu XR (2007) Renal calcinosis and stone formation in mice lacking osteopontin, Tamm–Horsfall protein, or both. Am J Physiol Renal Physiol 293:F1935–F1943CrossRefPubMedGoogle Scholar
  12. 12.
    Khan SR, Glenton PA (2008) Calcium oxalate crystal deposition in kidneys of hypercalciuric mice with disrupted type IIa sodium-phosphate cotransporter. Am J Physiol Renal Physiol 294:F1109–F1115CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Khan SR (2010) Nephrocalcinosis in animal models with and without stones. Urol Res 38:429–438CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Liu Y, Mo L, Goldfarb DS et al (2010) Progressive renal papillary calcification and ureteral stone formation in mice deficient for Tamm–Horsfall protein. Am J Physiol Renal Physiol 299:F469–F478CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Khan SR, Canales BK (2011) Ultrastructural investigation of crystal deposits in Npt2a knockout mice: are they similar to human Randall’s plaques? J Urol 186:1107–1113CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Wesson JA, Johnson RJ, Mazzali M et al (2003) Osteopontin is a critical inhibitor of calcium oxalate crystal formation and retention in renal tubules. J Am Soc Nephrol 14:139–147CrossRefPubMedGoogle Scholar
  17. 17.
    Khan SR, Hackett RL (1985) Developmental morphology of calcium oxalate foreign body stones in rats. Calcif Tissue Int 37:165–173CrossRefPubMedGoogle Scholar
  18. 18.
    Khan SR, Hackett RL (1987) Urolithogenesis of mixed foreign body stones. J Urol 138:1321–1328CrossRefPubMedGoogle Scholar
  19. 19.
    Vermeulen CW, Grove WJ, Goetz R, Ragins HD, Correll NO (1950) Experimental urolithiasis. I. Development of calculi upon foreign bodies surgically introduced into bladders of rats. J Urol 64:541–548CrossRefPubMedGoogle Scholar
  20. 20.
    Chidambaram A, Rodriguez D, Khan S, Gower L (2015) Biomimetic Randall’s plaque as an in vitro model system for studying the role of acidic biopolymers in idiopathic stone formation. Urolithiasis 43(Suppl 1):77–92CrossRefPubMedGoogle Scholar
  21. 21.
    Gower LB (2008) Biomimetic model systems for investigating the amorphous precursor pathway and its role in biomineralization. Chem Rev 108:4551–4627CrossRefPubMedGoogle Scholar
  22. 22.
    Gower L, Odom D (2000) Deposition of calcium carbonate films by a polymer-induced liquid-precursor (PILP) process. J Cryst Growth 210:719–734CrossRefGoogle Scholar
  23. 23.
    Wolf SE, Harris J, Lovett A, Gower L (2017) Non-classical crystallization processes: potential relevance to stone formation. In: Coe F, Worcester EM, Lingeman JE, Evan AP (eds) Kidney stones: medical and surgical management. Jaypee Brothers, Medical Publishers Pvt. Ltd, PhiladelphiaGoogle Scholar
  24. 24.
    Amos FF, Dai L, Kumar R, Khan SR, Gower LB (2009) Mechanism of formation of concentrically laminated spherules: implication to Randall’s plaque and stone formation. Urol Res 37:11–17CrossRefPubMedGoogle Scholar
  25. 25.
    Amos FF, Olszta MJ, Khan SR, Gower LB (2006) Relevance of a polymer-induced liquid-precursor (PILP) mineralization process to normal and pathological biomineralization. In: Königsberger E, Königsberger L (eds) Biomineralization—medical aspects of solubility. Wiley, West Sussex, pp 125–127CrossRefGoogle Scholar
  26. 26.
    Gower LB, Amos FF, Khan SR (2010) Mineralogical signatures of stone formation mechanisms. Urol Res 38:281–292CrossRefPubMedGoogle Scholar
  27. 27.
    Lovett AC, Khan SR, Gower LB (2018) Development of a two-stage in vitro model system to investigate the mineralization mechanisms involved in idiopathic stone formation: stage 1—biomimetic Randall’s plaque using decellularized porcine kidneys. Urolithiasis.  https://doi.org/10.1007/s00240-00018-01060-z CrossRefPubMedGoogle Scholar
  28. 28.
    Ross EA, Williams MJ, Hamazaki T et al (2009) Embryonic stem cells proliferate and differentiate when seeded into kidney scaffolds. J Am Soc Nephrol 20:2338–2347CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Khan SR, Hackett RL (1986) Identification of urinary stone and sediment crystals by scanning electron microscopy and X-ray microanalysis. J Urol 135:818–825CrossRefPubMedGoogle Scholar
  30. 30.
    Graeser S, Postl W, Bojar H-P et al (2008) Struvite-(K), KMgPO4· 6H2O, the potassium equivalent of struvite—a new mineral. Eur J Miner 20:629–633CrossRefGoogle Scholar
  31. 31.
    Wilsenach JA, Schuurbiers CA, van Loosdrecht MC (2007) Phosphate and potassium recovery from source separated urine through struvite precipitation. Water Res 41:458–466CrossRefPubMedGoogle Scholar
  32. 32.
    Khan SR, Finlayson B, Hackett RL (1983) Experimental induction of crystalluria in rats using mini-osmotic pumps. Urol Res 11:199–205CrossRefPubMedGoogle Scholar
  33. 33.
    Khan SR, Glenton PA (1995) Deposition of calcium phosphate and calcium oxalate crystals in the kidneys. J Urol 153:811–817CrossRefPubMedGoogle Scholar
  34. 34.
    Parks JH, Coe FL, Evan AP, Worcester EM (2009) Urine pH in renal calcium stone formers who do and do not increase stone phosphate content with time. Nephrol Dial Transplant 24:130–136CrossRefPubMedGoogle Scholar
  35. 35.
    Hallson PC, Rose GA (1989) Measurement of calcium phosphate crystalluria: influence of pH and osmolality and invariable presence of oxalate. Br J Urol 64:458–462CrossRefPubMedGoogle Scholar
  36. 36.
    Spradling K, Vernez SL, Khoyliar C et al (2016) Prevalence of hyperoxaluria in urinary stone formers: chronological and geographical trends and a literature review. J Endourol 30:469–475CrossRefPubMedGoogle Scholar
  37. 37.
    Daudon M, Letavernier E, Frochot V, Haymann J-P, Bazin D, Jungers P (2016) Respective influence of calcium and oxalate urine concentration on the formation of calcium oxalate monohydrate or dihydrate crystals. C R Chim 19:1504–1513CrossRefGoogle Scholar
  38. 38.
    Wesson JA, Worcester E (1996) Formation of hydrated calcium oxalates in the presence of poly-l-aspartic acid. Scanning Microsc 10:415–423 (423–414)PubMedGoogle Scholar
  39. 39.
    Sethmann I, Wendt-Nordahl G, Knoll T, Enzmann F, Simon L, Kleebe HJ (2017) Microstructures of Randall’s plaques and their interfaces with calcium oxalate monohydrate kidney stones reflect underlying mineral precipitation mechanisms. Urolithiasis 45:235–248CrossRefPubMedGoogle Scholar
  40. 40.
    Khan SR (2004) Crystal-induced inflammation of the kidneys: results from human studies, animal models, and tissue-culture studies. Clin Exp Nephrol 8:75–88CrossRefPubMedGoogle Scholar
  41. 41.
    Grases F, Costa-Bauza A, Gomila I, Conte A (2010) Origin and types of calcium oxalate monohydrate papillary renal calculi. Urology 76:1339–1345CrossRefPubMedGoogle Scholar
  42. 42.
    Frochot V, Daudon M (2016) Clinical value of crystalluria and quantitative morphoconstitutional analysis of urinary calculi. Int J Surg 36:624–632CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Urology, College of MedicineUniversity of FloridaGainesvilleUSA
  2. 2.Department of Small Animal Clinical Sciences, College of Veterinary MedicineUniversity of FloridaGainesvilleUSA
  3. 3.Department of Materials Science and EngineeringUniversity of FloridaGainesvilleUSA
  4. 4.Department of Pathology, College of MedicineUniversity of FloridaGainesvilleUSA

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