Skip to main content

Mechanisms of human kidney stone formation

Abstract

The precise mechanisms of kidney stone formation and growth are not completely known, even though human stone disease appears to be one of the oldest diseases known to medicine. With the advent of the new digital endoscope and detailed renal physiological studies performed on well phenotyped stone formers, substantial advances have been made in our knowledge of the pathogenesis of the most common type of stone former, the idiopathic calcium oxalate stone former as well as nine other stone forming groups. The observations from our group on human stone formers and those of others on model systems have suggested four entirely different pathways for kidney stone formation. Calcium oxalate stone growth over sites of Randall’s plaque appear to be the primary mode of stone formation for those patients with hypercalciuria. Overgrowths off the ends of Bellini duct plugs have been noted in most stone phenotypes, do they result in a clinical stone? Micro-lith formation does occur within the lumens of dilated inner medullary collecting ducts of cystinuric stone formers and appear to be confined to this space. Lastly, cystinuric stone formers also have numerous small, oval, smooth yellow appearing calyceal stones suggestive of formation in free solution. The scientific basis for each of these four modes of stone formation are reviewed and used to explore novel research opportunities.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

References

  1. Evan AP, Lingeman JE, Coe FL, Parks JH, Bledsoe SB, Shao Y, Sommer AJ, Patterson RF, Kuo RL, Grynpas M (2003) Randall Plaque of patients with nephrolithisis begins in basement membranes of thin loops of Henle. J Clin Invest 111:607–616

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  2. Evan AP, Lingeman JE, Coe FL, Shao Y, Parks JH, Bledsoe SB, Phillips CL, Bonsib S, Worcester EM, Sommer AJ, Kim SC, Tinmouth WW, Grynpas M (2005) Crystal-associated nephropathy in patients with brushite nephrolithiasis. Kidney Int 67:576–591

    CAS  PubMed  Article  Google Scholar 

  3. Evan AP, Coe FL, Lingeman JE, Shao Y, Matlaga BR, Kim SC, Bledsoe SB, Sommer AJ, Grynpas M, Philips CL, Worcester EM (2006) Renal crystal deposits and histopathology in patients with cystine stones. Kidney Int 69:2227–2235

    CAS  PubMed  Article  Google Scholar 

  4. Evan A, Lingeman J, Coe FL, Worcester E (2006) Randall’s plaque: pathogenesis and role in calcium oxalate nephrolithiasis. Kidney Int 69:1313–1318

    CAS  PubMed  Article  Google Scholar 

  5. Evan AP, Lingeman J, Coe F, Shao Y, Miller N, Matlaga B, Phillips C, Sommer A, Worcester EM (2007) Renal histopathology of stone-forming patients with distal renal tubular acidosis. Kidney Int 71:795–801

    CAS  PubMed  Article  Google Scholar 

  6. Evan AP, Coe FL, Gillen D, Lingeman JE, Bledsoe S, Worcester EM (2008) Renal intratubular crystals and hyaluronan staining occur in stone formers with bypass surgery but not with idiopathic calcium oxalate stones. Anat Rec 291:325–334

    Article  Google Scholar 

  7. Evan AP, Lingeman JE, Coe FL, Miller N, Bledsoe S, Sommer A, Williams J, Shao Y, Worcester E (2008) Histopathology and surgical anatomy of patients with primary hyperparathyroidism and calcium phosphate stones. Kidney Int 74:223–229

    CAS  PubMed  Article  Google Scholar 

  8. Evan AP, Lingeman JE, Coe FL, Bledsoe SB, Sommer AJ, Williams JC Jr, Krambeck AE, Worcester EM (2009) Intra-tubular deposits, urine and stone composition are divergent in patients with ileostomy. Kidney Int 76:1081–1088

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  9. Evan AP, Lingeman JE, Worcester EM, Bledsoe SB, Sommer AJ, Williams JC Jr, Krambeck AE, Phillips CL, Coe FL (2010) Renal histopathology and crystal deposits in patients with small bowel resection and calcium oxalate stone disease. Kidney Int 78:310–317

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  10. Worcester EM, Evan AE, Coe FL, Lingeman JE, Krambeck A, Sommer A, Philips CL, Milliner D (2013) A test of the hypothesis that oxalate secretion produces proximal tubule crystallization in primary hyperoxaluria type 1. AJP 305:F1574–F1584

    CAS  Google Scholar 

  11. Evan AP, Lingeman J., Worcester EM, Sommer AJ, Phillips CL, Williams JC, Coe FL. (2013) Contrasting histopathology and crystal deposits in kidneys of idiopathic stone formers who produce hydroxy apatite, brushite, or calcium oxalate stones. Anat Rec (In press)

  12. Miller NL, Gillen DL, Williams JC, Evan AP, Bledsoe SB, Coe FL, Worcester EM, Matlaga BR, Munch LC, Lingeman JE (2009) A formal test of the hypothesis that idiopathic calcium oxalate stones grow on Randall’s plaque. BJU Int 103:966–971

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  13. Coe FL, Evan AP, Lingeman JE, Worcester EM (2010) Plaque and deposits in nine human stone diseases. Urol Res 38:239–247

    PubMed Central  PubMed  Article  Google Scholar 

  14. Coe FL, Evan AP, Worcester EM, Lingeman JE (2010) Three pathways for human kidney stone formation. Urol Res 38:147–160

    PubMed Central  PubMed  Article  Google Scholar 

  15. Linnes MP, Krambeck AE, Cornell L, Williams JC, Korinek M, Bergstrald EJ, Rule AD, McCollough CM, Vritiska TJ, Lieske JC (2013) Phenotypic characterization of kidney stone formers by endoscopic and histological quantification of intra-renal calcifications. Kidney Int 84:818–825

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  16. Khan SR, Finlayson B, Hackett RL (1984) Renal papillary changes in patient with calcium oxalate lithiasis. Urol 23:194–199

    CAS  PubMed  Article  Google Scholar 

  17. Low RK, Stoller ML (1997) Endoscopic mapping of renal papillae for Randall’s plaques in patients with urinary stone disease. J Urol 158:2062–2064

    CAS  PubMed  Article  Google Scholar 

  18. Verkoelen CF, Verhulst A (2007) Proposed mechanisms in renal tubular crystal retention. Kidney Int 72:13–18

    CAS  PubMed  Article  Google Scholar 

  19. Vermeulen CW, Lyon ES (1968) Mechanisms of genesis and growth of calculi. Am J Med 45:684–692

    CAS  PubMed  Article  Google Scholar 

  20. Finlayson B, Reid F (1978) The expectation of free and fixed particles in urinary stone disease. Invest Urol 15:442–448

    CAS  PubMed  Google Scholar 

  21. Kok DJ, Khan SR (1994) Calcium oxalate nephrolithiasis, a free or fixed particle disease. Kidney Int 46:847–854

    CAS  PubMed  Article  Google Scholar 

  22. Randall A (1937) The origin and growth of renal calculi. Ann Surg 105:1009–1027

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  23. Miller NL, Williams JC, Evan AP, Bledsoe SB, Coe FL, Worcester EM, Munch LC, Handa S, Lingeman JE (2010) In idiopathic calcium oxalate stone formers, unattached stones show evidence of having originated as attached stones on Randall’s plaque: a micro CT study. BJU Int 105:242–245 PMC2807918

    PubMed Central  PubMed  Article  Google Scholar 

  24. Henneman PH, Benedict PH, Fotbes A, Dudley R (1958) Idiopathic hypercalcuria. N Engl J Med 259:802–907

    CAS  PubMed  Article  Google Scholar 

  25. Coe FL, Evan E, Worcester E (2005) Kidney stone disease. J Clin Invest 115:2598–2608

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  26. Evan AP (2007) Histopathology predicts the mechanism of stone formation. In: Evan AP, Lingeman JE, Williams JC (eds) Renal Stone Disease: Proceedings of the First International Urolithiasis Research Symposium. American Institute of Physics, Melville, NY, pp 15–25

    Google Scholar 

  27. Evan AP, Coe FL, Lingeman JE, Shao Y, Sommer AJ, Bledsoe SB, Anderson JC, Worcester EM (2007) Mechanism of formation of human calcium oxalate renal stones on Randall’s plaque. Anat Rec 290:1315–1323

    CAS  Article  Google Scholar 

  28. Gokhale JA, McKee MD, Khan SR (1996) Immunocytochemical localization of Tamm-Horsfall protein in the kidneys of normal and nephrolithic rats. Urol Res 24:201–209

    CAS  PubMed  Article  Google Scholar 

  29. Asplin JR, Mandel NS, Coe FL (1996) Evidence for calcium phosphate supersaturation in the loop of Henle. Am J Physiol 270:F604–F613

    CAS  PubMed  Google Scholar 

  30. Jamison RL, Frey NR, Lacy FB (1974) Calcium reabsorption in the thin loop of Henle. Am J Physiol 227:745–751

    CAS  PubMed  Google Scholar 

  31. Bergsland KJ, Worcester EM, Coe FL (2013) Role of proximal tubule in the hypocalciuric response to thiazide of patients with idiopathic hypercalciuria. Am J Physiol 305:F853–F860

    Google Scholar 

  32. Worcester EM, Coe FL, Evan AP, Bergsland KJ, Parks JH, Willis LR, Clark DL, Gillen DL (2008) Evidence for increased postprandial distal nephron calcium delivery in hypercalciuric stone-forming patients. Am J Physiol 295:F1286–F1294

    CAS  Google Scholar 

  33. Worcester EM, Gillen DL, Evan AP, Parks JH, Wright K, Trumbore L, Nakagawa Y, Coe FL (2007) Evidence that postprandial reduction of renal calcium reabsorption mediates hypercalciuria of patients with calcium nephrolithiasis. Am J Physiol 292:F66–F75

    CAS  Google Scholar 

  34. Brannan PG, Morawski S, Pak CY, Fordtran JS (1979) Selective jejunal hyperabsorption of calcium in absorptive hypercalciuria. Am J Med 66:425–428

    CAS  PubMed  Article  Google Scholar 

  35. Broadus AE, Dominguez M, Batter FC (1978) Pathophysiological studies in idiopathic hypercalciuria: use of an oral calcium tolerance test to characterize distinctive hypercalciuric subgroups. J Clin Endocrinol Metab 47:751–760

    CAS  PubMed  Article  Google Scholar 

  36. Evan AP, Bledsoe S, Worcester EM, Coe FL, Lingeman JE, Bergsland KJ (2007) Renal inter-alpha-trypsin inhibitor heavy chain 3 increases in calcium oxalate stone-forming patients. Kidney Intl 72:1503–1511

    CAS  Article  Google Scholar 

  37. Evan AP, Coe FL, Rittling SR, Bledsoe SM, Shao Y, Lingeman JE, Worcester EM (2005) Apatite plaque particles in inner medulla of kidneys of calcium oxalate stone formers: osteopontin localization. Kidney Intl 68:145–154

    CAS  Article  Google Scholar 

  38. Khan SR, Rodriguez DE, Gower LB, Monga M (2012) Association of Randall plaque with collagen fibers and membrane vesicles. J Urol 187:1094–1100

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  39. Bost F, arra-Mehrpour M, Martin JP (1998) Inter-alpha-trypsin inhibitor proteoglycan family—a group of proteins binding and stabilizing the extracellular matrix. Eur J Biochem 252:339–346

    CAS  PubMed  Article  Google Scholar 

  40. Merchant M, Cummins T, Wilkey D, Salyer S, Powell D, Klein J, Lederer ED (2008) Proteomic analysis of renal calculi indicates an important role for inflammatory processes in calcium stone formation. Am J Physiol 295:F1254–F1258

    CAS  Google Scholar 

  41. Canales B, Anderson l, Higgins L, Slaton J, Roberts K, Liu N, Monga M (2008) Second prize: comprehensive proteomic analysis of human calcium oxalate monohydrate kidney stone matrix. J Endourol 22:1161–1167

    PubMed  Article  Google Scholar 

  42. Mushtaq S, Siddiqui A, Naqvi Z, Rattani A, Talati J, Palmberg C, Shafqat J (2007) Identification of myeloperoxidase, alpha-defensin and calgranulin in calcium oxalate renal stones. Clin Chim Acata 384:41–47

    CAS  Article  Google Scholar 

  43. Kaneko K, Yamanobe T, Nakagomi K, Mawatari K, Onoda M, Fujimori S (2004) Detection of protein Z in a renal calculus composed of calcium oxalate monohydrate with the use of liquid chromatography-mass spectrometry/mass spectrometry following-two dimensional polyacrylamide gel electrophoresis separation. Anal Biochem 324:191–196

    CAS  PubMed  Article  Google Scholar 

  44. Kaneko K, Yamanobe T, Onoda M, Mawatari K, Nakagomi K, Fujimori S (2005) Analysis of urinary calculi obtained from a patient with idiopathic hypouricemia using micro area x-ray diffractometry and LC-MS. Urol Res 33:415–421

    PubMed  Article  Google Scholar 

  45. Kaneko K, Kobayashi R, Yasuda M, Izumi Y, Yamanobe T, Shimizu T (2012) Comparison of matrix proteins in different types of urinary stone by proteomic analysis using liquid chromatography-tandem mass spectrometry. Int J Urol 19:765–772

    CAS  PubMed  Article  Google Scholar 

  46. Jou YC, Fang CY, Chen SY, Chen FH, Cheng MC, Shen CH, Liao LW, Tsai YS (2012) Proteomic study of renal uric acid stone. Urology 80:260–266

    PubMed  Article  Google Scholar 

  47. Williams JC Jr, McAteer JA, Evan AP, Lingeman JE (2010) Micro-computed tomography for analysis of urinary calculi. Urol Res 38:477–484

    PubMed  Article  Google Scholar 

  48. Asplin JR, Parks JH, Coe FL (1997) Dependence of upper limit of metastability on supersaturation in nephrolithiasis. Kidney Intl 52:1602–1608

    CAS  Article  Google Scholar 

  49. Parks JH, Coward M, Coe FL (1997) Corresondence between stone composition and urine supersaturation in nephrolithiasis. Kidney Intl 51:894–900

    CAS  Article  Google Scholar 

  50. Boyce WH (1968) Organic matrix of human urinary concretions. Am J Med 45:673–683

    CAS  PubMed  Article  Google Scholar 

  51. Boyce W, Garvey FK (1956) The amount and nature of organic matrix in urinary calculi: a review. J Urol 76:213–227

    CAS  PubMed  Google Scholar 

  52. Willis LR, Evan AP, Connors BA, Blomgren PM, Fineberg N, Lingeman JE (1999) Relationship between kidney size, renal injury, and renal impairment induced by shock wave lithotripsy. J Am Soc Nephrol 10:1753–1762

    CAS  PubMed  Google Scholar 

  53. Evan A, Willis L, Lingeman J, McAteer J (1998) Renal trauma and the risk of long-term complications in shock wave lithotripsy. Nephron 78:1–8

    CAS  PubMed  Article  Google Scholar 

  54. McAteer JA, Evan AP (2008) The acute and long-term adverse effects of shock wave lithotripsy. Sem Nephrol 28:200–213

    Article  Google Scholar 

  55. Vervaet BA, Verhulst A, Dauwe SE, De Broe ME, D’Haese PC (2009) An active renal crystal clearance mechanism in rat and man. Kidney Intl 75:41–51

    CAS  Article  Google Scholar 

  56. Jennette JC, Falk RJ (2005) Glomerular clinicopathologic syndrome. In: A Greeburg, AK CHenug (eds.), Primer in kidney disease. Saunders, Philadelphia, pp. 150–169

  57. Khan SR, Hackett RL (1985) Calcium oxalate urolithiasis in the rat: is it a model for human stone disease? A review of recent literature. Scan Electron Microsc 2:759–774

    Google Scholar 

  58. Khan SR, Shevock PN, Rl Hackett (1992) Acute hyperoxaluria, renal injury and calcium oxalate urolithiasis. J Urol 147:226–230

    CAS  PubMed  Google Scholar 

  59. Khan SR (2010) Nephrocalcinosis in animal models with and without stones. Urol Res 38:429–438

    PubMed Central  PubMed  Article  Google Scholar 

  60. Vervaet BA, Verhulst A, D’Haese PC, De Broe ME (2009) Nephrocalcinosis: new insights into mechanisms and consequences. Nephrol Dial Transplant 24:2030–2035

    CAS  PubMed  Article  Google Scholar 

  61. Jiang Z, Asplin JR, Evan AP, Rajendran VM, Velazquez H, Notttoli TP, Binder HJ, Aronson PS (2006) Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6. Nat Genet 38:474–478

    CAS  PubMed  Article  Google Scholar 

  62. Evan AP, Weinman EJ, Wu XR, Lingeman JE, Worcester EM, Coe FL (2010) Comparison of the pathology of interstitial plaque in human ICSF stone patients to NHERF-1 and THP-null mice. Urol Res 38:439–452

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  63. Liu Y, Mo L, Goldfarb DS, Evan AP, Liang F, Khan SR, Lieske JC, Wu XR (2010) Progressive renal papillary calcification and ureteral stone formtion in mice deficent for Tamm-Horsfall protein. Am J Physiol 299:F469–F478

    Google Scholar 

  64. Verkoelen CF, van der Boom BG, Houtsmuller AB, Schroder FH, Romijn JC (1998) Increased calcium oxalate monohydrate crystal binding to injured renal tubular epithelial cells in culture. Am J Physiol 274:F958–F965

    CAS  PubMed  Google Scholar 

  65. Verkoelen CF, van der Boom BG, Kok DJ, Houtsmuller AB, Viser P, Schroder FH, Romijn JC (1999) Cell type-specific acquired protection from crystal adherence by renal tubule cells in culture. Kidney Int 55:1426–1433

    CAS  PubMed  Article  Google Scholar 

  66. Wiessner JH, Hasegawa AT, Hung LY, Mandel GS, Mandel NS (2001) Mechanisms of calcium oxalate crystal attachment to injured renal collecting duct cells. Kidney Int 59:637–644

    CAS  PubMed  Article  Google Scholar 

  67. Khan SR, Thamilselvan S (2000) Nephrolithiasis: a consequence of renal epithelial cell exposure to oxalate and calcium oxalate crystals. Mol Urol 4:305–312

    CAS  PubMed  Google Scholar 

  68. Verhulst A, Asselman M, Persy VP, Schepers MS, Helbert MF, Verkoelen CF, De Broe ME (2003) Crystal retention capacity of cells in the human nephron: involvement of CD44 and its ligands hyaluronic acid and osteopontin in the transition of a crystal binding- into a nonadherent epithelium. J Am Soc Nephrol 14:107–115

    CAS  PubMed  Article  Google Scholar 

  69. Verhulst A, Asselman M, De Naeyer S, Vervaet BA, Mengel M, Gwinnwr W, D’Haese PC, Verkoelen CF, Be Broe ME (2005) Preconditioning of the distal tubular epithelium of the human kidney precedes nephrocalcinosis. Kidney Int 68:1643–1647

    PubMed  Article  Google Scholar 

  70. Parks JH, Coe FL (2009) Evidence for durable kidney stone prevention over several decades. BJU Int 103:1238–1246

    PubMed Central  PubMed  Article  Google Scholar 

Download references

Acknowledgments

This work was supported by NIG grant P01 DK-56788.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Andrew P. Evan.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Evan, A.P., Worcester, E.M., Coe, F.L. et al. Mechanisms of human kidney stone formation. Urolithiasis 43, 19–32 (2015). https://doi.org/10.1007/s00240-014-0701-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00240-014-0701-0

Keywords

  • Interstitial plaque
  • Bellini duct plugs
  • Histopathology
  • Surgical anatomy
  • Renal physiology
  • Stone forming phenotypes