Skip to main content

Advertisement

Log in

Prevalence, pathophysiological mechanisms and factors affecting urolithiasis

  • Urology - Review
  • Published:
International Urology and Nephrology Aims and scope Submit manuscript

Abstract

The formation of urinary stone, urolithiasis, is one the oldest known disease affecting human throughout different civilizations and times. The exact pathophysiological mechanism of urolithiasis is not yet clear, as these calculi are of various types and too complex for simple understanding. A single theory cannot explain its formation; therefore, different theories are presented in various times for its explanation like free particle, fixed particle, Randall’s plaque theory. In addition, various factors and components are identified that play an important role in the formation of these urinary calculi. In this review, composition of kidney stones, its prevalence/incidence, explanation of pathophysiological mechanisms and role of various factors; urinary pH, uric acid, parathyroid hormone, citrate, oxalate, calcium and macromolecules; osteopontin, matrix Gla protein, kidney injury molecules, urinary prothrombin fragment-1, Tamm–Horsfall protein, inter-α-inhibitors, have been discussed in detail.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Lopez M, Hoppe B (2010) History, epidemiology and regional diversities of urolithiasis. Pediatr Nephrol 25(1):49–59

    Article  PubMed  Google Scholar 

  2. Lyu J, Wu R (2014) A brief history of recognition on urolithiasis before medieval period. Zhonghua Yi Shi Za Zhi 44(1):36–39

    PubMed  Google Scholar 

  3. Tefekli A, Cezayirli F (2013) The history of urinary stones: in parallel with civilization. Sci World J 2013:423964

    Google Scholar 

  4. Cloutier J et al (2015) Kidney stone analysis: “give me your stone, I will tell you who you are!”. World J Urol 33:157–169

    Article  PubMed  Google Scholar 

  5. Lemann J Jr (1993) Composition of the diet and calcium kidney stones. N Engl J Med 328(12):880–882

    Article  PubMed  Google Scholar 

  6. Evan AP (2010) Physiopathology and etiology of stone formation in the kidney and the urinary tract. Pediatr Nephrol 25(5):831–841

    Article  PubMed  Google Scholar 

  7. Almazroui M et al (2012) Recent climate change in the Arabian Peninsula: seasonal rainfall and temperature climatology of Saudi Arabia for 1979–2009. Atmos Res 111:29–45

    Article  Google Scholar 

  8. Lieske JC et al (2006) Diabetes mellitus and the risk of urinary tract stones: a population-based case–control study. Am J Kidney Dis 48:897–904

    Article  PubMed  Google Scholar 

  9. Obligado SH, Goldfarb DS (2008) The association of nephrolithiasis with hypertension and obesity: a review. Am J Hypertens 21:257–264

    Article  CAS  PubMed  Google Scholar 

  10. Rezaee ME et al (2017) Association between multiple chronic conditions and urolithiasis. Int Urol Nephrol 49(8):1361–1367

    Article  PubMed  Google Scholar 

  11. Polat EC et al (2015) Relationship between calcium stone disease and metabolic syndrome. Urol J 12:2391–2395

    PubMed  Google Scholar 

  12. Saucier NA et al (2010) Risk factors for CKD in persons with kidney stones: a case–control study in Olmsted County, Minnesota. Am J Kidney Dis 55(1):61–68

    Article  PubMed  Google Scholar 

  13. Grover PK, Kim DS, Ryall RL (2002) The effect of seed crystals of hydroxyapatite and brushite on the crystallization of calcium oxalate in undiluted human urine in vitro: implications for urinary stone pathogenesis. Mol Med 8(4):200–209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kirkali Z et al (2015) Urinary stone disease: progress, status, and needs. Urology 86(4):651–653

    Article  PubMed  PubMed Central  Google Scholar 

  15. Soucie JM et al (1994) Demographic and geographic variability of kidney stones in the United States. Kidney Int 46(3):893–899

    Article  CAS  PubMed  Google Scholar 

  16. Brikowski TH, Lotan Y, Pearle MS (2008) Climate-related increase in the prevalence of urolithiasis in the United States. Proc Natl Acad Sci USA 105(28):9841–9846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pak CY (1998) Kidney stones. Lancet 351(9118):1797–1801

    Article  CAS  PubMed  Google Scholar 

  18. Stamatelou KK et al (2003) Time trends in reported prevalence of kidney stones in the United States: 1976–1994. Kidney Int 63(5):1817–1823

    Article  PubMed  Google Scholar 

  19. Hussain M et al (2009) Management of stone disease: 17 years experience of a stone clinic in a developing country. J Pak Med Assoc 59(12):843–846

    PubMed  Google Scholar 

  20. Moe OW (2006) Kidney stones: pathophysiology and medical management. Lancet 367(9507):333–344

    Article  CAS  PubMed  Google Scholar 

  21. Resnick M, Pridgen DB, Goodman HO (1968) Genetic predisposition to formation of calcium oxalate renal calculi. N Engl J Med 278(24):1313–1318

    Article  CAS  PubMed  Google Scholar 

  22. Smith LH (1989) The medical aspects of urolithiasis: an overview. J Urol 141(3 Pt 2):707–710

    Article  CAS  PubMed  Google Scholar 

  23. Danpure CJ (2000) Genetic disorders and urolithiasis. Urol Clin N Am 27(2):287–299

    Article  CAS  Google Scholar 

  24. Curhan GC et al (1997) Family history and risk of kidney stones. J Am Soc Nephrol 8(10):1568–1573

    CAS  PubMed  Google Scholar 

  25. Ljunghall S (1979) Family history of renal stones in a population study of stone-formers and health subjects. Br J Urol 51(4):249–252

    Article  CAS  PubMed  Google Scholar 

  26. Knoll T et al (2011) Urolithiasis through the ages: data on more than 200,000 urinary stone analyses. J Urol 185(4):1304–1311

    Article  PubMed  Google Scholar 

  27. Garcia-Raia A, Conte A, Grases F (1991) The origin and causes of struvite stones. Int Urol Nephrol 23(6):537–542

    Article  CAS  PubMed  Google Scholar 

  28. Schey HM, Corbett WT, Resnick MI (1979) Prevalence rate of renal stone disease in Forsyth County, North Carolina during 1977. J Urol 122(3):288–291

    Article  CAS  PubMed  Google Scholar 

  29. Graves EJ, Gillum BS (1997) Detailed diagnoses and procedures, National Hospital Discharge Survey, 1995. Vital Health Stat 13(99):1–60

    Google Scholar 

  30. Kohri K et al (1991) Epidemiology of urolithiasis in the elderly. Int Urol Nephrol 23(5):413–421

    Article  CAS  PubMed  Google Scholar 

  31. Naghii MR, Hedayati M (2010) Determinant role of gonadal sex hormones in the pathogenesis of urolithiasis in a male subject—a document for male predominancy (case study). Endocr Regul 44(4):143–146

    Article  CAS  PubMed  Google Scholar 

  32. Yagisawa T et al (2001) The influence of sex hormones on renal osteopontin expression and urinary constituents in experimental urolithiasis. J Urol 166(3):1078–1082

    Article  CAS  PubMed  Google Scholar 

  33. Lee YH et al (1992) Determinant role of testosterone in the pathogenesis of urolithiasis in rats. J Urol 147(4):1134–1138

    Article  CAS  PubMed  Google Scholar 

  34. Aihara K, Byer KJ, Khan SR (2003) Calcium phosphate-induced renal epithelial injury and stone formation: involvement of reactive oxygen species. Kidney Int 64(4):1283–1291

    Article  CAS  PubMed  Google Scholar 

  35. Escobar C et al (2008) Apatite induced renal epithelial injury: insight into the pathogenesis of kidney stones. J Urol 180(1):379–387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Worcester EM, Coe FL (2008) Nephrolithiasis. Prim Care 35(2):369–391

    Article  PubMed  PubMed Central  Google Scholar 

  37. Baumann JM (1998) Stone prevention: why so little progress? Urol Res 26(2):77–81

    Article  CAS  PubMed  Google Scholar 

  38. Khan SR (2004) Role of renal epithelial cells in the initiation of calcium oxalate stones. Nephron Exp Nephrol 98(2):e55–e60

    Article  CAS  PubMed  Google Scholar 

  39. Khan SR, Kok DJ (2004) Modulators of urinary stone formation. Front Biosci 9:1450–1482

    Article  CAS  PubMed  Google Scholar 

  40. Coe FL, Evan A, Worcester E (2005) Kidney stone disease. J Clin Invest 115(10):2598–2608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Atmani F et al (2003) Prophylaxis of calcium oxalate stones by Herniaria hirsuta on experimentally induced nephrolithiasis in rats. BJU Int 92(1):137–140

    Article  CAS  PubMed  Google Scholar 

  42. Ryall RL (1997) Urinary inhibitors of calcium oxalate crystallization and their potential role in stone formation. World J Urol 15(3):155–164

    Article  CAS  PubMed  Google Scholar 

  43. Khan SR, Glenton PA, Byer KJ (2006) Modeling of hyperoxaluric calcium oxalate nephrolithiasis: experimental induction of hyperoxaluria by hydroxy-l-proline. Kidney Int 70(5):914–923

    Article  CAS  PubMed  Google Scholar 

  44. Kok DJ (1997) Intratubular crystallization events. World J Urol 15(4):219–228

    Article  CAS  PubMed  Google Scholar 

  45. Lieske JC, Deganello S (1999) Nucleation, adhesion, and internalization of calcium-containing urinary crystals by renal cells. J Am Soc Nephrol 10(Suppl 14):S422–S429

    CAS  PubMed  Google Scholar 

  46. Coe FL et al (2010) Three pathways for human kidney stone formation. Urol Res 38(3):147–160

    Article  PubMed  PubMed Central  Google Scholar 

  47. Byer K, Khan SR (2005) Citrate provides protection against oxalate and calcium oxalate crystal induced oxidative damage to renal epithelium. J Urol 173(2):640–646

    Article  CAS  PubMed  Google Scholar 

  48. Santhosh Kumar M, Selvam R (2003) Supplementation of vitamin E and selenium prevents hyperoxaluria in experimental urolithic rats. J Nutr Biochem 14(6):306–313

    Article  CAS  PubMed  Google Scholar 

  49. Thamilselvan S, Khan SR, Menon M (2003) Oxalate and calcium oxalate mediated free radical toxicity in renal epithelial cells: effect of antioxidants. Urol Res 31(1):3–9

    CAS  PubMed  Google Scholar 

  50. Khan SR, Canales BK (2015) A unified theory on the pathogenesis of Randall’s plaques and plugs. Urolithiasis 43(01):109–123

    Article  CAS  PubMed  Google Scholar 

  51. Li WM et al (2009) Association of body mass index and urine pH in patients with urolithiasis. Urol Res 37(4):193–196

    Article  PubMed  Google Scholar 

  52. Iida S (1991) Effects of urinary pH and acid-base balance on the formation of calcium oxalate stone. Nippon Hinyokika Gakkai Zasshi 82(1):33–40

    CAS  PubMed  Google Scholar 

  53. Wagner CA, Mohebbi N (2010) Urinary pH and stone formation. J Nephrol 23(Suppl 16):S165–S169

    PubMed  Google Scholar 

  54. Coe FL et al (1980) Uric acid saturation in calcium nephrolithiasis. Kidney Int 17(5):662–668

    Article  CAS  PubMed  Google Scholar 

  55. Grover PK, Ryall RL, Marshall VR (1990) Effect of urate on calcium oxalate crystallization in human urine: evidence for a promotory role of hyperuricosuria in urolithiasis. Clin Sci (Lond) 79(1):9–15

    Article  CAS  Google Scholar 

  56. Coe FL, Bushinsky DA (1984) Pathophysiology of hypercalciuria. Am J Physiol 247(1 Pt 2):F1–F13

    CAS  PubMed  Google Scholar 

  57. Parks J, Coe F, Favus M (1980) Hyperparathyroidism in nephrolithiasis. Arch Intern Med 140(11):1479–1481

    Article  CAS  PubMed  Google Scholar 

  58. Bek-Jensen H et al (1996) Is citrate an inhibitor of calcium oxalate crystal growth in high concentrations of urine? Urol Res 24(2):67–71

    Article  CAS  PubMed  Google Scholar 

  59. Caudarella R, Vescini F (2009) Urinary citrate and renal stone disease: the preventive role of alkali citrate treatment. Arch Ital Urol Androl 81(3):182–187

    PubMed  Google Scholar 

  60. Minisola S et al (1989) Studies on citrate metabolism in normal subjects and kidney stone patients. Miner Electrolyte Metab 15(5):303–308

    CAS  PubMed  Google Scholar 

  61. Goktas C et al (2012) The effect of citrate replacement in hypocitraturic cases on the results of SWL: a preliminary prospective randomized study. Int Urol Nephrol 44(5):1357–1362

    Article  PubMed  Google Scholar 

  62. Govaris A et al (2010) The antimicrobial effect of oregano essential oil, nisin and their combination against Salmonella Enteritidis in minced sheep meat during refrigerated storage. Int J Food Microbiol 137(2–3):175–180

    Article  CAS  PubMed  Google Scholar 

  63. Coe FL, Parks JH, Asplin JR (1992) The pathogenesis and treatment of kidney stones. N Engl J Med 327(16):1141–1152

    Article  CAS  PubMed  Google Scholar 

  64. Coe FL, Parks JH, Moore ES (1979) Familial idiopathic hypercalciuria. N Engl J Med 300(7):337–340

    Article  CAS  PubMed  Google Scholar 

  65. Mehes K, Szelid Z (1980) Autosomal dominant inheritance of hypercalciuria. Eur J Pediatr 133(3):239–242

    Article  CAS  PubMed  Google Scholar 

  66. Coe FL et al (1982) Effects of low-calcium diet on urine calcium excretion, parathyroid function and serum 1,25(OH)2D3 levels in patients with idiopathic hypercalciuria and in normal subjects. Am J Med 72(1):25–32

    Article  CAS  PubMed  Google Scholar 

  67. Price PA, Urist MR, Otawara Y (1983) Matrix Gla protein, a new gamma-carboxyglutamic acid-containing protein which is associated with the organic matrix of bone. Biochem Biophys Res Commun 117(3):765–771

    Article  CAS  PubMed  Google Scholar 

  68. Fraser J, Price P (1988) Lung, heart, and kidney express high levels of mRNA for the vitamin K-dependent matrix Gla protein. Implications for the possible functions of matrix Gla protein and for the tissue distribution of the gamma-carboxylase. J Biol Chem 263(23):11033–11036

    CAS  PubMed  Google Scholar 

  69. Murshed M et al (2004) Extracellular matrix mineralization is regulated locally; different roles of two Gla-containing proteins. J Cell Biol 165(5):625–630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Schurgers LJ, Cranenburg EC, Vermeer C (2008) Matrix Gla-protein: the calcification inhibitor in need of vitamin K. Thromb Haemost 100(4):593–603

    CAS  PubMed  Google Scholar 

  71. Luo G et al (1997) Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 386(6620):78–81

    Article  CAS  PubMed  Google Scholar 

  72. Proudfoot D, Shanahan C (2006) Molecular mechanisms mediating vascular calcification: role of matrix Gla protein. Nephrology (Carlton) 11(5):455–461

    Article  CAS  Google Scholar 

  73. Torres L et al (2009) Coagulation–flocculation process applied to wastewaters generated in hydrocarbon-contaminated soil washing: interactions among coagulant and flocculant concentrations and pH value. J Environ Sci Health A Tox Hazard Subst Environ Eng 44(13):1449–1456

    Article  CAS  PubMed  Google Scholar 

  74. Cranenburg EC et al (2009) Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification in haemodialysis patients. Thromb Haemost 101(2):359–366

    CAS  PubMed  Google Scholar 

  75. Cozzolino M (2009) Matrix-Gla protein and vascular calcification: the negative role of oral anticoagulant therapy. Thromb Haemost 101(4):605–606

    CAS  PubMed  Google Scholar 

  76. Gao B et al (2010) Matrix Gla protein expression in NRK-52E cells exposed to oxalate and calcium oxalate monohydrate crystals. Urol Int 85(2):237–241

    Article  CAS  PubMed  Google Scholar 

  77. Khan A, Wang W, Khan SR (2014) Calcium oxalate nephrolithiasis and expression of matrix GLA protein in the kidneys. World J Urol 32(1):123–130

    Article  CAS  PubMed  Google Scholar 

  78. Yasui T et al (1999) Expression of bone matrix proteins in urolithiasis model rats. Urol Res 27(4):255–261

    Article  CAS  PubMed  Google Scholar 

  79. Wang L et al (2000) Altered gene expression in kidneys of mice with 2,8-dihydroxyadenine nephrolithiasis. Kidney Int 58(2):528–536

    Article  CAS  PubMed  Google Scholar 

  80. Gao B et al (2007) A polymorphism of matrix Gla protein gene is associated with kidney stones. J Urol 177(6):2361–2365

    Article  CAS  PubMed  Google Scholar 

  81. Viuda-Martos M et al (2010) Antioxidant activity of essential oils of five spice plants widely used in a Mediterranean diet. Flavour Fragr J 25(1):13–19

    Article  CAS  Google Scholar 

  82. Zuo J et al (2011) Effect of NADPH oxidase inhibition on the expression of kidney injury molecule and calcium oxalate crystal deposition in hydroxy-l-proline-induced hyperoxaluria in the male Sprague-Dawley rats. Nephrol Dial Transplant 26(6):1785–1796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bonventre VSV, Victoria R, Takaharu I, Norma AB, Joseph V (2006) Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury. Am J Physiol Renal Physiol 290(2):F517–F529

    Article  PubMed  CAS  Google Scholar 

  84. Doyle IR, Ryall RL, Marshall VR (1991) Inclusion of proteins into calcium oxalate crystals precipitated from human urine: a highly selective phenomenon. Clin Chem 37(9):1589–1594

    CAS  PubMed  Google Scholar 

  85. Grover PK, Ryall RL (1999) Inhibition of calcium oxalate crystal growth and aggregation by prothrombin and its fragments in vitro: relationship between protein structure and inhibitory activity. Eur J Biochem 263(1):50–56

    Article  CAS  PubMed  Google Scholar 

  86. Boskey AL (1989) Phospholipids and calcification. In: Hukins D (ed) Calcified tissue. CRC Press, Boca Raton, pp 215–243

    Chapter  Google Scholar 

  87. Webber D, Rodgers AL, Sturrock ED (2002) Synergism between urinary prothrombin fragment 1 and urine: a comparison of inhibitory activities in stone-prone and stone-free population groups. Clin Chem Lab Med 40(9):930–936

    Article  CAS  PubMed  Google Scholar 

  88. Grover PK, Ryall RL (2002) Effect of prothrombin and its activation fragments on calcium oxalate crystal growth and aggregation in undiluted human urine in vitro: relationship between protein structure and inhibitory activity. Clin Sci (Lond) 102(4):425–434

    Article  CAS  Google Scholar 

  89. Webber D et al (2006) Sialylation of urinary prothrombin fragment 1 is implicated as a contributory factor in the risk of calcium oxalate kidney stone formation. FEBS J 273(13):3024–3037

    Article  CAS  PubMed  Google Scholar 

  90. Webber D, Rodgers AL, Sturrock ED (2007) Glycosylation of prothrombin fragment 1 governs calcium oxalate crystal nucleation and aggregation, but not crystal growth. Urol Res 35(6):277–285

    Article  CAS  PubMed  Google Scholar 

  91. Tamm I, Horsfall FL Jr (1950) Characterization and separation of an inhibitor of viral hemagglutination present in urine. Proc Soc Exp Biol Med 74(1):106–108

    Article  CAS  PubMed  Google Scholar 

  92. Hess B (1992) Tamm–Horsfall glycoprotein–inhibitor or promoter of calcium oxalate monohydrate crystallization processes? Urol Res 20(1):83–86

    Article  CAS  PubMed  Google Scholar 

  93. Hallson PC, Rose GA (1979) Uromucoids and urinary stone formation. Lancet 1(8124):1000–1002

    Article  CAS  PubMed  Google Scholar 

  94. Rose GA, Sulaiman S (1982) Tamm–Horsfall mucoproteins promote calcium oxalate crystal formation in urine: quantitative studies. J Urol 127(1):177–179

    Article  CAS  PubMed  Google Scholar 

  95. Tang Y et al (1995) Is nephrocalcin related to the urinary derivative (bikunin) of inter-α-trypsin inhibitor? Br J Urol 76(4):425–430

    Article  CAS  PubMed  Google Scholar 

  96. Witte J et al (1982) Disturbances of selected plasma proteins in hyperdynamic septic shock. Intensive Care Med 8(5):215–222

    Article  CAS  PubMed  Google Scholar 

  97. Franck C, Pedersen JZ (1983) Trypsin-inhibitory activities of acid-stable fragments of the inter-alpha-trypsin inhibitor in inflammatory and uraemic conditions. Scand J Clin Lab Invest 43(2):151–155

    Article  CAS  PubMed  Google Scholar 

  98. Owyang C et al (1982) Pancreatic exocrine function in severe human chronic renal failure. Gut 23(5):357–361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Thogersen IB, Enghild JJ (1995) Biosynthesis of bikunin proteins in the human carcinoma cell line HepG2 and in primary human hepatocytes. Polypeptide assembly by glycosaminoglycan. J Biol Chem 270(31):18700–18709

    Article  CAS  PubMed  Google Scholar 

  100. Yoshida E et al (1994) Immunohistochemical demonstration of bikunin, a light chain of inter-alpha-trypsin inhibitor, in human brain tumors. Inflammation 18(6):589–596

    Article  CAS  PubMed  Google Scholar 

  101. Toki N, Sumi H (1982) Urinary trypsin inhibitor and urokinase activities in renal diseases. Acta Haematol 67(2):109–113

    Article  CAS  PubMed  Google Scholar 

  102. Iida S et al (1999) Temporal changes in mRNA expression for bikunin in the kidneys of rats during calcium oxalate nephrolithiasis. J Am Soc Nephrol 10(5):986–996

    CAS  PubMed  Google Scholar 

  103. Bauer J (1911) Die Biologie des Kolostrums (einschliesslich Fermente). Ergebnisse der Physiologie, biologischen Chemie und experimentellen Pharmakologie 11(1):104–120

    Article  Google Scholar 

  104. Moriyama MT, Glenton PA, Khan SR (2001) Expression of inter-alpha inhibitor related proteins in kidneys and urine of hyperoxaluric rats. J Urol 165(5):1687–1692

    Article  CAS  PubMed  Google Scholar 

  105. Atmani F, Khan SR (1999) Role of urinary bikunin in the inhibition of calcium oxalate crystallization. J Am Soc Nephrol 10(Suppl 14):S385–S388

    CAS  PubMed  Google Scholar 

  106. Ebisuno S et al (1999) Bikunin prevents adhesion of calcium oxalate crystal to renal tubular cells in human urine. J Am Soc Nephrol 10(Suppl 14):S436–S440

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Aslam Khan.

Ethics declarations

Conflict of interest

The author declares that they have no conflict of interest.

Funding

This is not a funded study.

Ethical approval

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khan, A. Prevalence, pathophysiological mechanisms and factors affecting urolithiasis. Int Urol Nephrol 50, 799–806 (2018). https://doi.org/10.1007/s11255-018-1849-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11255-018-1849-2

Keywords

Navigation