Review Article | Published:

Current insights into the mechanisms and management of infection stones


Infection stones are complex aggregates of crystals amalgamated in an organic matrix that are strictly associated with urinary tract infections. The management of patients who form infection stones is challenging owing to the complexity of the calculi and high recurrence rates. The formation of infection stones is a multifactorial process that can be driven by urine chemistry, the urine microenvironment, the presence of modulator substances in urine, associations with bacteria, and the development of biofilms. Despite decades of investigation, the mechanisms of infection stone formation are still poorly understood. A mechanistic understanding of the formation and growth of infection stones — including the role of organics in the stone matrix, microorganisms, and biofilms in stone formation and their effect on stone characteristics — and the medical implications of these insights might be crucial for the development of improved treatments. Tools and approaches used in various disciplines (for example, engineering, chemistry, mineralogy, and microbiology) can be applied to further understand the microorganism–mineral interactions that lead to infection stone formation. Thus, the use of integrated multidisciplinary approaches is imperative to improve the diagnosis, prevention, and treatment of infection stones.

Key points

  • Urine chemistry has a key role in infection stone formation and is determined by the saturation conditions, pH, and the presence of modulators of crystallization and aggregation in the urine.

  • Organic substances associated with infection stones influence their physical characteristics (for example, hardness) and could also be involved in stone formation.

  • Struvite stones are associated with urinary tract infections and are formed as a result of biomineralization by urea-hydrolysing microorganisms.

  • Positive stone cultures suggest the association of bacteria with calcium-based stones; however, the role of bacteria (active or passive) in the lithogenesis of calcium-based stones requires further examination.

  • The development of microbial biofilms complicates renal conditions and treatments; biofilm mechanical stability and resistance to treatment is increased by the biomineralization process.

  • Infection stone management strategies should rely on the proper identification and characterization of stones and an understanding of stone formation, stone microbiology, and the influence of biofilms on stone characteristics.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Pearle, M. S., Calhoun, E. A. & Curhan, G. C. Urological diseases in America project: urolithiasis. J. Urol. 173, 848–857 (2005).

  2. 2.

    Saigal, C. S., Joyce, G. & Timilsina, A. R. Direct and indirect costs of nephrolithiasis in an employed population: opportunity for disease management? Kidney Int. 68, 1808–1814 (2005).

  3. 3.

    Foster, G., Stocks, C. & Borofsky, M. S. Emergency department visits and hospital admissions for kidney stone disease, 2009: statistical brief #139. NCBI (2012).

  4. 4.

    Romero, C. V., Akpinar, H. & Assimos, D. G. Kidney stones: a global picture of prevalence, incidence and associated risk factors. Rev. Urol. 12, e86–e96 (2010).

  5. 5.

    Brikowski, T. H., Lotan, Y. & Pearle, M. S. Climate-related increase in the prevalence of urolithiasis in the United States. Proc. Natl Acad. Sci. USA 105, 9841–9846 (2008).

  6. 6.

    Scales, Jr, C. D., Smith, A. C., Hanley, J. M. & Saigal, C. S. Prevalence of kidney stones in the United States. Eur. Urol. 62, 160–165 (2012).

  7. 7.

    Becker, G. The CARI guidelines. Kidney stones: uric acid stones. Nephrology 12 (Suppl. 1), 21–25 (2007).

  8. 8.

    Becker, G. The CARI guidelines. Kidney stones: cystine stones. Nephrology 12 (Suppl. 1), 4–10 (2007).

  9. 9.

    Evan, A. P. Physiopathology and etiology of stone formation in the kidney and the urinary tract. Pediatr. Nephrol. 25, 831–841 (2010).

  10. 10.

    Parmar, M. S. Kidney stones. BMJ 328, 1420–1424 (2004).

  11. 11.

    Bichler, K. H. et al. Urinary infection stones. Int. J. Antimicrob. Agents 19, 488–498 (2002).

  12. 12.

    Doyle, J. D. & Parsons, S. A. Struvite formation, control and recovery. Wat. Res. 36, 3925–3940 (2002).

  13. 13.

    Griffith, D. P. Struvite stones. Kidney Int. 13, 372–382 (1978).

  14. 14.

    Prywer, J. & Olszynski, M. Bacterially induced formation of infectious urinary stones: recent developments and future challenges. Curr. Med. Chem. 24, 292–311 (2017).

  15. 15.

    Resnick, M. Evaluation and management of infection stones. Urol. Clin. North Am. 8, 265–276 (1981).

  16. 16.

    Schultz, L. N., Connolly, J., Lauchnor, E., Hobbs, T. A. & Gerlach, R. in The Role of Bacteria in Urology (eds Lange, D. & Chew, B.) 41–49 (Springer International Publishing, 2016).

  17. 17.

    Trinchieri, A., Curhan, G., Karlsen, S. & Wu, K. J. in Proceedings of 1st International Consultation on Stone Disease (eds Segura, J., Conort, P. & Khoury, S.) 13 (Editions 21, Paris, 2003).

  18. 18.

    Worcester, E. M. & Coe, F. L. Nephrolithiasis. Prim. Care 35, 369–391 (2008).

  19. 19.

    Hodgkinson, A. & Pyrah, L. N. The urinary excretion of calcium and inorganic phosphate in 344 patients with calcium stone of renal origin. Br. J. Surg. 46, 10–18 (1958).

  20. 20.

    Chow, K., Dixon, J., Gilpin, S., Kavanagh, J. P. & Rao, P. N. Citrate inhibits growth of residual fragments in an in vitro model of calcium oxalate renal stones. Kidney Int. 65, 1724–1730 (2004).

  21. 21.

    Asplin, J. R. Hyperoxaluric calcium nephrolithiasis. Endocrinol. Metab. Clin. North Am. 31, 987–949 (2002).

  22. 22.

    Robertson, W. G., Peacock, M., Heyburn, P. J., Marshall, D. H. & Clark, P. B. Risk factors in calcium stone disease of the urinary tract. Br. J. Urol. 50, 449–454 (1978).

  23. 23.

    Parks, J. H., Coe, F. L., Evan, A. P. & Worcester, E. M. Urine pH in renal calcium stone formers who do and do not increase stone phosphate content with time. Nephrol. Dial. Transplant. 24, 130–136 (2009).

  24. 24.

    Parks, J. H., Worcester, E. M., Coe, F. L., Evan, A. P. & Lingeman, J. E. Clinical implications of abundant calcium phosphate in routinely analyzed kidney stones. Kidney Int. 66, 777–785 (2004).

  25. 25.

    Daudon, M., Bouzidi, H. & Bazin, D. Composition and morphology of phosphate stones and their relation with etiology. Urol. Res. 38, 459–467 (2010).

  26. 26.

    Wagner, C. A. & Mohebbi, N. Urinary pH and stone formation. J. Nephrol. 23, S165–S169 (2010).

  27. 27.

    Daudon, M. et al. Sex- and age-related composition of 10617 calculi analyzed by infrared spectroscopy. Urol. Res. 23, 319–326 (1995).

  28. 28.

    Sakhaee, K., Adams-Huet, B., Moe, O. W. & Pak, C. Y. C. Pathophysiologic basis for normouricosuric uric acid nephrolithiasis. Kidney Int. 62, 971–979 (2002).

  29. 29.

    Halabe, A. & Sperling, O. Uric acid nephrolithiasis. Miner. Electrolyte Metab. 20, 424–431 (1994).

  30. 30.

    Ahmed, K., Dasgupta, P. & Khan, M. S. Cystine calculi: challenging group of stones. Postgrad. Med. J. 82, 799–801 (2006).

  31. 31.

    Daudon, M. & Jungers, P. in Urinary Tract Stone Disease (eds Rao, N. P., Preminger, G. M. & Kavanagh, J. P.) 225–237 (Springer London, 2011).

  32. 32.

    Yarlagadda, S. G. & Perazella, M. A. Drug-induced crystal nephropathy: an update. Expert Opin. Drug Saf. 7, 147–158 (2008).

  33. 33.

    Cohen, T. D. & Preminger, G. M. Struvite calculi. Semin. Nephrol. 16, 425–434 (1996).

  34. 34.

    Lerner, S. P., Gleeson, M. J. & Griffith, D. P. Infection stones. J. Urol. 141, 753–758 (1989).

  35. 35.

    Singh, M., Chapman, R., Tresidder, G. C. & Blandy, J. The fate of the unoperated staghon calculus. BJU Int. 45, 581–585 (1973).

  36. 36.

    Deutsch, P. G. & Subramonian, K. Conservative management of staghorn calculi: a single-centre experience. BJU Int. 118, 444–450 (2016).

  37. 37.

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

  38. 38.

    Stasinou, T., Bourdoumis, A. & Masood, J. Forming a stone in pelviureteric junction obstruction: cause or effect? Int. Braz. J. Urol. 43, 13–19 (2017).

  39. 39.

    Becknell, B. et al. Struvite urolithiasis and chronic urinary tract infection in a murine model of urinary diversion. Urology 81, 943–948 (2013).

  40. 40.

    Becknell, B., Mohamed, A. Z., Li, B., Wilhide, M. E. & Ingraham, S. E. Urine stasis predisposes to urinary tract infection by an opportunistic uropathogen in the megabladder (Mgb) mouse. PLOS ONE 10, e0139077 (2015).

  41. 41.

    Dorsher, P. T. & McIntosh, P. M. Neurogenic bladder. Adv. Urol. 2012, 16 (2012).

  42. 42.

    Stickler, D. J. Clinical complications of urinary catheters caused by crystalline biofilms: something needs to be done. J. Int. Med. 276, 120–129 (2014).

  43. 43.

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

  44. 44.

    Preminger, G. M. et al. AUA guideline on management of staghorn calculi: diagnosis and treatment recommendations. J. Urol. 173, 1991–2000 (2005).

  45. 45.

    Iqbal, M. W. et al. Contemporary management of struvite stones using combined endourologic and medical treatment: predictors of unfavorable clinical outcome. J. Endourol. 30, 771–777 (2016).

  46. 46.

    Lingeman, J. E., Siegel, Y. I. & Steele, B. Metabolic evaluation of infected renal lithiasis: clinical relevance. J. Endourol. 9, 51–54 (1995).

  47. 47.

    Flannigan, R. K. et al. Evaluating factors that dictate struvite stone composition: a multi-institutional clinical experience from the EDGE Research Consortium. Can. Urol. Assoc. J. 12, 131–136 (2018).

  48. 48.

    Iqbal, M. W. et al. Should metabolic evaluation be performed in patients with struvite stones? Urolithiasis 45, 185–192 (2017).

  49. 49.

    Boyce, W. H. Organic matrix of human urinary concretions. Am. J. Med. 45, 673–683 (1968).

  50. 50.

    Boonla, C., Youngjermchan, P., Pumpaisanchai, S., Tungsanga, K. & Tosukhowong, P. Lithogenic activity and clinical relevance of lipids extracted from urines and stones of nephrolithiasis patients. Urol. Res. 39, 9–19 (2011).

  51. 51.

    Roberts, S. & Resnick, M. Glycosaminoglycans content of stone matrix. J. Urol. 135, 1078–1083 (1986).

  52. 52.

    Khan, S. R., Glenton, P. A., Backvov, R. & Talham, D. R. Presence of lipids in urine, crystals and stones: implications for the formation of kidney stones. Kidney Int. 62, 2062–2072 (2002).

  53. 53.

    Iida, S. et al. Analysis of matrix glycosaminoglycans (GAGs) in urinary stones by high-performance liquid chromatography. Scann. Microsc. 13, 173–181 (1999).

  54. 54.

    Nishio, S. et al. Matrix glycosaminoglycan in urinary stones. J. Urol. 134, 503–505 (1985).

  55. 55.

    Gilbert, P. U. P. A. The organic-mineral interface in biominerals. Rev. Miner. Geochem. 59, 157–185 (2005).

  56. 56.

    Chen, L. et al. Seed-mediated synthesis of unusual struvite hierarchical superstructures using bacterium. Cryst. Growth Des. 10, 2073–2082 (2010).

  57. 57.

    Prywer, J. & Torzewska, A. Bacterially induced struvite growth from synthetic urine: experimental and theoretical characterization of crystal morphology. Cryst. Growth Des. 9, 3538–3543 (2009).

  58. 58.

    Prywer, J. & Torzewska, A. Biomineralization of struvite crystals by Proteus mirabilis from artificial urine and their mesoscopic structure. Cryst. Res. Technol. 45, 1283–1289 (2010).

  59. 59.

    Prywer, J., Torzewska, A. & Plocinski, T. Unique surface and internal structure of struvite crystals formed by Proteus mirabilis. Urol. Res. 40, 699–707 (2012).

  60. 60.

    Sadowski, R. R., Prywer, J. & Torzewska, A. Morphology of struvite crystals as an evidence of bacteria mediated growth. Cryst. Res. Technol. 49, 478–489 (2014).

  61. 61.

    Sun, J. et al. Synthesis of struvite crystals by using bacteria Proteus mirabilis. Synt. React. Inorg. M. 42, 445–448 (2012).

  62. 62.

    Li, X. et al. In situ biomineralization and particle deposition distinctively mediate biofilm susceptibility to chlorine. Appl. Environ. Microbiol. 82, 2886–2892 (2016).

  63. 63.

    Sutherland, I. W. Biofilm exopolysaccharides: a strong and sticky framework. Microbiology 147, 3–9 (2001).

  64. 64.

    Tourney, J. & Ngwenya, B. T. The role of bacterial extracellular polymeric substances in geomicrobiology. Chem. Geol. 386, 115–132 (2014).

  65. 65.

    Ringdén, I. & Tiselius, H.-G. Composition and clinically determined hardness of urinary tract stones. Scand. J. Urol. Nephrol. 41, 316–323 (2007).

  66. 66.

    Zhong, P., Chuong, C. J. & Preminger, G. M. Characterization of fracture toughness of renal calculi using a microindentation technique. J. Mat. Sci. Lett. 12, 1460–1462 (1993).

  67. 67.

    Kohri, K. et al. Biomolecular mechanism of urinary stone formation involving osteopontin. Urol. Res. 40, 623–637 (2012).

  68. 68.

    Piechota, J., Prywer, J. & Torzewska, A. Ab initio predictions of structural and elastic properties of struvite: contribution to urinary stone research. Comput. Methods Biomech. Biomed. Engin. 15, 1329–1336 (2012).

  69. 69.

    Strakosha, R., Monga, M. & Wong, M. Y. C. The relevance of Randall’s plaques. Indian J. Urol. 30, 49–54 (2014).

  70. 70.

    Jaeger, C. D. et al. Endoscopic and pathologic characterization of papillary architecture in struvite stone formers. Urology 90, 39–44 (2016).

  71. 71.

    Evan, A. P. et al. Mechanism of formation of human calcium oxalate renal stones on Randall’s Plaque. Anat. Rec. 290, 1315–1323 (2007).

  72. 72.

    Coe, F. L., Evan, A. P., Worcester, E. M. & Lingeman, J. E. Three pathways for human kidney stone formation. Urol. Res. 38, 147–160 (2010).

  73. 73.

    Bouropoulos, N. C. & Koutsoukos, P. G. Spontaneous precipitation of struvite from aqueous solutions. J. Cryst. Growth 213, 381–388 (2000).

  74. 74.

    Khan, S. R. Renal tubular damage/dysfunction: key to the formation of kidney stones. Urol. Res. 34, 86–91 (2006).

  75. 75.

    Liu, X. Y. Heterogeneous nucleation or homogeneous nucleation? J. Chem. Phys. 112, 9949–9955 (2000).

  76. 76.

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

  77. 77.

    Prywer, J., Mielniczek-Brzóska, E. & Olszynski, M. Struvite crystal growth inhibition by trisodium citrate and the formation of chemical complexes in growth solution. J. Cryst. Growth 418, 92–101 (2015).

  78. 78.

    Wierzbicki, A., Sallis, J. D., Stevens, E. D., Smith, M. & Sikes, C. S. Crystal growth and molecular modeling studies of inhibition of struvite by phosphocitrate. Calcif. Tissue Int. 61, 216–222 (1997).

  79. 79.

    McLean, R. J. C. & Nickel, J. C. Glycosaminoglycans and struvite calculi. World J. Urol. 12, 49–51 (1994).

  80. 80.

    Torzewska, A. & Rozalski, A. In vitro studies on the role of glycosaminoglycans in crystallization intensity during infectious urinary stones formation. APMIS 122, 505–511 (2014).

  81. 81.

    De Yoreo, J. J. & Vekilov, P. G. Principles of crystal nucleation and growth. Rev. Min. Geochem. 54, 57–93 (2003).

  82. 82.

    Aggarwal, K. P., Narula, S., Kakkar, M. & Tandon, C. Nephrolithiasis: molecular mechanism of renal stone formation and the critical role played by modulators. Biomed. Res. Int. 2013, 292953 (2013).

  83. 83.

    Fleisch, H. Inhibitors and promoters of stone formation. Kidney Int. 13, 361–371 (1978).

  84. 84.

    Vermeulen, C. & Lyon, E. Mechanisms of genesis and growth of calculi. Am. J. Med. 45, 684–691 (1956).

  85. 85.

    He, J. Y., Deng, S. P. & Ouyang, J. M. Morphology, particle size distribution, aggregation, and crystal phase of nanocrystallites in the urine of healthy persons and lithogenic patients. IEEE Trans. Nanobioscience 9, 156–163 (2010).

  86. 86.

    Prywer, J., Sadowski, R. R. & Torzewska, A. Aggregation of struvite, carbonate apatite, and Proteus mirabilis as a key factor of infectious urinary stone formation. Cryst. Growth Des. 15, 1446–1451 (2015).

  87. 87.

    Witzmann, F. A. et al. Label-free proteomic methodology for the analysis of human kidney stone matrix composition. Proteome Sci. 14, 4 (2016).

  88. 88.

    Khan, S. R., Shevock, P. N. & Hackett, R. L. Presence of lipids in urinary stones: results of preliminary studies. Calcif. Tissue Int. 42, 91–96 (1988).

  89. 89.

    Boyce, W. H. in Urolithiasis — Physical Aspects: Proceedings of a Conference (eds Finlayson, B., Hench, L. L. & Smith, L. H.) 97 (National Academy of Sciences, Washington, 1972).

  90. 90.

    Boskey, A. L., Bullough, P. G., Vigorita, V. & di Carlo, E. Calcium-acidic phospholipid-phosphate complexes in human hydroxyapatite-containing pathologic deposits. Am. J. Pathol. 133, 22–29 (1988).

  91. 91.

    Boskey, A. L. The rote of calcium-phospholipid-phosphate complexes in tissue mineralization. Metab. Bone Dis. Relat. Res. 1, 137–142 (1978).

  92. 92.

    Khan, S. R., Shevock, P. N. & Hackett, R. L. In vitro precipitation of calcium oxalate in the presence of whole matrix or lipid components of the urinary stones. J. Urol. 139, 418–422 (1988).

  93. 93.

    Boonla, C. et al. Inflammatory and fibrotic proteins proteomically identified as key protein constituents in urine and stone matrix of patients with kidney calculi. Clin. Chim. Acta 429, 81–89 (2014).

  94. 94.

    Merchant, M. L. et al. Proteomic analysis of renal calculi indicates an important role for inflammatory processes in calcium stone formation. Am. J. Physiol. Renal Physiol. 295, F1254–F1258 (2008).

  95. 95.

    Canales, B. K. et al. Proteome of human calcium kidney stones. Urology 76, 1017.e13–1017.e20 (2010).

  96. 96.

    Jou, Y.-C. et al. Proteomic study of renal uric acid stone. Urology 80, 260–266 (2012).

  97. 97.

    Kaneko, K. et al. 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 (2012).

  98. 98.

    Kaneko, K. et al. Proteomic analysis after sequential extraction of matrix proteins in urinary stones composed of calcium oxalate monohydrate and calcium oxalate dihydrate. Anal. Sci. 31, 935–942 (2015).

  99. 99.

    Goldberg, J. M. & Cotlier, E. Specific isolation and analysis of mucopolysaccharides (glycosaminoglycans) from human urine. Clin. Chim. Acta 41, 19–27 (1972).

  100. 100.

    McLean, R., Lawrence, J. R., Korber, D. R. & Caldwell, D. E. Proteus mirabilis biofilm protection against struvite crystal dissolution and its implications in struvite urolithiasis. J. Urol. 146, 1138–1142 (1991).

  101. 101.

    Poon, N. W. & Gohel, M. D. Urinary glycosaminoglycans and glycoproteins in a calcium oxalate crystallization system. Carbohydr. Res. 347, 64–68 (2012).

  102. 102.

    Sun, X. et al. Analysis of total human urinary glycosaminoglycan disaccharides by liquid chromatography–tandem mass spectrometry. Anal. Chem. 87, 6220–6227 (2015).

  103. 103.

    Yamaguchi, S. et al. Heparan sulfate in the stone matrix and its inhibitory effect on calcium oxalate crystallization. Urol. Res. 21, 187–192 (1993).

  104. 104.

    Michelacci, Y. M., Glashan, R. Q. & Schor, N. Urinary excretion of glycosaminoglycans in normal and stone forming subjects. Kidney Int. 36, 1022–1028 (1989).

  105. 105.

    Frankel, R. B. & Bazylinski, D. A. Biologically induced mineralization by bacteria. Rev. Miner. Geochem. 54, 95–114 (2003).

  106. 106.

    Bazylinski, D. A. & Frankel, R. B. Biologically controlled mineralization in prokaryotes. Rev. Miner. Geochem. 54, 217–247 (2003).

  107. 107.

    Barr-Beare, E. et al. The Interaction between Enterobacteriaceae and calcium oxalate deposits. PLOS ONE 10, e0139575 (2015).

  108. 108.

    Dukic, I. et al. Pd8-04 transmogrifying infection stones: are calcium stones now the commoner infection stones in Pcnl? [abstract PD8-04]. J. Urol. 193, e191 (2015).

  109. 109.

    Romanova, Y. M. et al. Microbial communities on kidney stones. Mol. Genet. Microbiol. Virol. 30, 78–84 (2015).

  110. 110.

    Maier, A. et al. Bacteriological evaluation of the non-struvite nephrolithiasis and its association with urinary tract infections. Rev. Rom. Med. Lab. 23, 457–467 (2015).

  111. 111.

    Sohshang, H., Singh, M., Singh, N. & Singh, S. Biochemical and bacteriological study of urinary calculi. J. Commun. Dis. 32, 216–221 (2000).

  112. 112.

    Lewi, H. J. E., White, A., Hutchinson, A. G. & Scott, R. The bacteriology of the urine and renal calculi. Urol. Res. 12, 107–109 (1984).

  113. 113.

    Thompson, R. & Stamey, T. Bactriology of infected stones. Urology 2, 627–633 (1973).

  114. 114.

    Golechha, S. & Solanki, A. Bacteriology and chemical composition of renal calculi accompanying urinary tract infection. Indian J. Urol. 17, 111–117 (2001).

  115. 115.

    O’Kane, D., Kiosoglous, A. & Jones, K. Candida dubliniensis encrustation of an obstructing upper renal tract calculus. BMJ Case Rep. 2013, bcr2013009087 (2013).

  116. 116.

    Wachsmuth, I. K., Davis, B. R. & Allen, S. D. Ureolytic Escherichia coli of human origin: serological, epidemiological, and genetic analysis. J. Clin. Microbiol. 10, 897–902 (1979).

  117. 117.

    Parsons, C. L. The role of the glycosaminoglycan layer in bladder defense mechanisms and interstitial cystitis. Int. Urogynecol. J. 4, 373–379 (1993).

  118. 118.

    Khan, S. R. Histological aspects of the “fixed-particle” model of stone formation: animal studies. Urolithiasis 45, 75–87 (2016).

  119. 119.

    Chen, X. e., Ling, P., Duan, R. & Zhang, T. Effects of heparosan and heparin on the adhesion and biofilm formation of several bacteria in vitro. Carbohydr. Polym. 88, 1288–1292 (2012).

  120. 120.

    Schaffer, J. N. & Pearson, M. M. Proteus mirabilis and urinary tract infections. Microbiol. Spectr. (2015).

  121. 121.

    Jacobsen, S. M., Stickler, D. J., Mobley, H. L. T. & Shirtliff, M. E. Complicated catheter-associated urinary tract infections due to Escherichia coli and Proteus mirabilis. Clin. Microbiol. Rev. 21, 26–59 (2008).

  122. 122.

    Hung, E. W., Darouiche, R. O. & Trautner, B. W. Proteus bacteriuria is associated with significant morbidity in spinal cord injury. Spinal Cord 45, 616–620 (2007).

  123. 123.

    Armbruster, C. E. & Mobley, H. L. T. Merging mythology and morphology: the multifaceted lifestyle of Proteus mirabilis. Nat. Rev. Microbiol. 10, 743–754 (2012).

  124. 124.

    Coker, C., Poore, C. A., Li, X. & Mobley, H. L. T. Pathogenesis of Proteus mirabilis urinary tract infection. Microb. Infect. 2, 1497–1505 (2000).

  125. 125.

    Jones, B. D. & Mobley, H. L. Genetic and biochemical diversity of ureases of Proteus, Providencia, and Morganella species isolated from urinary tract infection. Infect. Immun. 55, 2198–2203 (1987).

  126. 126.

    Jones, B. V., Young, R., Mahenthiralingam, E. & Stickler, D. J. Ultrastructure of Proteus mirabilis swarmer cell rafts and role of swarming in catheter-associated urinary tract infection. Infect. Immun. 72, 3941–3950 (2004).

  127. 127.

    Mah, T.-F. C. & O’Toole, G. A. Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol. 9, 34–39 (2001).

  128. 128.

    Thomen, P. et al. Bacterial biofilm under flow: first a physical struggle to stay, then a matter of breathing. PLOS ONE 12, e0175197 (2017).

  129. 129.

    Edin-Liljegren, A., Hedelin, H. H., Grenabo, L. & Pettersson, S. Impact of Escherichia coli on urine citrate and urease-induced crystallization. Scanning Microsc. 9, 901–905 (1995).

  130. 130.

    Bazin, D. et al. Absence of bacterial imprints on struvite-containing kidney stones: a structural investigation at the mesoscopic and atomic scale. Urology 79, 786–790 (2012).

  131. 131.

    Carpentier, X. et al. Relationships between carbonation rate of carbapatite and morphologic characteristics of calcium phosphate stones and etiology. Urology 73, 968–975 (2009).

  132. 132.

    Hesse, A. & Heimbach, D. Causes of phosphate stone formation and the importance of metaphylaxis by urinary acidification: a review. World J. Urol. 17, 308–315 (1999).

  133. 133.

    Cohen, M. S., Warren, M. M., Baur, P., Vogel, J. J. & Davis, C. P. Intracellular crystal formation in bacteria from human urines: a contributing factor in urinary calculi. Urol. Res. 9, 55–61 (1981).

  134. 134.

    Stewart, P. S. & Franklin, M. J. Physiological heterogeneity in biofilms. Nat. Rev. Microbiol. 6, 199 (2008).

  135. 135.

    Marcus, R. J. et al. Biofilms in nephrology. Expert Opin. Biol. Ther. 8, 1159–1166 (2008).

  136. 136.

    Tenke, P. et al. Update on biofilm infections in the urinary tract. World J. Urol. 30, 51–57 (2012).

  137. 137.

    Jacobsen, S. M. & Shirtliff, M. E. Proteus mirabilis biofilms and catheter-associated urinary tract infections. Virulence 2, 460–465 (2011).

  138. 138.

    Flannigan, R., Choy, W. H., Chew, B. & Lange, D. Renal struvite stones — pathogenesis, microbiology, and management strategies. Nat. Rev. Urol. 11, 333–341 (2014).

  139. 139.

    Flemming, H.-C. & Wingender, J. The biofilm matrix. Nat. Rev. Micro. 8, 623–633 (2010).

  140. 140.

    An, Y. H. & Friedman, R. J. Concise review of mechanisms of bacterial adhesion to biomaterial surfaces. J. Biomed. Mat. Res. 43, 338–348 (1998).

  141. 141.

    Zunino, P. et al. Proteus mirabilis fimbriae (PMF) are important for both bladder and kidney colonization in mice. Microbiology 149, 3231–3237 (2003).

  142. 142.

    O’Toole, G., Kaplan, H. B. & Kolter, R. Biofilm formation as microbial development. Annu. Rev. Microbiol. 54, 49–79 (2000).

  143. 143.

    More, T. T., Yadav, J. S. S., Yan, S., Tyagi, R. D. & Surampalli, R. Y. Extracellular polymeric substances of bacteria and their potential environmental applications. J. Environ. Manage. 144, 1–25 (2014).

  144. 144.

    O’May, C., Amzallag, O., Bechir, K. & Tufenkji, N. Cranberry derivatives enhance biofilm formation and transiently impair swarming motility of the uropathogen Proteus mirabilis HI4320. Can. J. Microbiol. 62, 464–474 (2016).

  145. 145.

    Li, X. et al. Spatial patterns of carbonate biomineralization in biofilms. Appl. Environ. Microbiol. 81, 7403–7410 (2015).

  146. 146.

    Li, X., Lu, N., Brady, H. R. & Packman, A. I. Ureolytic biomineralization reduces Proteus mirabilis biofilm susceptibility to ciprofloxacin. Antimicrob. Agents Chemother. 60, 2993–3000 (2016).

  147. 147.

    Brisbane, W., Bailey, M. R. & Sorensen, M. D. An overview of kidney stone imaging techniques. Nat. Rev. Urol. 13, 654–662 (2016).

  148. 148.

    Westphalen, A. C., Hsia, R. Y., Maselli, J. H., Wang, R. & Gonzales, R. Radiological imaging of patients with suspected urinary tract stones: national trends, diagnoses, and predictors. Acad. Emerg. Med. 18, 699–707 (2011).

  149. 149.

    Weisenthal, K. et al. Evaluation of kidney stones with reduced–radiation dose CT: progress from 2011–2012 to 2015–2016 — not there yet. Radiology 286, 581–589 (2018).

  150. 150.

    Niemann, T., Kollmann, T. & Bongartz, G. Diagnostic performance of low-dose CT for the detection of urolithiasis: a meta-analysis. Am. J. Roentgenol. 191, 396–401 (2008).

  151. 151.

    Smith-Bindman, R. et al. Ultrasonography versus computed tomography for suspected nephrolithiasis. N. Engl. J. Med. 371, 1100–1110 (2014).

  152. 152.

    Ibrahim, E.-S. H. et al. Detection of different kidney stone types: an ex vivo comparison of ultrashort echo time MRI to reference standard CT. Clin. Imaging 40, 90–95 (2016).

  153. 153.

    Tonannavar, J. et al. Identification of mineral compositions in some renal calculi by FT Raman and IR spectral analysis. Spectrochim. Acta A 154, 20–26 (2016).

  154. 154.

    Kasidas, G. P., Samuell, C. T. & Weir, T. B. Renal stone analysis: why and how? Ann. Clin. Biochem. 41, 91–97 (2004).

  155. 155.

    Ghosh, S., Basu, S., Chakraborty, S. & Mukherjee, A. K. Structural and microstructural characterization of human kidney stones from eastern India using IR spectroscopy, scanning electron microscopy, thermal study and X-ray Rietveld analysis. J. Appl. Cryst. 42, 629–635 (2009).

  156. 156.

    Charafi, S. et al. A comparative study of two renal stone analysis methods. Int. J. Nephrol. Urol. 2, 469–475 (2010).

  157. 157.

    Bazin, D., Daudon, M., Combes, C. & Rey, C. Characterization and some physicochemical aspects of pathological microcalcifications. Chem. Rev. 112, 5092–5120 (2012).

  158. 158.

    Goeres, D. M. et al. Statistical assessment of a laboratory method for growing biofilms. Microbiology 151, 757–762 (2005).

  159. 159.

    Primak, A. N. et al. Noninvasive differentiation of uric acid versus non–uric acid kidney stones using dual-energy CT. Acad. Radiol. 14, 1441–1447 (2007).

  160. 160.

    Haley, W. E. et al. The clinical impact of accurate cystine calculi characterization using dual-energy computed tomography. Case Rep. Radiol. 2015, 5 (2015).

  161. 161.

    Zarse, C. A. et al. Nondestructive analysis of urinary calculi using micro computed tomography. BMC Urol. 4, 15 (2004).

  162. 162.

    Williams, J. C., McAteer, J. A., Evan, A. P. & Lingeman, J. E. Micro-computed tomography for analysis of urinary calculi. Urol. Res. 38, 477–484 (2010).

  163. 163.

    Gonzalez, R. D., Whiting, B. M. & Canales, B. K. The history of kidney stone dissolution therapy: 50 years of optimism and frustration with renacidin. J. Endourol. 26, 110–118 (2012).

  164. 164.

    Wall, I. & Tiselius, H. G. Long-term acidification of urine in patients treated for infected renal stones. Urol. Int. 45, 336–341 (1990).

  165. 165.

    Stock, I. Natural antibiotic susceptibility of Proteus spp., with special reference to P. mirabilis and P. penneri strains. J. Chemother. 15, 12–26 (2003).

  166. 166.

    Assimos, D. et al. Surgical management of stones: American Urological Association/Endourological Society Guideline, part I. J. Urol. 196, 1153–1160 (2016).

  167. 167.

    Clatworthy, A. E., Pierson, E. & Hung, D. T. Targeting virulence: a new paradigm for antimicrobial therapy. Nat. Chem. Biol. 3, 541–548 (2007).

  168. 168.

    Armbruster, C. E., Hodges, S. A. & Mobley, H. L. T. Initiation of swarming motility by Proteus mirabilis occurs in response to specific cues present in urine and requires excess l-glutamine. J. Bacteriol. 195, 1305–1319 (2013).

  169. 169.

    Torzewska, A. & Rozalski, A. Inhibition of crystallization caused by Proteus mirabilis during the development of infectious urolithiasis by various phenolic substances. Microbiol. Res. 169, 579–584 (2014).

  170. 170.

    Hassan, S. T. S. & Žemlicka, M. Plant-derived urease inhibitors as alternative chemotherapeutic agents. Arch. Pharm. 349, 507–522 (2016).

  171. 171.

    Pearle, M. S. et al. Medical management of kidney stones: AUA guideline. J. Urol. 192, 316–324 (2014).

  172. 172.

    Pareek, G., Armenakas, N. A., Panagopoulos, G., Bruno, J. J. & Fracchia, J. A. Extracorporeal shock wave lithotripsy success based on body mass index and Hounsfield units. Urology 65, 33–36 (2005).

  173. 173.

    El-Nahas, A. R., El-Assmy, A. M., Mansour, O. & Sheir, K. Z. A prospective multivariate analysis of factors predicting stone disintegration by extracorporeal shock wave lithotripsy: the value of high-resolution noncontrast computed tomography. Eur. Urol. 51, 1688–1694 (2007).

  174. 174.

    Messaoudi, N. et al. Prediction of successful treatment by extracorporeal shock wave lithotripsy based on crystalluria-composition correlations of urinary calculi. Asian Pac. J. Trop. Dis. 5, 987–992 (2015).

  175. 175.

    Harmon, W. J., Sershon, P. D., Blute, M. L., Patterson, D. E. & Segura, J. W. Ureteroscopy: current practice and long-term complications. J. Urol. 157, 28–32 (1997).

  176. 176.

    Wollin, T. A. & Denstedt, J. D. The Holmium laser in urology. J. Clin. Laser Med. Surg. 16, 13–20 (1998).

  177. 177.

    Bader, M. J., Eisner, B., Porpiglia, F., Preminger, G. M. & Tiselius, H.-G. Contemporary management of ureteral stones. Eur. Urol. 61, 764–772 (2012).

  178. 178.

    Ganpule, A. P., Vijayakumar, M., Malpani, A. & Desai, M. R. Percutaneous nephrolithotomy (PCNL) a critical review. Int. J. Surg. 36 (Suppl. D), 660–664 (2016).

  179. 179.

    Rassweiler, J., Rassweiler, M. C. & Klein, J. New technology in ureteroscopy and percutaneous nephrolithotomy. Curr. Opin. Urol. 26, 95–106 (2016).

  180. 180.

    Zhu, W. et al. Minimally invasive versus standard percutaneous nephrolithotomy: a meta-analysis. Urolithiasis 43, 563–570 (2015).

  181. 181.

    Desai, J. et al. A novel technique of ultra-mini-percutaneous nephrolithotomy: introduction and an initial experience for treatment of upper urinary calculi less than 2 cm. Biomed Res. Int. 2013, 490793 (2013).

  182. 182.

    Kang, S. K. et al. Systematic review and meta-analysis to compare success rates of retrograde intrarenal surgery versus percutaneous nephrolithotomy for renal stones >2 cm: an update. Medicine 96, e9119 (2017).

  183. 183.

    Mitropoulos, D. et al. Reporting and grading of complications after urologic surgical procedures: an ad hoc EAU Guidelines panel assessment and recommendations. Eur. Urol. 61, 341–349 (2012).

  184. 184.

    de la Rosette, J. et al. The clinical research office of the endourological society percutaneous nephrolithotomy global study: indications, complications, and outcomes in 5803 patients. J. Endourol. 25, 11–17 (2011).

  185. 185.

    Assimos, D. G. Anatrophic nephrolithotomy. Urology 57, 161–165 (2001).

  186. 186.

    Keshavamurthy, R. et al. Anatrophic nephrolithotomy in the management of large staghorn calculi – a single centre experience. J. Clin. Diagn. Res. 11, PC01–PC04 (2017).

  187. 187.

    Zhao, J., Ren, L., Zhang, B., Cao, Z. & Yang, K. In vitro study on infectious ureteral encrustation resistance of Cu-bearing stainless steel. J. Mat. Sci. Technol. 33, 1604–1609 (2017).

  188. 188.

    Tunney, M. M., Keane, P. F., Jones, D. S. & Gorman, S. P. Comparative assessment of ureteral stent biomaterial encrustation. Biomaterials 17, 1541–1546 (1996).

  189. 189.

    Gilmore, B. F., Hamill, T. M., Jones, D. S. & Gorman, S. P. Validation of the CDC biofilm reactor as a dynamic model for assessment of encrustation formation on urological device materials. J. Biomed. Mater. Res. B 93, 128–140 (2010).

  190. 190.

    Gultekinoglu, M. et al. Polyethyleneimine brushes effectively inhibit encrustation on polyurethane ureteral stents both in dynamic bioreactor and in vivo. Mater. Sci. Eng. C 71, 1166–1174 (2017).

  191. 191.

    Gorman, S. P., Garvin, C. P., Quigley, F. & Jones, D. S. Design and validation of a dynamic flow model simulating encrustation of biomaterials in the urinary tract. J. Pharm. Pharmacol. 55, 461–468 (2003).

  192. 192.

    Hobbs, T., Schultz, L. N., Lauchnor, E. G., Gerlach, R. & Lange, D. Evaluation of biofilm induced urinary infection stone formation in a novel laboratory model system. J. Urol. 199, 178–185 (2018).

  193. 193.

    Steefel, C. I., DePaolo, D. J. & Lichtner, P. C. Reactive transport modeling: an essential tool and a new research approach for the Earth sciences. Earth Planet. Sci. Lett. 240, 539–558 (2005).

  194. 194.

    Connolly, J. M., Jackson, B., Rothman, A. P., Klapper, I. & Gerlach, R. Estimation of a biofilm-specific reaction rate: kinetics of bacterial urea hydrolysis in a biofilm. NPJ Biofilms Microbiomes 1, 15014 (2015).

  195. 195.

    Morris, N. S., Stickler, D. J. & McLean, R. J. The development of bacterial biofilms on indwelling urethral catheters. World J. Urol. 17, 345–350 (2000).

  196. 196.

    Parkhurst, D. L. & Appelo, C. A. J. User’s guide to PHREEQC (version 2): report 99-4259 (US Geological Survey, 1999).

  197. 197.

    Gustafsson, J. P. Visual MINTEQ3.1. KTH (2000).

  198. 198.

    Brown, C. M., Purich, D. L. & Ackermann, D. K. EQUIL 93: a tool for experimental and clinical urolithiasis. Urol. Res. 22, 119–126 (1994).

  199. 199.

    Nardi, A., Idiart, A., Trinchero, P., de Vries, L. M. & Molinero, J. Interface COMSOL-PHREEQC (iCP), an efficient numerical framework for the solution of coupled multiphysics and geochemistry. Comput. Geosci. 69, 10–21 (2014).

  200. 200.

    Finlayson, B. Physicochemical aspects of urolithiasis. Kidney Int. 13, 344–360 (1978).

  201. 201.

    Cohen, N. P. & Whitfield, H. N. Mechanical testing of urinary calculi. World J. Urol. 11, 13–18 (1993).

  202. 202.

    Olszynski, M., Prywer, J. & Mielniczek- Brzóska, E. Inhibition of struvite crystallization by tetrasodium pyrophosphate in artificial urine: chemical and physical aspects of nucleation and growth. Cryst. Growth Des. 16, 3519–3529 (2016).

  203. 203.

    Chauhan, C. K., Joshi, M. J. & Vaidya, A. D. B. Growth inhibition of struvite crystals in the presence of herbal extract Commiphora wightii. J. Mater. Sci. Mater. Med. 20, 85 (2008).

  204. 204.

    Chauhan, C. K. & Joshi, M. J. In vitro crystallization, characterization and growth-inhibition study of urinary type struvite crystals. J. Cryst. Growth 362, 330–337 (2013).

  205. 205.

    Muryanto, S., Sutanti, S. & Kasmiyatun, M. Inhibition of struvite crystal growth in the presence of herbal extract Orthosiphon aristatus BL.MIQ. MATEC Web Conf. 58, 01013 (2016).

  206. 206.

    Basavaraj, D. R., Biyani, C. S., Browning, A. J. & Cartledge, J. J. The role of urinary kidney stone inhibitors and promoters in the pathogenesis of calcium containing renal stones. EAU-EBU Upd. Series 5, 126–136 (2007).

  207. 207.

    Rajasekharan, S. K., Ramesh, S., Bakkiyaraj, D., Elangomathavan, R. & Kamalanathan, C. Burdock root extracts limit quorum-sensing-controlled phenotypes and biofilm architecture in major urinary tract pathogens. Urolithiasis 43, 29–40 (2015).

  208. 208.

    Salini, R., Sindhulakshmi, M., Poongothai, T. & Pandian, S. K. Inhibition of quorum sensing mediated biofilm development and virulence in uropathogens by Hyptis suaveolens. Antonie Van Leeuwenhoek 107, 1095–1106 (2015).

  209. 209.

    Younis, K. M., Usup, G. & Ahmad, A. Secondary metabolites produced by marine streptomyces as antibiofilm and quorum-sensing inhibitor of uropathogen Proteus mirabilis. Environ. Sci. Pollut. Res. 23, 4756–4767 (2016).

  210. 210.

    Salini, R. & Pandian, S. K. Interference of quorum sensing in urinary pathogen Serratia marcescens by Anethum graveolens. Pathog. Dis. 73, ftv038 (2015).

  211. 211.

    Kazemian, H. et al. Antibacterial, anti-swarming and anti-biofilm formation activities of Chamaemelum nobile against Pseudomonas aeruginosa. Rev. Soc. Bras. Med. Trop. 48, 432–436 (2015).

  212. 212.

    Ranjbar-Omid, M. et al. Allicin from garlic inhibits the biofilm formation and urease activity of Proteus mirabilis in vitro. FEMS Microbiol. Lett. 362, fnv049 (2015).

Download references


The authors acknowledge the support by the Montana University System Research Initiative (grant 51040-MUSRI2015-03) and the Burroughs Wellcome Fund (grant #1017519). The authors also thankfully acknowledge the helpful comments of three anonymous reviewers.

Review criteria

A review of the literature was performed by conducting searches in the Web of Science database (until March 2018). Search terms included “kidney/urinary stones”, “kidney/urinary stone characterization”, “kidney/urinary stone matrix”, “kidney/urinary stone biomineralization”, “mechanisms of kidney/urinary stone formation”, “management of kidney/urinary stones”, “mechanisms of resistance biofilm”, and “Proteus mirabilis”. No restriction on date of publication was used. The references of recent review articles were also searched to identify key studies related to urinary stones in the areas of chemistry, engineering, mineralogy, microbiology, and medicine. Additional papers were included based on recommendations by the peer reviewers.

Author information

All authors researched data for the article, made substantial contributions to discussion of the article contents, wrote the manuscript, and reviewed and/or edited the manuscript before submission.

Correspondence to Dirk Lange or Robin Gerlach.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links




The presence of a solute at a higher concentration in a solution than that of its own solubility.


Microorganisms attached to a surface and embedded in an extracellular polymeric substance matrix.

Randall’s plaque

Plaques of calcifications deposited in the interstitial tissue of the renal papilla.

Zeta potential

Measure of the magnitude of the electrostatic or charge repulsion or attraction between particles in colloidal systems.

Swarming motility

Rapid multicellular bacterial movement across solid surfaces powered by rotating flagella.

Planktonic bacteria

Bacteria that are freely floating in a suspension.

EPS matrix

Matrix of biopolymers comprised of extracellular polymeric substances (EPS) of microbial origin, in which biofilm microorganisms are embedded.

Quorum sensing

Mechanism of cell–cell communication by which bacteria might share information about cell density and regulate gene expression.

Reactive transport modelling

Computer models that integrate the use of chemical reactions with the transport of fluids.

Geochemical modelling software

Computer models that use thermodynamics and/or kinetics to analyse chemical reactions that affect geological systems.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1: Physicochemical process of stone formation.
Fig. 2: Role of microorganisms and biofilms in stone formation.