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Randall’s plaque and calcium oxalate stone formation: role for immunity and inflammation

Abstract

Idiopathic calcium oxalate (CaOx) stones often develop attached to Randall’s plaque present on kidney papillary surfaces. Similar to the plaques formed during vascular calcification, Randall’s plaques consist of calcium phosphate crystals mixed with an organic matrix that is rich in proteins, such as inter-α-trypsin inhibitor, as well as lipids, and includes membrane-bound vesicles or exosomes, collagen fibres and other components of the extracellular matrix. Kidney tissue surrounding Randall’s plaques is associated with the presence of classically activated, pro-inflammatory macrophages (also termed M1) and downregulation of alternatively activated, anti-inflammatory macrophages (also termed M2). In animal models, crystal deposition in the kidneys has been associated with the production of reactive oxygen species, inflammasome activation and increased expression of molecules implicated in the inflammatory cascade, including osteopontin, matrix Gla protein and fetuin A (also known as α2-HS-glycoprotein). Many of these molecules, including osteopontin and matrix Gla protein, are well known inhibitors of vascular calcification. We propose that conditions of urine supersaturation promote kidney damage by inducing the production of reactive oxygen species and oxidative stress, and that the ensuing inflammatory immune response promotes Randall’s plaque initiation and calcium stone formation.

Key points

  • Randall’s plaques contain calcium phosphate (CaP) crystals mixed with membranous vesicles, collagen fibres and molecules involved in inflammatory responses, such as osteopontin and inter-α-trypsin inhibitor.

  • Calcification is modulated by many macromolecules that are generally involved in inflammation and osteogenesis; these molecules are also highly expressed in the kidneys of stone formers and in experimental models of nephrolithiasis.

  • Exposure of the kidney epithelium to crystals induces the production of reactive oxygen species that activate the NOD-, LRR- and pyrin domain-containing protein 3 inflammasome; inhibition of reactive oxygen species production and inflammasome activation reduces crystal deposition in animal models.

  • In rodent models, the inflammatory response to interstitial crystal deposition attracts macrophages, which leads to giant cell formation and may eventually result in crystal elimination.

  • Gene expression studies of kidneys from patients with kidney stones revealed pro-inflammatory macrophage gene signatures, whereas genes characteristic of anti-inflammatory macrophages were less abundant.

  • A better understanding of inflammasome activation and modulation of immune response to urine supersaturation and crystal deposition may provide new therapeutic options to reduce kidney stone recurrence.

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Fig. 1: Kidney papilla with Randall’s plaque and plug.
Fig. 2: Composition of Randall’s plaque in the kidney papilla.
Fig. 3: Calcium phosphate deposits in animal models.
Fig. 4: Proposed effects of reactive oxygen species production in response to intratubular crystals.
Fig. 5: Proposed model for the formation of Randall’s plaque.

References

  1. Sorokin, I. et al. Epidemiology of stone disease across the world. World J. Urol. 35, 1301–1320 (2017).

    PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  3. Xu, G. et al. Prevalence of diagnosed type 1 and type 2 diabetes among US adults in 2016 and 2017: population based study. BMJ 362, k1497 (2018).

    PubMed  PubMed Central  Google Scholar 

  4. Obligado, S. H. & Goldfarb, D. S. The association of nephrolithiasis with hypertension and obesity: a review. Am. J. Hypertens. 21, 257–264 (2008).

    CAS  PubMed  Google Scholar 

  5. Daudon, M. & Jungers, P. Diabetes and nephrolithiasis. Curr. Diab. Rep. 7, 443–448 (2007).

    PubMed  Google Scholar 

  6. West, B. et al. Metabolic syndrome and self-reported history of kidney stones: the National Health and Nutrition Examination Survey (NHANES III) 1988–1994. Am. J. Kidney Dis. 51, 741–747 (2008).

    PubMed  Google Scholar 

  7. Strazzullo, P. et al. Past history of nephrolithiasis and incidence of hypertension in men: a reappraisal based on the results of the Olivetti Prospective Heart Study. Nephrol. Dial. Transplant. 16, 2232–2235 (2001).

    CAS  PubMed  Google Scholar 

  8. Shoag, J., Halpern, J., Goldfarb, D. S. & Eisner, B. H. Risk of chronic and end stage kidney disease in patients with nephrolithiasis. J. Urol. 192, 1440–1445 (2014).

    PubMed  Google Scholar 

  9. Keddis, M. T. & Rule, A. D. Nephrolithiasis and loss of kidney function. Curr. Opin. Nephrol. Hypertens. 22, 390–396 (2013).

    PubMed  PubMed Central  Google Scholar 

  10. Tiselius, H. G. Possibilities for preventing recurrent calcium stone formation: principles for the metabolic evaluation of patients with calcium stone disease. BJU Int. 88, 158–168 (2001).

    CAS  PubMed  Google Scholar 

  11. Khan, S. R. et al. Kidney stones. Nat. Rev. Dis. Primers 2, 16008 (2016).

    PubMed  PubMed Central  Google Scholar 

  12. Uribarri, J., Oh, M. S. & Carroll, H. J. The first kidney stone. Ann. Intern. Med. 111, 1006–1009 (1989).

    CAS  PubMed  Google Scholar 

  13. D’Costa, M. R. et al. Symptomatic and radiographic manifestations of kidney stone recurrence and their prediction by risk factors: a prospective cohort study. J. Am. Soc. Nephrol. 30, 1251–1260 (2019).

    PubMed  PubMed Central  Google Scholar 

  14. Hyams, E. S. & Matlaga, B. R. Economic impact of urinary stones. Transl. Androl. Urol. 3, 278–283 (2014).

    PubMed  PubMed Central  Google Scholar 

  15. Antonelli, J. A., Maalouf, N. M., Pearle, M. S. & Lotan, Y. Use of the National Health and Nutrition Examination Survey to calculate the impact of obesity and diabetes on cost and prevalence of urolithiasis in 2030. Eur. Urol. 66, 724–729 (2014).

    PubMed  PubMed Central  Google Scholar 

  16. Ziemba, J. B. & Matlaga, B. R. Epidemiology and economics of nephrolithiasis. Investig. Clin. Urol. 58, 299–306 (2017).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Evan, A. P. et al. Randall’s plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle. J. Clin. Invest. 111, 607–616 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Khan, S. R. & Canales, B. K. Unified theory on the pathogenesis of Randall’s plaques and plugs. Urolithiasis 43, 109–123 (2015).

    CAS  PubMed  Google Scholar 

  20. Khan, S. R., Finlayson, B. & Hackett, R. Renal papillary changes in patient with calcium oxalate lithiasis. Urology 23, 194–199 (1984).

    CAS  PubMed  Google Scholar 

  21. Randall, A. Papillary pathology as a precursor of primary renal calculus. J. Urol. 44, 580–589 (1940).

    CAS  Google Scholar 

  22. Randall, A. Recent advances in knowledge relating to the formation, recognition and treatment of kidney calculi. Bull. N. Y. Acad. Med. 20, 473–484 (1944).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Khan, S. R. Histological aspects of the “fixed-particle” model of stone formation: animal studies. Urolithiasis 45, 75–87 (2017).

    PubMed  Google Scholar 

  24. Moe, O. W., Pearle, M. S. & Sakhaee, K. Pharmacotherapy of urolithiasis: evidence from clinical trials. Kidney Int. 79, 385–392 (2011).

    CAS  PubMed  Google Scholar 

  25. Mandel, N. S., Henderson, J. D. Jr, Hung, L. Y., Wille, D. F. & Wiessner, J. H. A porcine model of calcium oxalate kidney stone disease. J. Urol. 171, 1301–1303 (2004).

    CAS  PubMed  Google Scholar 

  26. Penniston, K. L., Patel, S. R., Schwahn, D. J. & Nakada, S. Y. Studies using a porcine model: what insights into human calcium oxalate stone formation mechanisms has this model facilitated? Urolithiasis 45, 109–125 (2017).

    PubMed  Google Scholar 

  27. Wu, X. R. Interstitial calcinosis in renal papillae of genetically engineered mouse models: relation to Randall’s plaques. Urolithiasis 43, 65–76 (2015).

    CAS  PubMed  Google Scholar 

  28. Haggit, R. C. & Pitcock, J. A. Renal medullary calcification: a light and electron microscopic study. J. Urol. 106, 342–347 (1971).

    Google Scholar 

  29. Stoller, M. L., Low, R. K., Shami, G. S., McCormick, V. D. & Kerschmann, R. L. High resolution radiography of cadaveric kidneys: unraveling the mystery of Randall’s plaque formation. J. Urol. 156, 1263–1266 (1996).

    CAS  PubMed  Google Scholar 

  30. Darves-Bornoz, A. et al. Renal papillary mapping and quantification of Randall’s plaque in pediatric calcium oxalate stone formers. J Endourol 33, 863–867 (2019).

    PubMed  Google Scholar 

  31. Bouchireb, K. et al. Papillary stones with Randall’s plaques in children: clinicobiological features and outcome. Nephrol. Dial. Transplant. 27, 1529–1534 (2012).

    PubMed  Google Scholar 

  32. Letavernier, E. et al. Demographics and characterization of 10,282 Randall plaque-related kidney stones: a new epidemic? Medicine 94, e566 (2015).

    PubMed  PubMed Central  Google Scholar 

  33. Khan, S. R., Rodriguez, D. E., Gower, L. B. & Monga, M. Association of Randall plaque with collagen fibers and membrane vesicles. J. Urol. 187, 1094–1100 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Evan, A. P. et al. Renal inter-alpha-trypsin inhibitor heavy chain 3 increases in calcium oxalate stone-forming patients. Kidney Int. 72, 1503–1511 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  36. Carpentier, X. et al. High Zn content of Randall’s plaque: a mu-X-ray fluorescence investigation. J. Trace. Elem. Med. Biol. 25, 160–165 (2011).

    CAS  PubMed  Google Scholar 

  37. Kuo, R. L. et al. Urine calcium and volume predict coverage of renal papilla by Randall’s plaque. Kidney Int. 64, 2150–2154 (2003).

    PubMed  Google Scholar 

  38. Coe, F. L., Worcester, E. M. & Evan, A. P. Idiopathic hypercalciuria and formation of calcium renal stones. Nat. Rev. Nephrol. 12, 519 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Evan, A. P., Coe, F. L., Lingeman, J., Bledsoe, S. & Worcester, E. M. Randall’s plaque in stone formers originates in ascending thin limbs. Am. J. Physiol. Renal Physiol. 315, F1236–F1242 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Khan, S. R. Nephrocalcinosis in animal models with and without stones. Urol. Res. 38, 429–438 (2010).

    PubMed  PubMed Central  Google Scholar 

  41. Khan, S. R. Calcium oxalate crystal interaction with renal tubular epithelium, mechanism of crystal adhesion and its impact on stone development. Urol. Res. 23, 71–79 (1995).

    CAS  PubMed  Google Scholar 

  42. de Bruijn, W. C. et al. Etiology of experimental calcium oxalate monohydrate nephrolithiasis in rats. Scanning Microsc. 8, 541–549; discussion 549–50 (1994).

    CAS  PubMed  Google Scholar 

  43. Khan, S. R. Tubular cell surface events during nephrolithiasis. Curr. Opin. Urol. 7, 240–247 (1997).

    Google Scholar 

  44. Khan, S. R., Finlayson, B. & Hackett, R. L. Experimental calcium oxalate nephrolithiasis in the rat. Role of the renal papilla. Am. J. Pathol. 107, 59–69 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Khan, S. R., Glenton, P. A. & Byer, K. J. Modeling of hyperoxaluric calcium oxalate nephrolithiasis: experimental induction of hyperoxaluria by hydroxy-L-proline. Kidney Int. 70, 914–923 (2006).

    CAS  PubMed  Google Scholar 

  46. Khan, S. R. & Glenton, P. A. Deposition of calcium phosphate and calcium oxalate crystals in the kidneys. J. Urol. 153, 811–817 (1995).

    CAS  PubMed  Google Scholar 

  47. Nguyen, H. T. & Woodard, J. C. Intranephronic calculosis in rats: an ultrastructural study. Am. J. Pathol. 100, 39–56 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Chi, T. et al. A Drosophila model identifies a critical role for zinc in mineralization for kidney stone disease. PLoS One 10, e0124150 (2015).

    PubMed  PubMed Central  Google Scholar 

  49. Chen, Y. H. et al. Ethylene glycol induces calcium oxalate crystal deposition in Malpighian tubules: a Drosophila model for nephrolithiasis/urolithiasis. Kidney Int. 80, 369–377 (2011).

    CAS  PubMed  Google Scholar 

  50. Khan, S. R. & Glenton, P. A. Calcium oxalate crystal deposition in kidneys of hypercalciuric mice with disrupted type IIa sodium-phosphate cotransporter. Am. J. Physiol. Renal Physiol. 294, F1109–F1115 (2008).

    CAS  PubMed  Google Scholar 

  51. Chau, H., El-Maadawy, S., McKee, M. D. & Tenenhouse, H. S. Renal calcification in mice homozygous for the disrupted type IIa Na/Pi cotransporter gene Npt2. J. Bone Miner. Res. 18, 644–657 (2003).

    CAS  PubMed  Google Scholar 

  52. Weinman, E. J. et al. Longitudinal study of urinary excretion of phosphate, calcium, and uric acid in mutant NHERF-1 null mice. Am. J. Physiol. Renal. Physiol. 290, F838–F843 (2006).

    CAS  PubMed  Google Scholar 

  53. Letavernier, E. et al. ABCC6 deficiency promotes development of randall plaque. J. Am. Soc. Nephrol. 29, 2337–2347 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Li, Q., Chou, D. W., Price, T. P., Sundberg, J. P. & Uitto, J. Genetic modulation of nephrocalcinosis in mouse models of ectopic mineralization: the Abcc6(tm1Jfk) and Enpp1(asj) mutant mice. Lab. Invest. 94, 623–632 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Bouderlique, E. et al. Vitamin D and calcium supplementation accelerates Randall’s plaque formation in a murine model. Am. J. Pathol. 189, 2171–2180 (2019).

    CAS  PubMed  Google Scholar 

  56. Pomozi, V. et al. Pyrophosphate supplementation prevents chronic and acute calcification in ABCC6-deficient mice. Am. J. Pathol. 187, 1258–1272 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Blazquez-Medela, A. M. et al. ABCC6 deficiency is associated with activation of BMP signaling in liver and kidney. FEBS Open Bio. 5, 257–263 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Mo, L. et al. Renal calcinosis and stone formation in mice lacking osteopontin, Tamm-Horsfall protein, or both. Am. J. Physiol. Renal Physiol. 293, F1935–F1943 (2007).

    CAS  PubMed  Google Scholar 

  59. Khan, S. R. & Kok, D. J. Modulators of urinary stone formation. Front. Biosci. 9, 1450–1482 (2004).

    CAS  PubMed  Google Scholar 

  60. Fleisch, H. & Bisaz, S. Mechanism of calcification: inhibitory role of pyrophosphate. Nature 195, 911 (1962).

    CAS  PubMed  Google Scholar 

  61. Villa-Bellosta, R. & O’Neill, W. C. Pyrophosphate deficiency in vascular calcification. Kidney Int. 93, 1293–1297 (2018).

    CAS  PubMed  Google Scholar 

  62. Liu, Y. et al. Progressive renal papillary calcification and ureteral stone formation in mice deficient for Tamm-Horsfall protein. Am. J. Physiol. Renal. Physiol. 299, F469–F478 (2010).

    PubMed  PubMed Central  Google Scholar 

  63. Wesson, J. A. et al. Osteopontin is a critical inhibitor of calcium oxalate crystal formation and retention in renal tubules. J. Am. Soc. Nephrol. 14, 139–147 (2003).

    CAS  PubMed  Google Scholar 

  64. Khan, S. R. Is oxidative stress, a link between nephrolithiasis and obesity, hypertension, diabetes, chronic kidney disease, metabolic syndrome? Urol. Res. 40, 95–112 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Krohn, J. B., Hutcheson, J. D., Martinez-Martinez, E. & Aikawa, E. Extracellular vesicles in cardiovascular calcification: expanding current paradigms. J. Physiol. 594, 2895–2903 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Zazzeroni, L., Faggioli, G. & Pasquinelli, G. Mechanisms of arterial calcification: the role of matrix vesicles. Eur. J. Vasc. Endovasc. Surg. 55, 425–432 (2018).

    PubMed  Google Scholar 

  67. Evan, A. P. et al. Apatite plaque particles in inner medulla of kidneys of calcium oxalate stone formers: osteopontin localization. Kidney Int. 68, 145–154 (2005).

    CAS  PubMed  Google Scholar 

  68. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

  70. 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).

    CAS  PubMed  Google Scholar 

  71. Stoller, M. L., Meng, M. V., Abrahams, H. M. & Kane, J. P. The primary stone event: a new hypothesis involving a vascular etiology. J. Urol. 171, 1920–1924 (2004).

    PubMed  Google Scholar 

  72. Chen, L. et al. Anatomically-specific intratubular and interstitial biominerals in the human renal medullo-papillary complex. PLoS One 12, e0187103 (2017).

    PubMed  PubMed Central  Google Scholar 

  73. Hsi, R. S., Ramaswamy, K., Ho, S. P. & Stoller, M. L. The origins of urinary stone disease: upstream mineral formations initiate downstream Randall’s plaque. BJU Int. 119, 177–184 (2017).

    PubMed  Google Scholar 

  74. Wiener, S. V. et al. Novel insights into renal mineralization and stone formation through advanced imaging modalities. Connect. Tissue Res. 59, 102–110 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Hsi, R. S. et al. Coronary artery calcium score and association with recurrent nephrolithiasis: the multi-ethnic study of atherosclerosis. J. Urol. 195, 971–976 (2016).

    CAS  PubMed  Google Scholar 

  76. Reiner, A. P. et al. Kidney stones and subclinical atherosclerosis in young adults: the CARDIA study. J. Urol. 185, 920–925 (2011).

    PubMed  Google Scholar 

  77. Masterson, J. H. et al. Dyslipidemia is associated with an increased risk of nephrolithiasis. Urolithiasis 43, 49–53 (2015).

    CAS  PubMed  Google Scholar 

  78. Khan, S. R. & Glenton, P. A. Increased urinary excretion of lipids by patients with kidney stones. Br. J. Urol. 77, 506–511 (1996).

    CAS  PubMed  Google Scholar 

  79. Sur, R. L. et al. Impact of statins on nephrolithiasis in hyperlipidemic patients: a 10-year review of an equal access health care system. Clin. Nephrol. 79, 351–355 (2012).

    Google Scholar 

  80. Wahl, P., Ducasa, G. M. & Fornoni, A. Systemic and renal lipids in kidney disease development and progression. Am. J. Physiol. Renal Physiol. 310, F433–F445 (2016).

    CAS  PubMed  Google Scholar 

  81. Tesfamariam, B. The effects of HMG-CoA reductase inhibitors on endothelial function. Am. J. Cardiovasc. Drugs 6, 115–120 (2006).

    CAS  PubMed  Google Scholar 

  82. Cohen, A. J. et al. Impact of statin intake on kidney stone formation. Urology 124, 57–61 (2019).

    PubMed  Google Scholar 

  83. Cappuccio, F. P. et al. A prospective study of hypertension and the incidence of kidney stones in men. J. Hypertens. 17, 1017–1022 (1999).

    CAS  PubMed  Google Scholar 

  84. Lopes, H. F. et al. DASH diet lowers blood pressure and lipid-induced oxidative stress in obesity. Hypertension 41, 422–430 (2003).

    CAS  PubMed  Google Scholar 

  85. Taylor, E. N., Fung, T. T. & Curhan, G. C. DASH-style diet associates with reduced risk for kidney stones. J. Am. Soc. Nephrol. 20, 2253–2259 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Umekawa, T., Hatanaka, Y., Kurita, T. & Khan, S. R. Effect of angiotensin II receptor blockage on osteopontin expression and calcium oxalate crystal deposition in rat kidneys. J. Am. Soc. Nephrol. 15, 635–644 (2004).

    CAS  PubMed  Google Scholar 

  87. Joshi, S., Saylor, B. T., Wang, W., Peck, A. B. & Khan, S. R. Apocynin-treatment reverses hyperoxaluria induced changes in NADPH oxidase system expression in rat kidneys: a transcriptional study. PLoS One 7, e47738 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  89. Khan, S. R. Reactive oxygen species, inflammation and calcium oxalate nephrolithiasis. Transl. Androl. Urol. 3, 256–276 (2014).

    PubMed  PubMed Central  Google Scholar 

  90. Joshi, S., Wang, W., Peck, A. B. & Khan, S. R. Activation of the NLRP3 inflammasome in association with calcium oxalate crystal induced reactive oxygen species in kidneys. J. Urol. 193, 1684–1691 (2015).

    CAS  PubMed  Google Scholar 

  91. Schwille, P. O., Manoharan, M. & Schmiedl, A. Is idiopathic recurrent calcium urolithiasis in males a cellular disease? Laboratory findings in plasma, urine and erythrocytes, emphasizing the absence and presence of stones, oxidative and mineral metabolism: an observational study. Clin. Chem. Lab. Med. 43, 590–600 (2005).

    CAS  PubMed  Google Scholar 

  92. Holoch, P. A. & Tracy, C. R. Antioxidants and self-reported history of kidney stones: the National Health and Nutrition Examination Survey. J. Endourol. 25, 1903–1908 (2011).

    PubMed  Google Scholar 

  93. Grewal, J. S., Tsai, J. Y. & Khan, S. R. Oxalate-inducible AMBP gene and its regulatory mechanism in renal tubular epithelial cells. Biochem. J. 387, 609–616 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Okada, A. et al. Renal macrophage migration and crystal phagocytosis via inflammatory-related gene expression during kidney stone formation and elimination in mice: detection by association analysis of stone-related gene expression and microstructural observation. J. Bone Miner. Res. 25, 2701–2711 (2010).

    PubMed  Google Scholar 

  95. Khan, A., Wang, W. & Khan, S. R. Calcium oxalate nephrolithiasis and expression of matrix GLA protein in the kidneys. World J. Urol. 32, 123–130 (2014).

    CAS  PubMed  Google Scholar 

  96. Khan, S. R. Crystal-induced inflammation of the kidneys: results from human studies, animal models, and tissue-culture studies. Clin. Exp. Nephrol. 8, 75–88 (2004).

    CAS  PubMed  Google Scholar 

  97. Umekawa, T., Byer, K., Uemura, H. & Khan, S. R. Diphenyleneiodium (DPI) reduces oxalate ion- and calcium oxalate monohydrate and brushite crystal-induced upregulation of MCP-1 in NRK 52E cells. Nephrol. Dial. Transplant. 20, 870–878 (2005).

    CAS  PubMed  Google Scholar 

  98. Shroff, R. C. & Shanahan, C. M. The vascular biology of calcification. Semin. Dial. 20, 103–109 (2007).

    PubMed  Google Scholar 

  99. Schurgers, L. J., Cranenburg, E. C. & Vermeer, C. Matrix Gla-protein: the calcification inhibitor in need of vitamin K. Thromb. Haemost. 100, 593–603 (2008).

    CAS  PubMed  Google Scholar 

  100. Shanahan, C. M., Proudfoot, D., Farzaneh-Far, A. & Weissberg, P. L. The role of Gla proteins in vascular calcification. Crit.Rev. Eukaryot. Gene Expr. 8, 357–375 (1998).

    CAS  PubMed  Google Scholar 

  101. Price, P. A., Urist, M. R. & Otawara, Y. Matrix Gla protein, a new gamma-carboxyglutamic acid-containing protein which is associated with the organic matrix of bone. Biochem. Biophys. Res. Commun. 117, 765–771 (1983).

    CAS  PubMed  Google Scholar 

  102. Fraser, J. D. & Price, P. A. 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, 11033–11036 (1988).

    CAS  PubMed  Google Scholar 

  103. Gourgas, O., Marulanda, J., Zhang, P., Murshed, M. & Cerruti, M. Multidisciplinary approach to understand medial arterial calcification. Arterioscler. Thromb. Vasc. Biol. 38, 363–372 (2018).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  105. Lu, X. et al. A polymorphism of matrix Gla protein gene is associated with kidney stone in the Chinese Han population. Gene 511, 127–130 (2012).

    CAS  PubMed  Google Scholar 

  106. Wang, Q. et al. High concentration of calcium promotes mineralization in NRK-52E cells via inhibiting the expression of matrix gla protein. Urology 119, 161 e1–161 e7 (2018).

    Google Scholar 

  107. Jahnen-Dechent, W., Schafer, C., Ketteler, M. & McKee, M. D. Mineral chaperones: a role for fetuin-A and osteopontin in the inhibition and regression of pathologic calcification. J. Mol. Med. 86, 379–389 (2008).

    CAS  PubMed  Google Scholar 

  108. Moe, S. M. et al. Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD). Kidney Int. 67, 2295–2304 (2005).

    CAS  PubMed  Google Scholar 

  109. Schinke, T. et al. The serum protein alpha2-HS glycoprotein/fetuin inhibits apatite formation in vitro and in mineralizing calvaria cells. A possible role in mineralization and calcium homeostasis. J. Biol. Chem. 271, 20789–20796 (1996).

    CAS  PubMed  Google Scholar 

  110. Ketteler, M. et al. Deficiencies of calcium-regulatory proteins in dialysis patients: a novel concept of cardiovascular calcification in uremia. Kidney Int. Suppl. 63, S84–S87 (2003).

    Google Scholar 

  111. Ford, M. L., Tomlinson, L. A., Chapman, T. P., Rajkumar, C. & Holt, S. G. Aortic stiffness is independently associated with rate of renal function decline in chronic kidney disease stages 3 and 4. Hypertension 55, 1110–1115 (2010).

    CAS  PubMed  Google Scholar 

  112. Mehrsai, A., Guitynavard, F., Nikoobakht, M. R., Gooran, S. & Ahmadi, A. The relationship between serum and urinary Fetuin-A levels and kidney stone formation among kidney stone patients. Cent. European J. Urol. 70, 394–399 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Liberman, M. & Marti, L. C. Vascular calcification regulation by exosomes in the vascular wall. Adv. Exp. Med. Biol. 998, 151–160 (2017).

    CAS  PubMed  Google Scholar 

  114. Heiss, A. et al. Structural basis of calcification inhibition by α2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles. J. Biol. Chem. 278, 13333–13341 (2003).

    CAS  PubMed  Google Scholar 

  115. Holt, S. G. & Smith, E. R. Fetuin-A-containing calciprotein particles in mineral trafficking and vascular disease. Nephrol. Dial. Transplant. 31, 1583–1587 (2016).

    CAS  PubMed  Google Scholar 

  116. Okumura, N. et al. Diversity in protein profiles of individual calcium oxalate kidney stones. PLoS One 8, e68624 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Taguchi, K. et al. Genome-wide gene expression profiling of Randall’s plaques in calcium oxalate stone formers. J. Am. Soc. Nephrol. 28, 333–347 (2017).

    CAS  PubMed  Google Scholar 

  118. Sun, A. Y. et al. Inflammatory cytokines in the papillary tips and urine of nephrolithiasis patients. J. Endourol. 32, 236–244 (2018).

    PubMed  Google Scholar 

  119. Taguchi, K. et al. M1/M2-macrophage phenotypes regulate renal calcium oxalate crystal development. Sci. Rep. 6, 35167 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Xi, J. et al. Sirtuin 3 suppresses the formation of renal calcium oxalate crystals through promoting M2 polarization of macrophages. J. Cell Physiol. 234, 11463–11473 (2019).

    CAS  PubMed  Google Scholar 

  121. Kovacevic, L., Lu, H., Caruso, J. A., Kovacevic, N. & Lakshmanan, Y. Urinary proteomics reveals association between pediatric nephrolithiasis and cardiovascular disease. Int. Urol. Nephrol. 50, 1949–1954 (2018).

    CAS  PubMed  Google Scholar 

  122. Kusumi, K. et al. Adolescents with urinary stones have elevated urine levels of inflammatory mediators. Urolithiasis 47, 461–466 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Tang, P. M., Nikolic-Paterson, D. J. & Lan, H. Y. Macrophages: versatile players in renal inflammation and fibrosis. Nat. Rev. Nephrol. 15, 144–158 (2019).

    PubMed  Google Scholar 

  124. Kusmartsev, S. et al. Calcium oxalate stone fragment and crystal phagocytosis by human macrophages. J. Urol. 195, 1143–1151 (2016).

    CAS  PubMed  Google Scholar 

  125. Umekawa, T., Chegini, N. & Khan, S. R. Increased expression of monocyte chemoattractant protein-1 (MCP-1) by renal epithelial cells in culture on exposure to calcium oxalate, phosphate and uric acid crystals. Nephrol. Dial. Transplant. 18, 664–669 (2003).

    CAS  PubMed  Google Scholar 

  126. Dominguez-Gutierrez, P. R., Kusmartsev, S., Canales, B. K. & Khan, S. R. Calcium oxalate differentiates human monocytes into inflammatory M1 macrophages. Front. Immunol. 9, 1863 (2018).

    PubMed  PubMed Central  Google Scholar 

  127. Taguchi, K. et al. Colony-stimulating factor-1 signaling suppresses renal crystal formation. J. Am. Soc. Nephrol. 25, 1680–1697 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Anders, H. J. et al. The macrophage phenotype and inflammasome component NLRP3 contributes to nephrocalcinosis-related chronic kidney disease independent from IL-1-mediated tissue injury. Kidney Int. 93, 656–669 (2018).

    CAS  PubMed  Google Scholar 

  129. Zhu, W. et al. Loss of the androgen receptor suppresses intrarenal calcium oxalate crystals deposition via altering macrophage recruitment/M2 polarization with change of the miR-185-5p/CSF-1 signals. Cell Death Dis. 10, 275 (2019).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  131. Okada, A. et al. Successful formation of calcium oxalate crystal deposition in mouse kidney by intraabdominal glyoxylate injection. Urol. Res. 35, 89–99 (2007).

    CAS  PubMed  Google Scholar 

  132. de Water, R. et al. Calcium oxalate nephrolithiasis: effect of renal crystal deposition on the cellular composition of the renal interstitium. Am. J. Kidney Dis. 33, 761–771 (1999).

    PubMed  Google Scholar 

  133. Khan, S. R. et al. Crystal-cell interaction and apoptosis in oxalate-associated injury of renal epithelial cells. J. Am. Soc. Nephrol. 10, 457–463 (1999).

    Google Scholar 

  134. de Bruijn, W. C. et al. Etiology of calcium oxalate nephrolithiasis in rats. I. Can this be a model for human stone formation? Scanning Microsc. 9, 103–114 (1995).

    PubMed  Google Scholar 

  135. Canton, J., Khezri, R., Glogauer, M. & Grinstein, S. Contrasting phagosome pH regulation and maturation in human M1 and M2 macrophages. Mol. Biol. Cell. 25, 3330–3341 (2014).

    PubMed  PubMed Central  Google Scholar 

  136. Zuo, J., Khan, A., Glenton, P. A. & Khan, S. R. 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, 1785–1796 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Joshi, S., Wang, W. & Khan, S. R. Transcriptional study of hyperoxaluria and calcium oxalate nephrolithiasis in male rats: inflammatory changes are mainly associated with crystal deposition. PLoS One 12, e0185009 (2017).

    PubMed  PubMed Central  Google Scholar 

  138. Joshi, G. N., Goetjen, A. M. & Knecht, D. A. Silica particles cause NADPH oxidase-independent ROS generation and transient phagolysosomal leakage. Mol. Biol. Cell. 26, 3150–3164 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Shanahan, C. M., Crouthamel, M. H., Kapustin, A. & Giachelli, C. M. Arterial calcification in chronic kidney disease: key roles for calcium and phosphate. Circ. Res. 109, 697–711 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Murshed, M. & McKee, M. D. Molecular determinants of extracellular matrix mineralization in bone and blood vessels. Curr. Opin. Nephrol. Hypertens. 19, 359–365 (2010).

    CAS  PubMed  Google Scholar 

  141. Golub, E. E. Biomineralization and matrix vesicles in biology and pathology. Semin. Immunopathol. 33, 409–417 (2010).

    PubMed  PubMed Central  Google Scholar 

  142. Fasano, J. M. & Khan, S. R. Intratubular crystallization of calcium oxalate in the presence of membrane vesicles: an in vitro study. Kidney Int. 59, 169–178 (2001).

    CAS  PubMed  Google Scholar 

  143. Khan, S. R., Glenton, P. A., Backov, 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).

    CAS  PubMed  Google Scholar 

  144. Khan, S. R. & Canales, B. K. Ultrastructural investigation of crystal deposits in Npt2a knockout mice: are they similar to human Randall’s plaques? J. Urol. 186, 1107–1113 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Khan, S. R. et al. Lipids and membranes in the organic matrix of urinary calcific crystals and stones. Calcif. Tissue Int. 59, 357–365 (1996).

    CAS  PubMed  Google Scholar 

  146. 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).

    CAS  PubMed  Google Scholar 

  147. Skotland, T., Hessvik, N. P., Sandvig, K. & Llorente, A. Exosomal lipid composition and the role of ether lipids and phosphoinositides in exosome biology. J. Lipid. Res. 60, 9–18 (2019).

    CAS  PubMed  Google Scholar 

  148. Joshi, S., Clapp, W. L., Wang, W. & Khan, S. R. Osteogenic changes in kidneys of hyperoxaluric rats. Biochim. Biophys. Acta 1852, 2000–2012 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Khan, S. R., Joshi, S. & Wang, W. Dedifferentiation of renal epithelial cells into osteogenic cells and formation of Randall’s plaque. J. Am. Soc. Nephrol. 25, 101A (2014).

    Google Scholar 

  150. Hunter, G. K. Role of osteopontin in modulation of hydroxyapatite formation. Calcif. Tissue Int. 93, 348–354 (2013).

    CAS  PubMed  Google Scholar 

  151. Liu, T. M. & Lee, E. H. Transcriptional regulatory cascades in Runx2-dependent bone development. Tissue Eng. B Rev. 19, 254–263 (2013).

    Google Scholar 

  152. Liu, W. et al. Overexpression of Cbfa1 in osteoblasts inhibits osteoblast maturation and causes osteopenia with multiple fractures. J. Cell. Biol. 155, 157–166 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Matsubara, T. et al. BMP2 regulates Osterix through Msx2 and Runx2 during osteoblast differentiation. J. Biol. Chem. 283, 29119–29125 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Lomashvili, K. A., Garg, P., Narisawa, S., Millan, J. L. & O’Neill, W. C. Upregulation of alkaline phosphatase and pyrophosphate hydrolysis: potential mechanism for uremic vascular calcification. Kidney Int. 73, 1024–1030 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Okada, A. et al. Genome-wide analysis of genes related to kidney stone formation and elimination in the calcium oxalate nephrolithiasis model mouse: detection of stone-preventive factors and involvement of macrophage activity. J. Bone Miner. Res. 24, 908–924 (2009).

    CAS  PubMed  Google Scholar 

  156. Thiery, J. P. & Sleeman, J. P. Complex networks orchestrate epithelial-mesenchymal transitions. Nat. Rev. Mol. Cell. Biol. 7, 131–142 (2006).

    CAS  PubMed  Google Scholar 

  157. Jia, Z. et al. Does crystal deposition in genetic hypercalciuric rat kidney tissue share similarities with bone formation? Urology 83, 509 e7–509 14 (2014).

    Google Scholar 

  158. Jia, Z. et al. Role of calcium in the regulation of bone morphogenetic protein 2, Runt-related transcription factor 2 and Osterix in primary renal tubular epithelial cells by the vitamin D receptor. Mol. Med. Rep. 12, 2082–2088 (2015).

    CAS  PubMed  Google Scholar 

  159. Convento, M., Pessoa, E., Aragao, A., Schor, N. & Borges, F. Oxalate induces type II epithelial to mesenchymal transition (EMT) in inner medullary collecting duct cells (IMCD) in vitro and stimulate the expression of osteogenic and fibrotic markers in kidney medulla in vivo. Oncotarget 10, 1102–1118 (2019).

    PubMed  PubMed Central  Google Scholar 

  160. Miyazawa, K., Aihara, K., Ikeda, R., Moriyama, M. T. & Suzuki, K. cDNA macroarray analysis of genes in renal epithelial cells exposed to calcium oxalate crystals. Urol. Res. 37, 27–33 (2009).

    CAS  PubMed  Google Scholar 

  161. Mezzabotta, F. et al. Spontaneous calcification process in primary renal cells from a medullary sponge kidney patient harbouring a GDNF mutation. J. Cell. Mol. Med. 19, 889–902 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Evan, A. P. et al. Biopsy proven medullary sponge kidney: clinical findings, histopathology, and role of osteogenesis in stone and plaque formation. Anat. Rec. 298, 865–877 (2015).

    Google Scholar 

  163. Khan, S. R. & Gambaro, G. Role of osteogenesis in the formation of Randall’s plaques. Anat. Rec. 299, 5–7 (2016).

    Google Scholar 

  164. Collett, G. D. & Canfield, A. E. Angiogenesis and pericytes in the initiation of ectopic calcification. Circ. Res. 96, 930–938 (2005).

    CAS  PubMed  Google Scholar 

  165. Doherty, M. J. et al. Vascular pericytes express osteogenic potential in vitro and in vivo. J. Bone Miner. Res. 13, 828–838 (1998).

    CAS  PubMed  Google Scholar 

  166. Cola, C., Almeida, M., Li, D., Romeo, F. & Mehta, J. L. Regulatory role of endothelium in the expression of genes affecting arterial calcification. Biochem. Biophys. Res. Commun. 320, 424–427 (2004).

    CAS  PubMed  Google Scholar 

  167. Sarica, K., Aydin, H., Yencilek, F., Telci, D. & Yilmaz, B. Human umbilical vein endothelial cells accelerate oxalate-induced apoptosis of human renal proximal tubule epithelial cells in co-culture system which is prevented by pyrrolidine dithiocarbamate. Urol. Res. 40, 461–466 (2012).

    CAS  PubMed  Google Scholar 

  168. Priante, G. et al. Human proximal tubular cells can form calcium phosphate deposits in osteogenic culture: role of cell death and osteoblast-like transdifferentiation. Cell Death Discov. 5, 57 (2019).

    PubMed  PubMed Central  Google Scholar 

  169. Chinetti-Gbaguidi, G. et al. Human alternative macrophages populate calcified areas of atherosclerotic lesions and display impaired RANKL-induced osteoclastic bone resorption activity. Circ. Res. 121, 19–30 (2017).

    CAS  PubMed  Google Scholar 

  170. Rogers, M. A., Aikawa, M. & Aikawa, E. Macrophage heterogeneity complicates reversal of calcification in cardiovascular tissues. Circ. Res. 121, 5–7 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Bushinsky, D. A., Frick, K. K. & Nehrke, K. Genetic hypercalciuric stone-forming rats. Curr. Opin. Nephrol. Hypertens. 15, 403–418 (2006).

    CAS  PubMed  Google Scholar 

  172. Agharazii, M. et al. Inflammatory cytokines and reactive oxygen species as mediators of chronic kidney disease-related vascular calcification. Am. J. Hypertens. 28, 746–755 (2015).

    CAS  PubMed  Google Scholar 

  173. Byon, C. H. et al. Oxidative stress induces vascular calcification through modulation of the osteogenic transcription factor Runx2 by AKT signaling. J. Biol. Chem. 283, 15319–15327 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Khan, S. R. Reactive oxygen species as the molecular modulators of calcium oxalate kidney stone formation: evidence from clinical and experimental investigations. J. Urol. 189, 803–811 (2013).

    CAS  PubMed  Google Scholar 

  175. Khan, S. R., Joshi, S., Wang, W. & Peck, A. B. Regulation of macromolecular modulators of urinary stone formation by reactive oxygen species: transcriptional study in an animal model of hyperoxaluria. Am. J. Physiol. Renal Physiol. 306, F1285–F1295 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Wen, C. et al. Nalp3 inflammasome is activated and required for vascular smooth muscle cell calcification. Int. J. Cardiol. 168, 2242–2247 (2013).

    PubMed  Google Scholar 

  177. Chen, T. C. et al. The antagonism of 6-shogaol in high-glucose-activated NLRP3 inflammasome and consequent calcification of human artery smooth muscle cells. Cell Biosci. 10, 5 (2020).

    PubMed  PubMed Central  Google Scholar 

  178. Jono, S. et al. Phosphate regulation of vascular smooth muscle cell calcification. Circ. Res. 87, E10–E17 (2000).

    CAS  PubMed  Google Scholar 

  179. Jono, S., Shioi, A., Ikari, Y. & Nishizawa, Y. Vascular calcification in chronic kidney disease. J. Bone Miner. Metab. 24, 176–181 (2006).

    PubMed  Google Scholar 

  180. Kapustin, A. N. et al. Calcium regulates key components of vascular smooth muscle cell-derived matrix vesicles to enhance mineralization. Circ. Res. 109, e1–e12 (2011).

    CAS  PubMed  Google Scholar 

  181. Kapustin, A. N. & Shanahan, C. M. Calcium regulation of vascular smooth muscle cell-derived matrix vesicles. Trends Cardiovasc. Med. 22, 133–137 (2012).

    CAS  PubMed  Google Scholar 

  182. Gambaro, G. et al. Crystals, Randall’s plaques and renal stones: do bone and atherosclerosis teach us something? J. Nephrol. 17, 774–777 (2004).

    PubMed  Google Scholar 

  183. Zhu, F., Friedman, M. S., Luo, W., Woolf, P. & Hankenson, K. D. The transcription factor Osterix (SP7) regulates BMP6-induced human osteoblast differentiation. J. Cell. Physiol. 227, 2677–2685 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Durham, A. L., Speer, M. Y., Scatena, M., Giachelli, C. M. & Shanahan, C. M. Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness. Cardiovasc. Res. 114, 590–600 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Shroff, R. C. et al. The circulating calcification inhibitors, fetuin-A and osteoprotegerin, but not matrix Gla protein, are associated with vascular stiffness and calcification in children on dialysis. Nephrol. Dial. Transplant. 23, 3263–3271 (2008).

    CAS  PubMed  Google Scholar 

  186. Kapustin, A. N. & Shanahan, C. M. Osteocalcin: a novel vascular metabolic and osteoinductive factor? Arterioscler. Thromb. Vasc. Biol. 31, 2169–2171 (2011).

    CAS  PubMed  Google Scholar 

  187. Shanahan, C. M. et al. Expression of mineralisation-regulating proteins in association with human vascular calcification. Z. Kardiol. 89, 63–68 (2000).

    CAS  PubMed  Google Scholar 

  188. Shanahan, C. M. Vascular calcification. Curr. Opin. Nephrol. Hypertens. 14, 361–367 (2005).

    CAS  PubMed  Google Scholar 

  189. Shioi, A. & Ikari, Y. Plaque calcification during atherosclerosis progression and regression. J. Atheroscler. Thromb. 25, 294–303 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Cho, K. I., Sakuma, I., Sohn, I. S., Jo, S. H. & Koh, K. K. Inflammatory and metabolic mechanisms underlying the calcific aortic valve disease. Atherosclerosis 277, 60–65 (2018).

    CAS  PubMed  Google Scholar 

  191. Li, G. et al. The shift of macrophages toward M1 phenotype promotes aortic valvular calcification. J. Thorac. Cardiovasc. Surg. 153, 1318–1327 e1 (2017).

    CAS  PubMed  Google Scholar 

  192. Anderson, L. & Mc, D. J. The origin, frequency, and significance of microscopic calculi in the kidney. Surg. Gynecol. Obstet. 82, 275–282 (1946).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  194. Talham, D. R. et al. Role of lipids in urinary stones: studies of calcium oxalate precipitation at phospholipid langmuir monolayers. Langmuir 22, 2450–2456 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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S.R.K. and P.R.D.-G. researched data for the article. All authors made substantial contributions to discussions of the content, wrote the manuscript, and reviewed or edited the manuscript before submission.

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Correspondence to Saeed R. Khan.

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B.K.C. receives grant support through Alnylam Pharmaceuticals and the National Institutes of Health, is paid for his services on the AUA Content Review Committee and has ownership/stock options with AP LifeSciences and ForTec Litho, LLC. The other authors declare no competing interests.

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Glossary

Lithogenic

Mineralization-inducing.

Concretions

Masses formed by the accumulation and aggregation of crystals.

Ectopic mineralization

A pathological biomineralization that occurs in soft tissue and generally involves the deposition of calcium phosphate.

Matrix vesicles

Small, membrane-bound and mostly spherical bodies present at mineralization sites.

Crystal nucleation

The first step of crystal formation in which ions reorganize to form a solid phase.

Transwell culture system

Culture system with two chambers separated by a permeable membrane that is used to investigate the role of soluble mediators in interactions between cells.

Giant cells

Multinucleated cells formed by the fusion of several distinct cells such as macrophages.

Medullary sponge kidney

A rare congenital kidney disorder in which small cysts form in the kidney tubules.

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Khan, S.R., Canales, B.K. & Dominguez-Gutierrez, P.R. Randall’s plaque and calcium oxalate stone formation: role for immunity and inflammation. Nat Rev Nephrol 17, 417–433 (2021). https://doi.org/10.1038/s41581-020-00392-1

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