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Idiopathic hypercalciuria and formation of calcium renal stones

Nature Reviews Nephrology volume 12, pages 519–533 (2016)Cite this article

Subjects

Key Points

  • Idiopathic calcium stones are always accompanied by mineral deposits: interstitial deposits of apatite in patients with calcium oxalate (CaOx) stones or calcium phosphate (CaP) plugs in those with CaP stones

  • Overgrowth of CaOx stones on plaque depends on the formation of an initial CaP phase; urine saturations of CaP and CaOx might, therefore, be equally important

  • Microliths form on the open ends of tubule plugs but proof that these microliths can grow into clinically relevant stones is lacking

  • Patients with tubule plugs who form CaP stones show varying degrees of cortical fibrosis and nephron loss

  • Trial data support the use of high fluid intake, potassium citrate, thiazide diuretic agents and a reduced sodium diet for prevention of recurrent calcium renal stones

  • As idiopathic hypercalciuria arises from reduced renal tubule calcium reabsorption and is associated with negative calcium balance and bone disease, management with a low calcium diet is contraindicated

Abstract

The most common presentation of nephrolithiasis is idiopathic calcium stones in patients without systemic disease. Most stones are primarily composed of calcium oxalate and form on a base of interstitial apatite deposits, known as Randall's plaque. By contrast some stones are composed largely of calcium phosphate, as either hydroxyapatite or brushite (calcium monohydrogen phosphate), and are usually accompanied by deposits of calcium phosphate in the Bellini ducts. These deposits result in local tissue damage and might serve as a site of mineral overgrowth. Stone formation is driven by supersaturation of urine with calcium oxalate and brushite. The level of supersaturation is related to fluid intake as well as to the levels of urinary citrate and calcium. Risk of stone formation is increased when urine citrate excretion is <400 mg per day, and treatment with potassium citrate has been used to prevent stones. Urine calcium levels >200 mg per day also increase stone risk and often result in negative calcium balance. Reduced renal calcium reabsorption has a role in idiopathic hypercalciuria. Low sodium diets and thiazide-type diuretics lower urine calcium levels and potentially reduce the risk of stone recurrence and bone disease.

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Figure 1: Interstitial plaque and corresponding attachment site on a calcium oxalate (CaOx) stone.
Figure 2: Sites of interstitial plaque in idiopathic calcium oxalate (CaOx) stone formers.
Figure 3: Bellini duct plugs with overgrowths in patients who formed calcium stones.
Figure 4: Renal papilla of a patient who formed brushite stones.
Figure 5: Renal papilla of patients who formed idiopathic apatite stones.
Figure 6: Renal cortical changes in patients who formed calcium stones.
Figure 7: Effect of urine flow rate on calcium oxalate and calcium phosphate supersaturations.

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References

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

    Article  PubMed  PubMed Central  Google Scholar 

  2. Kirkali, Z., Rasooly, R., Star, R. A. & Rodgers, G. P. Urinary stone disease: progress, status, and needs. Urology 86, 651–653 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  4. Worcester, E. M. & Coe, F. L. New insights into the pathogenesis of idiopathic hypercalciuria. Semin. Nephrol. 28, 120–132 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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).

    Article  CAS  PubMed  Google Scholar 

  6. Evan, A. P. et al. Mechanisms of human kidney stone formation. Urolithiasis. 43 (Suppl. 1), 19–32 (2015).

    Article  PubMed  Google Scholar 

  7. Miller, N. L. et al. A formal test of the hypothesis that idiopathic calcium oxalate stones grow on Randall's plaque. BJU Int. 103, 966–971 (2009). This paper provides evidence for the importance of Randall's plaque as the site of attachment of idiopathic calcium oxalate stones.

    Article  CAS  PubMed  Google Scholar 

  8. Miller, N. L. et al. In idiopathic calcium oxalate stone-formers, unattached stones show evidence of having originated as attached stones on Randall's plaque. BJU Int. 105, 242–245 (2010).

    Article  PubMed  Google Scholar 

  9. Linnes, M. P. et al. Phenotypic characterization of kidney stone formers by endoscopic and histological quantification of intrarenal calcification. Kidney Int. 84, 818–825 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang, X. et al. Distinguishing characteristics of idiopathic calcium oxalate kidney stone formers with low amounts of Randall's plaque. Clin. J. Am. Soc. Nephrol. 9, 1757–1763 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Viers, B. R. et al. Endoscopic and histologic findings in a cohort of uric acid and calcium oxalate stone formers. Urology 85, 771–776 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  Google Scholar 

  13. Evan, A. E. et al. Histopathology and surgical anatomy of patients with primary hyperparathyroidism and calcium phosphate stones. Kidney Int. 74, 223–229 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Evan, A. P. et al. Intra-tubular deposits, urine and stone composition are divergent in patients with ileostomy. Kidney Int. 76, 1081–1088 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Evan, A. P. et al. Renal histopathology and crystal deposits in patients with small bowel resection and calcium oxalate stone disease. Kidney Int. 78, 310–317 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Evan, A. P. et al. Contrasting histopathology and crystal deposits in kidneys of idiopathic stone formers who produce hydroxy apatite, brushite, or calcium oxalate stones. Anat. Rec. (Hoboken) 297, 731–748 (2014).

    Article  CAS  Google Scholar 

  17. Evan, A. P. et al. Crystal-associated nephropathy in patients with brushite nephrolithiasis. Kidney Int. 67, 576–591 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Coe, F. L., Evan, A. P., Lingeman, J. E. & Worcester, E. M. Plaque and deposits in nine human stone diseases. Urol. Res. 38, 239–247 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  19. 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). Initial description of the papillary anatomy of calcium stone formers and the earliest site of appearance of Randall's plaque.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Williams, J. C. et al. Micro-CT imaging of Randall's plaques. Urolithiasis 43 (Suppl. 1), 13–17 (2015).

    Article  PubMed  Google Scholar 

  23. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  Google Scholar 

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

    Article  PubMed  Google Scholar 

  26. Kriz, W. & Kaissling, B. in Structural Organization of the Mammalian Kidney in Seldin and Giebisch's The Kidney: Physiology and Pathophysiology (eds Alpern, R. J. et al.) 595–691 (Elsevier, 2013).

    Book  Google Scholar 

  27. Bernardo, J. F. & Friedman, P. A. in Renal calcium metabolism in Seldin and Giebisch's The Kidney: Physiology and Pathophysiology (eds Alpern, R. J. et al.) 2225–2247 (Academic Press, 2013).

    Book  Google Scholar 

  28. Coe, F. L., Evan, A. & Worcester, E. Pathophysiology-based treatment of idiopathic calcium kidney stones. Clin. J. Am. Soc. Nephrol. 6, 2083–2092 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Stoller, M. L., 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).

    Article  CAS  PubMed  Google Scholar 

  30. Alexander, R. T. et al. Kidney stones and cardiovascular events: a cohort study. Clin. J. Am. Soc. Nephrol. 9, 506–512 (2014).

    Article  PubMed  Google Scholar 

  31. Ferraro, P. M. et al. History of kidney stones and the risk of coronary heart disease. JAMA 310, 408–415 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Evan, A. P. et al. Comparison of the pathology of interstitial plaque in human ICSF stone patients to NHERF-1 and THP-null mice. Urol. Res. 38, 439–452 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Evan, A. P. et al. Mechanism of formation of human calcium oxalate renal stones on Randall's plaque. Anat. Rec. (Hoboken.) 290, 1315–1323 (2007). A description of the ultrastructure of the interface between plaque and the earliest phase of calcium oxalate stone formation.

    Article  CAS  Google Scholar 

  34. Evan, A. P. et al. Renal intratubular crystals and hyaluronan staining occur in stone formers with bypass surgery but not with idiopathic calcium oxalate stones. Anat. Rec. (Hoboken.) 291, 325–334 (2008).

    Article  Google Scholar 

  35. Evan, A. P. et al. Renal histopathology of stone-forming patients with distal renal tubular acidosis. Kidney Int. 71, 795–801 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Evan, A. P. et al. Renal crystal deposits and histopathology in patients with cystine stones. Kidney Int. 69, 2227–2235 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Worcester, E. M. et al. A test of the hypothesis that oxalate secretion produces proximal tubule crystallization in primary hyperoxaluria type I. Am. J. Physiol. Renal Physiol. 305, F1574–F1584 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Worcester, E. M., Parks, J. H., Evan, A. P. & Coe, F. L. Renal function in patients with nephrolithiasis. J. Urol. 176, 600–603 (2006).

    Article  PubMed  Google Scholar 

  39. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Rule, A. D., Krambeck, A. E. & Lieske, J. C. Chronic kidney disease in kidney stone formers. Clin. J. Am. Soc. Nephrol. 6, 2069–2075 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Coe, F. L. & Parks, J. H. in Physical Chemistry of Calcium Stone Disease in Nephrolithiasis: Pathogenesis and Treatment (eds Coe, F. L. & Parks, J. H.) 38–58 (Year Book Medical Publishers, 1988).

    Google Scholar 

  42. Qiu, S. R. & Orme, C. A. Dynamics of biomineral formation at the near-molecular level. Chem. Rev. 108, 4784–4822 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Finlayson, B. in Calcium stones: some physical and clinical aspects in Calcium metabolism in renal failure and nephrolithiasis (eds David, D. S.) 337–382 (John Wiley & Sons, 1977). A description of the method for computation of urinary supersaturation in stone formers.

    Google Scholar 

  44. Parks, J. H., Coward, W. M. & Coe, F. L. Correspondence between stone composition and urine supersaturation in nephrolithiasis. Kidney Int. 51, 894–900 (1997).

    Article  CAS  PubMed  Google Scholar 

  45. Bergsland, K. J., Zisman, A. L., Asplin, J. R., Worcester, E. M. & Coe, F. L. Evidence for net renal tubule oxalate secretion in patients with calcium kidney stones. Am. J. Physiol. Renal Physiol. 300, F311–F318 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Santucci, L. et al. Urinary proteome in a snapshot: normal urine and glomerulonephritis. J. Nephrol. 26, 610–616 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Wright, C. A. et al. Label-free quantitative proteomics reveals differentially regulated proteins influencing urolithiasis. Mol. Cell. Proteomics 10, M110 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kumar, V. & Lieske, J. C. Protein regulation of intrarenal crystallization. Curr. Opin. Nephrol. Hypertens. 15, 374–380 (2006). A review of the role of urinary crystallization inhibitors in preventing kidney stones.

    Article  CAS  PubMed  Google Scholar 

  49. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Canales, B. K. et al. Proteome of human calcium kidney stones. Urology 76, 1017–1020 (2010).

    Article  PubMed  Google Scholar 

  51. Pak, C. Y. C. Physicochemical basis for formation of renal stones of calcium phosphate origin: calculation of the degree of supersaturation of urine with respect to brushite. J. Clin. Invest. 48, 1914–1922 (1969). A fundamental explanation of urinary supersaturation with respect to calcium phosphate.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Nancollas, G. H. & Henneman, Z. J. Calcium oxalate: calcium phosphate transformations. Urol. Res. 38, 277–280 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Costa-Bauza, A. et al. Type of renal calculi: variation with age and sex. World J. Urol. 25, 415–421 (2007).

    Article  PubMed  Google Scholar 

  54. Joseph, N. R. The dissociation constants of organic calcium complexes. J. Biol. Chem. 164, 529–541 (1946).

    CAS  PubMed  Google Scholar 

  55. Rodgers, A. L., Allie-Hamdulay, S., Jackson, G. E. & Sutton, R. A. Enteric hyperoxaluria secondary to small bowel resection: use of computer simulation to characterize urinary risk factors for stone formation and assess potential treatment protocols. J. Endourol. 28, 985–994 (2014).

    Article  PubMed  Google Scholar 

  56. De Yoreo, J. J., Qiu, S. R. & Hoyer, J. R. Molecular modulation of calcium oxalate crystallization. Am. J. Physiol. Renal Physiol. 291, F1123–F1131 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Coe, F. L., Parks, J. H. & Moore, E. S. Familial idiopathic hypercalciuria. N. Engl. J. Med. 300, 337–340 (1979).

    Article  CAS  PubMed  Google Scholar 

  58. Albright, F., Henneman, P., Benedict, P. H. & Forbes, A. P. Idiopathic hypercalciuria: a preliminary report. Proc. R. Soc. Med. 46, 1077–1081 (1953).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Heilberg, I. P. & Weisinger, J. R. Bone disease in idiopathic hypercalciuria. Curr. Opin. Nephrol. Hypertens. 15, 394–402 (2006). An excellent review of the nature of the bone disease in patients with idiopathic hypercalciuria.

    Article  CAS  PubMed  Google Scholar 

  60. Curhan, G. C. & Taylor, E. N. 24-h uric acid excretion and the risk of kidney stones. Kidney Int. 73, 489–496 (2008). A presentation of data from a large prospective observational study that sheds light on urinary risk factors for stone formation.

    Article  CAS  PubMed  Google Scholar 

  61. Blaine, J., Chonchol, M. & Levi, M. Renal control of calcium, phosphate, and magnesium homeostasis. Clin. J. Am. Soc. Nephrol. 10, 1257–1272 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Liberman, U. A. et al. Metabolic and calcium kinetic studies in idiopathic hypercalciuria. J. Clin. Invest. 47, 2580–2590 (1968).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Heaney, R. P. & Skillman, T. G. Secretion and excretion of calcium by the human gastrointestinal tract. J. Lab. Clin. Med. 64, 29–41 (1964).

    CAS  PubMed  Google Scholar 

  64. Nassim, J. R. & Higgins, B. A. Control of idiopathic hypercalciuria. Br. Med. J. 1, 675–681 (1965).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Edwards, N. A. & Hodgekinson, A. Metabolic studies in patients with idiopathic hypercalciuria. Clin. Sci. 29, 143–157 (1965).

    CAS  PubMed  Google Scholar 

  66. Henneman, P. H., Benedict, P. H., Forbes, A. P. & Dudley, H. R. Idiopathic hypercalciuria. N. Engl. J. Med. 259, 802–807 (1958).

    Article  CAS  PubMed  Google Scholar 

  67. Jackson, W. P. U. & Dancaster, C. A consideration of the hypercalciuria in sarcoidosis, idiopathic hypercalciuria, and that produced by vitamin D. A new suggestion regarding calcium metabolism. J. Clin. Endocrinol. Metab. 19, 658 (1959).

    Article  CAS  PubMed  Google Scholar 

  68. Harrison, A. R. Some results of metabolic investigations in cases of renal stone. Br. J. Urol. 31, 398 (1959).

    Article  CAS  PubMed  Google Scholar 

  69. Dent, C. E., Harper, C. M. & Parfitt, A. M. The effect of cellulose phosphate on calcium metabolism in patients with hypercalciuria. Clin. Sci. 27, 417–425 (1964).

    CAS  PubMed  Google Scholar 

  70. Parfitt, A. M., Higgins, B. A., Nassim, J. R., Collins, J. A. & Hilb, A. Metabolic studies in patients with hypercalciuria. Clin. Sci. 27, 463–482 (1964).

    CAS  PubMed  Google Scholar 

  71. Yendt, E. R., Gagne, R. J. A. & Cohanim, M. The effects of thiazides in idiopathic hypercalciuria. Trans. Am. Clin. Climatol. Assoc. 77, 96–110 (1966).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Dent, C. E. & Watson, L. Metabolic studies in a patient with idiopathic hypercalciuria. Br. Med. J. 2, 449–452 (1965).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Anderson, J., Lee, H. A. & Tomlinson, R. W. Some metabolic aspects of idiopathic hypercalciuria. Nephron 4, 129–138 (1967).

    Article  CAS  PubMed  Google Scholar 

  74. Khanal, R. C. & Nemere, I. Regulation of intestinal calcium transport. Annu. Rev. Nutr. 28, 179–196 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. Insogna, K. L., Broadus, A. E., Dreyer, B. E., Ellison, A. F. & Gertner, J. M. Elevated production rate of 1,25-dihydroxyvitamin D in patients with absorptive hypercalciuria. J. Clin. Endocrinol. Metab. 61, 490–495 (1985).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  77. Worcester, E. M. et al. Evidence that postprandial reduction of renal calcium reabsorption mediates hypercalciuria of patients with calcium nephrolithiasis. Am. J. Physiol. Renal Physiol. 292, F66–F75 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Worcester, E. M., Bergsland, K. J., Gillen, D. L. & Coe, F. L. Evidence for increased renal tubule and parathyroid gland sensitivity to serum calcium in human idiopathic hypercalciuria. Am. J. Physiol. Renal Physiol. 305, F853–F860 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Worcester, E. M. et al. Evidence for increased postprandial distal nephron calcium delivery in hypercalciuric stone-forming patients. Am. J. Physiol. Renal Physiol. 295, F1286–F1294 (2008). This paper provides evidence that proximal tubule sodium and calcium reabsorption is lower in patients with idiopathic hypercalciuria than in normal individuals, and that this difference contributes to elevated urine calcium excretion.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Coe, F. L. et al. 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, 25–32 (1982). An important study showing that altered renal calcium reabsorption is a key feature of idiopathic hypercalciuria.

    Article  CAS  PubMed  Google Scholar 

  81. Qaseem, A., Dallas, P., Forciea, M. A., Starkey, M. & Denberg, T. D. Dietary and pharmacologic management to prevent recurrent nephrolithiasis in adults: a clinical practice guideline from the American College of Physicians. Ann. Intern. Med. 161, 659–667 (2014).

    Article  PubMed  Google Scholar 

  82. Bergsland, K. J., Coe, F. L., Gillen, D. L. & Worcester, E. M. A test of the hypothesis that the collecting duct calcium-sensing receptor limits rise of urine calcium molarity in hypercalciuric calcium kidney stone formers. Am. J. Physiol. Renal Physiol. 297, F1017–F1023 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Pak, C. Y. C., Sakhaee, K., Crowther, C. & Brinkley, L. Evidence justifying a high fluid intake in treatment of nephrolithiaisis. Ann. Intern. Med. 93, 36–39 (1980).

    Article  CAS  PubMed  Google Scholar 

  84. Borghi, L. et al. Urinary volume, water and recurrences of idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. J. Urol. 155, 839–843 (1996). Evidence for the importance of fluid intake as a way to prevent recurrence of calcium stones.

    Article  CAS  PubMed  Google Scholar 

  85. Breslau, N. A., Mcguire, J. L., Zerwekh, J. E. & Pak, C. Y. C. The role of dietary sodium on renal excretion and intstinal absorption of calicum and on vitamin D metabolism. J. Clin. Endocrinol. Metab. 55, 369–373 (1982).

    Article  CAS  PubMed  Google Scholar 

  86. Sakhaee, K., Harvey, J. A., Padalino, P., Whitson, P. & Pak, C. Y. C. The potential role of salt abuse on the risk for kidney stone formation. J. Urol. 150, 310–312 (1993).

    Article  CAS  PubMed  Google Scholar 

  87. McCarron, D. A. et al. Urinary calcium excretion at extremes of sodium intake in normal man. Am. J. Nephrol. 1, 84–90 (1981).

    Article  CAS  PubMed  Google Scholar 

  88. Phillips, M. J. & Cooke, J. N. C. Relation between urinary calcium and sodium in patients with idiopathic hypercalciuria. Lancet 1, 1354–1357 (1967).

    Article  CAS  PubMed  Google Scholar 

  89. Teucher, B. et al. Sodium and bone health: impact of moderately high and low salt intakes on calcium metabolism in postmenopausal women. J. Bone Miner. Res. 23, 1477–1485 (2008).

    Article  CAS  PubMed  Google Scholar 

  90. McParland, B. E., Goulding, A. & Campbell, A. J. Dietary salt affects biochemical markers of resorption and formation of bone in elderly women. BMJ 299, 834–835 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Frings-Meuthen, P., Baecker, N. & Heer, M. Low-grade metabolic acidosis may be the cause of sodium chloride-induced exaggerated bone resorption. J. Bone Miner. Res. 23, 517–524 (2008).

    Article  CAS  PubMed  Google Scholar 

  92. Nascimento, L., Oliveros, F. H. & Cunningham, E. Renal handling of sodium and calcium in hypercalciuria. Clin. Pharmacol. Ther. 35, 342–347 (1984).

    Article  CAS  PubMed  Google Scholar 

  93. Pak, C. Y. et al. Effect of dietary modification on urinary stone risk factors. Kidney Int. 68, 2264–2273 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Muldowney, F. P., Freaney, R. & K.Moloney, M. F. Importance of dietary sodium in the hypercalciuria syndrome. Kidney Int. 22, 292–296 (1982).

    Article  CAS  PubMed  Google Scholar 

  95. Silver, J., Rubinger, D., Friedlaender, M. M. & Popovtzer, M. M. Sodium-dependent idiopathic hypercalciuria in renal-stone formers. Lancet 2, 484–486 (1983).

    Article  CAS  PubMed  Google Scholar 

  96. Nouvenne, A. et al. Diet to reduce mild hyperoxaluria in patients with idiopathic calcium oxalate stone formation: a pilot study. Urology 73, 725–730. e1 (2009).

    Article  PubMed  Google Scholar 

  97. Nouvenne, A. et al. Effects of a low-salt diet on idiopathic hypercalciuria in calcium-oxalate stone formers: a 3-mo randomized controlled trial. Am. J. Clin. Nutr. 91, 565–570 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. Burtis, W. J., Gay, L., Insogna, K. L., Ellison, A. & Broadus, A. E. Dietary hypercalciuria in patients with calcium oxalate kidney stones. Am. J. Clin. Nutr. 60, 424–429 (1994).

    Article  CAS  PubMed  Google Scholar 

  99. Blackwood, A. M., Sagnella, G. A., Cook, D. G. & Cappuccio, F. P. Urinary calcium excretion, sodium intake and blood pressure in a multi-ethnic population: results of the Wandsworth Heart and Stroke Study. J. Hum. Hypertens. 15, 229–237 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Taylor, E. N. & Curhan, G. C. Demographic, dietary, and urinary factors and 24-h urinary calcium excretion. Clin. J. Am. Soc. Nephrol. 4, 1980–1987 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Damasio, P. C. et al. The role of salt abuse on risk for hypercalciuria. Nutr. J. 10, 3 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Borghi, L. et al. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N. Engl. J. Med. 346, 77–84 (2002). This study documents the efficacy of a low sodium, normal calcium, moderately low protein diet to prevent recurrent calcium oxalate stones.

    Article  CAS  PubMed  Google Scholar 

  103. U.S. Department of Agriculture & U.S. Department of Health and Human Services. Dietary Guidelines for Americans (U.S. Government Printing Office, 2010).

  104. Yendt, E. R., Gagne, R. J. A. & Cohanim, M. The effects of thiazides in idiopathic hypercalciuria. Am. J. Med. Sci. 261, 449–460 (1966).

    Article  Google Scholar 

  105. Fink, H. A. et al. Medical management to prevent recurrent nephrolithiasis in adults: a systematic review for an American College of Physicians Clinical Guideline. Ann. Intern. Med. 158, 535–543 (2013).

    Article  PubMed  Google Scholar 

  106. Laerum, E. & Larsen, S. Thiazide prophylaxis of urolithiasis: a double-blind study in general practice. Acta Med. Scand. 215, 383–389 (1984).

    Article  CAS  PubMed  Google Scholar 

  107. Ettinger, B., Citron, J. T., Livermore, B. & Dolman, L. I. Chlorthalidone reduces calcium oxalate calculous recurrence but magnesium hydroxide does not. J. Urol. 139, 679–684 (1988).

    Article  CAS  PubMed  Google Scholar 

  108. Borghi, L., Meschi, T., Guerra, A. & Novarini, A. Randomized prospective study of a nonthiazide diuretic, indapamide, in preventing calcium stone recurrences. J. Cardiovasc. Pharmacol. 22, S78–S86 (1993).

    Article  PubMed  Google Scholar 

  109. Bergsland, K. J., Worcester, E. M. & Coe, F. L. Role of proximal tubule in the hypocalciuric response to thiazide of patients with idiopathic hypercalciuria. Am. J. Physiol. Renal Physiol. 305, F592–F599 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Coe, F. L., Parks, J. H., Bushinsky, D. A., Langman, C. B. & Favus, M. J. Chlorthalidone promotes mineral retention in patients with idiopathic hypercalciuria. Kidney Int. 33, 1140–1146 (1988).

    Article  CAS  PubMed  Google Scholar 

  111. Bolland, M. J. et al. The effect of treatment with a thiazide diuretic for 4 years on bone density in normal postmenopausal women. Osteoporos. Int. 18, 479–486 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Aung, K. & Htay, T. Thiazide diuretics and the risk of hip fracture. Cochrane Database Syst. Rev. 10, CD005185 (2011).

    Google Scholar 

  113. Caudarella, R., Vescini, F., Buffa, A. & Stefoni, S. Citrate and mineral metabolism: kidney stones and bone disease. Front. Biosci. 8, s1084–s1106 (2003).

    Article  PubMed  Google Scholar 

  114. Curthoys, N. P. & Moe, O. W. Proximal tubule function and response to acidosis. Clin. J. Am. Soc. Nephrol. 9, 1627–1638 (2014).

    Article  CAS  PubMed  Google Scholar 

  115. Halperin, M. L., Cheema, D. S. & Kamel, K. S. Physiology of acid-base balance: links with kidney stone prevention. Semin. Nephrol. 26, 441–446 (2006).

    Article  CAS  PubMed  Google Scholar 

  116. Pinheiro, V. B., Baxmann, A. C., Tiselius, H. G. & Heilberg, I. P. The effect of sodium bicarbonate upon urinary citrate excretion in calcium stone formers. Urology 82, 33–37 (2013).

    Article  PubMed  Google Scholar 

  117. Moseley, K. F., Weaver, C. M., Appel, L., Sebastian, A. & Sellmeyer, D. E. Potassium citrate supplementation results in sustained improvement in calcium balance in older men and women. J. Bone Miner. Res. 28, 497–504 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Menegon, L. F., Figueiredo, J. F. & Gontijo, J. A. Effect of metabolic acidosis on renal tubular sodium handling in rats as determined by lithium clearance. Braz. J. Med. Biol. Res. 31, 1269–1273 (1998).

    Article  CAS  PubMed  Google Scholar 

  119. Safirstein, R., Glassman, V. P. & DiScala, V. A. Effects of an NH4Cl-induced metabolic acidosis on salt and water reabsorption in dog kidney. Am. J. Physiol. 225, 805–809 (1973).

    Article  CAS  PubMed  Google Scholar 

  120. Wang, T., Egbert, A. L. Jr., Aronson, P. S. & Giebisch, G. Effect of metabolic acidosis on NaCl transport in the proximal tubule. Am. J. Physiol. 274, F1015–F1019 (1998).

    CAS  PubMed  Google Scholar 

  121. Balkovetz, D. F., Chumley, P. & Amlal, H. Downregulation of claudin-2 expression in renal epithelial cells by metabolic acidosis. Am. J. Physiol. Renal Physiol. 297, F604–F611 (2009).

    Article  CAS  PubMed  Google Scholar 

  122. Barcelo, P., Wuhl, O., Servitge, E., Rousaud, A. & Pak, C. Y. C. Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis. J. Urol. 150, 1761–1764 (1993).

    Article  CAS  PubMed  Google Scholar 

  123. Ettinger, B. et al. Potassium-magnesium citrate is an effective prophylaxis against recurrent calcium oxalate nephrolithiasis. J. Urol. 158, 2069–2073 (1997).

    Article  CAS  PubMed  Google Scholar 

  124. Hofbauer, J., Hobarth, K., Szabo, N. & Marberger, M. Alkali citrate prophylaxis in idiopathic recurrent calcium oxalate urolithiasis — a prospective randomized study. Br. J. Urol. 73, 362–365 (1994).

    Article  CAS  PubMed  Google Scholar 

  125. Soygur, T., Akbay, A. & Kupeli, S. Effect of potassium citrate therapy on stone recurrence and residual fragments after shockwave lithotripsy in lower caliceal calcium oxalate urolithiasis: a randomized controlled trial. J. Endourol. 16, 149–152 (2002).

    Article  PubMed  Google Scholar 

  126. Lojanapiwat, B. et al. Alkaline citrate reduces stone recurrence and regrowth after shockwave lithotripsy and percutaneous nephrolithotomy. Int. Braz. J. Urol. 37, 611–616 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Johnsson, M. S. & Nancollas, G. H. The role of brushite and octacalcium phosphate in apatite formation. Crit. Rev. Oral Biol. Med. 3, 61–82 (1992).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors' work is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (PO1 DK56788).

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Authors and Affiliations

  1. Nephrology Section MC 5100, University of Chicago Medicine, 5841 S. Maryland Avenue, Chicago, 60637, Illinois, USA

    Fredric L. Coe & Elaine M. Worcester

  2. Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Drive, MS 5055, Indianapolis, IN 46220, Indiana, USA

    Andrew P. Evan

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Coe, F., Worcester, E. & Evan, A. Idiopathic hypercalciuria and formation of calcium renal stones. Nat Rev Nephrol 12, 519–533 (2016). https://doi.org/10.1038/nrneph.2016.101

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