Laboratory Investigation

Kidney International (1994) 45, 58–65; doi:10.1038/ki.1994.7

Increased urinary saturation and kidney calcium content in genetic hypercalciuric rats

David A Bushinsky, Mark Kim, Nelson E Sessler, Yasushi Nakagawa and Fredric L Coe

Nephrology Unit, University of Rochester, Rochester, New York, and Nephrology Program, University of Chicago, Chicago, Illinois, USA

Correspondence: David A Bushinsky MD, Nephrology Unit, Department Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 675, Rochester, New York, New York 14642, USA.

Received 21 May 1993; Revised 9 August 1993; Accepted 9 August 1993.

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Abstract

Increased urinary saturation and kidney calcium content in genetic hypercalciuric rats. We have established a colony of genetic hypercalciuric (IH) rats as a model of idiopathic hypercalciuria in humans. To test the hypothesis that hypercalciuria can cause crystallization in kidneys through increased supersaturation, in the absence of confounding effects of diet and whatever complex inhibitor disorders underlay stone disease, we fed males and females of the 21st generation of IH rats 13 g per day of a low calcium (LCD, 0.02% Ca), followed by a normal calcium (NCD, 0.6% Ca) and then a high calcium (HCD, 1.2% Ca) diet, each for seven days. During the last 24 hours of each period complete urine collections were obtained and analyzed for all substances known to affect urinary calcium oxalate (CaOx) and brushite (CaHPO4) supersaturation. Relative supersaturation with respect to the solid phases of CaOx and CaHPO4 were then calculated. Compared to same gender controls (Ctl) urine calcium excretion was higher in the female IH rats on all diets and in the male IH rats on NCD and HCD. The female and male IH rats on NCD and HCD were supersaturated with respect to CaOx; however, the male and female Ctl were supersaturated with respect CaOx only on HCD. The female IH rats on NCD and HCD and the male IH rats on NCD were supersaturated with respect to CaHPO4; however, neither the male nor female Ctl rats were supersaturated with respect to CaHPO4 on any diet. On NCD and HCD urine supersaturation with respect to CaHP04 by females exceeded that of males. Kidney calcium content was greater in the female IH rat (120 plusminus 13 microg/g kidney) than in any other group (male IH, 68 plusminus 6; female Ctl, 74 plusminus 4 and male Ctl 62 plusminus 4; all P < 0.01 vs. female IH) and calcium content was correlated with CaHPO4 but not CaOx. Thus, female IH rats have greater urinary CaHPO4 supersaturation than Ctl rats or male IH rats, and these female IH rats have a greater kidney calcium content. The increased urinary calcium concentration in this inbred strain of hypercalciuric rats leads to urinary supersaturation, leading to calcium precipitation within the kidney.

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References

  1. Coe FL: Treated and untreated recurrent calcium nephrolithiasis in patients with idiopathic hypercalciuria, hyperuricosuria, or no metabolic disorder. Ann Intern Med 87:404–410, 1977 | PubMed | ISI | ChemPort |
  2. Pak CYC, Hayashi Y, Finlayson B: Estimation of the state of saturation of brushite and calcium oxalate in urine: A comparison of three methods. J Lab Clin Med 89:891–909, 1977 | PubMed | ISI | ChemPort |
  3. Lonsdale K: Epitaxy as a growth factor in urinary calculi and gallstones. Nature 217:56–58, 1968 | Article | PubMed | ISI | ChemPort |
  4. Sutor DJ, Wooley SE: The structure and formation of urinary calculi: I. Oriented crystal growth. Br J Urol 44:532–536, 1972
  5. Yendt ER, Cohanim M: Prevention of calcium stones with thiazides. (abstract) Kidney Int 13:397, 1978 | PubMed | ISI | ChemPort |
  6. Coe FL, Favus MJ: Nephrolithiasis, in The Kidney, edited by Brenner BM Rector FC Jr, Philadelphia, W.B. Saunders Company, 1991, pp. 1728–1767
  7. Coe FL, Parks JH: Familial (idiopathic) hypercalciuria, in Nephrolithiasis: Pathogenesis and Treatment, edited by Coe FL, Parks JH, Chicago, Year Book Medical Publishers, Inc., 1990, pp. 108–138
  8. Meyer JL, Smith LH: Growth of calcium oxalate crystals: II. Inhibition by natural urinary crystal growth inhibitors. Invest Urol 13:36–39, 1975 | PubMed | ISI | ChemPort |
  9. Hoyer JR, Seiler MW: Pathophysiology of Tamm-Horsfall protein. Kidney Int 16:279–289, 1979 | PubMed | ISI | ChemPort |
  10. Nakagawa Y, Margolis HC, Yokoyama S, Kezdy FJ, Kaiser ET, Coe FL: Purification and characterization of a calcium oxalate monohydrate crystal growth inhibitor from human kidney tissue culture medium. J Biol Chem 256:3936–3944, 1981 | PubMed |
  11. Nakagawa Y, Abram V, Kezdy FJ, Kaiser ET, Coe FL: The purification and characterization of the principal inhibitor of calcium oxalate monohydrate crystal growth in human urine. J Biol Chem 258:12594–12600, 1983 | PubMed | ChemPort |
  12. Nakagawa Y, Abram V, Parks JH, Lau HS, Kawooya JK, Coe FL: Urine glycoprotein crystal growth inhibitors. Evidence for a molecular abnormality in calcium oxalate nephrolithiasis. J Clin Invest 76:1455–1462, 1985
  13. Velazquez H, Wright FS: Effects of diuretic drugs on Na, Cl, and K transport by rat renal distal tubule. Am J Physiol 250:F1013–F1023, 1986 | PubMed | ChemPort |
  14. Herring LC: Observations on the analysis often thousand urinary calculi. J Urol 88:545–562, 1962 | PubMed | ISI | ChemPort |
  15. Strates BS, Neuman WF, Levinskas GJ: The solubility of bone mineral: II. Precipitation of near-neutral solutions of calcium and phosphoru. J Physiol Chem 61:279–282, 1957
  16. Pak CYC, Eanes ED, Ruskin B: Spontaneous precipitation of brushite in urine: Evidence that brushite is the nidus of renal stones originating as calcium phosphat. Proc Natl Acad Sci USA 68:1456–1460, 1971 | Article | PubMed | ChemPort |
  17. Meyer JL, Bergert JH, Smith LH: Epitaxial relationships in urolithiasis: The calcium oxalate monohydrate-hydroxyapatite system. (abstract) Clin Sci Molec Med 49:369, 1975
  18. Bushinsky DA, Favus MJ: Mechanism of hypercalciuria in genetic hypercalciuric rats: Inherited defect in intestinal calcium transport. J Clin Invest 82:1585–1591, 1988 | PubMed | ISI | ChemPort |
  19. Kim M, Sessler NE, Favus MJ, Bushinsky DA: Response of genetic hypercalciuric rats to a low calcium diet. Kidney Int 43:189–196, 1993 | PubMed | ISI | ChemPort |
  20. Li X-Q, Tembe V, Horwitz GM, Bushinsky DA, Favus MJ: Increased intestinal vitamin D receptor in genetic hypercalciuric rats: A cause of intestinal calcium hyperabsorption. J Clin Invest 91:661–667, 1993 | PubMed | ISI | ChemPort |
  21. Bushinsky DA, Favus MJ, Coe FL: Elevated 1,25(OH)2D3, intestinal absorption and renal mineral conservation in male rats. Am J Physiol 246 (Renal Fluid Electrol Physiol 15):F140–F145, 1984 | PubMed | ISI | ChemPort |
  22. Bushinsky DA, Kittaka MK, Weisinger JF, Langman CB, Favus MJ: Effects of chronic metabolic alkalosis on Ca++, PTH and 1,25(OH)2D3 in the rat. Am J Physiol (Endocrinol Metab Physiol 20) 257:E579–E582, 1989
  23. Bushinsky DA, Favus MJ, Langman C, Coe FL: Mechanism of chronic hypercalciuria with furosemide: Increased calcium absorption. Am J Physiol 251 (Renal Fluid Electrol Physiol 20):F17–F24, 1986 | PubMed | ChemPort |
  24. Bushinsky DA, Riera G, Favus MJ, Coe FL: Evidence that blood ionized calcium can regulate serum 1,25(OH)2D3 independently of PTH and phosphorus in the rat. J Clin Invest 76:1599–1604, 1985
  25. Bushinsky DA, Favus MJ, Coe FL: Mechanism of chronic hypercalciuria with chlorthalidone: Reduced calcium absorption. Am J Physiol (Renal Fluid Electrol Physiol 16) 247:F746–F752, 1984 | PubMed | ChemPort |
  26. Ma RSW, Chan JCM: Endogenous sulphuric acid production: A method of measurement by extrapolation. Clin Biochem 6:82–87, 1973 | PubMed | ISI | ChemPort |
  27. Liddle L, Seegmiller JE, Laster L: The enzymatic spectrophotometric method for determination of uric acid. J Lab Clin Med 54:903–913, 1959 | PubMed | ChemPort |
  28. Hodgkinson A, Williams A: An improved colorimetric procedure for urine oxalate. Clin Chim Acta 36:127–132, 1972
  29. Finlayson B: Calcium stone: Some physical and clinical aspects, in Calcium Metabolism in Renal Failure and Nephrolithiasis, edited by David DS, New York, Wiley, 1977, pp. 337–382
  30. Bushinsky DA, Chabala JM, Levi-Setti R: Comparison of in vitro and in vivo44Ca labeling of bone by scanning ion microprobe. Am J Physiol (Endocrinol Metab 22) 259:E586–E592, 1990 | PubMed | ISI | ChemPort |
  31. Bushinsky DA, Lechleider RJ: Mechanism of proton-induced bone calcium release: Calcium carbonate dissolution. Am J Physiol (Renal Fluid Electrol Physiol 22) 253:F998–F1005, 1987 | PubMed | ISI | ChemPort |
  32. Worcester EM, Nakagawa T, Bushinsky DA, Coe FL: Evidence that serum calcium oxalate supersaturation is a consequence of oxalate retention in patients with chronic renal failure. J Clin Invest 77:1888–1896, 1986 | PubMed | ISI | ChemPort |
  33. Neuman WF, Neuman MW: The Chemical Dynamics of Bone Mineral. Chicago, University Chicago Press, 1958
  34. Nicas MJ, Skurla C, Sakhaee K, Pak CYC: Low urinary citrate excretion in nephrolithiasis. Urology 21:8–14, 1983
  35. Bisaz S, Felix R, Newman WF, Fleisch H: Quantitative determination of inhibitors of calcium phosphate precipitation in whole urine. (abstract) Miner Electrol Metab 1:74, 1978
  36. Crawford MA, Milne MD, Scribner BH: The effects of changes in acid-base balance of urinary citrate in the rat. J Physiol 149:413–432, 1959 | PubMed |
  37. Brennan S, Hering-Smith K, Hamm LL: Effect of pH on citrate reabsorption in the proximal convoluted tubule. Am J Physiol 255 (Renal Fluid Electrol Physiol 24):F301–F306, 1988 | PubMed | ChemPort |
  38. Sirivongs D, Nakagawa Y, Vishny WK, Favus MJ, Coe FL: Evidence that mouse renal proximal tubule cells produce nephrocalcin. Am J Physiol 257 (Renal Fluid Electrol Physiol 26):F390–F398, 1989 | PubMed |
  39. Worcester EM, Blumenthal SS, Beshensky AM, Lewand DL: The calcium oxalate crystal growth inhibitor protein produced by mouse kidney cortical cells in culture is osteopontin. J Bone Miner Res 7:1029–1036, 1992 | PubMed | ISI | ChemPort |
  40. Shiraga H, Min W, Vandusen WJ, Clayman MD, Miner D, Terrell CH, Sherbotie Jr, Foreman JW, Przysiecki C, Neilson EG, Hoyer JR: Inhibition of calcium oxalate crystal grown in vitro by uropontin: Another member of the aspartic acid-rich protein superfamily. Proc Natl Acad Sci USA 89:426–430, 1992 | Article | PubMed | ChemPort |

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