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. 1986 Oct;78(4):1097–1102. doi: 10.1172/JCI112666

Hypocalcemia may not be essential for the development of secondary hyperparathyroidism in chronic renal failure.

S Lopez-Hilker, T Galceran, Y L Chan, N Rapp, K J Martin, E Slatopolsky
PMCID: PMC423770  PMID: 3760186

Abstract

Hypocalcemia is the main factor responsible for the genesis of secondary hyperparathyroidism in chronic renal disease. Studies with parathyroid cells obtained from uremic patients indicate that there is a shift in the set point for calcium-regulated hormone (parathyroid hormone [PTH] secretion. Studies were performed in dogs to further clarify this new potential mechanism. Hypocalcemia was prevented in uremic dogs by the administration of a high calcium diet. Initially, ionized calcium was 4.79 +/- 0.09 mg/dl and gradually increased up to 5.30 +/- 0.05 mg/dl. Despite a moderate increase in ionized calcium, immunoreactive PTH (iPTH) increased from 64 +/- 7.7 to 118 +/- 21 pg/ml. Serum 1,25(OH)2D3 decreased from 25.4 +/- 3.8 to 12.2 +/- 3.6 pg/ml. Further studies were performed in two other groups of dogs. One group received 150-200 ng and the second group 75-100 ng of 1,25(OH)2D3 twice daily. The levels of 1,25(OH)2D3 increased from 32.8 +/- 3.5 to a maximum of 69.6 +/- 4.4 pg/ml. In the second group the levels of serum 1,25(OH)2D3 after nephrectomy remained normal during the study. Amino-terminal iPTH did not increase in either of the two groups treated with 1,25(OH)2D3. In summary, the dogs at no time developed hypocalcemia; however, there was an 84% increase in iPTH levels, suggesting that hypocalcemia, per se, may not be the only factor responsible for the genesis of secondary hyperparathyroidism.

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Selected References

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  1. Bellorin-Font E., Martin K. J., Freitag J. J., Anderson C., Sicard G., Slatopolsky E., Klahr S. Altered adenylate cyclase kinetics in hyperfunctioning human parathyroid glands. J Clin Endocrinol Metab. 1981 Mar;52(3):499–507. doi: 10.1210/jcem-52-3-499. [DOI] [PubMed] [Google Scholar]
  2. Brown E. M., Brennan M. F., Hurwitz S., Windeck R., Marx S. J., Spiegel A. M., Koehler J. O., Gardner D. G., Aurbach G. D. Dispersed cells prepared from human parathyroid glands: distinct calcium sensitivity of adenomas vs. primary hyperplasia. J Clin Endocrinol Metab. 1978 Feb;46(2):267–275. doi: 10.1210/jcem-46-2-267. [DOI] [PubMed] [Google Scholar]
  3. Brown E. M., Wilson R. E., Eastman R. C., Pallotta J., Marynick S. P. Abnormal regulation of parathyroid hormone release by calcium in secondary hyperparathyroidism due to chronic renal failure. J Clin Endocrinol Metab. 1982 Jan;54(1):172–179. doi: 10.1210/jcem-54-1-172. [DOI] [PubMed] [Google Scholar]
  4. Cantley L. K., Russell J., Lettieri D., Sherwood L. M. 1,25-Dihydroxyvitamin D3 suppresses parathyroid hormone secretion from bovine parathyroid cells in tissue culture. Endocrinology. 1985 Nov;117(5):2114–2119. doi: 10.1210/endo-117-5-2114. [DOI] [PubMed] [Google Scholar]
  5. Chan Y. L., McKay C., Dye E., Slatopolsky E. The effect of 1,25 dihydroxycholecalciferol on parathyroid hormone secretion by monolayer cultures of bovine parathyroid cells. Calcif Tissue Int. 1986 Jan;38(1):27–32. doi: 10.1007/BF02556591. [DOI] [PubMed] [Google Scholar]
  6. Chertow B. S., Baylink D. J., Wergedal J. E., Su M. H., Norman A. W. Decrease in serum immunoreactive parathyroid hormone in rats and in parathyroid hormone secretion in vitro by 1,25-dihydroxycholecalciferol. J Clin Invest. 1975 Sep;56(3):668–678. doi: 10.1172/JCI108137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cloix J. F., Ulmann A., Bachelet M., Funck-Brentano J. L. Cholecalciferol metabolites binding in porcine parathyroid glands. Steroids. 1976 Nov;28(5):743–749. doi: 10.1016/0039-128x(76)90011-8. [DOI] [PubMed] [Google Scholar]
  8. Coburn J. W., Hartenbower D. L., Massry S. G. Intestinal absorption of calcium and the effect of renal insufficiency. Kidney Int. 1973 Aug;4(2):96–104. doi: 10.1038/ki.1973.88. [DOI] [PubMed] [Google Scholar]
  9. Dietel M., Dorn G., Montz R., Altenähr E. Influence of vitamin D3, 1,25-dihydroxyvitamin D3, and 24,25-dihydroxyvitamin D3 on parathyroid hormone secretion, adenosine 3',5'-monophosphate release, and ultrastructure of parathyroid glands in organ culture. Endocrinology. 1979 Jul;105(1):237–245. doi: 10.1210/endo-105-1-237. [DOI] [PubMed] [Google Scholar]
  10. Fraser D. R., Kodicek E. Unique biosynthesis by kidney of a biological active vitamin D metabolite. Nature. 1970 Nov 21;228(5273):764–766. doi: 10.1038/228764a0. [DOI] [PubMed] [Google Scholar]
  11. Freitag J., Martin K. J., Hruska K. A., Anderson C., Conrades M., Ladenson J., Klahr S., Slatopolsky E. Impaired parathyroid hormone metabolism in patients with chronic renal failure. N Engl J Med. 1978 Jan 5;298(1):29–32. doi: 10.1056/NEJM197801052980107. [DOI] [PubMed] [Google Scholar]
  12. Haddad J. G., Walgate J., Min C., Hahn T. J. Vitamin D metabolite-binding proteins in human tissue. Biochim Biophys Acta. 1976 Oct 22;444(3):921–925. doi: 10.1016/0304-4165(76)90339-1. [DOI] [PubMed] [Google Scholar]
  13. Henry H. L., Norman A. W. Studies on the mechanism of action of calciferol VII. Localization of 1,25-dihydroxy-vitamin D3 in chick parathyroid glands. Biochem Biophys Res Commun. 1975 Feb 17;62(4):781–788. doi: 10.1016/0006-291x(75)90391-5. [DOI] [PubMed] [Google Scholar]
  14. Hruska K. A., Kopelman R., Rutherford W. E., Klahr S., Slatopolsky E., Greenwalt A., Bascom T., Markham J. Metabolism in immunoreactive parathyroid hormone in the dog. The role of the kidney and the effects of chronic renal disease. J Clin Invest. 1975 Jul;56(1):39–48. doi: 10.1172/JCI108077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. KENNY A. D., MUNSON P. L. A method for the biological assay of phosphaturic activity in parathyroid extracts. Endocrinology. 1959 Apr;64(4):513–521. doi: 10.1210/endo-64-4-513. [DOI] [PubMed] [Google Scholar]
  16. Llach F., Coburn J. W., Brickman A. S., Kurokawa K., Norman A. W., Canterbury J. M., Reiss E. Acute actions of 1,25-dihydroxy-vitamin D3 in normal man: effect on calcium and parathyroid status. J Clin Endocrinol Metab. 1977 Jun;44(6):1054–1060. doi: 10.1210/jcem-44-6-1054. [DOI] [PubMed] [Google Scholar]
  17. Llach F., Massry S. G. On the mechanism of secondary hyperparathyroidism in moderate renal insufficiency. J Clin Endocrinol Metab. 1985 Oct;61(4):601–606. doi: 10.1210/jcem-61-4-601. [DOI] [PubMed] [Google Scholar]
  18. Madsen S., Olgaard K., Ladefoged J. Suppressive effect of 1,25-dihydroxyvitamin D3 on circulating parathyroid hormone in acute renal failure. J Clin Endocrinol Metab. 1981 Oct;53(4):823–827. doi: 10.1210/jcem-53-4-823. [DOI] [PubMed] [Google Scholar]
  19. Massry S. G., Stein R., Garty J., Arieff A. I., Coburn J. W., Norman A. W., Friedler R. M. Skeletal resistance to the calcemic action of parathyroid hormone in uremia: role of 1,25 (OH)2 D3. Kidney Int. 1976 Jun;9(6):467–474. doi: 10.1038/ki.1976.60. [DOI] [PubMed] [Google Scholar]
  20. Massry S. G., Tuma S., Dua S., Goldstein D. A. Reversal of skeletal resistance to parathyroid hormone in uremia by vitamin D metabolites: evidence for the requirement of 1,25(OH)2D3 and 24,25(OH)2D3. J Lab Clin Med. 1979 Jul;94(1):152–157. [PubMed] [Google Scholar]
  21. Oldham S. B., Fischer J. A., Shen L. H., Arnaud C. D. Isolation and properties of a calcium-binding protein from porcine parathyroid glands. Biochemistry. 1974 Nov 5;13(23):4790–4796. doi: 10.1021/bi00720a017. [DOI] [PubMed] [Google Scholar]
  22. Oldham S. B., Smith R., Hartenbower D. L., Henry H. L., Norman A. W., Coburn J. W. The acute effects of 1,25-dihydroxycholecalciferol on serum immunoreactive parathyroid hormone in the dog. Endocrinology. 1979 Jan;104(1):248–254. doi: 10.1210/endo-104-1-248. [DOI] [PubMed] [Google Scholar]
  23. Portale A. A., Booth B. E., Halloran B. P., Morris R. C., Jr Effect of dietary phosphorus on circulating concentrations of 1,25-dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest. 1984 Jun;73(6):1580–1589. doi: 10.1172/JCI111365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Reinhardt T. A., Horst R. L., Orf J. W., Hollis B. W. A microassay for 1,25-dihydroxyvitamin D not requiring high performance liquid chromatography: application to clinical studies. J Clin Endocrinol Metab. 1984 Jan;58(1):91–98. doi: 10.1210/jcem-58-1-91. [DOI] [PubMed] [Google Scholar]
  25. Rutherford W. E., Bordier P., Marie P., Hruska K., Harter H., Greenwalt A., Blondin J., Haddad J., Bricker N., Slatopolsky E. Phosphate control and 25-hydroxycholecalciferol administration in preventing experimental renal osteodystrophy in the dog. J Clin Invest. 1977 Aug;60(2):332–341. doi: 10.1172/JCI108781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Silver J., Russell J., Sherwood L. M. Regulation by vitamin D metabolites of messenger ribonucleic acid for preproparathyroid hormone in isolated bovine parathyroid cells. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4270–4273. doi: 10.1073/pnas.82.12.4270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Slatopolsky E., Caglar S., Gradowska L., Canterbury J., Reiss E., Bricker N. S. On the prevention of secondary hyperparathyroidism in experimental chronic renal disease using "proportional reduction" of dietary phosphorus intake. Kidney Int. 1972 Sep;2(3):147–151. doi: 10.1038/ki.1972.84. [DOI] [PubMed] [Google Scholar]
  28. Slatopolsky E., Caglar S., Pennell J. P., Taggart D. D., Canterbury J. M., Reiss E., Bricker N. S. On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog. J Clin Invest. 1971 Mar;50(3):492–499. doi: 10.1172/JCI106517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Slatopolsky E., Weerts C., Thielan J., Horst R., Harter H., Martin K. J. Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxy-cholecalciferol in uremic patients. J Clin Invest. 1984 Dec;74(6):2136–2143. doi: 10.1172/JCI111639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Somerville P. J., Kaye M. Resistance to parathyroid hormone in renal failure: role of vitamin D metabolites. Kidney Int. 1978 Sep;14(3):245–254. doi: 10.1038/ki.1978.116. [DOI] [PubMed] [Google Scholar]
  31. Tanaka Y., Deluca H. F. The control of 25-hydroxyvitamin D metabolism by inorganic phosphorus. Arch Biochem Biophys. 1973 Feb;154(2):566–574. doi: 10.1016/0003-9861(73)90010-6. [DOI] [PubMed] [Google Scholar]
  32. Tennant B., Lowe J. E., Tasker J. B. Hypercalcemia and hypophosphatemia in ponies following bilateral nephrectomy. Proc Soc Exp Biol Med. 1981 Jul;167(3):365–368. doi: 10.3181/00379727-167-41180. [DOI] [PubMed] [Google Scholar]
  33. Tuma S. N., Mallette L. E. Hypercalcemia after nephrectomy in the dog: role of the kidneys and parathyroid glands. J Lab Clin Med. 1983 Aug;102(2):213–219. [PubMed] [Google Scholar]

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