Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1977 Aug;60(2):332–341. doi: 10.1172/JCI108781

Phosphate Control and 25-Hydroxycholecalciferol Administration in Preventing Experimental Renal Osteodystrophy in the Dog

W E Rutherford 1,2,3, P Bordier 1,2,3,†, P Marie 1,2,3, K Hruska 1,2,3, H Harter 1,2,3, A Greenwalt 1,2,3, J Blondin 1,2,3, J Haddad 1,2,3, N Bricker 1,2,3, E Slatopolsky 1,2,3
PMCID: PMC372373  PMID: 874095

Abstract

Previous studies from this laboratory demonstrated that secondary hyperparathyroidism in dogs with chronic renal disease may occur, at least in part, as a consequence of the need for progressive adaptation in renal phosphorus (P) excretion that occurs as glomerular filtration rate falls. However, the studies were of relatively short duration. Moreover, no information emerged regarding a potential role of calcium malabsorption in the pathogenesis of secondary hyperparathyroidism. The short duration of the protocol did not lend itself to the study of the effect of P control or the administration of vitamin D in the pathogenesis of renal osteodystrophy. In the present studies, 14 dogs with experimental chronic renal disease were studied serially for a period of 2 yr. Each animal was studied first with two normal kidneys on an intake of P of 1,200 mg/day. Then, renal insufficiency was produced by 5/6 nephrectomy. The dogs then were divided into three groups. In group I, 1,200 mg/day P intake was administered for the full 2 yr. In group II, P intake was reduced from the initial 1,200 mg/day, in proportion to the measured fall in glomerular filtration rate, in an effort to obviate the renal adaptation in P excretion. In group III, “proportional reduction” of P intake also was employed; but in addition, 20 μg of 25(OH)D3 were administered orally three times a week.

In group I, parathyroid hormone (PTH) levels rose throughout the 2-yr period reaching a final concentration of 557±70 U (normal 10-60). In group II, values for PTH remained normal throughout the 1st yr, increased modestly between the 12th and the 18th mo, but then did not rise after the 18th mo. In group III, no elevation of PTH levels was observed at any time; however, these animals were hypercalcemic.

Histomorphologic analyses of the ribs of these dogs were performed serially throughout the 2-yr period. A linear relationship was obtained between the osteoclastic resorption surface and the concentration of circulating immunoreactive PTH. The osteoid volume was greater in group I animals when compared to those in group II. None of the morphologic abnormalities associated with renal osteodystrophy were observed in the animals in the third group.

Full text

PDF
332

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Avioli L. V., Birge S., Lee S. W., Slatopolsky E. The metabolic fate of vitamin D3-3H in chronic renal failure. J Clin Invest. 1968 Oct;47(10):2239–2252. doi: 10.1172/JCI105909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Avioli L. V., Scott S., Lee S. W., De Luca H. F. Intestinal calcium absorption: nature of defect in chronic renal disease. Science. 1969 Nov 28;166(3909):1154–1156. doi: 10.1126/science.166.3909.1154. [DOI] [PubMed] [Google Scholar]
  3. Baxter L. A., DeLuca H. F. Stimulation of 25-hydroxyvitamin D3-1alpha-hydroxylase by phosphate depletion. J Biol Chem. 1976 May 25;251(10):3158–3161. [PubMed] [Google Scholar]
  4. Baylink D., Wergedal J., Stauffer M. Formation, mineralization, and resorption of bone in hypophosphatemic rats. J Clin Invest. 1971 Dec;50(12):2519–2530. doi: 10.1172/JCI106752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Boyle I. T., Miravet L., Gray R. W., Holick M. F., Deluca H. F. The response of intestinal calcium transport to 25-hydroxy and 1,25-dihydroxy vitamin D in nephrectomized rats. Endocrinology. 1972 Mar;90(3):605–608. doi: 10.1210/endo-90-3-605. [DOI] [PubMed] [Google Scholar]
  6. Bricker N. S., Slatopolsky E., Reiss E., Avioli L. V. Caclium, phosphorus, and bone in renal disease and transplantation. Arch Intern Med. 1969 May;123(5):543–553. [PubMed] [Google Scholar]
  7. Brickman A. S., Coburn J. W., Norman A. W. Action of 1,25-dihydroxycholecalciferol, a potent, kidney-produced metabolite of vitamin D, in uremic man. N Engl J Med. 1972 Nov 2;287(18):891–895. doi: 10.1056/NEJM197211022871801. [DOI] [PubMed] [Google Scholar]
  8. Brickman A. S., Coburn J. W., Norman A. W., Massry S. G. Short-term effects of 1,25-dihydroxycholecalciferol on disordered calcium metabolism of renal failure. Am J Med. 1974 Jul;57(1):28–33. doi: 10.1016/0002-9343(74)90764-5. [DOI] [PubMed] [Google Scholar]
  9. Brumbaugh P. F., Hughes M. R., Haussler M. R. Cytoplasmic and nuclear binding components for 1alpha25-dihydroxyvitamin D3 in chick parathyroid glands. Proc Natl Acad Sci U S A. 1975 Dec;72(12):4871–4875. doi: 10.1073/pnas.72.12.4871. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chen T. C., Castillo L., Korycka-Dahl M., DeLuca H. F. Role of vitamin D metabolites in phosphate transport of rat intestine. J Nutr. 1974 Aug;104(8):1056–1060. doi: 10.1093/jn/104.8.1056. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. 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]
  13. Coburn J. W., Koppel M. H., Brickman A. S., Massry S. G. Study of intestinal absorption of calcium in patients with renal failure. Kidney Int. 1973 Apr;3(4):264–272. doi: 10.1038/ki.1973.40. [DOI] [PubMed] [Google Scholar]
  14. DeLuca H. F. Third F. Raymond Keating, Jr., Memorial Symposium--parathyroid hormone, calcitonin and vitamin D: clinical considerations. II. Vitamin D--1973. Am J Med. 1974 Jul;57(1):1–12. doi: 10.1016/0002-9343(74)90761-x. [DOI] [PubMed] [Google Scholar]
  15. Eastwood J. B., Bordier P., de Wardener H. E. Comparison of the effect of vitamin D and calcium carbonate in renal osteomalacia. Q J Med. 1971 Oct;40(160):569–570. [PubMed] [Google Scholar]
  16. HARRISON H. E., HARRISON H. C. Intestinal transport of phosphate: action of vitamin D, calcium, and potassium. Am J Physiol. 1961 Dec;201:1007–1012. doi: 10.1152/ajplegacy.1961.201.6.1007. [DOI] [PubMed] [Google Scholar]
  17. Haddad J. G., Chyu K. J. Competitive protein-binding radioassay for 25-hydroxycholecalciferol. J Clin Endocrinol Metab. 1971 Dec;33(6):992–995. doi: 10.1210/jcem-33-6-992. [DOI] [PubMed] [Google Scholar]
  18. Harrison H. E., Harrison H. C. THE RENAL EXCRETION OF INORGANIC PHOSPHATE IN RELATION TO THE ACTION OF VITAMIN D AND PARATHYROID HORMONE. J Clin Invest. 1941 Jan;20(1):47–55. doi: 10.1172/JCI101194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Holick M. F., Schnoes H. K., DeLuca H. F., Suda T., Cousins R. J. Isolation and identification of 1,25-dihydroxycholecalciferol. A metabolite of vitamin D active in intestine. Biochemistry. 1971 Jul 6;10(14):2799–2804. doi: 10.1021/bi00790a023. [DOI] [PubMed] [Google Scholar]
  20. Horsting M., DeLuca H. F. In vitro production of 25-hydroxycholecalciferol. Biochem Biophys Res Commun. 1969 Jul 23;36(2):251–256. doi: 10.1016/0006-291x(69)90322-2. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Lawson D. E., Fraser D. R., Kodicek E., Morris H. R., Williams D. H. Identification of 1,25-dihydroxycholecalciferol, a new kidney hormone controlling calcium metabolism. Nature. 1971 Mar 26;230(5291):228–230. doi: 10.1038/230228a0. [DOI] [PubMed] [Google Scholar]
  23. Norman A. W., Midgett R. J., Myrtle J. F., Nowicki H. G. Studies on calciferol metabolism. I. Production of vitamin D metabolite 4B from 25-OH-cholecalciferol by kidney homogenates. Biochem Biophys Res Commun. 1971 Mar 19;42(6):1082–1087. doi: 10.1016/0006-291x(71)90015-5. [DOI] [PubMed] [Google Scholar]
  24. Pavlovitch H., Garabedian M., Balsan S. Calcium-mobilizing effect of large doses of 25-hydroxycholecalciferol in anephric rats. J Clin Invest. 1973 Oct;52(10):2656–2659. doi: 10.1172/JCI107458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ponchon G., Kennan A. L., DeLuca H. F. "Activation" of vitamin D by the liver. J Clin Invest. 1969 Nov;48(11):2032–2037. doi: 10.1172/JCI106168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Puschett J. B., Moranz J., Kurnick W. S. Evidence for a direct action of cholecalciferol and 25-hydroxycholecalciferol on the renal transport of phosphate, sodium, and calcium. J Clin Invest. 1972 Feb;51(2):373–385. doi: 10.1172/JCI106823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Russell J. E., Avioli L. V. Effect of experimental chronic renal insufficiency on bone mineral and collagen maturation. J Clin Invest. 1972 Dec;51(12):3072–3079. doi: 10.1172/JCI107134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rutherford W. E., Blondin J., Hruska K., Kopelman R., Klahr S., Slatopolsky E. Effect of 25-hydroxycholecalciferol on calcium absorption in chronic renal disease. Kidney Int. 1975 Nov;8(5):320–324. doi: 10.1038/ki.1975.119. [DOI] [PubMed] [Google Scholar]
  29. Shen F-H, Baylink D. J., Sherrard D. J., Shen L., Maloney N. A., Wergedal J. E. Serum immunoreactive parathyroid hormone and 25-hydroxyvitamin D in patients with uremic bone diseases. J Clin Endocrinol Metab. 1975 Jun;40(6):1009–1017. doi: 10.1210/jcem-40-6-1009. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. 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]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES