Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1983 Jun;71(6):1562–1569. doi: 10.1172/JCI110912

Impaired phosphorus conservation and 1,25 dihydroxyvitamin D generation during phosphorus deprivation in familial hypophosphatemic rickets.

K L Insogna, A E Broadus, J M Gertner
PMCID: PMC370362  PMID: 6306051

Abstract

The pathogenesis of familial hypophosphatemic rickets (FHR) is incompletely understood. We therefore examined the effects of acute dietary phosphorus deprivation to see whether renal phosphate conservation and increased 1,25 dihydroxyvitamin D [1,25(OH)2D] plasma levels, which normally follow restriction of phosphorus intake, could be induced in patients with FHR. Six healthy male volunteers (age 26 +/- 3 yr) and seven male patients with FHR (age 24 +/- 3 yr) were placed on a low phosphorus diet supplemented with aluminum hydroxide and studied over a 4-d period. The patients with FHR excreted more than five times as much phosphorus per day at the conclusion of the study than did the controls (176 +/- 61 mg/24 h vs. 33 +/- 11 mg/h). In the normal subjects, maximum tubular reabsorptive capacity for phosphorus/glomerular filtration rate (TmP/GFR) rose progressively during phosphorus deprivation, and the rise from base line was more than two times greater than that seen in patients with FHR. Immunoreactive parathyroid hormone levels and nephrogenous cyclic AMP were initially normal in both groups and no change was seen in either group with phosphorus deprivation. In the normal subjects, 1,25(OH)2D levels rose progressively over the 96 h of the study (49 +/- 3 to 63 +/- 6 pg/ml, P less than 0.05), while mean circulating 1,25(OH)2D in the patients with FHR did not change (34 +/- 3 to 29 +/- 3 pg/ml). The changes in individual plasma 1,25(OH)2D levels correlated strongly with the change in individual nephrogenous cyclic AMP measurements in the patients with FHR (r = +0.93), while no such correlation was observed in the normal subjects. These data demonstrate a defective renal response to phosphorus deprivation in patients with FHR including a qualitatively abnormal response in 1,25(OH)2D generation.

Full text

PDF
1562

Selected References

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

  1. Arnaud C., Glorieux F., Scriver C. Serum parathyroid hormone in X-linked hypophosphatemia. Science. 1971 Aug 27;173(3999):845–847. doi: 10.1126/science.173.3999.845. [DOI] [PubMed] [Google Scholar]
  2. Broadus A. E., Mahaffey J. E., Bartter F. C., Neer R. M. Nephrogenous cyclic adenosine monophosphate as a parathyroid function test. J Clin Invest. 1977 Oct;60(4):771–783. doi: 10.1172/JCI108831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cowgill L. D., Goldfarb S., Lau K., Slatopolsky E., Agus Z. S. Evidence for an intrinsic renal tubular defect in mice with genetic hypophosphatemic rickets. J Clin Invest. 1979 Jun;63(6):1203–1210. doi: 10.1172/JCI109415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Daly J. A., Ertingshausen G. Direct method for determining inorganic phosphate in serum with the "CentrifiChem". Clin Chem. 1972 Mar;18(3):263–265. [PubMed] [Google Scholar]
  5. Dominguez J. H., Gray R. W., Lemann J., Jr Dietary phosphate deprivation in women and men: effects on mineral and acid balances, parathyroid hormone and the metabolism of 25-OH-vitamin D. J Clin Endocrinol Metab. 1976 Nov;43(5):1056–1068. doi: 10.1210/jcem-43-5-1056. [DOI] [PubMed] [Google Scholar]
  6. GREENBERG B. G., WINTERS R. W., GRAHAM J. B. The normal range of serum inorganic phosphorus and its utility as a discriminant in the diagnosis of congenital hypophosphatemia. J Clin Endocrinol Metab. 1960 Mar;20:364–379. doi: 10.1210/jcem-20-3-364. [DOI] [PubMed] [Google Scholar]
  7. Glorieux F. H., Holick M. F., Scriver C. R., DeLuca H. F. X-linked hypophosphataemic rickets: Inadequate therapeutic response to 1,25-dihydroxycholecalciferol. Lancet. 1973 Aug 11;2(7824):287–289. doi: 10.1016/s0140-6736(73)90793-9. [DOI] [PubMed] [Google Scholar]
  8. Glorieux F. H., Marie P. J., Pettifor J. M., Delvin E. E. Bone response to phosphate salts, ergocalciferol, and calcitriol in hypophosphatemic vitamin D-resistant rickets. N Engl J Med. 1980 Oct 30;303(18):1023–1031. doi: 10.1056/NEJM198010303031802. [DOI] [PubMed] [Google Scholar]
  9. Glorieux F. H., Morin C. L., Travers R., Delvin E. E., Poirier R. Intestinal phosphate transport in familial hypophosphatemic rickets. Pediatr Res. 1976 Jul;10(7):691–696. doi: 10.1203/00006450-197607000-00012. [DOI] [PubMed] [Google Scholar]
  10. Glorieux F., Scriver C. R. Loss of a parathyroid hormone-sensitive component of phosphate transport in X-linked hypophosphatemia. Science. 1972 Mar 3;175(4025):997–1000. doi: 10.1126/science.175.4025.997. [DOI] [PubMed] [Google Scholar]
  11. Gray R. W., Wilz D. R., Caldas A. E., Lemann J., Jr The importance of phosphate in regulating plasma 1,25-(OH)2-vitamin D levels in humans: studies in healthy subjects in calcium-stone formers and in patients with primary hyperparathyroidism. J Clin Endocrinol Metab. 1977 Aug;45(2):299–306. doi: 10.1210/jcem-45-2-299. [DOI] [PubMed] [Google Scholar]
  12. Hahn T. J., Scharp C. R., Halstead L. R., Haddad J. G., Karl D. M., Avioli L. V. Parathyroid hormone status and renal responsiveness in familial hypophosphatemic rickets. J Clin Endocrinol Metab. 1975 Nov;41(5):926–937. doi: 10.1210/jcem-41-5-926. [DOI] [PubMed] [Google Scholar]
  13. Haussler M., Hughes M., Baylink D., Littledike E. T., Cork D., Pitt M. Influence of phosphate depletion on the biosynthesis and circulating level of 1alpha,25-dihydroxyvitamin D. Adv Exp Med Biol. 1977;81:233–250. doi: 10.1007/978-1-4613-4217-5_24. [DOI] [PubMed] [Google Scholar]
  14. Horst R. L., Shepard R. M., Jorgensen N. A., DeLuca H. F. The determination of the vitamin D metabolites on a single plasma sample: changes during parturition in dairy cows. Arch Biochem Biophys. 1979 Feb;192(2):512–523. doi: 10.1016/0003-9861(79)90121-8. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Insogna K. L., Bordley D. R., Caro J. F., Lockwood D. H. Osteomalacia and weakness from excessive antacid ingestion. JAMA. 1980 Dec 5;244(22):2544–2546. [PubMed] [Google Scholar]
  17. Kleerekoper M., Coffey R., Creco T., Nichols S., Cooke N., Murphy W., Avioli L. V. Hypercalcemic hyperparathyroidism in hypophosphatemic rickets. J Clin Endocrinol Metab. 1977 Jul;45(1):86–94. doi: 10.1210/jcem-45-1-86. [DOI] [PubMed] [Google Scholar]
  18. Lotz M., Zisman E., Bartter F. C. Evidence for a phosphorus-depletion syndrome in man. N Engl J Med. 1968 Feb 22;278(8):409–415. doi: 10.1056/NEJM196802222780802. [DOI] [PubMed] [Google Scholar]
  19. Lyles K. W., Clark A. G., Drezner M. K. Serum 1,25-dihydroxyvitamin D levels in subjects with X-linked hypophosphatemic rickets and osteomalacia. Calcif Tissue Int. 1982 Mar;34(2):125–130. doi: 10.1007/BF02411222. [DOI] [PubMed] [Google Scholar]
  20. Lyles K. W., Drezner M. K. Parathyroid hormone effects on serum 1,25-dihydroxyvitamin D levels in patients with X-linked hypophosphatemic rickets: evidence for abnormal 25-hydroxyvitamin D-1-hydroxylase activity. J Clin Endocrinol Metab. 1982 Mar;54(3):638–644. doi: 10.1210/jcem-54-3-638. [DOI] [PubMed] [Google Scholar]
  21. Meyer R. A., Jr, Gray R. W., Meyer M. H. Abnormal vitamin D metabolism in the X-linked hypophosphatemic mouse. Endocrinology. 1980 Nov;107(5):1577–1581. doi: 10.1210/endo-107-5-1577. [DOI] [PubMed] [Google Scholar]
  22. O'Doherty P. J., DeLuca H. F., Eicher E. M. Lack of effect of vitamin D and its metabolites on intestinal phosphate transport in familial hypophosphatemia of mice. Endocrinology. 1977 Oct;101(4):1325–1330. doi: 10.1210/endo-101-4-1325. [DOI] [PubMed] [Google Scholar]
  23. Scriver C. R., Reade T. M., DeLuca H. F., Hamstra A. J. Serum 1,25-dihydroxyvitamin D levels in normal subjects and in patients with hereditary rickets or bone disease. N Engl J Med. 1978 Nov 2;299(18):976–979. doi: 10.1056/NEJM197811022991803. [DOI] [PubMed] [Google Scholar]
  24. Scriver C. R. Rickets and the pathogenesis of impaired tubular transport of phosphate and other solutes. Am J Med. 1974 Jul;57(1):43–49. doi: 10.1016/0002-9343(74)90766-9. [DOI] [PubMed] [Google Scholar]
  25. Short E. M., Binder H. J., Rosenberg L. E. Familial hypophosphatemic rickets: defective transport of inorganic phosphate by intestinal mucosa. Science. 1973 Feb 16;179(4074):700–702. doi: 10.1126/science.179.4074.700. [DOI] [PubMed] [Google Scholar]
  26. Short E., Morris R. C., Jr, Sebastian A., Spencer M. Exaggerated phosphaturic response to circulating parathyroid hormone in patients with familial X-linked hypophosphatemic rickets. J Clin Invest. 1976 Jul;58(1):152–163. doi: 10.1172/JCI108444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Stickler G. B., Beabout J. W., Riggs B. L. Vitamin D-resistant rickets: clinical experience with 41 typical familial hypophosphatemic patients and 2 atypical nonfamilial cases. Mayo Clin Proc. 1970 Mar;45(3):197–218. [PubMed] [Google Scholar]
  28. 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]
  29. Tenenhouse H. S., Fast D. K., Scriver C. R., Koltay M. Intestinal transport of phosphate anion is not impaired in the Hyp (hypophosphatemic) mouse. Biochem Biophys Res Commun. 1981 May 29;100(2):537–543. doi: 10.1016/s0006-291x(81)80210-0. [DOI] [PubMed] [Google Scholar]
  30. Tenenhouse H. S., Scriver C. R., McInnes R. R., Glorieux F. H. Renal handling of phosphate in vivo and in vitro by the X-linked hypophosphatemic male mouse: evidence for a defect in the brush border membrane. Kidney Int. 1978 Sep;14(3):236–244. doi: 10.1038/ki.1978.115. [DOI] [PubMed] [Google Scholar]
  31. Tenenhouse H. S., Scriver C. R. Renal brush border membrane adaptation to phosphorus deprivation in the Hyp/Y mouse. Nature. 1979 Sep 20;281(5728):225–227. doi: 10.1038/281225a0. [DOI] [PubMed] [Google Scholar]
  32. Tröhler U., Bonjour J. P., Fleisch H. Inorganic phosphate homeostasis. Renal adaptation to the dietary intake in intact and thyroparathyroidectomized rats. J Clin Invest. 1976 Feb;57(2):264–273. doi: 10.1172/JCI108277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. WINTERS R. W., GRAHAM J. B., WILLIAMS T. F., McFALLS V. W., BURNETT C. H. A genetic study of familial hypophosphatemia and vitamin D resistant rickets with a review of the literature. Medicine (Baltimore) 1958 May;37(2):97–142. doi: 10.1097/00005792-195805000-00001. [DOI] [PubMed] [Google Scholar]
  34. Wilkinson J. H., Vodden A. V. Phenolphthalein monophosphate as a substrate for serum alkaline phosphatase. An appraisal. Clin Chem. 1966 Oct;12(10):701–708. [PubMed] [Google Scholar]
  35. ZETTNER A., SELIGSON D. APPLICATION OF ATOMIC ABSORPTION SPECTROPHOTOMETRY IN THE DETERMINATION OF CALCIUM IN SERUM. Clin Chem. 1964 Oct;10:869–890. [PubMed] [Google Scholar]

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

RESOURCES