Elsevier

Seminars in Nephrology

Volume 24, Issue 1, January 2004, Pages 39-47
Seminars in Nephrology

Renal phosphate wasting disorders: clinical features and pathogenesis

https://doi.org/10.1053/j.semnephrol.2003.08.016Get rights and content

Abstract

Rickets and osteomalacia are associated with hypophosphatemia in several disease states, including X-linked hypophosphatemic rickets, autosomal-dominant hypophosphatemic rickets, and tumor-induced osteomalacia. Recent advances in the understanding of these diseases include discovery of mutations in the genes encoding human phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and fibroblast growth factor 23 (FGF-23) and the finding of overproduction of FGF-23 and other proteins including matrix extracellular phosphoglycoprotein (MEPE) and frizzled-related protein 4 (FRP-4) in tumor-induced osteomalacia. Research is ongoing to better define how these proteins relate to each other and to the sodium-phosphate cotransporter in both normal and abnormal phosphate metabolism. New and improved therapies for disorders of phosphate metabolism, osteomalacia, and rickets will develop as our knowledge of phosphate metabolism grows.

Section snippets

XLH

XLH is a relatively common cause of rickets, with a prevalence of approximately 1 in 20,000. It is inherited in an X-linked dominant manner, with no evidence of a gene dosage effect, imprinting, or genetic anticipation.2 The disease is highly penetrant but has a wide range of expressivity.3 In other words, those carrying the mutation are likely to have the disease, but the severity of disease and specific clinical manifestations are variable, even among members of the same family.

Hyp mice and the phex gene

A murine model known as Hyp has been essential to our understanding of hypophosphatemic rickets. The Hyp mouse is characterized by renal phosphate wasting, growth retardation, and impaired bone mineralization.14 Corresponding to the inappropriately normal calcitriol levels in humans with XLH, 25-hydroxyvitamin D-1 α-hydroxylase activity in the Hyp mouse is inappropriately low for the level of hypophosphatemia.15 Hyp mice also have a primary osteoblast defect.16

To evaluate whether the phosphate

Treatment

Treatment of XLH and ADHR is similar, although no data exist on optimal treatment for ADHR.60 High doses of calcitriol are combined with high-dose phosphate supplementation until growth is complete. To minimize diarrhea and gastrointestinal upset from the phosphate, the dose should be increased gradually. Serum calcium, phosphorus, creatinine, and urine calcium and creatinine are monitored to allow titration of the calcitriol and phosphate dosage. It is not usually possible to normalize serum

References (72)

  • L.C. Gowen et al.

    Targeted disruption of the osteoblast/osteocyte factor 45 gene (OF45) results in increased bone formation and bone mass

    J Biol Chem

    (2003)
  • K.E. White et al.

    Autosomal-dominant hypophosphatemic rickets (adhr) mutations stabilize fgf-23

    Kidney Int

    (2001)
  • A.E. Bowe et al.

    Fgf-23 inhibits renal tubular phosphate transport and is a phex substrate

    Biochem Biophys Res Commun

    (2001)
  • H.S. Tenenhouse et al.

    Renal Na(+)-phosphate cotransporter gene expression in X-linked Hyp and Gy mice

    Kidney Int

    (1996)
  • S. Balsan et al.

    Linear growth in patients with hypophosphatemic vitamin d-resistant ricketsInfluence of treatment regimen and parental height

    J Pediatr

    (1990)
  • P.R. Goodyer et al.

    Nephrocalcinosis and its relationship to treatment of hereditary rickets

    J Pediatr

    (1987)
  • R.G. Firth et al.

    Development of hypercalcemic hyperparathyroidism after long-term phosphate supplementation in hypophosphatemic osteomalacia. Report of two cases

    Am J Med

    (1985)
  • H. Rasmussen et al.

    Long-term treatment of familial hypophosphatemic rickets with oral phosphate and 1 alpha-hydroxyvitamin d3

    J Pediatr

    (1981)
  • N.H. Bell

    Osteomalacia and rickets

  • M.P. Whyte et al.

    X-linked hypophosphatemiaA search for gender, race, anticipation, or parent of origin effects on disease expression in children

    J Clin Endocrinol Metab

    (1996)
  • R.W. Winters et al.

    A genetic study of familial hypophosphatemia and vitamin d resistant rickets with a review of the literature

    Medicine

    (1991)
  • R.P. Polisson et al.

    Calcification of entheses associated with x-linked hypophosphatemic osteomalacia

    N Engl J Med

    (1985)
  • M.J. Econs et al.

    X-linked hypophosphatemic rickets without “rickets.”

    Skeletal Radiol

    (1991)
  • D.C. Hardy et al.

    X-linked hypophosphatemia in adultsPrevalence of skeletal radiographic and scintigraphic features

    Radiology

    (1989)
  • M.J. Econs et al.

    Autosomal dominant hypophosphatemic rickets/osteomalaciaClinical characterization of a novel renal phosphate-wasting disorder

    J Clin Endocrinol Metab

    (1997)
  • C.R. Scriver et al.

    Hypophosphatemic nonrachitic bone diseaseAn entity distinct from x-linked hypophosphatemia in the renal defect, bone involvement, and inheritance

    Am J Med Genet

    (1977)
  • Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. The ADHR consortium

    Nat Genet

    (2000)
  • M. Tieder et al.

    Hereditary hypophosphatemic rickets with hypercalciuria

    N Engl J Med

    (1985)
  • M. Tieder et al.

    “Idiopathic” hypercalciuria and hereditary hypophosphatemic rickets. Two phenotypical expressions of a common genetic defect

    N Engl J Med

    (1987)
  • M.K. Drezner

    Tumor-induced osteomalacia

  • E.M. Eicher et al.

    HypophosphatemiaMouse model for human familial hypophosphatemic (vitamin d-resistant) rickets

    Proc Natl Acad Sci U S A

    (1976)
  • B. Lobaugh et al.

    Abnormal regulation of renal 25-hydroxyvitamin d-1 alpha-hydroxylase activity in the x-linked hypophosphatemic mouse

    J Clin Invest

    (1983)
  • B. Ecarot-Charrier et al.

    Defective bone formation by transplanted hyp mouse bone cells into normal mice

    Endocrinology

    (1988)
  • R.A. Meyer et al.

    Parabiosis suggests a humoral factor is involved in x-linked hypophosphatemia in mice

    J Bone Miner Res

    (1989)
  • T. Nesbitt et al.

    Crosstransplantation of kidneys in normal and hyp mice. Evidence that the hyp mouse phenotype is unrelated to an intrinsic renal defect

    J Clin Invest

    (1992)
  • M.J. Econs et al.

    Tumor-induced osteomalacia—unveiling a new hormone

    N Engl J Med

    (1994)
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    Supported by National Institutes of Health grants R01AR42228, R01DK063934, and K24-AR02095.

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