Abstract
Inherited diseases of renal phosphate handling lead to urinary phosphate wasting and depletion of total body phosphorus stores. Clinical sequelae of inherited disorders that are associated with increased urinary phosphate excretion are deleterious and can lead to abnormal skeletal growth and deformities. This Review describes hereditary disorders of renal phosphate wasting taking into account developments in our understanding of renal phosphate handling from the last decade. The cloning of genes involved in these disorders and further studies on their pathophysiological mechanisms have given important insights in to how phosphatonins, such as FGF-23, regulate renal phosphate reabsorption in health and disease. X-linked dominant hypophosphatemic rickets results from mutation of a metalloprotease (PHEX) that has an unidentified role in FGF-23 degradation. Mutation of an RXXR proteolytic cleavage site in FGF-23 prevents degradation and increases circulating levels of FGF-23 in autosomal dominant hypophosphatemic rickets. FGF-23 acts to remove sodium phosphate co-transporters from the luminal membrane of proximal tubular cells with resultant renal phosphate wasting. Loss of function mutations in genes encoding the transporters NaPi-IIc and NaPi-IIa also result in renal phosphate wasting and rickets.
Key Points
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Hereditary disorders of renal phosphate wasting are rare genetic diseases
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X-linked dominant hypophosphatemic rickets is more frequent than autosomal dominant or recessive hypophosphatemic rickets
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Depending on the disease entity, patients with hereditary disorders of renal phosphate wasting can be symptomatic during childhood or in adulthood
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Clinically, these disease entities often have similar presentation to nutritional rickets during childhood and to osteomalacia in adults
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Early diagnosis and treatment could prevent growth retardation and skeletal deformities in children and decrease osteomalacia in adults
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References
Reilly, R. F. & Perazella, M. A. Nephrology in 30 Days (McGraw-Hill Medical Pub. Division, New York, 2005).
Amanzadeh, J. & Reilly, R. F. Jr. Hypophosphatemia: an evidence-based approach to its clinical consequences and management. Nat. Clin. Pract. Nephrol. 2, 136–148 (2006).
Hilfiker, H. et al. Characterization of a murine type II sodium-phosphate cotransporter expressed in mammalian small intestine. Proc. Natl Acad. Sci. USA 95, 14564–14569 (1998).
Giral, H. et al. Regulation of rat intestinal Na-dependent phosphate transporters by dietary phosphate. Am. J. Physiol. Renal Physiol. 297, F1466–F1475 (2009).
Danisi, G., Bonjour, J. P. & Straub, R. W. Regulation of Na-dependent phosphate influx across the mucosal border of duodenum by 1,25-dihydroxycholecalciferol. Pflugers Arch. 388, 227–232 (1980).
Danisi, G., Caverzasio, J., Trechsel, U., Bonjour, J. P. & Straub, R. W. Phosphate transport adaptation in rat jejunum and plasma level of 1,25-dihydroxyvitamin D3. Scand. J. Gastroenterol. 25, 210–215 (1990).
Hildmann, B., Storelli, C., Danisi, G. & Murer, H. Regulation of Na+-Pi cotransport by 1,25-dihydroxyvitamin D3 in rabbit duodenal brush-border membrane. Am. J. Physiol. 242, G533–G539 (1982).
Radanovic, T., Wagner, C. A., Murer, H. & Biber, J. Regulation of intestinal phosphate transport. I. Segmental expression and adaptation to low-P(i) diet of the type IIb Na(+)-P(i) cotransporter in mouse small intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G496–G500 (2005).
Xu, H., Bai, L., Collins, J. F. & Ghishan, F. K. Age-dependent regulation of rat intestinal type IIb sodium-phosphate cotransporter by 1,25-(OH)2 vitamin D3 . Am. J. Physiol. Cell Physiol. 282, C487–C493 (2002).
Coe, F. L. & Favus, M. J. Disorders of Bone and Mineral Metabolism, 2nd edn (Lippincott Williams & Wilkins, Philadelphia, 2002).
Lang, F., Greger, R., Marchand, G. R. & Knox, F. G. Stationary microperfusion study of phosphate reabsorption in proximal and distal nephron segments. Pflugers Arch. 368, 45–48 (1977).
Villa-Bellosta, R. et al. The Na+-Pi cotransporter PiT-2 (SLC20A2) is expressed in the apical membrane of rat renal proximal tubules and regulated by dietary Pi. Am. J. Physiol. Renal Physiol. 296, F691–F699 (2009).
Segawa, H. et al. Npt2a and Npt2c in mice play distinct and synergistic roles in inorganic phosphate metabolism and skeletal development. Am. J. Physiol. Renal Physiol. 297, F671–F678 (2009).
Murer, H., Forster, I. & Biber, J. The sodium phosphate cotransporter family SLC34. Pflugers Arch. 447, 763–767 (2004).
Werner, A. et al. Cloning and expression of cDNA for a Na/Pi cotransport system of kidney cortex. Proc. Natl Acad. Sci. USA 88, 9608–9612 (1991).
Busch, A. E. et al. Expression of a renal type I sodium/phosphate transporter (NaPi-1) induces a conductance in Xenopus oocytes permeable for organic and inorganic anions. Proc. Natl Acad. Sci. USA 93, 5347–5351 (1996).
Virkki, L. V., Biber, J., Murer, H. & Forster, I. C. Phosphate transporters: a tale of two solute carrier families. Am. J. Physiol. Renal Physiol. 293, F643–F654 (2007).
Reimer, R. J. & Edwards, R. H. Organic anion transport is the primary function of the SLC17/type I phosphate transporter family. Pflugers Arch. 447, 629–635 (2004).
Beck, L. et al. Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc. Natl Acad. Sci. USA 95, 5372–5377 (1998).
Prie, D. et al. Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. N. Engl. J. Med. 347, 983–991 (2002).
Virkki, L. V., Forster, I. C., Hernando, N., Biber, J. & Murer, H. Functional characterization of two naturally occurring mutations in the human sodium-phosphate cotransporter type IIa. J. Bone Miner. Res. 18, 2135–2141 (2003).
Lapointe, J. Y. et al. NPT2a gene variation in calcium nephrolithiasis with renal phosphate leak. Kidney Int. 69, 2261–2267 (2006).
Magen, D. et al. A loss-of-function mutation in NaPi-IIa and renal Fanconi's syndrome. N. Engl. J. Med. 362, 1102–1109 (2010).
Kavanaugh, M. P. et al. Cell-surface receptors for gibbon ape leukemia virus and amphotropic murine retrovirus are inducible sodium-dependent phosphate symporters. Proc. Natl Acad. Sci. USA 91, 7071–-7075 (1994).
Miller, D. G. & Miller, A. D. A family of retroviruses that utilize related phosphate transporters for cell entry. J. Virol. 68, 8270–8276 (1994).
Tenenhouse, H. S., Roy, S., Martel, J. & Gauthier, C. Differential expression, abundance, and regulation of Na+-phosphate cotransporter genes in murine kidney. Am. J. Physiol. 275, F527–F534 (1998).
Leung, J. C., Barac-Nieto, M., Hering-Smith, K. & Silverstein, D. M. Expression of the rat renal PiT-2 phosphate transporter. Horm. Metab. Res. 37, 265–269 (2005).
Nowik, M. et al. Renal phosphaturia during metabolic acidosis revisited: molecular mechanisms for decreased renal phosphate reabsorption. Pflugers Arch. 457, 539–549 (2008).
Breusegem, S. Y. et al. Differential regulation of the renal sodium-phosphate cotransporters NaPi-IIa, NaPi-IIc, and PiT-2 in dietary potassium deficiency. Am. J. Physiol. Renal Physiol. 297, F350–F361 (2009).
Villa-Bellosta, R. & Sorribas, V. Compensatory regulation of the sodium/phosphate cotransporters NaPi-IIc (SCL34A3) and Pit-2 (SLC20A2) during Pi deprivation and acidosis. Pflugers Arch. 459, 499–508 (2010).
Moe, O. W. PiT-2 coming out of the pits. Am. J. Physiol. Renal Physiol. 296, F689–F690 (2009).
Forster, I. C., Loo, D. D. & Eskandari, S. Stoichiometry and Na+ binding cooperativity of rat and flounder renal type II Na+-Pi cotransporters. Am. J. Physiol. 276, F644–F649 (1999).
Segawa, H. et al. Growth-related renal type II Na/Pi cotransporter. J. Biol. Chem. 277, 19665–19672 (2002).
Ravera, S., Virkki, L. V., Murer, H. & Forster, I. C. Deciphering PiT transport kinetics and substrate specificity using electrophysiology and flux measurements. Am. J. Physiol. Cell Physiol. 293, C606–C620 (2007).
Berndt, T. & Kumar, R. Phosphatonins and the regulation of phosphate homeostasis. Annu. Rev. Physiol. 69, 341–359 (2007).
Miyamoto, K., Ito, M., Tatsumi, S., Kuwahata, M. & Segawa, H. New aspect of renal phosphate reabsorption: the type IIc sodium-dependent phosphate transporter. Am. J. Nephrol. 27, 503–515 (2007).
Murer, H., Hernando, N., Forster, I. & Biber, J. Proximal tubular phosphate reabsorption: molecular mechanisms. Physiol. Rev. 80, 1373–1409 (2000).
Cai, Q. et al. Brief report: inhibition of renal phosphate transport by a tumor product in a patient with oncogenic osteomalacia. N. Engl. J. Med. 330, 1645–1649 (1994).
Econs, M. J. & Drezner, M. K. Tumor-induced osteomalacia—unveiling a new hormone. N. Engl. J. Med. 330, 1679–1681 (1994).
Weidner, N. & Santa Cruz, D. Phosphaturic mesenchymal tumors. A polymorphous group causing osteomalacia or rickets. Cancer 59, 1442–1454 (1987).
ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat. Genet. 26, 345–348 (2000).
Carpenter, T. O. et al. Fibroblast growth factor 7: an inhibitor of phosphate transport derived from oncogenic osteomalacia-causing tumors. J. Clin. Endocrinol. Metab. 90, 1012–1020 (2005).
Dobbie, H., Unwin, R. J., Faria, N. J. & Shirley, D. G. Matrix extracellular phosphoglycoprotein causes phosphaturia in rats by inhibiting tubular phosphate reabsorption. Nephrol. Dial. Transplant. 23, 730–733 (2008).
Berndt, T. et al. Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. J. Clin. Invest. 112, 785–794 (2003).
Shaikh, A., Berndt, T. & Kumar, R. Regulation of phosphate homeostasis by the phosphatonins and other novel mediators. Pediatr. Nephrol. 23, 1203–1210 (2008).
Shimada, T. et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J. Bone Miner. Res. 19, 429–435 (2004).
Perwad, F., Zhang, M. Y., Tenenhouse, H. S. & Portale, A. A. Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1-alpha-hydroxylase expression in vitro. Am. J. Physiol. Renal Physiol. 293, F1577–F1583 (2007).
Perwad, F. et al. Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinology 146, 5358–5364 (2005).
Antoniucci, D. M., Yamashita, T. & Portale, A. A. Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men. J. Clin. Endocrinol. Metab. 91, 3144–3149 (2006).
Nishida, Y. et al. Acute effect of oral phosphate loading on serum fibroblast growth factor 23 levels in healthy men. Kidney Int. 70, 2141–2147 (2006).
Shimada, T. et al. FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem. Biophys. Res. Commun. 314, 409–414 (2004).
Shimada, T. et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc. Natl Acad. Sci. USA 98, 6500–6505 (2001).
Urakawa, I. et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444, 770–774 (2006).
Farrow, E. G. & White, K. E. Recent advances in renal phosphate handling. Nat. Rev. Nephrol. 6, 207–217 (2010).
Prie, D., Urena Torres, P. & Friedlander, G. Latest findings in phosphate homeostasis. Kidney Int. 75, 882–889 (2009).
Gaasbeek, A. & Meinders, A. E. Hypophosphatemia: an update on its etiology and treatment. Am. J. Med. 118, 1094–1101 (2005).
Young, J. A., Lichtman, M. A. & Cohen, J. Reduced red cell 2,3-diphosphoglycerate and adenosine triphosphate, hypophosphatemia, and increased hemoglobin-oxygen affinity after cardiac surgery. Circulation 47, 1313–1318 (1973).
Hettleman, B. D., Sabina, R. L., Drezner, M. K., Holmes, E. W. & Swain, J. L. Defective adenosine triphosphate synthesis. An explanation for skeletal muscle dysfunction in phosphate-deficient mice. J. Clin. Invest. 72, 582–589 (1983).
de Menezes Filho, H., de Castro, L. C. & Damiani, D. Hypophosphatemic rickets and osteomalacia. Arq. Bras. Endocrinol. Metabol. 50, 802–813 (2006).
Hypophosphatemic rickets, X-linked dominant Online Mendelian Inheritance in Man [online].
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) 37, 97–142 (1958).
Morgan, J. M., Hawley, W. L, Chenoweth, A. I., Retan, W. J. & Diethelm, A. G. Renal transplantation in hypophosphatemia with vitamin D-resistant rickets. Arch. Intern. Med. 134, 549–552 (1974).
Phosphate-regulating endopeptidase homolog, X-linked; PHEX Online Mendelian Inheritance in Man [online].
HYP Consortium. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium. Nat. Genet. 11, 130–136 (1995).
Guo, R. & Quarles, L. D. Cloning and sequencing of human PEX from a bone cDNA library: evidence for its developmental stage-specific regulation in osteoblasts. J. Bone Miner. Res. 12, 1009–1017 (1997).
Holm, I. A., Huang, X. & Kunkel, L. M. Mutational analysis of the PEX gene in patients with X-linked hypophosphatemic rickets. Am. J. Hum. Genet. 60, 790–797 (1997).
Dixon, P. H. et al. Mutational analysis of PHEX gene in X-linked hypophosphatemia. J. Clin. Endocrinol. Metab. 83, 3615–3623 (1998).
Filisetti, D. et al. Non-random distribution of mutations in the PHEX gene, and under-detected missense mutations at non-conserved residues. Eur. J. Hum. Genet. 7, 615–619 (1999).
Bowe, A. E. et al. FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochem. Biophys. Res. Commun. 284, 977–981 (2001).
Benet-Pages, A. et al. FGF23 is processed by proprotein convertases but not by PHEX. Bone 35, 455–462 (2004).
Liu, S. et al. Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J. Biol. Chem. 278, 37419–37426 (2003).
Strom, T. M. & Juppner, H. PHEX, FGF23, DMP1 and beyond. Curr. Opin. Nephrol. Hypertens. 17, 357–362 (2008).
Hypophosphatemic rickets, Autosomal dominant; ADHR Online Mendelian Inheritance in Man [online].
Bianchine, J. W., Stambler, A. A. & Harrison, H. E. Familial hypophosphatemic rickets showing autosomal dominant inheritance. Birth Defects Orig. Artic. Ser. 7, 287–295 (1971).
Riminucci, M. et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J. Clin. Invest. 112, 683–692 (2003).
Mirams, M., Robinson, B. G., Mason, R. S. & Nelson, A. E. Bone as a source of FGF23: regulation by phosphate? Bone 35, 1192–1199 (2004).
Shimada, T. et al. Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism. Am. J. Physiol. Renal Physiol. 289, F1088–F1095 (2005).
Larsson, T. et al. Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. Endocrinology 145, 3087–3094 (2004).
Fibroblast growth factor 23; FGF23 Online Mendelian Inheritance in Man, [online].
Gribaa, M. et al. An autosomal dominant hypophosphatemic rickets phenotype in a Tunisian family caused by a new FGF23 missense mutation. J. Bone Miner. Metab. 28, 111–115 (2009).
Econs, M. J. & McEnery, P. T. Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J. Clin. Endocrinol. Metab. 82, 674–681 (1997).
Hypophosphatemic rickets, autosomal recessive, 1; ARHR1 Online Mendelian Inheritance in Man, [online].
Feng, J. Q. et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat. Genet. 38, 1310–1315 (2006).
Lorenz-Depiereux, B. et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat. Genet. 38, 1248–1250 (2006).
Dentin matrix acidic phosphoprotein 1; DMP1 Online Mendelian Inheritance in Man, [online].
George, A., Sabsay, B., Simonian, P. A. & Veis, A. Characterization of a novel dentin matrix acidic phosphoprotein. Implications for induction of biomineralization. J. Biol. Chem. 268, 12624–12630 (1993).
George, A., Ramachandran, A., Albazzaz, M. & Ravindran, S. DMP1-a key regulator in mineralized matrix formation. J. Musculoskelet. Neuronal Interact. 7, 308 (2007).
Narayanan, K. et al. Dual functional roles of dentin matrix protein 1. Implications in biomineralization and gene transcription by activation of intracellular Ca2+ store. J. Biol. Chem. 278, 17500–17508 (2003).
Levy-Litan, V. et al. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am. J. Hum. Genet. 86, 273–278 (2010).
Rutsch, F. et al. Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification. Nat. Genet. 34, 379–381 (2003).
Hypophosphatemic rickets with hypercalciuria, hereditary; HHRH Online Mendelian Inheritance in Man, [online].
Lorenz-Depiereux, B. et al. Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am. J. Hum. Genet. 78, 193–201 (2006).
Bergwitz, C. et al. SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis. Am. J. Hum. Genet. 78, 179–192 (2006).
Solute carrier family 34 (sodium/phosphate cotransporter), member 3; SLC34A3 Online Mendelian Inheritance in Man, [online].
Tieder, M. et al. Hereditary hypophosphatemic rickets with hypercalciuria. N. Engl. J. Med. 312, 611–617 (1985).
Tencza, A. L. et al. Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/type IIc sodium-phosphate cotransporter: presentation as hypercalciuria and nephrolithiasis. J. Clin. Endocrinol. Metab. 94, 4433–4438 (2009).
Kremke, B. et al. Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/NaPi-IIc can be masked by vitamin D deficiency and can be associated with renal calcifications. Exp. Clin. Endocrinol. Diabetes 117, 49–56 (2009).
Page, K., Bergwitz, C., Jaureguiberry, G., Harinarayan, C. V. & Insogna, K. A patient with hypophosphatemia, a femoral fracture, and recurrent kidney stones: report of a novel mutation in SLC34A3. Endocr. Pract. 14, 869–874 (2008).
Tieder, M. et al. Elevated serum 1,25-dihydroxyvitamin D concentrations in siblings with primary Fanconi's syndrome. N. Engl. J. Med. 319, 845–849 (1988).
McCune-albright syndrome; MAS Online Mendelian Inheritance in Man, [online].
Weinstein, L. S. et al. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N. Engl. J. Med. 325, 1688–1695 (1991).
Chapurlat, R. D. & Orcel, P. Fibrous dysplasia of bone and McCune-Albright syndrome. Best Pract. Res. Clin. Rheumatol. 22, 55–69 (2008).
Yamamoto, T. et al. The role of fibroblast growth factor 23 for hypophosphatemia and abnormal regulation of vitamin D metabolism in patients with McCune-Albright syndrome. J. Bone Miner. Metab. 23, 231–237 (2005).
Collins, M. T. et al. Renal phosphate wasting in fibrous dysplasia of bone is part of a generalized renal tubular dysfunction similar to that seen in tumor-induced osteomalacia. J. Bone Miner. Res. 16, 806–813 (2001).
Kobayashi, K. et al. Expression of FGF23 is correlated with serum phosphate level in isolated fibrous dysplasia. Life Sci. 78, 2295–2301 (2006).
Faroqui, S., Levi, M., Soleimani, M. & Amlal, H. Estrogen downregulates the proximal tubule type IIa sodium phosphate cotransporter causing phosphate wasting and hypophosphatemia. Kidney Int. 73, 1141–1150 (2008).
Ishiguro, M. et al. Thyroid hormones regulate phosphate homoeostasis through transcriptional control of the renal type IIa sodium-dependent phosphate co-transporter (Npt2a) gene. Biochem. J. 427, 161–169 (2010).
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Alizadeh Naderi, A., Reilly, R. Hereditary disorders of renal phosphate wasting. Nat Rev Nephrol 6, 657–665 (2010). https://doi.org/10.1038/nrneph.2010.121
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