1208 FGF-23 fragments, however, have shown that carboxyl- terminal fragments are biologically active [66]. At present, there is uncertainty as to the precise mechanism by which GALNT3 mutations cause the syndrome. The second class of mutations responsible for TC occur in the gene encoding FGF-23 [22, 24]. This mutation results in defective processing of FGF-23 and its retention in the Golgi apparatus. Failure to secrete FGF-23 results in low serum concentrations of FGF-23, which, in turn, results in hyper- phosphatemia due reduced renal Pi excretion. A third class of mutations responsible for TC occurs in the gene for Klotho [67], which encodes the co-receptor for FGF-23. Renal failure Serum FGF-23 concentrations are elevated in patients with chronic renal failure (CRF), and the increase in FGF-23 correlates with the decline in glomerular filtration rate [68–70]. Elevated plasma Pi seen in renal failure could increase FGF-23 production, although it is possible that reduced clearance of the peptide might also be responsible. Whether or not the elevated serum FGF-23 concentrations found in chronic renal insufficiency are sufficient to correct the hyperphosphatemia of early and advanced CRF is not completely clear. Elevated FGF-23 could play a role in the suppression of 1,25(OH)2D production and the development of secondary hyperparathy- roidism. The role of FGF-23 in renal osteodystrophy has not been established. Indeed, a recent study shows no effect of FGF-23 on bone histology in end-stage renal disease [71]. Recently, Fliser et al. [72] showed a correlation between increased FGF-23 concentrations and the progression of chronic renal failure in subjects with mild-to-moderate chronic renal disease, suggesting that FGF-23 may play a role in the progression of renal failure. It should be noted, however, that the number of other variables such as the calcium X phosphate product, parathyroid hormone, and vitamin D usage also correlated with progression in the subjects. Finally, there are no data available at present suggesting a direct role of FGF-23 on renal fibrogenesis. Post-transplant hypophosphatemia In some patients fol- lowing transplantation, persistent hypophosphatemia is noted, despite relatively modest increases in concentrations of circulating parathyroid hormone [68, 70, 73, 74]. In such subjects, FGF-23 concentrations have been noted to be elevated, and it is possible that elevations in the concentrations of this growth factor are responsible for the hypophosphatemia seen in this situation. Elevations in FGF-23 in patients with tumors In patients with humoral hypercalcemia of malignancy, and with metastatic ovarian cancer, FGF-23 concentrations are ele- vated without significant hypophosphatemia [75–77]. This would suggest that tumors produce FGF-23, and that FGF- Pediatr Nephrol (2008) 23:1203–1210 23 concentrations must reach a certain significant threshold in order to increase phosphate excretion in the kidney. In conclusion, phosphatonins play a vital role in the pathogenesis of a wide array of disorders. The presence of several phosphatonins and their differential effects affirm the complexity of Pi regulation in both normal and disease states. Future studies are needed to better understand the role of these proteins. Acknowledgments Supported by National Institutes of Health (NIH) grants DK 65830, DK 76829, DK 77669 and DK 79858. References 1. Diem K, Lentner C (1970) Scientific tables, Documenta Geigy. Ciba-Geigy Pharmaceuticals, New York 2. Fleisch H (1980) Homeostasis of inorganic phosphate. In: Urist MR (ed) Fundamental and clinical bone physiology. Lippincott, Philadelphia 3. Berndt T, Kumar R (2007) Phosphatonins and the regulation of phosphate homeostasis. Annu Rev Physiol 69:341–359 4. Forster IC, Virkki L, Bossi E, Murer H, Biber J (2006) Electrogenic kinetics of a mammalian intestinal type IIb Na(+)/P(I) cotrans- porter. J Membr Biol 212:177–190 5. Werner A, Kinne RK (2001) Evolution of the Na-P(I) cotransport systems. Am J Physiol Regul Integr Comp Physiol 280:R301–R312 6. Forster IC, Hernando N, Biber J, Murer H (2006) Proximal tubular handling of phosphate: a molecular perspective. Kidney Int 70:1548–1559 7. Berndt TJ, Schiavi S, Kumar R (2005) “Phosphatonins” and the regulation of phosphorus homeostasis. Am J Physiol Renal Physiol 289:F1170–F1182 8. Berndt T, Knox F (1992) Renal regulation of phosphate excretion. In: Giebisch G (ed) The kidney: physiology and pathophysiology. Raven Press, New York, pp 2511–2532 9. Berndt T, Thomas LF, Craig TA, Sommer S, Li X, Bergstralh EJ, Kumar R (2007) Evidence for a signaling axis by which intestinal phosphate rapidly modulates renal phosphate reabsorption. Proc Natl Acad Sci U S A 104:11085–11090 10. Cai Q, Hodgson SF, Kao PC, Lennon VA, Klee GG, Zinsmiester AR, Kumar R (1994) Brief report: inhibition of renal phosphate transport by a tumor product in a patient with oncogenic osteomalacia. N Engl J Med 330:1645–1649 11. Econs MJ, Drezner MK (1994) Tumor-induced osteomalacia— unveiling a new hormone. N Engl J Med 330:1679–1681 12. Drezner MK (2000) PHEX gene and hypophosphatemia. Kidney Int 57:9–18 13. Econs MJ, McEnery PT (1997) Autosomal dominant hypophospha- temic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J Clin Endocrinol Metab 82:674–681 14. Lorenz-Depiereux B, Bastepe M, Benet-Pages A, Amyere M, Wagenstaller J, Muller-Barth U, Badenhoop K, Kaiser SM, Rittmaster RS, Shlossberg AH, Olivares JL, Loris C, Ramos FJ, Glorieux F, Vikkula M, Juppner H, Strom TM (2006) DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet 38:1248–1250 15. The HYP Consortium (1995) A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophos- phatemic rickets. The HYP Consortium. Nat Genet 11:130–136