New Insights Into the FGF23-Klotho Axis Hannes Olauson, MD, PhD, * Marc G. Vervloet, MD, PhD, † Mario Cozzolino, MD, PhD, ‡ Ziad A. Massy, MD, PhD, §,|| Pablo Ureña Torres, MD, PhD, ¶ and Tobias E. Larsson, MD, PhD *, # Summary: Abnormal mineral metabolism is a hallmark in patients with advanced chronic kidney disease (CKD). Hyperphosphatemia, and the homeostatic mechanisms controlling phosphate metabolism, have received particular attention over the past decade. The phosphate-regulating hormone fibroblast growth factor- 23 (FGF23) was discovered through studies of rare hypophosphatemic disorders, whereas Klotho, which subsequently turned out to be a co-receptor for FGF23, was identified in a mouse model showing hyperphosphatemia and multiple aging-like traits. The FGF23–Klotho endocrine axis is a pivotal regulator of mineral metabolism. In CKD, early onset of Klotho deficiency contributes to renal FGF23 resistance and a maladaptive increase in circulating FGF23. FGF23 is an early biomarker of renal injury and increased FGF23 predicts adverse clinical outcomes, in particular cardiovascular disease. A paradigm of FGF23 excess and Klotho deficiency is proposed, in which FGF23 preferentially stimulates left ventricular hypertrophy, and loss of Klotho augments fibrosis, endothelial dysfunction, and vascular calcification. The clinical benefit of FGF23 and Klotho measurements remain uncertain, nevertheless, the FGF23–Klotho axis is a solid candidate for a novel diagnostic and therapeutic target in CKD. Semin Nephrol 34:586-597 C 2014 Elsevier Inc. All rights reserved. Keywords: Fibroblast growth factor-23, FGF-23, calcium, phosphate, vitamin D, parathyroid hormone, chronic kidney disease T he existence of novel phosphate-regulating hormones (phosphatonins) was predicted seve- ral decades ago based on observations in patients with hereditary and acquired disorders of hypophosphatemia caused by excessive renal phosphate wasting. Autosomal-dominant hypophosphatemic rickets (ADHR) (online mendelian inheritance in man 193100), X-linked hypophosphatemic rickets (XLH) (online mendelian inheritance in man 307800), and tumor-induced osteomalacia (TIO) are 3 model dis- eases that supported the presence of a humoral factor (s) causing phosphaturia independent of parathyroid hormone (PTH). White et al 1 identified the FGF23 gene by positional cloning techniques and unraveled activating FGF23 mutations as the causative factor of ADHR as a result of stabilization of its encoded protein. In parallel, Shimada et al 2 isolated FGF23 as a differentially expressed transcript in a surgically resected TIO tumor and showed that systemic admin- istration of recombinant FGF23 recapitulated the TIO phenotype of hypophosphatemia, inappropriately low 1,25-dihydroxyvitamin D levels, and severe rickets/ osteomalacia (which are also the principal features in ADHR and XLH). Subsequently, it was shown that XLH patients, who carry a large set of inactivating mutations in a membrane-bound metalloproteinase gene termed PHEX, show high FGF23 expression in bone, which produces a phenotype virtually indistin- guishable from ADHR. 3 Collectively, FGF23 was the long sought-after phosphatonin that unified the under- lying pathophysiology of renal phosphate wasting in ADHR, XLH, and TIO. Type I, membrane-bound, α-Klotho (referred to as Klotho) was discovered in 1997 by Kuro-o et al, 4 who, by a random insertional mutation approach in mice, identified hypomorph Klotho alleles owing to disrup- tions in its gene promoter region. Downstream conse- 0270-9295/ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semnephrol.2014.09.005 Financial support: none Conflict of interest statement: Marc Vervloet has received speaker honoraria from Amgen, AbbVie, Sanofi-Genzyme, and Baxter, and research grants from Sanofi, AbbVie, FMC, and Pfizer, and consultant fees from Amgen and Astellas; Ziad Massy has received speaker honoraria and research grants from Amgen, Sanofi-Genzyme, Baxter, and FMC; Pablo Ureña Torres has received personal fees and grants from Amgen, AbbVie, Genzyme- Sanofi, Hemotech, and Fresenius; and Tobias Larsson is a Medical Director at Astellas Pharma. * Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden. † Department of Nephrology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands. ‡ Department of Health Sciences, University of Milan, Renal Divi- sion, San Paolo Hospital, Milan, Italy. § Inserm U-1088, Université de Picardie Jules Verne (UPJV), Amiens, France. || Division of Nephrology, Ambroise Paré Hospital, Paris-Ile-de- France-Ouest University (Université de Versailles Saint-Quentin- en-Yvelines (UVSQ)), Paris-Boulogne Billancourt, France. ¶ Service of Nephrology and Dialysis, Clinique du Landy and Department of Renal Physiology, Necker Hospital, University of Paris Descartes, Paris, France. # Department of Nephrology, Karolinska University Hospital, Stock- holm, Sweden. Address reprint requests to Tobias E. Larsson, MD, PhD, Clinical Research Center (KFC), 6th Floor, Novum, Karolinska University Hospital in Huddinge, SE-141 86 Stockholm, Sweden. E-mail: tobias.larsson@ki.se 586 Seminars in Nephrology, Vol 34, No 6, November 2014, pp 586–597