REVIEW Phosphate is a vascular toxin Rukshana Shroff Received: 25 July 2012 / Revised: 7 October 2012 / Accepted: 9 October 2012 / Published online: 17 November 2012 # IPNA 2012 Abstract Elevated phosphate (P) levels are seen in ad- vanced renal failure and, together with dysregulated calci- um, parathyroid hormone and vitamin D levels, contribute to the complex of chronic kidney disease–mineral and bone disease (CKD-MBD). Converging evidence from in vitro, clinical and epidemiological studies suggest that increased P is associated with vascular calcification and mortality. When vessels are exposed to high P conditions in vitro, they develop apoptosis, convert to bone-like cells and develop extensive calcification. Clinical studies in children on dial- ysis show that high P is associated with increased vessel wall thickness, arterial stiffness and coronary calcification. Epidemiological studies in adult dialysis patients demon- strate a significant and independent association between raised P and mortality. Importantly, raised P is associated with cardiovascular changes even in pre-dialysis CKD, and also in subjects with normal renal function but high P. All P binders can effectively reduce serum P, and this decrease is linked to improved survival. Raised serum P triggers the release of fibroblast growth factor 23 (FGF-23), which has the beneficial effect of increasing P excretion in early CKD, but is increased several 1,000-fold in dialysis, and may be an independent cardiovascular risk factor. Both FGF-23 and its co-receptor Klotho may have direct effects on the vascu- lature leading to calcification. Fascinatingly, disturbances in FGF-23–Klotho and raised P have also been associated with premature aging. These data suggest that high P levels have adverse vascular effects and that maintaining the serum P levels in the normal range reduces cardiovascular risk and mortality. Keywords Phosphate . Chronic kidney disease . Cardiovascular disease . Vascular calcification . Dialysis Introduction Phosphorus is an essential element that forms a key compo- nent of nucleic acids and cell membranes and is required for maintaining the normal homeostatic control of the cell, in- cluding energy metabolism and cell signaling. In biological systems, phosphorus is bound with oxygen and exists as phosphate (P). As P is predominantly excreted by the kidneys, P retention occurs in chronic kidney disease (CKD) [1]. In the early stages of CKD, secretion of fibroblast growth factor 23 (FGF-23) by the osteocyte [2] promotes P excretion in an attempt to regulate P homeostasis [3]. With advancing CKD, progressive hyperphosphatemia can occur, and is associated with dysregulation in calcium (Ca), parathyroid hormone (PTH) and vitamin D homeostasis [1]. Dysregulation of the Ca–P–PTH–vitamin D axis can result in bone demineralization and ectopic soft tissue cal- cification, resulting in the complex of CKD–mineral and bone disorder [4]. Children with CKD have both cardiac dysfunction [5] and vascular damage and calcification [6] that is present even from pre-dialysis CKD stages and increases in prevalence and severity on dialysis [1, 6]. Cardiovascular disease (CVD) in childhood CKD has been associated with increased circulating P and Ca×P levels in virtually all pediatric and adult studies [6–12]. While CVD is clearly multifactorial and hyperphosphatemia is only one among several risk factors contributing to the development and progression of CVD, clinical and epidemiological stud- ies have linked increased P levels with mortality [13]. In this review the effects of P on the vasculature are discussed, and the results of important epidemiological and clinical studies and in vitro data are presented. The vascular toxicity of P leading to vascular calcification, role of FGF23 R. Shroff (*) Renal Unit, Great Ormond Street Hospital for Children, Great Ormond Street, London WC1N 3JH, UK e-mail: Rukshana.Shroff@gosh.nhs.uk Pediatr Nephrol (2013) 28:583–593 DOI 10.1007/s00467-012-2347-x