Phosphate is a vascular toxin
ABSTRACT Elevated phosphate (P) levels are seen in advanced renal failure and, together with dysregulated calcium, 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 dialysis show that high P is associated with increased vessel wall thickness, arterial stiffness and coronary calcification. Epidemiological studies in adult dialysis patients demonstrate 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 vasculature 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.
SourceAvailable from: Rukshana Shroff[Show abstract] [Hide abstract]
ABSTRACT: In children with chronic kidney disease (CKD) optimal control of mineral and bone disorder (MBD) is essential not only for the prevention of debilitating skeletal complications and for achieving adequate growth, but also for preserving long-term cardiovascular health. The growing skeleton is particularly vulnerable to the effects of CKD, and bone pain, fractures and deformities are common in children on dialysis. Defective bone mineralisation has been linked with ectopic calcification, which in turn leads to significant morbidity and mortality. Despite national and international guidelines for the management of CKD-MBD, the management of mineral dysregulation in CKD can be extremely challenging, and a significant proportion of patients have calcium, phosphate or parathyroid hormone levels outside the normal ranges. Clinical and experimental studies have shown that, in the setting of CKD, low serum calcium levels are associated with poor bone mineralisation, whereas high serum calcium levels can lead to arterial calcification, even in children. The role of calcium in CKD-MBD is the focus of this review.Pediatric Nephrology 12/2014; DOI:10.1007/s00467-014-3017-y · 2.88 Impact Factor
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ABSTRACT: The inefficient use of phosphorus (P) in the food chain is a threat to the global aquatic environment and the health and well-being of citizens, and it is depleting an essential finite natural resource critical for future food security and ecosystem function. We outline a strategic framework of 5R stewardship (Re-align P inputs, Reduce P losses, Recycle P in bioresources, Recover P in wastes, and Redefine P in food systems) to help identify and deliver a range of integrated, cost-effective, and feasible technological innovations to improve P use efficiency in society and reduce Europe's dependence on P imports. Their combined adoption facilitated by interactive policies, co-operation between upstream and downstream stakeholders (researchers, investors, producers, distributors, and consumers), and more harmonized approaches to P accounting would maximize the resource and environmental benefits and help deliver a more competitive, circular, and sustainable European economy. The case of Europe provides a blueprint for global P stewardship.AMBIO A Journal of the Human Environment 03/2015; 44(Supplement 2):193-206. DOI:10.1007/s13280-014-0614-8 · 2.97 Impact Factor
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ABSTRACT: Skeletal regenerative medicine frequently incorporates deliverable growth factors to stimulate osteogenesis. However, the cost and side effects secondary to supraphysiologic dosages of growth factors warrant investigation of alternative methods of stimulating osteogenesis for clinical utilization. In this work, we describe growth factor independent osteogenic induction of human mesenchymal stem cells (hMSCs) on a novel nanoparticulate mineralized collagen glycosaminoglycan scaffold (MC-GAG). hMSCs demonstrated elevated osteogenic gene expression and mineralization on MC-GAG with minimal to no effect upon addition of BMP-2 when compared to non-mineralized scaffolds (Col-GAG). To investigate the intracellular pathways responsible for the increase in osteogenesis, we examined the canonical and non-canonical pathways downstream from BMP receptor activation. Constitutive Smad1/5 phosphorylation with nuclear translocation occurred on MC-GAG independent of BMP-2, whereas Smad1/5 phosphorylation depended on BMP-2 stimulation on Col-GAG. When non-canonical BMPR signaling molecules were examined, ERK1/2 phosphorylation was found to be decreased in MC-GAG but elevated in Col-GAG. No differences in Smad2/3 or p38 activation were detected. Collectively, these results demonstrated that MC-GAG scaffolds induce osteogenesis without exogenous BMP-2 addition via endogenous activation of the canonical BMP receptor signaling pathway. Published by Elsevier Ltd.Biomaterials 05/2015; 50. DOI:10.1016/j.biomaterials.2015.01.059 · 8.31 Impact Factor