Phosphate is a vascular toxin

Renal Unit, Great Ormond Street Hospital for Children, Great Ormond Street, London, WC1N 3JH, UK, .
Pediatric Nephrology (Impact Factor: 2.86). 11/2012; 28(4). DOI: 10.1007/s00467-012-2347-x
Source: PubMed


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.

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Available from: Rukshana Shroff, Nov 18, 2015
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    • "During recent years the bone derived phosphaturic hormone, FGF23 and its co-receptor, Klotho, have been extensively studied and their role in phosphate homeostasis is now well established, although many questions regarding the regulation of FGF23 and Klotho still remain unanswered [16]. It is well documented that disturbed phosphate metabolism plays a critical role in the pathophysiology of uremia and that hyperphosphatemia is an important factor in the development of vascular calcification in CKD [17]. Plasma FGF23 increases very early in the development of CKD and is associated with cardiovascular mortality. "
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    ABSTRACT: High iron load might have a number of toxic effects in the organism. Recently intravenous (iv) iron has been proposed to induce elevation of fibroblast growth factor 23 (FGF23), hypophosphatemia and osteomalacia in iron deficient subjects. High levels of FGF23 are associated with increased mortality in the chronic kidney disease (CKD) population. CKD patients are often treated with iv iron therapy in order to maintain iron stores and erythropoietin responsiveness, also in the case of not being iron depleted. Therefore, the effect of a single high iv dose of two different iron preparations, iron isomaltoside 1000 (IIM) and ferric carboxymaltose (FCM), on plasma levels of FGF23 and phosphate was examined in normal and uremic iron repleted rats. Iron was administered iv as a single high dose of 80 mg/kg bodyweight and the effects on plasma levels of iFGF23, phosphate, Ca2+, PTH, transferrin, ferritin and iron were examined in short and long term experiments (n = 99). Blood samples were obtained at time 0, 30, 60, 180 minutes, 24 and 48 hours and in a separate study after 1 week. Uremia was induced by 5/6-nephrectomy. Nephrectomized rats had significant uremia, hyperparathyroidism and elevated FGF23. Iron administration resulted in significant increases in plasma ferritin levels. No significant differences were seen in plasma levels of iFGF23, phosphate and PTH between the experimental groups at any time point within 48 hours or at 1 week after infusion of the iron compounds compared to vehicle. In non-iron depleted normal and uremic rats a single high dose of either of two intravenous iron preparations, iron isomaltoside 1000, and ferric carboxymaltose, had no effect on plasma levels of iFGF23 and phosphate for up to seven days.
    Full-text · Article · Dec 2013 · BMC Nephrology
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    ABSTRACT: In chronic kidney disease (CKD), increased plasma phosphate concentrations cause vascular calcification which substantially contribute to cardiovascular events and increased mortality of CKD patients. Similar to CKD patients, klotho-hypomorphic mice (kl/kl) also suffer from excessive vascular calcification leading to growth deficit, rapid ageing and early death. The hyperphosphataemia of kl/kl mice results from excessive formation of 1,25(OH)2D3 causing excessive intestinal phosphate absorption. Further, kl/kl mice further suffer from hyperaldosteronism and compelling evidence points to an active role of mineralocorticoids in triggering osteoinductive programmes in the vasculature, thus further contributing to the development of vascular calcification. Conversely, in kl/kl mice, the mineralocorticoid receptor antagonist spironolactone decreased the vascular osteoinductive processes and reversed the excessive expression of osteogenic programmes, i.e. type III sodium-dependent phosphate transporter Pit1, tumour necrosis factor α (Tnfα), transcription factors Msx2, Cbfa1/Runx2 and osterix as well as alkaline phosphatase (Alp). In human aortic vascular smooth muscle cells (HAoSMCs), aldosterone alone similarly triggered an 'osteogenic' programme, thus increasing PIT1, TNFα, MSX2, CBFA1/RUNX2 and ALP expression as well as ALP activity and potentiated the effects of phosphate treatment. These effects were again reversed by spironolactone and in addition by PIT1 silencing. The above observations reveal that the severe vascular calcification is not only the result of high plasma phosphate concentrations, but also promoted by aldosterone-driven osteoinductive signalling. Future studies in CKD patients will be required to define the role of aldosterone and the potential impact of its inhibition by spironolactone in the pathophysiology of vascular calcification.
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    ABSTRACT: Soluble Klotho is an anti-aging phosphaturic protein associated with vascular-renal protection. In vitro and in vivo studies have demonstrated that renin-angiotensin system (RAS) blockade increases soluble Klotho levels. The effect of RAS blockers on soluble Klotho in patients with diabetic kidney disease (DKD) is unknown. Plasma-soluble Klotho was measured in a secondary analysis of a randomized controlled clinical trial performed at a single university hospital center ( number NCT001715, from March 2003 to September 2006). Seventy-six patients with type 2 diabetes and DKD (all with albuminuria and serum creatinine <1.7 mg/dl) were studied at baseline and at 24 weeks (study end) after randomization to valsartan/hydrochlorothiazide (n=37) or amlodipine (n=39) treatment. Aortic-pulse wave velocity by applanation tonometry and albuminuria (from three timed urine collections) were also measured at baseline and 24 weeks. Valsartan/hydrochlorothiazide treatment significantly increased mean (± SD) soluble Klotho (from 432.7±179 to 506.4±226.8 pg/ml; P=0.01) and reduced serum phosphate (from 3.25±1.18 to 2.60±0.96 mg/dl; P=0.04) compared with amlodipine (from 430.1±145.8 to 411.9±157.6 pg/ml and from 2.94±0.56 to 2.69±1.52 mg/dl, respectively). There was a significant difference between treatment groups in soluble Klotho (mean 91.9 pg/ml; 95% confidence interval, 19.9 to 162) and serum phosphate levels (mean -0.68 mg/dl; 95% confidence interval, -0.15 to -1.33) with valsartan/hydrochlorothiazide treatment (P=0.03 and P=0.04, respectively). Attained BP was similar in the two groups and levels of soluble Klotho were not associated with aortic-pulse wave velocity and albuminuria, variables that fell significantly only with valsartan/hydrochlorothiazide. Treatment with a RAS blocker, valsartan, is associated with an increase in soluble Klotho, which may contribute to the BP-independent cardiorenal benefits of these drugs in DKD.
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