Phosphate Handling Research Articles

Neonatal Iron Deficiency Causes Abnormal Phosphate Metabolism by Elevating FGF23 in Normal and ADHR Mice

Fibroblast growth factor 23 (FGF23) gain of function mutations can lead to autosomal dominant hypophosphatemic rickets (ADHR) disease onset at birth, or delayed onset following puberty or pregnancy. We previously demonstrated that the combination of iron deficiency and a knock-in R176Q FGF23 mutation in mature mice induced FGF23 expression and hypophosphatemia that paralleled the late-onset ADHR phenotype. Because anemia in pregnancy and in premature infants is common, the goal of this study was to test whether iron deficiency alters phosphate handling in neonatal life. Wild-type (WT) and ADHR female breeder mice were provided control or iron-deficient diets during pregnancy and nursing. Iron-deficient breeders were also made iron replete. Iron-deficient WT and ADHR pups were hypophosphatemic, with ADHR pups having significantly lower serum phosphate (p < 0.01) and widened growth plates. Both genotypes increased bone FGF23 mRNA (>50 fold; p < 0.01). WT and ADHR pups receiving low iron had elevated intact serum FGF23; ADHR mice were affected to a greater degree (p < 0.01). Iron-deficient mice also showed increased Cyp24a1 and reduced Cyp27b1, and low serum 1,25-dihydroxyvitamin D (1,25D). Iron repletion normalized most abnormalities. Because iron deficiency can induce tissue hypoxia, oxygen deprivation was tested as a regulator of FGF23, and was shown to stimulate FGF23 mRNA in vitro and serum C-terminal FGF23 in normal rats in vivo. These studies demonstrate that FGF23 is modulated by iron status in young WT and ADHR mice and that hypoxia independently controls FGF23 expression in situations of normal iron. Therefore, disturbed iron and oxygen metabolism in neonatal life may have important effects on skeletal function and structure through FGF23 activity on phosphate regulation.

Incidence and aetiology of renal phosphate loss in patients with hypophosphatemia in the intensive care unit

Hypophosphatemia is a common finding in patients in the intensive care unit (ICU). Its cause is often poorly understood. The aim of this study was to understand the incidence of renal phosphate loss in ICU-related hypophosphatemia, and to examine the role of phosphaturic hormones in its etiology. Plasma phosphate levels were measured on day 1, 3, 5 and 7 in 290 consecutive patients admitted to the ICU. Renal phosphate handling and phosphaturic hormones were studied in a subset of patients with phosphate levels <0.6 mmol/L. Renal phosphate loss was defined as a TmP/gfr < 0.6 mmol/L. Hypophosphatemia developed in 24% of all patients. This mainly occurred within the first 3 days of stay and in patients with serum creatinine levels <150 μmol/L. Renal phosphate loss was present in 80% of patients who developed hypophosphatemia, and was not related to serum levels of parathyroid hormone (PTH), PTH-related protein (PTH-rp), fibroblast growth factor 23 (FGF-23), or calcitonin. Hypophosphatemia in the ICU is commonly associated with renal phosphate loss. It mainly occurs within the first 3 days of admission, in particular in patients with preserved renal function. Renal phosphate loss is not explained by elevated PTH, PTH-rp, FGF-23 or calcitonin levels.

New insights in regulation of calcium homeostasis

Regulation of calcium homeostasis during a lifetime is a complex process reflecting a balance among intestinal calcium absorption, bone calcium influx and efflux, and renal calcium excretion. Perturbations can result in hypocalcemia or hypercalcemia and adaptations in calcium handling must occur during growth and aging. Study of the calcium sensing receptor in the thick ascending limb of Henle and TRPV5 in the distal tubule continues to provide insights into regulation of renal calcium excretion. Hypercalcemia-induced secretion of calcitonin via activation of the calcium-sensing receptor may protect against the development of hypercalcemia. A calcilytic was shown to increase serum calcium by decreasing renal calcium excretion. Ezrin, a cross-linking protein important for renal phosphate handling, is also involved in the regulation of intestinal calcium absorption. Increased 1,25-hydroxyvitamin D (1,25D) values were shown to protect against the development of hypocalcemia by increasing calcium efflux and decreasing calcium influx in bone. Finally, fibroblast growth factor 23 stimulation, which should result in suppression of 1,25D, was shown to be prevented in a model of vitamin D deficiency in which maintenance of 1,25D is important in minimizing hypocalcemia. Recent information has provided new insights on how intestinal, bone and renal mechanisms are regulated to maintain calcium homeostasis.

Gastrointestinal Phosphate Handling in CKD and Its Association With Cardiovascular Disease

Increases in serum concentrations of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) and ultimately phosphate and decreases in 1,25-dihydroxyvitamin D level are thought to play a central role in the progressive nature of kidney disease and the development of cardiovascular disease in patients with chronic kidney disease. The initial changes in PTH and FGF-23 levels are adaptive to maintain serum phosphate concentration and phosphate load within defined levels by increasing urinary excretion of phosphate. Less well appreciated is the unanticipated finding that absorption of phosphate from the gastrointestinal tract is not downregulated in chronic kidney disease. This maladaptive response maintains higher levels of phosphate absorption, thereby contributing to the phosphate burden. Moreover, in response to a low-phosphate diet, as often is prescribed to such patients, gut phosphate absorption may be enhanced, undermining the potential beneficial effects of this intervention. Given the poor response to limiting phosphate intake and the use of phosphate binders, we suggest that research efforts be oriented toward better understanding of the factors that affect phosphate absorption in the gastrointestinal tract and the development of agents that directly inhibit phosphate transporters in the small intestine and/or their associated binding proteins.

Role of calcium and phosphate in atherosclerosis and vascular calcification

Serum calcium and phosphate levels are tightly regulated by parathyroid hormone and vitamin D. Dysregulation of this homeostasis in patients with chronic kidney disease (CKD) contributes to the development of secondary hyperparathyroidism, which in turn induces cardiovascular disease as well as the further deterioration of the kidney function and bone abnormality, and eventually increases mortality and morbidity. Evidence for the relationship between circulating fibroblast growth factor 23 (FGF23) levels and the incidence of cardiovascular mortality has been accumulated. With the discovery of FGF23/klotho axis, we gained the understanding of adaptation and maladaptation of the phosphate handling in CKD patients. The research for the direct or indirect sequelae of increased serum FGF23 concentrations should be warranted.

Phosphate handling by end‐stage kidneys and benefits of residual renal function on phosphate removal in patients on haemodialysis

We investigated the handling of phosphate by end-stage kidneys and the contribution of residual renal function (RRF) to phosphate homeostasis in haemodialysis patients. Blood and 24 h urinary specimens were obtained from 79 consecutive chronic haemodialysis patients with a urinary output greater than 100 mL/day. Thirty-five patients with a glomerular filtration rate (GFR) ≥ 3.0 mL/min were included as group A, and 44 patients with GFR < 3.0 mL/min as group B. Additionally, the whole dialysed fluids during a session of haemodialysis were collected from another nine patients. Concentrations of phosphate, creatinine, urea nitrogen, intact parathyroid hormone (iPTH) and fibroblast growth factor 23 (FGF-23) were measured. Twenty-four hour urinary phosphate excretion (UPE) was 283 ± 115 and 139 ± 57 mg/day (9.1 ± 3.5 and 4.5 ± 1.8 mmol/day) in groups A and B, respectively. Tubular reabsorption of phosphate (TRP) was 39.2 ± 13.3 and 31.7 ± 13.6% in groups A and B, respectively (P = 0.02). UPE significantly correlated with GFR (r = 0.85, P < 0.001) and PTH (r = 0.44, P < 0.001), but not with FGF-23, in the entire patient population. The correlation between UPE and intact PTH levels was absent in group B. Weekly UPE in group A was significantly greater (P < 0.001), while that in group B was similar to the amount of phosphate removed by a haemodialysis session. Urinary phosphate excretion by end-stage kidneys depends more on GFR than diminishing TRP. The action of PTH on the kidneys remains until GFR decreases to as low as 3 mL/min. Residual renal function plays a significant role in phosphate elimination, and it is possible that FGF-23 no longer acts effectively to excrete phosphate in the urine in these patients.

Effects of Acute Sodium Fluoride Exposure on Kidney Function, Water Homeostasis, and Renal Handling of Calcium and Inorganic Phosphate

Fluoride compounds are abundant and widely distributed in the environment at a variety of concentrations. Further, fluoride induces toxic effects in target organs such as the liver and kidney. In this study, we performed an early analysis of renal function using a clearance technique in Wistar rats acutely exposed to fluoride at a plasma concentration of 0.625μg/ml. Our results revealed that fluoride, at a concentration close to the concentration present in the serum after environmental exposure, induced a significant tubular dysfunction, resulting in diluted urine, impaired protein reabsorption, and increased calcium and phosphate urinary excretion. Our work demonstrates that even acute exposures to low concentrations of NaF may induce renal damage and confirms that, after exposure, the kidney participates directly in the calcium and phosphate deficiencies observed in fluoride-exposed populations.

Renal phosphate handling and long-term outcomes after kidney transplantation

Renal phosphate handling and long-term outcomes after kidney transplantation

High Expression of the Pi-Transporter SLC20A1/Pit1 in Calcific Aortic Valve Disease Promotes Mineralization through Regulation of Akt-1

The regulation of phosphate (Pi) handling is crucial during calcification of the aortic valve. Gene profiling of Pi transporters revealed that VIC culture expresses SLC201A1/Pit1 and SLC20A2/Pit2. On exposure to a mineralizing medium (2 mM Pi), the expression of Pi transporters in VIC culture is increased several folds, with the highest magnitude for SLC20A1. By using siRNAs, we established that silencing SLC20A1 significantly reduced Pi-induced mineralization of VICs. In human pathological specimens, we found that the expression of SCL20A1 was increased in CAVD tissues compared to control non-mineralized aortic valves. Treatment of VIC culture with Pi promoted the loss of mitochondrial membrane potential (ΔΨm) and cytochrome c release within the cytosol, leading to apoptosis. Inhibition of Pi transporters with phosphonoformic acid (PFA) prevented Pi-mediated apoptosis of VICs. Moreover, we discovered that the level of the Akt-1 transcript is diminished in CAVD tissues compared with control valves. Accordingly, treatment with Pi caused a reduction of the Akt-1 transcript in VIC culture, and treatment with PFA or siRNA against SLC20A1 restored the level of Akt-1. Overexpression of Akt-1 (pCMVAkt-1) prevented both Pi-induced apoptosis and mineralization of VIC culture. These results strongly suggest that overexpression of SLC20A1 promotes apoptosis and mineralization by altering the level of Akt-1.

Renal phosphate handling: Physiology

Phosphorus is a common anion. It plays an important role in energy generation. Renal phosphate handling is regulated by three organs parathyroid, kidney and bone through feedback loops. These counter regulatory loops also regulate intestinal absorption and thus maintain serum phosphorus concentration in physiologic range. The parathyroid hormone, vitamin D, Fibrogenic growth factor 23 (FGF23) and klotho coreceptor are the key regulators of phosphorus balance in body.

FGF23 antagonism: the thin line between adaptation and maladaptation in chronic kidney disease

For more than 10 years, we have been convinced by overwhelming epidemiological evidence with a high biological plausibility that hyperphosphataemia imposes one of the most sustained cardiovascular and mortality risks on patients suffering from chronic kidney disease (CKD). With the discovery of the fibroblast growth factor-23 (FGF23)/klotho axis, we not only gained a new and mechanistic understanding of phosphate handling of the body, we also felt that novel therapeutic strategies may arise counteracting the deleterious consequences of phosphate retention, dysregulation and maldistribution. Two recent experimental studies shed additional and important light on what we can expect from such new insights. Faul et al. showed us that FGF23 excess may directly induce left ventricular hypertrophy (LVH) and that FGF-receptor antagonism ameliorates CKD-induced LVH in rats. Shalhoub et al. demonstrated that FGF23 antibodies successfully ameliorated the development and progression of most features of secondary hyperparathyroidism in a rat model of CKD, however, at the expense of hyperphosphataemia, progressive vascular calcification and death. Such studies not only help to continuously improve our understanding, but also especially sharpen our perception of how thin the line may be between adaptation and maladaptation in chronic disease scenarios.

Circulating αKlotho influences phosphate handling by controlling FGF23 production

The FGF23 coreceptor αKlotho (αKL) is expressed as a membrane-bound protein (mKL) that forms heteromeric complexes with FGF receptors (FGFRs) to initiate intracellular signaling. It also circulates as an endoproteolytic cleavage product of mKL (cKL). Previously, a patient with increased plasma cKL as the result of a translocation [t(9;13)] in the αKLOTHO (KL) gene presented with rickets and a complex endocrine profile, including paradoxically elevated plasma FGF23, despite hypophosphatemia. The goal of this study was to test whether cKL regulates phosphate handling through control of FGF23 expression. To increase cKL levels, mice were treated with an adeno-associated virus producing cKL. The treated groups exhibited dose-dependent hypophosphatemia and hypocalcemia, with markedly elevated FGF23 (38 to 456 fold). The animals also manifested fractures, reduced bone mineral content, expanded growth plates, and severe osteomalacia, with highly increased bone Fgf23 mRNA (>150 fold). cKL activity in vitro was specific for interactions with FGF23 and was FGFR dependent. These results demonstrate that cKL potently stimulates FGF23 production in vivo, which phenocopies the KL translocation patient and metabolic bone syndromes associated with elevated FGF23. These findings have important implications for the regulation of αKL and FGF23 in disorders of phosphate handling and biomineralization.

Renal phosphate handling in Gitelman syndrome—the results of a case–control study

Patients with Gitelman syndrome, a hereditary salt-wasting tubulopathy, have loss-of-function mutations in the SLC12A3 gene coding for the thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule. Since the bulk of filtered phosphate is reabsorbed in the proximal tubule, renal phosphate wasting is considered exceptional in Gitelman syndrome. We investigated the renal handling of inorganic phosphate in 12 unselected Italian patients affected with Gitelman syndrome (5 females and 7 males, aged 6.0-18 years, median age 12 years) and in 12 healthy subjects matched for gender and age (controls). The diagnosis of Gitelman syndrome among the patients had been made clinically and confirmed by molecular biology studies. The biochemical hallmarks of Gitelman syndrome, namely hypochloremia, hypokalemia, hypomagnesemia, increased urinary excretion of sodium, chloride, potassium and magnesium and reduced urinary excretion of calcium, were present in the 12 patients. In addition, both the plasma inorganic phosphate concentration (median and interquartile range: 1.28 [1.12-1.36] vs. 1.61 [1.51-1.66)] mmol/L) and the maximal tubular reabsorption of inorganic phosphate (1.08 [0.99-1.22] vs. 1.41 [1.38-1.47] mmol/L) were significantly lower (P < 0.001) in Gitelman patients than in control subjects. Circulating levels of 25-hydroxyvitamin D, intact parathyroid hormone and osteocalcin were similar in patients and controls. The results of our case-control study disclose a hitherto unrecognized tendency towards renal phosphate wasting with mild to moderate hypophosphatemia in Gitelman syndrome.

Promoter methylation confers kidney‐specific expression of the Klotho gene

The aging suppressor geneKlotho is predominantly expressed in the kidney irrespective of species. Because Klotho protein is an essential component of an endocrine axis that regulates renal phosphate handling, the kidney-specific expression is biologically relevant; however, little is known about its underlying mechanisms. Here we provide in vitro and in vivo evidence indicating that promoter methylation restricts the expression of the Klotho gene in the kidney. Based on evolutionary conservation and histone methylation patterns, the region up to -1200 bp was defined as a major promoter element of the human Klotho gene. This region displayed promoter activity equally in Klotho-expressing and -nonexpressing cells in transient reporter assays, but the activity was reduced to ∼20% when the constructs were integrated into the chromatin in the latter. Both endogenous and transfected Klotho promoters were 30-40% methylated in Klotho-nonexpressing cells, but unmethylated in Klotho-expressing renal tubular cells. DNA demethylating agents increased Klotho expression 1.5- to 3.0-fold in nonexpressing cells and restored the activity of silenced reporter constructs. Finally, we demonstrated that a severe hypomorphic allele of Klotho had aberrant CpG methylation in kl/kl mice. These findings might be useful in therapeutic intervention for accelerated aging and several complications caused by Klotho down-regulation.

INTERACTION BETWEEN DIETARY PHOSPHATE AND CARBOHYDRATE ON GLUCOSE AND PHOSPHATE METABOLISMS IN HEALTHY YOUNG MEN.

Interaction between the nutrients should be considered to understand the relationship between nutrient intake and disease. Here, we investigated the effects of combination of dietary phosphate and carbohydrate (glycemic index; GI) on urinary phosphate excretion, serum glucose, insulin, phosphate, PTH levels after the digestion of experimental meal in 11 young healthy men. We employed 4 different meals; high GI and high phosphate (HGHP), high GI and low phosphate (HGLP), low GI and high phosphate (LGHP), and low GI and low phosphate (LGLP). Barley was used for staple food in low GI meals, inversely white rice in high GI meals. Low phosphate meals contained 400 mg of phosphate, high phosphate meals contained 1200 mg of phosphate added as sodium phosphate. This study was performed as a crossover study, and approved by the ethical committee of the University of Tokushima. Ingestion of HGHP meal revealed higher postprandial phosphate excretion than LGHP meal. This difference was not observed between HGLP and LGLP meals. HGHP meals was also involved in higher postprandial increases in blood glucose and insulin than HGLP. Meanwhile intact PTH level in the ingestion of LGHP meals was significantly higher than that in HGHP. No significant difference in serum phosphate level between HGHP and LGHP groups. These data indicate that interaction between dietary phosphate and carbohydrate affected postprandial changes in serum glucose and phosphate handling in healthy young men.

Renal Phosphate Loss in Long-Term Kidney Transplantation

Renal phosphate wasting occurs early postkidney transplantation as a result of an accumulation of parathyroid hormone and fibroblast growth factor 23 from the CKD period. Serum phosphate, parathyroid hormone, and fibroblast growth factor 23 return to baseline 1 year postkidney transplantation. What happens beyond this period is unknown. Mineral parameters were obtained from 229 kidney transplant recipients at least 1 year posttransplantation; 46 normal subjects and 202 CKD patients with similar GFR served as controls. Factors associated with phosphate metabolism were analyzed. Despite the reduced graft function, most kidney transplant recipients had lower serum phosphate than normal subjects accompanied by renal phosphate loss. Fibroblast growth factor 23 was mostly lower or comparable with normal subjects, whereas parathyroid hormone was elevated in most patients. Hyperparathyroidism is also more common among kidney transplant recipients compared with CKD patients. Both parathyroid hormone and fibroblast growth factor 23 showed relationships with renal phosphate excretion, but only parathyroid hormone displayed an independent association. Parathyroid hormone showed the highest area under the curve in predicting renal phosphate leak. When patients were categorized according to parathyroid hormone and fibroblast growth factor 23 levels, only subset of patients with high parathyroid hormone had an increased renal phosphate excretion. Relatively low serum phosphate from renal phosphate leak continued to present in long-term kidney transplantation. Both parathyroid hormone and fibroblast growth factor 23 participated in renal tubular phosphate handling, but persistent hyperparathyroidism seemed to have a greater influence in this setting.

Evaluation of Hypophosphatemia: Lessons From Patients With Genetic Disorders

Phosphate is a key component of several physiologic pathways, such as skeletal development, bone mineralization, membrane composition, nucleotide structure, maintenance of plasma pH, and cellular signaling. The kidneys have a key role in phosphate homeostasis, with 3 hormones having important roles in renal phosphate handling: parathyroid hormone, fibroblast growth factor 23 (FGF-23), and 1,25-dihydroxyvitamin D. Independent of the genetic diseases affecting the FGF-23 pathway (such as hypophosphatemic rickets), hypophosphatemia is a frequent condition encountered in daily practice, and untreated critical hypophosphatemia can induce hemolysis, rhabdomyolysis, respiratory failure, cardiac dysfunction, and neurologic impairment. Rapid correction thus is necessary to avoid severe complications. The aims of this teaching case are to summarize the causes and biological evaluation of hypophosphatemia and provide an overview of our current understanding of phosphate metabolism.

The Vitamin D Analog 1α,25-Dihydroxy-2β-(3-Hydroxypropyloxy) Vitamin D3 (Eldecalcitol) is a Potent Regulator of Calcium and Phosphate Metabolism

The vitamin D analog 1α,25-dihydroxy-2β-(3-hydroxypropyloxy)vitamin D(3) (ED-71 or eldecalcitol) has been developed for treatment of osteoporosis, but its effects on mineral metabolism have not been investigated in detail. In the present study, we compared the effects of eldecalcitol and calcitriol on calcium (Ca) and phosphate (Pi) handling in rats. Oral administration of eldecalcitol (0, 7.5, 20, or 50pmol) q.o.d. for 2weeks dose-dependently increased ionized Ca, intestinal Ca absorption, and urinary Ca excretion, while these doses of calcitriol had no significant effects. The highest dose of eldecalcitol did not alter serum Pi but stimulated both intestinal Pi absorption and urinary Pi excretion; the latter was attributable, in part, to increased serum FGF-23. The effects of high-dose eldecalcitol on Ca and Pi absorption and urinary excretion and FGF-23 persisted for several days following cessation of treatment. The higher potency of eldecalcitol on Ca and Pi handling was also observed in parathyroidectomized rats infused with PTH, excluding a role for differential regulation of PTH. Direct measurement of duodenal Ca absorption by the in situ loop method confirmed the higher potency of eldecalcitol in this segment via induction of TRPV6. These studies indicated that with chronic administration eldecalcitol is more potent than calcitriol at stimulating intestinal absorption of Ca and Pi, as well as FGF-23. The mechanisms responsible for the higher potency of eldecalcitol are speculated to be its higher vitamin D-binding protein (DBP) affinity and resistance to metabolism.

Phosphate Metabolism in CKD Stages 3–5: Dietary and Pharmacological Control

When compared to the available information for patients on dialysis (CKD stage 5D), data on the epidemiology and appropriate treatment of calcium and phosphate metabolism in the predialysis stages of chronic kidney disease (CKD) are quite limited. Perceptible derangements of calcium and phosphate levels start to become apparent when GFR falls below 30 mL/min in some, but not all, patients. However, hyperphosphatemia may be a significant morbidity and mortality risk predictor in predialysis CKD stages. The RIND study, evaluating progression of coronary artery calcification in incident hemodialysis patients, indirectly demonstrated that vascular calcification processes start to manifest in CKD patients prior to the dialysis stage, which may be closely linked to early and invisible derangements in calcium and phosphate homeostasis. Novel insights into the pathophysiology of calcium and phosphate handling such as the discovery of FGF23 and other phosphatonins suggest that a more complex assessment of phosphate balance is warranted, possibly including measurements of fractional phosphate excretion and phosphatonin levels in order to appropriately evaluate disordered metabolism in earlier stages of kidney disease. As a consequence, early and preventive treatment approaches may have to be developed for patients in CKD stages 3-5 to halt progression of CKD-MBD.

The Phosphorus and the Vascular Calcification in ESRD between Old Adventures and New Horizons

Phosphate plays a central role in the pathophysiology of CKD-MBD and the progression of chronic kidney disease (CKD) and contributes to the disproportionate cardiovascular risk faced by patients with CKD. Adaptation of nephrons attempting to preserve phosphate homeostasis requires endocrine tradeoff that fuel adverse events of hyperphosphatemia in CKD—secondary hyperparathyroidism, calcium and vitamin D derangements, vascular calcifi cation, and metabolic bone disorder. In fact, in advancing CKD there is a multitude of biochemical, physiological, and clinical alterations, and mechanistic understanding of secondary hyperparathyroidism, vascular calcification, and regulation of phosphate metabolism in CKD has advanced significantly in the past five decades. The principal hormones that regulate renal phosphate handling are parathyroid hormone (PTH), which is produced by the parathyroid gland, and fibroblast growth factor (FGF)-23, which is produced by osteocytes and osteoblasts in bone. In healthy individuals, increasing serum phosphate concentration induces secretion of PTH and FGF-23, and Kloto decline. It has been established (and now accepted by nephrologists) that observational studies strongly suggest that phosphorus is associated with cardiovascular risk, and definitive prospective animal studies are supportive. However, prospective studies demonstrating that modulation of the putative risk factor affects clinical outcomes are lacking, and phosphorus, as yet, does not qualify as a cardiovascular risk factor. This special issue provides an identification of the complex mechanisms that determine the phosphorus and calcium metabolism in CKD-3 and CKD-4; a verify the association of serum phosphate and related factors in ESRD-related vascular calcification. It has also addressed mineral metabolism in patients with CKG in the Era of KDIGO Guidelines, the effect of vitamin D on clinical outcomes in chronic kidney disease, and the effect of paricalcitol on vascular calcification and cardiovascular disease in uremia. Finally, were also discussed the effect of the use of non-calcium-phosphate binders in the control of vascular calcifications; the clinical significance of FGF-23 in patients with CKD, the the relationship between arterial stiffness and vascular damage; the treatment of severe metastatic calcification and calciphylaxis in dialysis patients; the clinical impact of hypercalcemia in kidney transplant patients. Biagio Raffaele Di Iorio Markus Ketteler Domenico Russo Angela Wang