Phosphorus May Induce Phenotypic Transdifferentiation of Vascular Smooth Muscle Cells through the Reduction of microRNA-145.

Phosphorus is a vital element for life found in most foods as a natural component, but it is also one of the most used preservatives added during food processing. High serum phosphorus contributes to develop vascular calcification in chronic kidney disease; however, it is not clear its effect in a population without kidney damage. The objective of this in vivo and in vitro study was to investigate the effect of high phosphorus exposure on the aortic and serum levels of miR-145 and its effect on vascular smooth muscle cell (VSMCs) changes towards less contractile phenotypes. The study was performed in aortas and serum from rats fed standard and high-phosphorus diets, and in VSMCs exposed to different concentrations of phosphorus. In addition, miR-145 silencing and overexpression experiments were carried out. In vivo results showed that in rats with normal renal function fed a high P diet, a significant increase in serum phosphorus was observed which was associated to a significant decrease in the aortic α-actin expression which paralleled the decrease in aortic and serum miR-145 levels, with no changes in the osteogenic markers. In vitro results using VSMCs corroborated the in vivo findings. High phosphorus first reduced miR-145, and afterwards α-actin expression. The miR-145 overexpression significantly increased α-actin expression and partially prevented the increase in calcium content. These results suggest that miR-145 could be an early biomarker of vascular calcification, which could give information about the initiation of the transdifferentiation process in VSMCs.

Serum and Urinary Soluble α-Klotho as Markers of Kidney and Vascular Impairment.

This study was designed to investigate the controversy on the potential role of sKlotho as an early biomarker in Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD), to assess whether sKlotho is a reliable marker of kidney α-Klotho, to deepen the effects of sKlotho on vascular smooth muscle cells (VSMCs) osteogenic differentiation and to evaluate the role of autophagy in this process. Experimental studies were conducted in CKD mice fed a normal phosphorus (CKD+NP) or high phosphorus (CKD+HP) diet for 14 weeks. The patients' study was performed in CKD stages 2-5 and in vitro studies which used VSMCs exposed to non-calcifying medium or calcifying medium with or without sKlotho. The CKD experimental model showed that the CKD+HP group reached the highest serum PTH, P and FGF23 levels, but the lowest serum and urinary sKlotho levels. In addition, a positive correlation between serum sKlotho and kidney α-Klotho was found. CKD mice showed aortic osteogenic differentiation, together with increased autophagy. The human CKD study showed that the decline in serum sKlotho is previous to the rise in FGF23. In addition, both serum sKlotho and FGF23 levels correlated with kidney function. Finally, in VSMCs, the addition of sKlotho prevented osteogenic differentiation and induced autophagy. It can be concluded that serum sKlotho was the earliest CKD-MBD biomarker, a reliable indicator of kidney α-Klotho and that might protect against osteogenic differentiation by increasing autophagy. Nevertheless, further studies are needed to investigate the mechanisms of this possible protective effect.

MicroRNA-145 and microRNA-486 are potential serum biomarkers for vascular calcification.

INTRODUCTION: MicroRNAs (miRs) regulate vascular calcification (VC), and their quantification may contribute to suspicion of the presence of VC. METHODS: The study was performed in four phases. Phase 1: miRs sequencing of rat calcified and non-calcified aortas. Phase 2: miRs with the highest rate of change, plus miR-145 [the most abundant miR in vascular smooth muscle cells (VSMCs)], were validated in aortas and serum from rats with and without VC. Phase 3: the selected miRs were analyzed in epigastric arteries from kidney donors and recipients, and serum samples from general population. Phase 4: VSMCs were exposed to different phosphorus concentrations, and miR-145 and miR-486 were overexpressed to investigate their role in VC. RESULTS: miR-145, miR-122-5p, miR-486 and miR-598-3p decreased in the rat calcified aortas, but only miR-145 and miR-486 were detected in serum. In human epigastric arteries, miR-145 and miR-486 were lower in kidney transplant recipients compared with donors. Both miRs inversely correlated with arterial calcium content and with VC (Kauppila index). In the general population, the severe VC was associated with the lowest serum levels of both miRs. The receiver operating characteristic curve showed that serum miR-145 was a good biomarker of VC. In VSMCs exposed to high phosphorus, calcium content, osteogenic markers (Runx2 and Osterix) increased, and the contractile marker (α-actin), miR-145 and miR-486 decreased. Overexpression of miR-145, and to a lesser extent miR-486, prevented the increase in calcium content induced by high phosphorus, the osteogenic differentiation and the loss of the contractile phenotype. CONCLUSION: miR-145 and miR-486 regulate the osteogenic differentiation of VSMCs, and their quantification in serum could serve as a marker of VC.

Interdisciplinary management of FGF23-related phosphate wasting syndromes: a Consensus Statement on the evaluation, diagnosis and care of patients with X-linked hypophosphataemia.

X-linked hypophosphataemia (XLH) is the most frequent cause of hypophosphataemia-associated rickets of genetic origin and is associated with high levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23). In addition to rickets and osteomalacia, patients with XLH have a heavy disease burden with enthesopathies, osteoarthritis, pseudofractures and dental complications, all of which contribute to reduced quality of life. This Consensus Statement presents the outcomes of a working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, and provides robust clinical evidence on management in XLH, with an emphasis on patients' experiences and needs. During growth, conventional treatment with phosphate supplements and active vitamin D metabolites (such as calcitriol) improves growth, ameliorates leg deformities and dental manifestations, and reduces pain. The continuation of conventional treatment in symptom-free adults is still debated. A novel therapeutic approach is the monoclonal anti-FGF23 antibody burosumab. Although promising, further studies are required to clarify its long-term efficacy, particularly in adults. Given the diversity of symptoms and complications, an interdisciplinary approach to management is of paramount importance. The focus of treatment should be not only on the physical manifestations and challenges associated with XLH and other FGF23-mediated hypophosphataemia syndromes, but also on the major psychological and social impact of the disease.

Safety and effectiveness of sucroferric oxyhydroxide in Spanish patients on dialysis: sub-analysis of the VERIFIE study.

BACKGROUND AND AIMS: In this study, we show the results of the subset of Spanish patients of the VERIFIE study, the first post-marketing study assessing the long-term safety and effectiveness of sucroferric oxyhydroxide (SFOH) in patients with hyperphosphatemia undergoing dialysis during clinical practice. PATIENTS AND METHODS: Patients undergoing hemodialysis and peritoneal dialysis with indication of SFOH treatment were included. Follow-up duration was 12-36 months after SFOH initiation. Primary safety variables were the incidence of adverse drug reactions (ADRs), medical events of special interest (MESIs), and variations in iron-related parameters. SFOH effectiveness was evaluated by the change in serum phosphorus levels. RESULTS: A total of 286 patients were recruited and data from 282 were analyzed. Among those 282 patients, 161 (57.1%) withdrew the study prematurely and 52.5% received concomitant treatment with other phosphate binders. ADRs were observed in 35.1% of patients, the most common of which were gastrointestinal disorders (77.1%) and mild/moderate in severity (83.7%). MESIs were reported in 14.2% of patients, and 93.7% were mild/moderate. An increase in ferritin (386.66ng/mL vs 447.55ng/mL; p=0.0013) and transferrin saturation (28.07% vs 30.34%; p=0.043) was observed from baseline to the last visit (p=0.0013). Serum phosphorus levels progressively decreased from 5.69mg/dL at baseline to 4.84mg/dL at the last visit (p<0.0001), increasing by 32.2% the proportion of patients who achieved serum phosphorus levels ≤5.5mg/dL, with a mean daily SFOH dose of 1.98 pills/day. CONCLUSIONS: SFOH showed a favorable effectiveness profile, a similar safety profile to that observed in the international study with most adverse events of mild/moderate severity, and a low daily pill burden in Spanish patients in dialysis.

Contribution of phosphorus and PTH to the development of cardiac hypertrophy and fibrosis in an experimental model of chronic renal failure.

BACKGROUND AND OBJECTIVE: Adequate serum phosphorus levels in patients with chronic kidney disease is essential for their clinical management. However, the control of hyperphosphatemia is difficult because is normally associated with increases in serum PTH. In the present study, the effects of hyperphosphatemia, in the presence of elevated and normal PTH, on cardiac inflammation, hypertrophy and fibrosis in an experimental renal failure model were analyzed. MATERIALS AND METHODS: 4 groups of rats were formed. Two groups underwent total parathyroidectomy (PTx). Rats with Ca <7.5 mg/dL and PTH < 50 pg/mL underwent 7/8 nephrectomy (CRF) and a subcutaneous pellet was placed that releases PTH 1-34 (5 µg/kg/day). One group received a diet with normal P (NP) (CRF + PTx + rPTH + NP group) and another with a high P diet (0.9% - HP) (CRF + PTx + rPTH + HP group). Other 2 groups that only had CRF received NP (CRF + NP) and HP (CRF + HP) diet. A SHAM group for nephrectomy and parathyroidectomy was also added. After 14 weeks the rats were sacrificed. RESULTS: The groups with a diet high in phosphorus (CRF + H A and CRF + PTx + rPTH + HP) had a significant reduction in creatinine clearance and also in body weight with an increase in serum phosphorus regardless of parathyroidectomy, but not serum levels of calcium, FGF23 and calcitriol that were 2-3 times higher in the group with secondary hyperparathyroidism (CRF + HP). The diameter of the cardiomyocytes was greater in the CRF + HP group, while parathyroidectomy (CRF + PTx + rPTH + HP) significantly reduced them, despite the high and similar serum phosphorus values. TNF-α, Adam17 and cardiac fibrosis at the histological and molecular level showed a similar pattern with increases in the group with severe secondary hyperparathyroidism (CRF + HP). CONCLUSIONS: Hyperphosphatemia confirmed its importance in the genesis of secondary hyperparathyroidism, but also of kidney damage that was independent of PTH levels. However, inflammation, fibrosis, and cardiomyocyte growth were more closely related to PTH levels, since in the presence of similar severe hyperphosphatemia, parathyroidectomy reduced the values ​​of inflammatory parameters, cardiac hypertrophy, and fibrosis.

The receptor activator of nuclear factor κΒ ligand receptor leucine-rich repeat-containing G-protein-coupled receptor 4 contributes to parathyroid hormone-induced vascular calcification.

BACKGROUND: In chronic kidney disease, serum phosphorus (P) elevations stimulate parathyroid hormone (PTH) production, causing severe alterations in the bone-vasculature axis. PTH is the main regulator of the receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, which is essential for bone maintenance and also plays an important role in vascular smooth muscle cell (VSMC) calcification. The discovery of a new RANKL receptor, leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), which is important for osteoblast differentiation but with an unknown role in vascular calcification (VC), led us to examine the contribution of LGR4 in high P/high PTH-driven VC. METHODS: In vivo studies were conducted in subtotally nephrectomized rats fed a normal or high P diet, with and without parathyroidectomy (PTX). PTX rats were supplemented with PTH(1-34) to achieve physiological serum PTH levels. In vitro studies were performed in rat aortic VSMCs cultured in control medium, calcifying medium (CM) or CM plus 10-7 versus 10-9 M PTH. RESULTS: Rats fed a high P diet had a significantly increased aortic calcium (Ca) content. Similarly, Ca deposition was higher in VSMCs exposed to CM. Both conditions were associated with increased RANKL and LGR4 and decreased OPG aorta expression and were exacerbated by high PTH. Silencing of LGR4 or parathyroid hormone receptor 1 (PTH1R) attenuated the high PTH-driven increases in Ca deposition. Furthermore, PTH1R silencing and pharmacological inhibition of protein kinase A (PKA), but not protein kinase C, prevented the increases in RANKL and LGR4 and decreased OPG. Treatment with PKA agonist corroborated that LGR4 regulation is a PTH/PKA-driven process. CONCLUSIONS: High PTH increases LGR4 and RANKL and decreases OPG expression in the aorta, thereby favouring VC. The hormone's direct pro-calcifying actions involve PTH1R binding and PKA activation.

High-serum phosphate and parathyroid hormone distinctly regulate bone loss and vascular calcification in experimental chronic kidney disease.

BACKGROUND: In chronic kidney disease (CKD), increases in serum phosphate and parathyroid hormone (PTH) aggravate vascular calcification (VC) and bone loss. This study was designed to discriminate high phosphorus (HP) and PTH contribution to VC and bone loss. METHODS: Nephrectomized rats fed a HP diet underwent either sham operation or parathyroidectomy and PTH 1-34 supplementation to normalize serum PTH. RESULTS: In uraemic rats fed a HP diet, parathyroidectomy with serum PTH 1-34 supplementation resulted in (i) reduced aortic calcium (80%) by attenuating osteogenic differentiation (higher α-actin; reduced Runx2 and BMP2) and increasing the Wnt inhibitor Sclerostin, despite a similar degree of hyperphosphataemia, renal damage and serum Klotho; (ii) prevention of bone loss mostly by attenuating bone resorption and increases in Wnt inhibitors; and (iii) a 70% decrease in serum calcitriol levels despite significantly reduced serum Fgf23, calcium and renal 24-hydroxylase, which questions that Fgf23 is the main regulator of renal calcitriol production. Significantly, when vascular smooth muscle cells (VSMCs) were exposed exclusively to high phosphate and calcium, high PTH enhanced while low PTH attenuated calcium deposition through parathyroid hormone 1 receptor (PTH1R) signalling. CONCLUSIONS: In hyperphosphataemic CKD, a defective suppression of high PTH exacerbates HP-mediated osteogenic VSMC differentiation and reduces vascular levels of anti-calcifying sclerostin.

Bone and mineral metabolism at 55 haemodialysis centres in Lima. / Influencia de la sobrecarga de calcio sobre el metabolismo óseo y mineral en 55 centros de hemodiálisis de Lima.

BACKGROUND: Mineral and bone metabolism disorders are common complications in haemodialysis patients that present significant geographical variability. OBJECTIVES: The objective of this study was to assess these disorders for the first time in haemodialysis patients from Peru. METHODS: The study included 1551 haemodialysis patients from 55 centres affiliated with the Social Health System of Peru in the city of Lima. Demographic data, comorbidities, treatments and biochemical parameters were collected from each patient. Serum calcium, phosphorus and PTH levels were categorised according to the recommended ranges in the KDOQI and KDIGO guidelines. RESULTS: The mean age of the patients was 59.5±15.6 years, with a mean time on haemodialysis of 58.0±54.2 months. All patients were dialysed with a calcium concentration in the dialysis fluid of 3.5 mEq/l and 68.9% of patients were prescribed phosphate-binding agents (98.4% of them calcium carbonate). A high percentage of patients showed serum calcium above, and serum phosphorus below, the recommended ranges in the KDOQI guidelines (32.8% and 37.3%, respectively). More than half of the patients had serum PTH values below the recommended ranges of both the KDOQI and KDIGO guidelines (56.4% and 51.6%, respectively). CONCLUSIONS: Patients included in this study were younger than those from other studies and showed both hypophosphataemia and suppressed PTH, probably due to an excessive calcium overload through dialysis fluid and the use of calcium-containing phosphate binding agents.

Direct inhibition of osteoblastic Wnt pathway by fibroblast growth factor 23 contributes to bone loss in chronic kidney disease.

Bone loss and increased fractures are common complications in chronic kidney disease. Because Wnt pathway activation is essential for normal bone mineralization, we assessed whether Wnt inhibition contributes to high-phosphorus-induced mineralization defects in uremic rats. By week 20 after 7/8 nephrectomy, rats fed a high-phosphorus diet had the expected high serum creatinine, phosphorus, parathyroid hormone, and fibroblast growth factor 23 (FGF23) levels and low serum calcium. There was a 15% reduction in tibial mineral density and a doubling of bone cortical porosity compared to uremic rats fed a normal-phosphorus diet. The decreases in tibial mineral density were preceded by time-dependent increments in gene expression of bone formation (Osteocalcin and Runx2) and resorption (Cathepsin K) markers, which paralleled elevations in gene expression of the Wnt inhibitors Sfrp1 and Dkk1 in bone. Similar elevations of Wnt inhibitors plus an increased phospho-ß-catenin/ß-catenin ratio occurred upon exposure of the osteoblast cell line UMR106-01 either to uremic serum or to the combination of parathyroid hormone, FGF23, and soluble Klotho, at levels present in uremic serum. Strikingly, while osteoblast exposure to parathyroid hormone suppressed the expression of Wnt inhibitors, FGF23 directly inhibited the osteoblastic Wnt pathway through a soluble Klotho/MAPK-mediated process that required Dkk1 induction. Thus, the induction of Dkk1 by FGF23/soluble Klotho in osteoblasts inactivates Wnt/ß-catenin signaling. This provides a novel autocrine/paracrine mechanism for the adverse impact of high FGF23 levels on bone in chronic kidney disease.

Lamin A is involved in the development of vascular calcification induced by chronic kidney failure and phosphorus load.

Vascular calcification remains one of the main factors associated to morbidity and mortality in both ageing and chronic kidney disease. Both hyperphosphataemia, a well-known promoter of vascular calcification, and abnormal processing defects of lamin A/C have been associated to ageing. The main aim of this study was to analyse the effect of phosphorus load in the differential expression pattern of genes and proteins, particularly of lamin A/C, which are involved in phenotypic change of the vascular smooth muscle cells to osteoblast-like cells. The in vivo study of the calcified abdominal aortas from nephrectomized rats receiving a high phosphorus diet showed among others, a repression of muscle related proteins and overexpression of lamin A/C. Similar results were observed in vitro, where primary vascular smooth muscle cells cultured in calcifying medium showed increased expression of prelamin A and lamin A and abnormalities in the nuclear morphology. Co-immunoprecipitation assays showed novel and important physical interactions between lamin A and RUNX2 during the process of calcification. In fact, the knockdown of prelamin A and lamin A inhibited the increase of Runx2, osteocalcin and osteopontin gene expression, calcium deposition, nuclear abnormalities and the RUNX2 protein translocation into the nucleus of the cell. These in vivo and in vitro results highlight the important role played by lamin A in the process of vascular calcification.

MicroRNAs 29b, 133b, and 211 Regulate Vascular Smooth Muscle Calcification Mediated by High Phosphorus.

Vascular calcification is a frequent cause of morbidity and mortality in patients with CKD and the general population. The common association between vascular calcification and osteoporosis suggests a link between bone and vascular disorders. Because microRNAs (miRs) are involved in the transdifferentiation of vascular smooth muscle cells into osteoblast-like cells, we investigated whether miRs implicated in osteoblast differentiation and bone formation are involved in vascular calcification. Different levels of uremia, hyperphosphatemia, and aortic calcification were induced by feeding nephrectomized rats a normal or high-phosphorus diet for 12 or 20 weeks, at which times the levels of eight miRs (miR-29b, miR-125, miR-133b, miR-135, miR-141, miR-200a, miR-204, and miR-211) in the aorta were analyzed. Compared with controls and uremic rats fed a normal diet, uremic rats fed a high-phosphorous diet had lower levels of miR-133b and miR-211 and higher levels of miR-29b that correlated respectively with greater expression of osteogenic RUNX2 and with lower expression of several inhibitors of osteoblastic differentiation. Uremia per se mildly reduced miR-133b levels only. Similar results were obtained in two in vitro models of vascular calcification (uremic serum and high-calcium and -phosphorus medium), and experiments using antagomirs and mimics to modify miR-29b, miR-133b, and miR-211 expression levels in these models confirmed that these miRs regulate the calcification process. We conclude that miR-29b, miR-133b, and miR-211 have direct roles in the vascular smooth muscle calcification induced by high phosphorus and may be new therapeutic targets in the management of vascular calcification.

The challenge of controlling phosphorus in chronic kidney disease.

The pathogenesis and management of chronic kidney disease-mineral bone disorders (CKD-MBD) has experienced major changes, but the control of serum phosphorus at all stages of CKD still seems to be a key factor to improve clinical outcomes. High serum phosphorus is the most important uremia-related, non-traditional risk factor associated with vascular calcification in CKD patients and in the general population. Phosphorus may also be one of the key elements linking vascular calcification with low bone turnover. The main hormones and factors that contribute to the kidney regulation of phosphorus and calcium include parathyroid hormone, FGF-23, klotho and 1,25-dihydroxyvitamin D (1,25(OH)2D). Serum phosphorus did not start rising until CKD 3b in contrast with the earlier changes observed with fibroblast growth factor-23 (FGF-23), Klotho, calcitriol and parathyroid hormone (PTH). Despite FGF-23 and PTH having synergic effects regarding phosphorus removal, they have opposite effects on 1,25(OH)2D3. At the same stages of CKD in which phosphorus retention appears to occur, calcium retention also occurs. As phosphorus accumulation is associated with poor outcomes, an important question without a clear answer is at which level-range should serum phosphorus be maintained at different stages of CKD to improve clinical outcomes. There are four main strategies to manage phosphate homeostasis; phosphorus dietary intake, administration of phosphate binder agents, effective control of hyperparathyroidism and to ensure in the CKD 5D setting, an adequate scheme of dialysis. Despite all the available strategies, and the introduction of new phosphate binder agents in the market, controlling serum phosphorus remains challenging, and hyperphosphatemia continues to be extremely common in CKD 5 patients. Furthermore, despite phosphate binding agents having proved to be effective in reducing serum phosphorus, their ultimate effects on clinical outcomes remain controversial. Thus, we still need well-designed, large-scale, placebo-controlled studies to definitively prove that the reduction of serum phosphorus by phosphate binders improves clinical outcomes.

Improvement of mineral and bone metabolism markers is associated with better survival in haemodialysis patients: the COSMOS study.

BACKGROUND: Abnormalities in serum phosphorus, calcium and parathyroid hormone (PTH) have been associated with poor survival in haemodialysis patients. This COSMOS (Current management Of Secondary hyperparathyroidism: a Multicentre Observational Study) analysis assesses the association of high and low serum phosphorus, calcium and PTH with a relative risk of mortality. Furthermore, the impact of changes in these parameters on the relative risk of mortality throughout the 3-year follow-up has been investigated. METHODS: COSMOS is a 3-year, multicentre, open-cohort, prospective study carried out in 6797 adult chronic haemodialysis patients randomly selected from 20 European countries. RESULTS: Using Cox proportional hazard regression models and penalized splines analysis, it was found that both high and low serum phosphorus, calcium and PTH were associated with a higher risk of mortality. The serum values associated with the minimum relative risk of mortality were 4.4 mg/dL for serum phosphorus, 8.8 mg/dL for serum calcium and 398 pg/mL for serum PTH. The lowest mortality risk ranges obtained using as base the previous values were 3.6-5.2 mg/dL for serum phosphorus, 7.9-9.5 mg/dL for serum calcium and 168-674 pg/mL for serum PTH. Decreases in serum phosphorus and calcium and increases in serum PTH in patients with baseline values of >5.2 mg/dL (phosphorus), >9.5 mg/dL (calcium) and <168 pg/mL (PTH), respectively, were associated with improved survival. CONCLUSIONS: COSMOS provides evidence of the association of serum phosphorus, calcium and PTH and mortality, and suggests survival benefits of controlling chronic kidney disease-mineral and bone disorder biochemical parameters in CKD5D patients.

Estudio REFOS: eficacia y seguridad del carbonato de lantano en la práctica clínica en España / REFOS study: Efficacy and safety of Lanthanum Carbonate in clinical practice in Spain

El carbonato de lantano es un potente captor de fósforo que en ensayos clínicos ha mostrado eficacia y seguridad para el manejo de la hiperfosforemia, aunque existen pocos datos en la práctica clínica habitual. El objetivo del estudio fue evaluar, en la práctica clínica habitual, su eficacia y seguridad en pacientes en diálisis. Se recogieron, retrospectivamente, datos de 15 meses de seguimiento, correspondientes a los 3 meses previos al inicio del tratamiento con carbonato de lantano y 12 meses después del inicio. Los datos incluían valores séricos de calcio, fósforo, fosfatasa alcalina, PTH, enzimas hepáticas y hemograma, así como la dosis diaria prescrita de carbonato de lantano, la medicación concomitante, el cumplimiento terapéutico y los eventos adversos. Se incluyeron 674 pacientes, de los cuales completaron el estudio 522. Los abandonos se debieron en mayor medida a trastornos gastrointestinales (26 %) e hipofosfatemia (19 %). El fósforo sérico disminuyó de 6,4 ± 1,7 mg/dl (inicio) a 4,9 ± 1,4 mg/dl (12 meses) (p < 0,001). Al final del seguimiento el 47 % se encontraba dentro del rango de fósforo deseado (3,5-5 mg/dl). No hubo variaciones significativas en el resto de los parámetros. Dosis inicial de carbonato de lantano: 1900 mg/día, y dosis final: 2300 mg/día. Las variables que se asociaron de forma independiente con la fosforemia final fueron el fósforo sérico basal y el cumplimiento terapéutico. Respecto a la seguridad, se observaron 238 efectos adversos leves o moderados que ocurrieron en 117 pacientes, estando el 88 % relacionado con alteraciones gastrointestinales. En conclusión, el carbonato de lantano reduce los valores séricos de fósforo en pacientes en diálisis con un buen perfil de seguridad y aceptable adherencia a este, siendo los trastornos gastrointestinales el efecto adverso más frecuente (AU)

Lanthanum carbonate is a powerful phosphate binder that has shown efficacy and safety in clinical trials for hyperphosphataemia management, although there are few data in regular clinical practice. The study's objective was to evaluate, in regular clinical practice, its efficacy and safety in patients on dialysis. We retrospectively collected data from 15 months of monitoring, corresponding to 3 months prior to the start of treatment with lanthanum carbonate until 12 months after the start. Results included values of serum calcium, phosphorus, alkaline phosphatase, iPTH, hepatic enzymes and haemogram, as well as the daily-prescribed dose of lanthanum carbonate, the concomitant medication, treatment compliance and adverse events. 647 patients were included of which 522 completed the study. Abandonment, for the most part, was due to gastrointestinal disorders (26%) and hypophosphatemia (19%). Serum phosphorus decreased from 6.4 ± 1.7mg/dl (start) to 4.9 ± 1.4mg/dl (12 months) (P<.001). At the end of the monitoring period, 47% were within the desired phosphorus range (3.5-5mg/dl). There were no significant variations in the remaining parameters. Initial dose of lanthanum carbonate: 1900mg/day; and end dose: 2300mg/day. The variables independently associated with phosphataemia were baseline serum phosphorus and treatment compliance. In relation to safety, we observed 238 slight or moderate adverse effects in 117 patients, with 88% linked to gastrointestinal abnormalities. In conclusion, lanthanum carbonate reduces the serum phosphorus values in patients on dialysis with a good safety profile and acceptable adherence to that profile, with gastrointestinal disorders being the most frequent adverse effect (AU)

Los nefrólogos españoles y el manejo de las alteraciones del metabolismo óseo-mineral en la enfermedad renal crónica / Spanish nephrologists and the management of mineral and bone metabolism disorders in chronic kidney disease

El presente estudio fue diseñado para evaluar la percepción actual de los nefrólogos españoles en el manejo clínico de las alteraciones del metabolismo óseo y mineral en la enfermedad renal crónica (CKD-MBD). Para ello se empleó un procedimiento semiestructurado de consenso profesional a distancia, por correo electrónico (método Delphi modificado), a un panel representativo del colectivo nefrológico, bajo la dirección de un comité coordinador. Para analizar la opinión grupal y el tipo de consenso alcanzado sobre cada cuestión planteada, se empleó la posición de la mediana de puntuaciones del grupo y el «nivel de concordancia» alcanzado por los encuestados. Sobre un total de 86 cuestiones se logró un consenso en acuerdo y desacuerdo en 70 (81,4 %), de los cuales un 60,5 % (52 ítems) lo fueron en términos de acuerdo con la aseveración y un 20,9 % (18 ítems) en desacuerdo. En 16 ítems (18,6 %) no se consiguió suficiente unanimidad de criterio en el panel, bien por disparidad de opinión profesional, bien por falta de criterio establecido en una mayoría del comité de expertos. Aceptando las limitaciones del estudio, consideramos que los ítems en los que hubo consenso refuerzan algunos conceptos de CKD-MBD con su repercusión en la práctica clínica diaria y permiten valorar el grado de homogeneidad que podríamos esperar en esta área. Los ítems en los que no hubo consenso nos ayudan a conocer las áreas de incertidumbre y resultan de gran utilidad para precisar en qué aspectos existe una mayor necesidad de profundización y de emprender estudios prospectivos que permitan mejorar el manejo de estas alteraciones (AU)

This study was designed to assess the current perception of Spanish nephrologists in the clinical management of mineral and bone metabolism disorders in chronic kidney disease (CKD-MBD). As such, we used a semi-structured distance professional consensus procedure via e-mail (modified Delphi method) on a representative nephrologist panel, under the direction of a coordinating committee. To analyse the group's opinion and the type of consensus reached on each issue raised, we used the median of the group's scores and the "level of agreement" reached by those surveyed. On a total of 86 issues, a consensus agreement and disagreement was achieved in 70 (81.4%), of which 60.5% (52 items) agreed with the statement and 20.9% (18 items) disagreed. In 16 items (18.6%), there was insufficient unanimity in the panel's opinion, either due to professional opinion disparity or due to the lack of opinion established in the majority of the expert committee. Accepting the study's limitations, we considered that the items for which there was a consensus reinforce some CKD-MBD concepts with their impact on daily clinical practice and allow the degree of homogeneity that we could expect in this area to be assessed. The items in which there was no consensus help us to know the areas of uncertainty and are very useful for clarifying which aspects have a greater need for further knowledge and which areas require prospective studies to be conducted to improve the management of these disorders (AU)

Natural antioxidants and vascular calcification: a possible benefit.

BACKGROUND: Several studies have demonstrated the impact of vascular calcification on morbidity and mortality both in the general and chronic kidney disease populations. The process of vascular calcification involves complex mechanisms including the overexpression of genes and proteins associated with mineralization and increments of reactive oxygen species (ROS). Taking into account previous findings, we decided to analyze in vitro the likely inhibitory effect of natural antioxidants in the process of vascular calcification. METHODS: Primary vascular smooth muscle cells (VSMCs) were cultured with either normal medium or normal medium supplemented with calcium and phosphorus (P + Ca) in combination with several antioxidants. Mineralization, intracellular reactive oxygen species levels and the protein expression of Cbfa1/RUNX2 and Mn-superoxide dismutase-2 (SOD-2) were investigated. RESULTS: Curcumin and silybin were the more effective, inhibiting both ROS increase and VSMC mineralization. Curcumin was able to prevent the increase in Cbfa1/RUNX2 expression, but did not modify SOD-2 expression in the VSMCs cultured with the P + Ca medium. CONCLUSIONS: These findings support the importance of performing further studies in this field, as some antioxidants might have potential benefits in the management of vascular calcification.

Recomendaciones de la Sociedad Española de Nefrología para el manejo de las alteraciones del metabolismo óseo-mineral en los pacientes con enfermedad renal crónica (SEN.-MM) / No disponible

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