RANKL, but Not R-Spondins, Is Involved in Vascular Smooth Muscle Cell Calcification through LGR4 Interaction.

Vascular calcification has a global health impact that is closely linked to bone loss. The Receptor Activator of Nuclear Factor Kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, fundamental for bone metabolism, also plays an important role in vascular calcification. The Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), a novel receptor for RANKL, regulates bone remodeling, and it appears to be involved in vascular calcification. Besides RANKL, LGR4 interacts with R-spondins (RSPOs), which are known for their roles in bone but are less understood in vascular calcification. Studies were conducted in rats with chronic renal failure fed normal or high phosphorus diets for 18 weeks, with and without control of circulating parathormone (PTH) levels, resulting in different degrees of aortic calcification. Additionally, vascular smooth muscle cells (VSMCs) were cultured under non-calcifying (1 mM phosphate) and calcifying (3 mM phosphate) media with different concentrations of PTH. To explore the role of RANKL in VSMC calcification, increasing concentrations of soluble RANKL were added to non-calcifying and calcifying media. The effects mediated by RANKL binding to its receptor LGR4 were investigated by silencing the LGR4 receptor in VSMCs. Furthermore, the gene expression of the RANK/RANKL/OPG system and the ligands of LGR4 was assessed in human epigastric arteries obtained from kidney transplant recipients with calcification scores (Kauppila Index). Increased aortic calcium in rats coincided with elevated systolic blood pressure, upregulated Lgr4 and Rankl gene expression, downregulated Opg gene expression, and higher serum RANKL/OPG ratio without changes in Rspos gene expression. Elevated phosphate in vitro increased calcium content and expression of Rankl and Lgr4 while reducing Opg. Elevated PTH in the presence of high phosphate exacerbated the increase in calcium content. No changes in Rspos were observed under the conditions employed. The addition of soluble RANKL to VSMCs induced genotypic differentiation and calcification, partly prevented by LGR4 silencing. In the epigastric arteries of individuals presenting vascular calcification, the gene expression of RANKL was higher. While RSPOs show minimal impact on VSMC calcification, RANKL, interacting with LGR4, drives osteogenic differentiation in VSMCs, unveiling a novel mechanism beyond RANKL-RANK binding.

Soluble Klotho, a Potential Biomarker of Chronic Kidney Disease-Mineral Bone Disorders Involved in Healthy Ageing: Lights and Shadows.

Shortly after the discovery of Klotho, interest grew in its potential role in chronic kidney disease (CKD). There are three isoforms of the Klotho protein: αKlotho, ßKlotho and γKlotho. This review will focus on αKlotho due to its relevance as a biomarker in CKD. αKlotho is synthesized mainly in the kidneys, but it can be released into the bloodstream and urine as soluble Klotho (sKlotho), which undertakes systemic actions, independently or in combination with FGF23. It is usually accepted that sKlotho levels are reduced early in CKD and that lower levels of sKlotho might be associated with the main chronic kidney disease-mineral bone disorders (CKD-MBDs): cardiovascular and bone disease. However, as results are inconsistent, the applicability of sKlotho as a CKD-MBD biomarker is still a matter of controversy. Much of the inconsistency can be explained due to low sample numbers, the low quality of clinical studies, the lack of standardized assays to assess sKlotho and a lack of consensus on sample processing, especially in urine. In recent decades, because of our longer life expectancies, the prevalence of accelerated-ageing diseases, such as CKD, has increased. Exercise, social interaction and caloric restriction are considered key factors for healthy ageing. While exercise and social interaction seem to be related to higher serum sKlotho levels, it is not clear whether serum sKlotho might be influenced by caloric restriction. This review focuses on the possible role of sKlotho as a biomarker in CKD-MBD, highlighting the difference between solid knowledge and areas requiring further research, including the role of sKlotho in healthy ageing.

Serum phosphate is associated with increased risk of bone fragility fractures in hemodialysis patients.

BACKGROUND: Bone fragility fractures are associated with high morbidity and mortality. This study analysed the association between the current biochemical parameters of CKD-MBD and bone fragility fractures in the COSMOS project. METHODS: COSMOS is a 3-year, multicentre, open cohort, prospective, observational study carried out in 6797 hemodialysis patients (227 centres from 20 European countries). The association of bone fragility fractures (outcome) with serum calcium, phosphate and PTH (exposure), was assessed using Standard Cox proportional hazards regression and Cox proportional hazards regression for recurrent events. Additional analyses were performed considering all-cause mortality as a competitive event for bone fragility fracture occurrence. Multivariable models were used in all strategies, with the fully adjusted model including a total of 24 variables. RESULTS: During a median follow-up of 24 months 252 (4%) patients experienced at least one bone fragility fracture (incident bone fragility fracture rate 28.5 per 1000 patient-years). In the fractured and non-fractured patients, the percentage of men was 43.7% and 61.4%, mean age 68.1 and 63.8 years and a haemodialysis vintage of 55.9 and 38.3 months respectively. Baseline serum phosphate > 6.1 mg/dL (reference value 4.3-6.1 mg/dL) was significantly associated with a higher bone fragility fracture risk in both regression models (HR: 1.53[95%CI: 1.10-2.13] and HR: 1.44[95%CI: 1.02-2.05]. The significant association persisted after competitive risk analysis (subHR: 1.42[95%CI: 1.02-1.98]) but the finding was not confirmed when serum phosphate was considered as a continuous variable. Baseline serum calcium showed no association with bone fragility fracture risk in any regression model. Baseline serum PTH > 800 pg/mL was significantly associated with a higher bone fragility fracture risk in both regression models, but the association disappeared after a competitive risk analysis. CONCLUSIONS: Hyperphosphatemia was independently and consistently associated with an increased bone fracture risk, suggesting serum phosphate could be a novel risk factor for bone fractures in hemodialysis patients.

Apricot Seed Shells and Walnut Shells as Unconventional Sugars and Lignin Sources.

The present study focuses on using apricot seeds shells and walnut shells as a potential renewable material for biorefinery in Ukraine. The goal of the research work was to determine the relationship between the chemical composition of solid residues from biomass after acid pretreatment with H2SO4, alkaline pretreatment with NaOH, and a steam explosion pretreatment and the recovery of sugars and lignin after further enzymatic hydrolysis with the application of an industrial cellulase Cellic CTec2. Apricot seeds shells and walnut shells consist of lots of cellulose (35.01 and 24.19%, respectively), lignin (44.55% and 44.63%, respectively), hemicelluloses (10.77% and 26.68%, respectively), and extractives (9.97% and 11.41%, respectively), which affect the efficiency of the bioconversion of polysaccharides to sugars. The alkaline pretreatment was found to be more efficient in terms of glucose yield in comparison with that of acid and steam explosion, and the maximum enzymatic conversions of cellulose reached were 99.7% and 94.6% for the solids from the apricot seeds shells and the walnut shells, respectively. The maximum amount of lignin (82%) in the residual solid was obtained during the processing of apricot seed shells submitted to the acid pretreatment. The amount of lignin in the solids interferes with the efficiency of enzymatic hydrolysis. The results pave the way for the efficient and perspective utilization of shells through the use of inexpensive, simple and affordable chemical technologies, obtaining value-added products, and thus, reducing the amount of environmental pollution (compared to the usual disposal practice of direct burning) and energy and material external dependency (by taking advantage of these renewable, low-cost materials).

The Non-invasive Diagnosis of Bone Disorders in CKD.

Abnormal bone metabolism is an integral part of the chronic kidney disease-mineral bone disorder (CKD-MBD). For several reasons, the difficult bone compartment was neglected for some time, but there has been renewed interest as a result of the conception of bone as a new endocrine organ, the increasing recognition of the cross-talk between bone and vessels, and, especially, the very high risk of osteoporotic fractures (and associated mortality) demonstrated in patients with CKD. Therefore, it has been acknowledged in different guidelines that action is needed in respect of fracture risk assessment and the diagnosis and treatment of osteoporosis in the context of CKD and CKD-MBD, even beyond renal osteodystrophy. These updated guidelines clearly underline the need to improve a non-invasive approach to these bone disorders in order to guide treatment decisions aimed at not only controlling CKD-MBD but also decreasing the risk of fracture. In this report, we review the current role of the most often clinically used or promising biochemical circulating biomarkers such as parathyroid hormone, alkaline phosphatases, and other biochemical markers of bone activity as alternatives to some aspects of bone histomorphometry. We also mention the potential role of classic and new imaging techniques for CKD patients. Information on many aspects is still scarce and heterogeneous, but many of us consider that it is indeed time for action, recognizing our definitely limited ability to base certain treatment decisions only on our current non-comprehensive knowledge.

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.

Evaluation of ToxA and Vibrio parahaemolyticus lysate on humoral immune response and immune-related genes in Pacific red snapper.

Immunogenicity of ToxA and Vibrio parahaemolyticus lysate was evaluated in a double immunostimulation scheme in Pacific red snapper after V. parahaemolyticus infection. Three groups of Pacific red snapper were intraperitonealy (i.p.) injected with phosphate-buffered saline (PBS group), ToxA of V. parahaemolyticus (ToxA-Vp group) or V. parahaemolyticus lysate (lysate-Vp group) (first injection, day 1; second injection, day 7). Fish were subsequently infected with live V. parahaemolyticus. Humoral immune parameters in skin mucus and serum were evaluated on days 1, 7, 8 and 14 days post-immunostimulation and 7 days post-infection. Moreover expression of immune-related genes was quantified by real time PCR in head-kidney leukocytes, spleen, liver, and intestine. The ToxA-Vp-treated group showed a higher anti-protease and catalase activity in skin mucus when compared with the PBS group. Measurements of SOD and CAT activities showed an increment in both activities a day after the second boost with ToxA-Vp or lysate-Vp. Interestingly, IgM levels in mucus and transcripts were enhanced followed the ToxA-Vp treatment even after challenge. Furthermore, IL-1ß was strongly expressed in all analyzed cell or tissues followed ToxA-Vp or Vp-lysate treatments. Finally, SOD and CAT gene expression was up-regulated in fish immunostimulated with either treatment ToxA-Vp or lysate-Vp, mainly after infection in head-kidney leukocytes and intestine. This is the first study where the effects of ToxA from V. parahaemolyticus in the immune system of Pacific red snapper was evaluated. These results suggest that ToxA-Vp would positively affect humoral immune response and up-regulate expression of genes involved in the immune system function; and could help in the control of V. parahaemolyticus infection in Pacific red snapper Lutjanus peru, an economic important fish in Mexico.

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.

Cinacalcet for hypercalcaemic secondary hyperparathyroidism after renal transplantation: a multicentre, retrospective, 3-year study.

AIMS: Our aim was to evaluate the long-term effect of cinacalcet in patients with hypercalcaemic secondary hyperparathyroidism (SHPT) after renal transplantation (RT) in order to expand real-world data in this population. METHODS: We performed a multicentre, observational, retrospective study in 17 renal transplant units from Spain. We collected data from renal recipients with hypercalcaemic (calcium >10.2 mg/dL) SHPT (intact parathyroid hormone (iPTH) > 120 pg/mL) who initiated cinacalcet in the clinical practice. RESULTS: We included 193 patients with a mean (standard deviation (SD)) age of 52 (12) years, 58% men. Cinacalcet treatment was initiated at a median of 20 months after RT (median dose 30 mg/day). Mean calcium levels decreased from a mean (SD) of 11.1 (0.6) at baseline to 10.1 (0.8) at 6 months (9.0% reduction, P < 0.0001). Median iPTH was reduced by 23.0% at 6 months (P = 0.0005) and mean phosphorus levels increased by 11.1% (P < 0.0001). The effects were maintained up to 3-years. No changes were observed in renal function or anticalcineurin drug levels. Only 4.1% of patients discontinued cinacalcet due to intolerance and 1.0% due to lack of efficacy. CONCLUSIONS: In renal transplant patients with hypercalcaemic SHPT, cinacalcet controlled serum calcium, iPTH and phosphorus levels up to 3 years. Tolerability was good.

Cyrtocarpa edulis fruit and its immunostimulant effect on Almaco Jack Seriola rivoliana: in vitro, in vivo and ex vivo studies.

The present study investigates for the first time chemical, proximate analyses and immunostimulant effect of Cyrtocarpa edulis fruit (CeF). Three design experiments were carried out to evaluate immunostimulant effect of C. edulis fruit: in vitro, in vivo and ex vivo studies in juveniles Almaco jack Seriola rivoliana. In general, nutraceutical studies performed by gas chromatography/mass spectrometry (GC-MS) in CeF revealed a major quantity of the carbohydrate groups and phytosterols such as ß-sitosterol. Their phytochemical and antioxidant values exposed a significant content of total phenols, flavonoids, and tannins, showing an antioxidant capacity against hydroxyl and superoxide radical. The in vitro results confirm that CeF is edible and enhanced the innate immune response in head-kidney leukocytes after 24 h of immunostimulation. The in vivo results showed that myeloperoxidase, nitric oxide production, as well as antioxidant enzymes were enhanced in skin mucus of those fish fed with CeF. Interestingly in the intestine, IL-ß, TNF-α, MARCO and Piscidin gene expression were up-regulated in fish fed with C. edulis after 4 weeks. Finally, ex vivo experiments showed an important enhancement on cellular parameters (phagocytosis, respiratory burst, myeloperoxidase, and nitric oxide production) in head-kidney leukocytes of fish fed CeF and intraperitoneally infected with A. hydrophila. The results demonstrate that C. edulis fruit (0.5%) represents an available phytochemical and antioxidant rich alternative with great potential as fish immunostimulant additive.

Osteoporosis management in patients with chronic kidney disease (ERCOS Study): A challenge in nephrological care.

Fracture risk assessment in patients with chronic kidney disease (CKD) has been included in the CKD-MBD ("Chronic Kidney Disease-Mineral and Bone Disorders") complex in international and national nephrology guidelines, suggesting for the first time the assessment of bone mineral density (BMD) if the results can influence therapeutic decision-making. However, there is very little information on actual clinical practice in this population. The main objective of the ERCOS (ERC-Osteoporosis) study is to describe the profile of patients with CKD G3-5D with osteoporosis (OP) and/or fragility fractures treated in specialized nephrology, rheumatology and internal medicine clinics in Spain. Fifteen centers participated and 162 patients (mostly women [71.2%] postmenopausal [98.3%]) with a median age of 77 years were included. Mean estimated glomerular filtration rate (eGFR) was 36 mL/min/1.73 m2 and 38% of the included patients were on dialysis. We highlight the high frequency of prevalent fragility fractures [37.7%), mainly vertebral (52.5%) and hip (24.6%)], the disproportionate history of patients with glomerular disease compared to purely nephrological series (corticosteroids) and undertreatment for fracture prevention, especially in nephrology consultations. This study is an immediate call to action with the dissemination of the new, more proactive, clinical guidelines, and underlines the need to standardize a coordinated and multidisciplinary care/therapeutic approach to these patients in an efficient way to avoid current discrepancies and therapeutic nihilism.

COSMOS: the dialysis scenario of CKD-MBD in Europe.

BACKGROUND: Chronic kidney disease-mineral and bone disorders (CKD-MBD) are important complications of CKD5D patients that are associated with mortality. METHODS: COSMOS is a multicentre, open cohort, prospective, observational 3-year study carried out in haemodialysis patients from 20 European countries during 2005-07. The present article describes the main characteristics of the European dialysis population, the current practice for the prevention, diagnosis and treatment of secondary hyperparathyroidism and the differences across different European regions. RESULTS: The haemodialysis population in Europe is an aged population (mean age 64.8±14.2 years) with a high prevalence of diabetes (29.5%) and cardiovascular disease (76.0%), and 28.7% of patients have been on haemodialysis more than 5 years. Patients from the former Eastern countries are younger (59.3±14.3 versus 66.0±13.9), having a lower proportion of diabetics (24.1 versus 30.7%). There were relevant differences in the frequency of measurement of the main CKD-MBD biochemical parameters [Ca, P and parathyroid hormone (PTH)] and the Eastern countries showed a poorer control of these biochemical parameters (K/DOQI and K/DIGO targets). Overall, 48.0% of the haemodialysis patients received active vitamin D treatment. Calcitriol use doubled that of alfacalcidiol in the Mediterranean countries, whereas the opposite was found in the non-Mediterranean countries. The criteria followed to perform parathyroidectomy were different across Europe. In the Mediterranean countries, the level of serum PTH considered to perform parathyroidectomy was higher than in non-Mediterranean countries; as a result, in the latter, more parathyroidectomies were performed in the year previous to inclusion to COSMOS. CONCLUSIONS: The COSMOS baseline results show important differences across Europe in the management of CKD-MBD.

Pathophysiology of bone disease in chronic kidney disease: from basics to renal osteodystrophy and osteoporosis.

Chronic kidney disease (CKD) is a highly prevalent disease that has become a public health problem. Progression of CKD is associated with serious complications, including the systemic CKD-mineral and bone disorder (CKD-MBD). Laboratory, bone and vascular abnormalities define this condition, and all have been independently related to cardiovascular disease and high mortality rates. The "old" cross-talk between kidney and bone (classically known as "renal osteodystrophies") has been recently expanded to the cardiovascular system, emphasizing the importance of the bone component of CKD-MBD. Moreover, a recently recognized higher susceptibility of patients with CKD to falls and bone fractures led to important paradigm changes in the new CKD-MBD guidelines. Evaluation of bone mineral density and the diagnosis of "osteoporosis" emerges in nephrology as a new possibility "if results will impact clinical decisions". Obviously, it is still reasonable to perform a bone biopsy if knowledge of the type of renal osteodystrophy will be clinically useful (low versus high turnover-bone disease). However, it is now considered that the inability to perform a bone biopsy may not justify withholding antiresorptive therapies to patients with high risk of fracture. This view adds to the effects of parathyroid hormone in CKD patients and the classical treatment of secondary hyperparathyroidism. The availability of new antiosteoporotic treatments bring the opportunity to come back to the basics, and the knowledge of new pathophysiological pathways [OPG/RANKL (LGR4); Wnt-ß-catenin pathway], also affected in CKD, offers great opportunities to further unravel the complex physiopathology of CKD-MBD and to improve outcomes.

Vascular calcification in patients with chronic kidney disease: types, clinical impact and pathogenesis.

Vascular calcification plays a major role in cardiovascular disease, which is one of the main causes of mortality in chronic kidney disease patients. Vascular calcification is determined by prevalent traditional and uraemia-related (non-traditional) risk factors. It occurs mainly in the arteries, which are classified into three types according to their size and structural characteristics. In addition, vascular calcification has been associated with bone loss and fractures in chronic kidney disease patients and the general population, stressing the fact that both disorders can share pathogenetic pathways. The strategies to control vascular calcification involve several measures, chief among them the control of hyperphosphataemia. Furthermore, it has been recently described that strategies that reduce bone resorption and increase bone mineralization may decrease the risk of vascular calcifications; however, this approach still remains controversial. The mechanisms involved in vascular calcification are complex and not yet fully understood. Phosphorus plays a major role, while other factors related to bone formation have been recently identified.

Novel Immune Cell Subsets Exhibit Different Associations With Vascular Outcomes in Chronic Kidney Disease Patients-Identifying Potential Biomarkers.

Background and Aims: Alterations in novel immune cell subsets, such as angiogenic T cells (Tang), senescent T cells (CD4+CD28null), and monocyte subsets are associated with impaired vascular homeostasis in several inflammatory conditions. However, mediators underlying vascular deterioration in chronic kidney disease (CKD) are poorly characterized. This study assessed their role in the vascular deterioration of CKD using a broad spectrum of surrogate markers ranging from altered functionality to overt calcification. Methods: Tang (CD3+CD31+CXCR4+), CD4+CD28null cells, and monocytes [CD14/CD16 subsets and angiotensin-converting enzyme (ACE) expression] were measured in peripheral blood by flow cytometry in 33 CKD stage 5 patients undergoing peritoneal dialysis (CKD5-PD) and 15 healthy controls (HCs). Analyses were replicated in a hemodialysis cohort. Vascular surrogate markers (including adventitial vasa vasorum, pulse wave velocity, intima-media thickness, and vascular calcification) were assessed by appropriate imaging methods. Results: In CKD5-PD, decreased Tang levels (p < 0.001) were unrelated to clinical features or traditional cardiovascular (CV) risk factors but correlated negatively with troponin T levels (r = -0.550, p = 0.003). Instead, CD4+CD28null frequency was increased (p < 0.001), especially in those with vascular calcifications. Quantitative and qualitative differences were also observed within the monocyte pool, a shift toward CD16+ subsets and ACE expression being found in CKD. Equivalent results were observed in the replication cohort. Each subset associated distinctly with adverse vascular outcomes in univariate and multivariate analyses: while Tang depletion was linked to poor vascular function and subclinical atherosclerosis, increases in CD4+CD28null were associated with overt vascular thickening and calcification. Monocytes were not independently associated with vascular outcomes in CKD patients. Conclusions: Novel T cell and monocyte subsets are altered in CKD. Altered T-cell subpopulations, but not monocytes, exhibited distinct associations with different vascular outcomes in CKD. Tang are emerging biomarkers of subclinical vascular deterioration in CKD.

Survival with low- and high-flux dialysis.

BACKGROUND: Besides advances in haemodialysis (HD), mortality rates are still high. The effect of the different types of HD membranes on survival is still a controversial issue. The aim of this COSMOS (Current management Of Secondary hyperparathyroidism: a Multicentre Observational Study) analysis was to survey, in HD patients, the relationship between the use of conventional low- or high-flux membranes and all-cause and cardiovascular mortality. METHODS: COSMOS is a multicentre, open-cohort, 3-year prospective study, designed to evaluate mineral and bone disorders in the European HD population. The present analysis included 5138 HD patients from 20 European countries, 3502 randomly selected at baseline (68.2%), plus 1636 new patients with <1 year on HD (31.8%) recruited to replace patients who died, were transplanted, switched to peritoneal dialysis or lost to follow-up by other reasons. Cox-regression analysis with time-dependent variables, propensity score matching and the use of an instrumental variable (facility-level analysis) were used. RESULTS: After adjustments using three different multivariate models, patients treated with high-flux membranes showed a lower all-cause and cardiovascular mortality risks {hazard ratio (HR) = 0.76 [95% confidence interval (CI) 0.61-0.96] and HR = 0.61 (95% CI 0.42-0.87), respectively}, that remained significant after matching by propensity score for all-cause mortality (HR = 0.69, 95% CI 0.52-0.93). However, a facility-level analysis showed no association between the case-mix-adjusted facility percentage of patients dialysed with high-flux membranes and all-cause and cardiovascular mortality. CONCLUSIONS: High-flux dialysis was associated with a lower relative risk of all-cause and cardiovascular mortality. However, dialysis facilities using these dialysis membranes to a greater extent did not show better survival.

Lymphocytic choriomeningitis virus meningitis, New York, NY, USA, 2009.

We describe a case of lymphocytic choriomeningitis virus (LCMV) meningitis in a New York, NY, resident who had no apparent risk factors. Clues leading to the diagnosis included aseptic meningitis during winter and the finding of hypoglycorrachia and lymphocytosis in the cerebrospinal fluid. LCMV continues to be an underdiagnosed zoonotic disease.

New therapies: calcimimetics, phosphate binders and vitamin D receptor activators.

At present, new compounds are available to treat secondary hyperparathyroidism, namely calcimimetics, novel phosphorus binders and also novel vitamin D receptor activators. Calcimimetics increase the sensitivity of the parathyroid gland to calcium through spatial configurational changes of the calcium-sensing receptor. In addition, experimental studies have demonstrated that calcimimetics also upregulate both the calcium-sensing receptor and the vitamin D receptor. They are efficacious in children, though the experience in paediatric chronic kidney disease is still limited. Sevelamer, lanthanum carbonate and magnesium iron hydroxycarbonate are novel phosphorus binders available on the market. Several studies have demonstrated their efficacy and safety up to 6 years, though costs are the main limitation for a wider use. Since almost all the experience available on the new phosphorus binders comes from its use in adults, studies on children are needed in order to confirm the efficacy and safety of these products. Other new salts and polymers are also being developed. New vitamin D receptor activators, such as paricalcitol, are as effective at suppressing parathyroid hormone (PTH) as the traditional vitamin D receptor activators used for the past two decades, but they have a better and safer profile, showing fewer calcaemic and phosphoraemic effects while preserving the desirable effects of the vitamin D receptor activators on the cardiovascular system, hypertension, inflammation and fibrosis. Their use in children with chronic kidney disease has revealed similar responses to those of adults. The novel compounds discussed in this review should facilitate and improve the management of mineral and bone disorders in children with chronic kidney disease.

Vascular calcifications, vertebral fractures and mortality in haemodialysis patients.

BACKGROUND: Vascular calcifications and the bone fractures caused by abnormal bone fragility, also called osteoporotic fractures, are frequent complications associated with chronic kidney diseases (CKD). The aim of this study was to investigate the association between vascular calcifications, osteoporotic bone fractures and survival in haemodialysis (HD) patients. METHODS: A total of 193 HD patients were followed up to 2 years. Vascular calcifications and osteoporotic vertebral fractures (quoted just as vertebral fractures in the text) were assessed by thoracic, lumbar spine, pelvic and hand X-rays and graded according to their severity. Clinical, biochemical and therapeutic data gathered during the total time spent on HD were collected. RESULTS: The prevalence of aortic calcifications was higher in HD patients than in a random-based general population (79% versus 37.5%, P < 0.001). Total time on any renal replacement therapy (RRT) and diabetes were positively associated with a higher prevalence of vascular calcifications. In addition to these factors, time on HD was also positively associated with the severity of vascular calcifications, and higher haemoglobin levels were associated with a lower prevalence of severe vascular calcifications in large and medium calibre arteries. The prevalence of vertebral fractures in HD patients was similar to that of the general population (26.5% versus 24.1%). Age and time on HD showed a positive and statistically significant association with the prevalence of vertebral fractures. Vascular calcifications in the medium calibre arteries were associated with a higher rate of prevalent vertebral fractures. In women, severe vascular calcifications and vertebral fractures were positively associated with mortality [RR = 3.2 (1.0-10.0) and RR = 4.8 (1.7-13.4), respectively]. CONCLUSIONS: Positive associations between vascular calcifications, vertebral fractures and mortality have been found in patients on HD.

Manejo de la osteoporosis en el paciente con enfermedad renal crónica (Estudio ERCOS): un desafío en la asistencia nefrológica / Osteoporosis management in patients with chronic kidney disease (ERCOS Study): A challenge in nephrological care

La valoración del riesgo de fractura del paciente con enfermedad renal crónica (ERC) ha sido incluida en el complejo Chronic Kidney Disease-Mineral and Bone Disorders (CKD-MBD) en guías nefrológicas internacionales y nacionales, sugiriéndose por primera vez la evaluación de la densidad mineral ósea (DMO) si los resultados pueden condicionar la toma de decisiones terapéuticas. Sin embargo, existe muy poca información en práctica clínica real en esta población. El objetivo principal del estudio ERC-Osteoporosis (ERCOS) es describir el perfil de los pacientes con ERC G3-5D con osteoporosis (OP) y/o fracturas por fragilidad atendidos en consultas especializadas de nefrología, reumatología y medicina interna en España. Participaron 15 centros y se incluyeron 162 pacientes (siendo en su mayoría mujeres [71,2%] posmenopáusicas [98,3%]) con una mediana de edad de 77 años. La mediana del filtrado glomerular estimado (FGe) fue de 36ml/min/1,73m2 y el 38% de pacientes incluidos estaban en diálisis. Destacamos la elevada frecuencia de fracturas por fragilidad prevalentes ([37,7%), principalmente vertebrales [52,5%] y de cadera 24,6%]), el antecedente desproporcionado de pacientes con enfermedad glomerular en comparación con series puramente nefrológicas (corticoides) y el infratratamiento para la prevención de fracturas, fundamentalmente en consultas nefrológicas. Este estudio supone una inmediata llamada a la acción con la difusión de las nuevas guías clínicas, más proactivas, y subraya la necesidad de homogeneizar el enfoque asistencial/terapéutico multidisciplinar coordinado de estos pacientes de un modo eficiente para evitar las actuales discrepancias y el nihilismo terapéutico. (AU)

Fracture risk assessment in patients with chronic kidney disease (CKD) has been included in the Chronic Kidney Disease-Mineral and Bone Disorders (CKD-MBD) complex in international and national nephrology guidelines, suggesting for the first time the assessment of bone mineral density (BMD) if the results will impact treatment decisions. However, there is very little information on actual clinical practice in this population. The main objective of the ERC-Osteoporosis (ERCOS) study is to describe the profile of patients with CKD G3-5D with osteoporosis (OP) and/or fragility fractures treated in specialized nephrology, rheumatology and internal medicine clinics in Spain. Fifteen centers participated and 162 patients (mostly women [71.2%] postmenopausal [98.3%]) with a median age of 77 years were included. Mean estimated glomerular filtration rate (eGFR) was 36ml/min/1.73m2 and 38% of the included patients were on dialysis. We highlight the high frequency of prevalent fragility fractures ([37.7%], mainly vertebral [52.5%] and hip [24.6%]), the disproportionate history of patients with glomerular disease compared to purely nephrological series (corticosteroids) and undertreatment for fracture prevention, especially in nephrology consultations. This study is an immediate call to action with the dissemination of the new, more proactive, clinical guidelines, and underlines the need to standardize a coordinated and efficient multidisciplinary care/therapeutic approach to these patients to avoid current discrepancies and therapeutic nihilism. (AU)