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Hyperkalaemia (HK) is one of the most common electrolyte disorders and a frequent reason for nephrological consultations. High serum potassium (K+) levels are associated with elevated morbidity and mortality, mainly due to life-threatening arrhythmias. In the majority of cases, HK is associated with chronic kidney disease (CKD), or with the use of renin-angiotensin-aldosterone system inhibitors (RAASis) and/or mineral corticoid antagonists (MRAs). These drugs represent the mainstays of treatment in CKD, HF, diabetes, hypertension, and even glomerular diseases, in consideration of their beneficial effect on hard outcomes related to cardiovascular events and CKD progression. However, experiences in relation to the Randomised Aldactone Evaluation Study (RALES) cast a long shadow that extends to the present day, since the increased risk for HK remains a major concern. In this article, we summarise the physiology of K+ homeostasis, and we review the effects of dietary K+ on blood pressure and cardiovascular risk in the general population and in patients with early CKD, who are often not aware of this disease. We conclude with a note of caution regarding the recent publication of the SSaSS trial and the use of salt substitutes, particularly in patients with a limited capacity to increase K+ secretion in response to an exogenous load, particularly in the context of "occult" CKD, HF, and in patients taking RAASis and/or MRAs.

Point-of-Care Ultrasonography (PoCUS) aims to include a fifth pillar (insonation) in the classical physical examination in order to obtain images to answer specific questions by the clinician at the patient's bedside, allowing rapid identification of structural or functional abnormalities, enabling more accurate volume assessment and supporting diagnosis, as well as guiding procedures. In recent years, PoCUS has started becoming a valuable tool in day-to-day clinical practice, adopted by healthcare professionals from various medical specialties, never replacing physical examination but improving patient and medical care and experience. Renal patients represent a wide range of diseases, which lends PoCUS a special role as a valuable tool in different scenarios, not only for volume-related information but also for the assessment of a wide range of acute and chronic conditions, enhancing the sensitivity of conventional physical examination in nephrology. PoCUS in the hands of a nephrologist is a precision medicine tool.

The situation of secondary hyperparathyroidism (SHPT) in chronic kidney disease patients not on dialysis (ND-CKD) is probably best characterised by the Kidney Disease: Improving Global Outcomes Chronic Kidney Disease-Mineral and Bone Disorder Update 2017 guideline 4.2.1 stating that the optimal parathyroid hormone levels are not known in these stages. Furthermore, new caution became recommended with regard to the routine use of active vitamin D analogues in early CKD stages and moderate SHPT phenotypes, due to their potential risks for hypercalcaemia and hyperphosphataemia aggravation. Nevertheless, there is still a substantial clinical need to prevent the development of parathyroid gland autonomy, with its associated consequences of bone and vascular damage, including fracture risks and cardiovascular events. Therefore we now attempt to review the current guideline-based and clinical practice management of SHPT in ND-CKD, including their strengths and weaknesses, favouring individualised approaches respecting calcium and phosphate homeostasis. We further comment on extended-release calcifediol (ERC) as a new differential therapeutic option now also available in Europe and on a potentially novel understanding of a required vitamin D saturation in more advanced CKD stages. There is no doubt, however, that knowledge gaps will remain unless powerful randomised controlled trials with hard and meaningful endpoints are performed.

Patients with chronic kidney disease have a higher risk of fractures than the general population due to the added factor of uraemia. Although the mechanisms behind uraemia associated fractures are not fully understood, it is widely accepted that the decrease in bone mineral content and alteration in bone architecture both increase bone fragility. As chronic kidney disease progresses, the risk of fracture increases, especially once the patient requires dialysis. Among the many causes of the increased risk are advanced age, amenorrhoea, steroid exposure, decreased vitamin D, increased parathyroid hormone (PTH), malnutrition and chronic inflammation. Serum phosphorus, whether high or very low, seems to correlate with the risk of fracture. Moreover, increased serum phosphate is known to directly and indirectly affect bone metabolism through the development of adaptive hormonal mechanisms aimed at preventing hyperphosphataemia, such as the increase in PTH and fibroblast growth factor 23 (FGF23) and the reduction in calcitriol. These adaptive mechanisms are less intense if the intestinal absorption of phosphorus is reduced with the use of phosphorus captors, which seem to have a positive impact in reducing the risk of fractures. We describe here the possible mechanisms associating serum phosphorus levels, the adaptive mechanisms typical in kidney disease and the use of drugs to control hyperphosphataemia with the risk of fractures. We found no studies in the literature providing evidence on the influence of different treatments on the risk of fractures in patients with chronic kidney disease. We suggest that control of phosphorus should be an objective to consider. (C) 2020 Sociedad Espanola de Nefrologia. Published by Elsevier Espana, S.L.U.

Background and objectives In the CaLIPSO study, intravenous administration of SNF472 (300 or 600 mg) during hemodialysis significantly attenuated progression of coronary artery and aortic valve calcification. SNF472 selectively inhibits formation of hydroxyapatite, the final step in cardiovascular calcification. Because bone mineral is predominantly hydroxyapatite, we assessed changes in bone mineral density in CaLIPSO. Design, setting, participants, & measurements Patients with coronary artery calcification at screening (Agatston score of 100-3500 U) were randomized 1:1:1 to receive placebo, 300 mg SNF472, or 600 mg SNF472 as an intravenous infusion during hemodialysis three times weekly for 52 weeks. Dual-energy x-ray absorptiometry (DXA) scans were obtained at baseline (screening) and end of treatment, and between-group changes from baseline were compared using analysis of covariance. Results Among 274 randomized patients, 202 had evaluable DXA scans at baseline and postrandomization (the DXA-modified intention-to-treat population). Mean (95% confidence interval) changes in total-hip bone mineral density from baseline to week 52 were -1.5% (-2.7% to -0.3%), -1.5% (-2.7% to -0.4%), and -2.5% (-3.8% to -1.2%) in the placebo, 300 mg SNF472, and 600 mg SNF472 groups, respectively. Mean (95% confidence interval) changes in femoral-neck bone mineral density from baseline to week 52 were -0.3% (-1.6% to 1.0%), -1.0% (-2.3% to 0.2%), and -2.6% (-4.0% to -1.3%), respectively. Regression analyses showed no correlation between change in coronary artery calcium volume and change in bone mineral density at either location. Changes in serum alkaline phosphatase, calcium, magnesium, phosphate, and intact parathyroid hormone levels were similar across treatment groups. Clinical fracture events were reported for four of 90, three of 92, and six of 91 patients in the placebo, 300 mg SNF472, and 600 mg SNF472 groups, respectively. Conclusions Bone mineral density decreased modestly in all groups over 1 year. In the 600 mg SNF472 group, the reduction appeared more pronounced. Reported fractures were infrequent in all groups.

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.

Chronic kidney diseases (CKD) are associated with mineral and bone diseases (MBD), including pain, bone loss, and fractures. Bone fragility related to CKD includes the risk factors observed in osteoporosis in addition to those related to CKD, resulting in a higher risk of mortality related to fractures. Unawareness of such complications led to a poor management of fractures and a lack of preventive approaches. The current guidelines of the Kidney Disease Improving Global Outcomes (KDIGO) recommend the assessment of bone mineral density if results will impact treatment decision. In addition to bone density, circulating biomarkers of mineral, serum bone turnover markers, and imaging techniques are currently available to evaluate the fracture risk. The purpose of this review is to provide an overview of the epidemiology and pathogenesis of CKD-associated bone loss. The contribution of the current tools and other techniques in development are discussed. We here propose a current view of how to better predict bone fragility and the therapeutic options in CKD.

Chronic kidney disease (CKD) is associated with a very high morbimortality, mainly from cardiovascular origin, and CKD is currently considered in the high- or very high risk- cardiovascular risk category. CKD-mineral and bone disorders (CKD-MBDs), including vascular and/or valvular calcifications, are also associated with these poor outcomes. Vascular calcification (VC) is very prevalent (both intimal and medial), even in non-dialysis dependent patients, with a greater severity and more rapid progression. Simple X-ray based-scores such as Adragao's (AS) are useful prognostic tools and AS (even AS based on hand-X-ray only) may be superior to the classic Kauppila's score when evaluating non-dialysis CKD patients. Thus, in this mini-review, we briefly review CKD-MBD-related aspects of VC and its complex pathophysiology including the vast array of contributors and inhibitors. Furthermore, although VC is a surrogate marker and is not yet considered a treatment target, we consider that the presence of VC may be relevant in guiding therapeutic interventions, unless all patients are treated with the mindset of reducing the incidence or progression of VC with the currently available armamentarium. Avoiding phosphate loading, restricting calcium-based phosphate binders and high doses of vitamin D, and avoiding normalizing (within the normal limits for the assay) parathyroid hormone levels seem logical approaches. The availability of new drugs and future studies, including patients in early stages of CKD, may lead to significant improvements not only in patient risk stratification but also in attenuating the accelerated progression of VC in CKD.

Ischaemic heart disease, sudden cardiac death and arrhythmias, heart failure, stroke and peripheral arterial disease make up >50% of the causes of death in advanced chronic kidney disease (CKD). Calcification of the vascular tree and heart valves is partially related to these complications and has received growing attention in the literature. However, the main focus of research has been on the pathophysiology and consequences of vascular calcification, with less attention being paid to valvular calcification (VC) and its impact on the survival of CKD patients. Although VC has long been seen as an age-related degenerative disorder with minimal functional impact, several studies proved that it carries an increased risk of death and clinical consequences different from those of vascular calcification. In dialysis patients, the annual incidence of aortic valve calcification is nearly 3.3% and the reported prevalence of aortic and mitral VC varies between 25% and 59%. Moreover, calcification of both valves occurs 10–20 years earlier in CKD patients compared with the general population. Therefore, the purpose of this review is to summarize the current knowledge on the pathophysiology and relevance of VC in CKD patients, and to highlight specific clinical consequences and potential therapeutic implications. © The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Bisphenol A (BPA) is a compound that is especially widespread in most commonly used objects due to its multiple uses in the plastic industry. However, several data support the need to restrict its use. In recent years, new implications of BPA on the renal system have been discovered, which denotes the need to expand studies in patients. To this end, a systematic review and a meta-analysis was performed to explore existing literature that examines the BPA-kidney disease paradigm and to determine what and how future studies will need to be carried out. Our systematic review revealed that only few relevant publications have focused on the problem. However, the subsequent meta-analysis revealed that high blood concentrations of BPA could be a factor in developing kidney disease, at least in people with previous pathologies such as diabetes or hypertension. Furthermore, BPA could also represent a risk factor in healthy people whose urinary excretion is higher. Finally, the data analyzed from the NHANES 03-16 cohort provided new evidence on the possible involvement of BPA in kidney disease. Therefore, our results underline the need to carry out a thorough and methodologically homogeneous study, delving into the relationship between urinary and blood BPA, glomerular filtration rate, and urine albumin-to-creatinine ratio, preferably in population groups at risk, and subsequently in the general population, to solve this relevant conundrum with critical potential implications in Public Health.

Increasing knowledge on inflammatory mediators and bone metabolism highlights the relationship between inflammation and bone disease. During acute illness, inflammatory cells and cytokines modulate bone cells activity so as to mobilize calcium seemingly to supply the metabolic requirements for immune response. In case of long lasting, chronic inflammatory states a condition of maladaptive, smouldering inflammation is realized and negatively affects calcium bone balance. Aging, now nicknamed inflammaging, is regarded as a chronic inflammatory condition, characterized by increased circulating inflammatory cytokines, that contributes to the development of osteoporosis, cardiovascular diseases and chronic kidney disease. In patients with renal insufficiency, the development of bone and mineral disorders (so called CKD-MBD "syndrome") is now a recognized pathogenic factor for the seemingly accelerated process of aging and for the increased risk of cardiovascular death in these patients. The adaptive changes in mineral and bone metabolism developing in the early stages of chronic kidney disease could represent a hypothetical model of accelerated aging, osteoporosis and cardiovascular disease.

Background: The prevalence of vertebral fractures (VF) and their association with clinical risk factors and outcomes are poorly documented in chronic kidney disease (CKD) cohorts. The aim of the study was to evaluate the prevalence of VF in patients with non-dialysis dependent CKD (NDD-CKD), their value in predicting mortality and its correlation with parameters of bone mineral metabolism and vascular calci?cation. Materials and Methods: 612 NDD 3-5 stage CKD patients participating in the OSERCE-2 study, a prospective, multicenter, cohort study, were prospectively evaluated and categorized into two groups according to presence or absence of VF at enrollment. VF were assessed with lateral radiographs and Genant semi-quantitative method was applied. Three radiologists specialized in musculoskeletal radiology performed consensual reading of individual images obtained using a Raim DICOM Viewer and a Canon EOS 350 camera to measure with Java Image software in those who had traditional acetate X-ray. Factors related to VF were assessed by logistic regression analysis. Association between VF and death over a 3-year follow-up was assessed by Kaplan-Meier survival curves and Cox-proportional hazard models. Results: VF were detected in 110patients(18%). Serumphosphatelevels(OR0.719,95%CI0.532to0.972,p = 0.032),ankle-brachial index < 0.9 (OR 1.694, 95% CI 1.056-2.717, p = 0.029) and treatment with bisphosphonates (OR 5.636, 95% CI 1.876-16.930, p = 0.002) were independently related to the presence of VF. After a median follow-up of 35 months (IQR: 17-37 months), 62 patients (10%) died. The causes of death were cardiovascular (n = 21, 34%) and infectious (n = 11, 18%). In the crude analysis, fractured patients group had poorer survival (log-rank test, p = 0.02). After multivariate adjustment for age, MDRD, albumin, diabetes mellitus, comorbidity, Adragao Score > 3 and serum phosphate, the presence of VF (HR 1.983, 95% CI 1.009-3.898, p = 0.047) were an independent predictor of all-cause mortality. Conclusions: In our study 18% of patients with NDD-CKD have VF. Factors associated with VF were age, low serum phosphate levels and peripheral vascular disease. The presence of VF was an independent risk factor for mortality in stages 3-5 NDD-CKD patients. Clinical trials are needed to con?rm whether this relationship is causal and reversible with treatment for osteoporosis. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is one of the many important complications associated with CKD and may at least partially explain the extremely high morbidity and mortality among CKD patients. The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline document was based on the best information available at that time and was designed not only to provide information but also to assist in decision-making. In addition to the international KDIGO Work Group, which included worldwide experts, an independent Evidence Review Team was assembled to ensure rigorous review and grading of the existing evidence. Based on the evidence from new clinical trials, an updated Clinical Practice Guideline was published in 2017. In this review, we focus on the conceptual and practical evolution of clinical guidelines (from eMinence-based medicine to eVidence-based medicine and 'living' guidelines), highlight some of the current important CKD-MBD-related changes, and underline the poor or extremely poor level of evidence present in those guidelines (as well as in other areas of nephrology). Finally, we emphasize the importance of individualization of treatments and shared decision-making (based on important ethical considerations and the 'best available evidence'), which may prove useful in the face of the uncertainty over the decision whether 'to treat' or 'to wait'. © The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Osteoporosis (OP) and chronic kidney disease (CKD) both independently affect bone health. A significant number of patients with CKD have decreased bone mineral density (BMD), are at high risk of fragility fractures and have an increased morbidity and mortality risk. With an ageing population, these observations are not only dependent on "renal osteodystrophy" but also on the associated OP. As BMD predicts incident fractures in CKD patients (part I), we now aim to analyse the potential therapeutic consequences. Post-hoc analyses of randomised studies have shown that the efficacy of drugs such as alendronate, risedronate, raloxifene, teriparatide and denosumab is similar to that of the general population in patients with a mild/moderate decline in their glomerular filtration rate (especially CKD-3). These studies have some flaws however, as they included mostly "healthy" women with no known diagnosis of CKD and generally with normal lab test results. Nevertheless, there are also some positive preliminary data in more advanced stages (CKD-4), even though in CKD-5D they are more limited. Therefore, at least in the absence of significant mineral metabolism disorders (i.e. severe hyperparathyroidism), the potential benefit of these drugs should be considered in patients with a high or very high fracture risk. It is an important change that the new guidelines do not make it a requirement to first perform a bone biopsy and that the risk/benefit ratio of these drugs may be justified. However, we must also be aware that most studies are not consistent and the level of evidence is low. Consequently, any pharmacological intervention (risk/benefit) should be prudent and individualised. (C) 2019 Sociedad Espanola de Nefrologia. Published by Elsevier Espana, S.L.U.

Bover, J., Ureña-Torres, P., Laiz Alonso, A.M., Torregrosa, J.-V., Rodríguez-García, M., Castro-Alonso, C., Górriz, J.L., Benito, S., López-Báez, V., Lloret Cora, M.J., Cigarrán, S., DaSilva, I., Sánchez-Bayá, M., Mateu Escudero, S., Guirado, L., Cannata-Andía, J.

Chronic kidney disease (CKD) is often associated with a mineral and bone disorder globally described as CKD-Mineral and Bone Disease (MBD), including renal osteodystrophy, the latter ranging from high bone turnover, as in case of secondary hyperparathyroidism (SHPT), to low bone turnover. The present article summarizes the important subjects that were covered during The Parathyroid Day in Chronic Kidney Disease' CME course organized in Paris in September 2017. It includes the latest insights on parathyroid gland growth, parathyroid hormone (PTH) synthesis, secretion and regulation by the calcium-sensing receptor, vitamin D receptor and fibroblast growth factor 23 (FGF23)-Klotho axis, as well as on parathyroid glands imaging. The skeletal action of PTH in early CKD stages to the steadily increasing activation of the often downregulated PTH receptor type 1 has been critically reviewed, emphasizing that therapeutic strategies to decrease PTH levels at these stages might not be recommended. The effects of PTH on the central nervous system, in particular cognitive functions, and on the cardiovascular system are revised, and the reliability and exchangeability of second- and third-generation PTH immunoassays discussed. The article also reviews the different circulating biomarkers used for the diagnosis and monitoring of CKD-MBD, including PTH and alkaline phosphatases isoforms. Moreover, it presents an update on the control of SHPT by vitamin D compounds, old and new calcimimetics, and parathyroidectomy. Finally, it covers the latest insights on the persistence and de novo occurrence of SHPT in renal transplant recipients.

Osteoporosis (OP) and chronic kidney disease (CKD) independently influence bone and cardiovascular health. A considerable number of patients with CKD, especially those with stages 3a to 5D, have a significantly reduced bone mineral density leading to a high risk of fracture and a significant increase in associated morbidity and mortality. Independently of classic OP related to age and/or gender, the mechanical properties of bone are also affected by inherent risk factors for CKD ("uraemic OP"). In the first part of this review, we will analyse the general concepts regarding bone mineral density, OP and fractures, which have been largely undervalued until now by nephrologists due to the lack of evidence and diagnostic difficulties in the context of CKD. It has now been proven that a reduced bone mineral density is highly predictive of fracture risk in CKD patients, although it does not allow a distinction to be made between the causes which generate it (hyperparathyroidism, adynamic bone disease and/or senile osteoporosis, etc.). Therefore, in the second part, we will analyse the therapeutic indications in different CKD stages. In any case, the individual assessment of factors which represent a higher or lower risk of fracture, the quantification of this risk (i.e. using tools such as FRAX (R)) and the potential indications for densitometry in patients with CKD could represent an important first step pending new clinical guidelines based on randomised studies which do not exclude CKD patients, all the while avoiding therapeutic nihilism in an area of growing importance. (c) 2018 Sociedad Espanola de Nefrologia. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY-NC-ND license.

Alkaline phosphatases (APs) remove the phosphate (dephosphorylation) needed in multiple metabolic processes (from many molecules such as proteins, nucleotides, or pyrophosphate). Therefore, APs are important for bone mineralization but paradoxically they can also be deleterious for other processes, such as vascular calcification and the increasingly known cross-talk between bone and vessels. A proper balance between beneficial and harmful activities is further complicated in the context of chronic kidney disease (CKD). In this narrative review, we will briefly update the complexity of the enzyme, including its different isoforms such as the bone-specific alkaline phosphatase or the most recently discovered B1x. We will also analyze the correlations and potential discrepancies with parathyroid hormone and bone turnover and, most importantly, the valuable recent associations of AP's with cardiovascular disease and/or vascular calcification, and survival. Finally, a basic knowledge of the synthetic and degradation pathways of APs promises to open new therapeutic strategies for the treatment of the CKD-Mineral and Bone Disorder (CKD-MBD) in the near future, as well as for other processes such as sepsis, acute kidney injury, inflammation, endothelial dysfunction, metabolic syndrome or, in diabetes, cardiovascular complications. However, no studies have been done using APs as a primary therapeutic target for clinical outcomes, and therefore, AP's levels cannot yet be used alone as an isolated primary target in the treatment of CKD-MBD. Nonetheless, its diagnostic and prognostic potential should be underlined.

The patient with chronic kidney disease (CKD) represents an extreme model for arteriosclerosis, vascular calcification, and bone disorders, all of which are also associated with ageing in the general population. These pathological features are also relevant to other common chronic health disorders such as diabetes, and chronic inflammatory and cardiovascular diseases. Although management and interventions for these major risk factors are now incorporated into most public health guidelines (eg, smoking cessation and control of bodyweight and blood pressure, as well as glucose and cholesterol concentrations), some residual cardiovascular risk is not reduced by implementation of these interventions. CKD should be regarded as an atypical disease in which both traditional and novel cardiovascular risk factors have effects on outcomes. But CKD can also be viewed conceptually as an accelerator of traditional cardiovascular risk factors. Findings from research into mineral bone disorder associated with CKD (CKD–MBD) could help the medical community to better understand the vascular actions of certain molecules, such as phosphates, fibroblast growth factor 23, parathyroid hormone, sclerostin, or vitamin D and their relevance to the management of different pathologies in the general population. Importantly, these components, which are recognised in nephrology, could help to explain residual risk of cardiovascular events in the general population. Thus, achieving a better understanding of CKD–MBDs could provide substantial insight into future treatments for arteriosclerosis and osteoporosis, which are strongly associated with ageing and morbidity in the general population. © 2018 Elsevier Ltd

Recent improvements in our understanding of physiology have altered the way in which bone is perceived: no longer is it considered as simply the repository of divalent ions, but rather as a sophisticated endocrine organ with potential extraskeletal effects. Indeed, a number of pathologic conditions involving bone in different ways can now be reconsidered from a bone-centred perspective. For example, in metabolic bone diseases like osteoporosis (OP) and renal osteodystrophy (ROD), the association with a worse cardiovascular outcome can be tentatively explained by the possible derangements of three recently discovered bone hormones (osteocalcin, fibroblast growth factor 23 and sclerostin) and a bone-specific enzyme (alkaline phosphatase). Further, in recent years the close link between bone and inflammation has been better appreciated and a wide range of chronic inflammatory states (from rheumatoid arthritis to ageing) are being explored to discover the biochemical changes that ultimately lead to bone loss and OP. Also, it has been acknowledged that the concept of the bone-vascular axis may explain, for example, the relationship between bone metabolism and vessel wall diseases like atherosclerosis and arteriosclerosis, with potential involvement of a number of cytokines and metabolic pathways. A very important discovery in bone physiology is the bone marrow (BM) niche, the functional unit where stem cells interact, exchanging signals that impact on their fate as bone-forming cells or immune-competent haematopoietic elements. This new element of bone physiology has been recognized to be dysfunctional in diabetes (so-called diabetic mobilopathy), with possible clinical implications. In our opinion, ROD, the metabolic bone disease of renal patients, will in the future probably be identified as a cause of BM niche dysfunction. An integrated view of bone, which includes the BM niche, now seems necessary in order to understand the complex clinical entity of chronic kidney disease-mineral and bone disorders and its cardiovascular burden. Bone is thus becoming a recurrently considered paradigm for different inter-organ communications that needs to be considered in patients with complex diseases.

Secondary hyperparathyroidism (SHPT) is one of the most frequent and deleterious complication of chronic kidney disease (CKD). SHPT is also one of the principal components of the now called CKD-mineral and bone disorders (MBD) syndrome. It is usually prevented and treated by vitamin D derivatives. However, the rationale for the prescription of vitamin D sterols in those patients is still a matter of hotly debates, mainly because of unsatisfactory results from numerous observational and not well-controlled studies. Scanty clinical data on head-to-head comparisons between the multiple vitamin D sterols are currently available. Moreover, there is crescent expectations on nutritional vitamin D, as well as vitamin D receptor activators (VDRA), regarding their putative pleiotropic effects even in CKD patients, and the promising effects of VDRA against proteinuria and myocardial hypertrophy in diabetic CKD cohorts. Nevertheless, additional randomized controlled trials (RCT) are needed to answer to many open questions and incertitude considering the effect of nutritional vitamin D and VDRA on hard end points including the risk of skeletal fractures and of mortality in CKD patients. RCT comparing VDRA to calcimimetics in the control of SHPT are also needed in dialysis patients. The present review will visit these open questions that nephrologists should ask before starting a treatment by nutritional vitamin D or VDRA. (C) 2017 Societe francophone de nephrologie, dialyse et transplantation. Published by ElsevierMasson SAS. All rights reserved.

Osteoporosis and chronic kidney disease (CKD) have both independently important potential impact on bone health. A significant number of patients with CKD stages 3a-5D have been shown to have low bone mineral density (BMD), leading to a strikingly elevated risk of fractures (mainly hip fractures) and higher associated morbidity and mortality. Mechanical properties of bone beyond age and menopausal status are additionally affected by intrinsic uremic factors. Therefore, we review in this article not only general concepts of osteoporosis and related consequences, but also the diagnostic and therapeutic implications of low BMD and bone fractures in CKD, beyond increased vascular calcification. Antiresorptive agents (mainly bisphosphonates) were not previously recommended when the estimated glomerular filtration rate (GFR) was lower than 30 ml/min/1.73 m(2). However, post-hoc analysis of large randomized clinical trials found that these drugs (i.e. alendronate, ribandronate, denosumab) had comparable efficacy in improving BMD and reducing fracture risk in individuals (mainly women) with moderate reductions of GFR (mostly CKD stages 3-4). Therefore, at least in the absence of clear abnormalities of CKD-related mineral metabolism disturbances, bone antiresorptive agents (and maybe anabolic agents) that are or will be approved for general osteoporosis may be appropriate for CKD. Nephrologists should probably not ignore any longer fracture risk assessment, especially in patients with additional risk factors for osteoporosis if results will impact treatment decisions. However, although different therapeutic agents have been shown to reduce the risk of fracture in CKD patients with low BMD, specific prospective studies, with or without bone biopsies, in CKD are urgently needed.

Renal osteodystrophy is a feature of chronic kidney disease (CKD), with increasing prevalence as CKD progresses. This bone disease is responsible for major morbidity, including fractures, and a deterioration in the quality of life and its sequelae. Circulating biomarkers of renal osteodystrophy typically indicate bone turnover, but not other features of bone, like bone volume, mineralization, quality or strength. Bone turnover can be considered to be primarily a reflection of bone cell activity, in particular that of osteoblasts and osteoclasts. Since current treatments for bone disease usually target cellular activity, biomarkers are considered to be able to contribute to the decision-making for treatment and its follow-up. In CKD, one has to consider the impact of a diminished clearance of biomarkers or their altered metabolism, both potentially limiting its clinical use. Here, several aspects of the most frequently used biomarkers of bone turnover are reviewed, with an emphasis on the specific situation represented by CKD. This review is based on the overview lecture at the symposium held in Amsterdam, September 23, 2016: "The Bone In CKD", organized by the CKD-MBD working group of ERA-EDTA.

The spectrum of activity of vitamin D goes beyond calcium and bone homeostasis, and growing evidence suggests that vitamin D contributes to maintain musculoskeletal health in healthy subjects as well as in patients with chronic kidney disease (CKD), who display the combination of bone metabolism disorder, muscle wasting, and weakness. Here, we review how vitamin D represents a pathway in which bone and muscle may interact. In vitro studies have confirmed that the vitamin D receptor is present on muscle, describing the mechanisms whereby vitamin D directly affects skeletal muscle. These include genomic and non-genomic (rapid) effects, regulating cellular differentiation and proliferation. Observational studies have shown that circulating 25-hydroxyvitamin D levels correlate with the clinical symptoms and muscle morphological changes observed in CKD patients. Vitamin D deficiency has been linked to low bone formation rate and bone mineral density, with an increased risk of skeletal fractures. The impact of low vitamin D status on skeletal muscle may also affect muscle metabolic pathways, including its sensitivity to insulin. Although some interventional studies have shown that vitamin D may improve physical performance and protect against the development of histological and radiological signs of hyperparathyroidism, evidence is still insufficient to draw definitive conclusions.

Symposium on Bone in Chronic Kidney Disease (CKD), CKD 2016, Amsterdam, Netherlands, 13 Sep 2016 - 13 Sep 2016; Journal of nephrology 30(5), 663-670 (2017). doi:10.1007/s40620-017-0408-8 special issue: "Special issue on “Bone in Chronic Kidney Disease” an activity of the ERA-EDTA WG on CKD-MBD", Published by Springer, Milano

Background: The ankle-brachial index (ABI) is widely used to diagnose subclinical peripheral artery disease (PAD) in the general population, but data assessing its prevalence and related factors in different chronic kidney disease (CKD) stages are scarce. The aim of this study is to evaluate the prevalence and associated factors of pathological ABI values in CKD patients. Methods: NEFRONA is a multicentre prospective project that included 2445 CKD patients from 81 centres and 559 non-CKD subjects from 9 primary care centres across Spain. A trained team collected clinical and laboratory data, performed vascular ultrasounds and measured the ABI. Results: PAD prevalence was higher in CKD than in controls (28.0 versus 12.3%, P < 0.001). Prevalence increased in more advanced CKD stages, due to more patients with an ABI >= 1.4, rather than = 1.4. A stratified analysis showed different associated factors in each CKD stage, with phosphate being especially important in earlier CKD, and LDLcholesterol being an independent predictor only in Sage 5D CKD. Conclusions: Asymptomatic PAD is very prevalent in all CKD stages, but factors related to a low or high pathological ABI differ, revealing different pathogenic pathways. Diabetes, dyslipidaemia, inflammation and mineral-bone disorders play a role in the appearance of PAD in CKD.

This paper reflects the position of the CKD-MBD workgroup, an official working group of ERA-EDTA and of the ERBP advisory board, the official guideline-producing body of ERA-EDTA, on the topic of the use of calcimimetics in patients with CKD stage 5D, as based on two recent meta-analysis.