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There is scarce clinical experience with etelcalcetide in patients with secondary hyperparathyroidism uncontrolled with cinacalcet. The effect of etelcalcetide on serum sclerostin levels remains to be clarified.Prospective cohort study in prevalent hemodialysis patients with uncontrolled sHPT under cinacalcet for at least 3 months, mean parathyroid hormone (PTH)800pg/mL and calcium (Ca)8.3mg/dL. Etelcalcetide 5mg IV/HD was initiated after cinacalcet washout. Levels of PTH, Ca, and phosphorus (Pi) followed monthly for 6 months. Plasma sclerostin levels measured before etelcalcetide treatment and after 6 months.Thirty-four patients were enrolled, 19 (55.9%) male gender. Mean age 60.7 (± 12.3) years; median time on HD 82.5 (7-296) months and median cinacalcet dose was 180mg/week (Interquartile Range: 180-270). Serum Ca, Pi and PTH levels showed a significant reduction after etelcalcetide treatment from 8.8mg/dL, 5.4mg/dL and 1005pg/mL to 8.1mg/dL (p=0.08), 4.9mg/dL (p=0.01) and 702pg/mL (p0.001), respectively. Median etelcalcetide dose remained at 5mg/HD. Plasma sclerostin concentration increased from 35.66pmol/L (IQR11.94-54.58) to 71.05pmol/L (IQR54.43-84.91) (p0.0001).Etelcalcetide improved sHPT control in this group of patients, previously under cinacalcet treatment, and significantly increased plasma sclerostin concentration. The impact of etelcalcetide treatment on sclerostin levels is a novel finding.

Background Disordered mineral and bone metabolism is a common complication of chronic kidney disease (CKD). Bone biopsy remains the gold standard tool for evaluating renal osteodystrophy (ROD), but it is an invasive procedure. Despite a growing interest in the ability of newer bone biomarkers to discriminate between different forms of ROD, data on pre-dialysis patients are scarce. Methods A cross-sectional study was conducted in a cohort of 56 patients with CKD Stages 3 and 4. Participants underwent a transiliac bone biopsy after a course of double tetracycline labelling. Circulating levels of Wnt signalling inhibitors sclerostin and Dickkopf-1 (DKK1), soluble receptor activator of nuclear factor-κB ligand (sRANKL) and osteoprotegerin were measured and correlated with histomorphometric analysis results. Results Most patients had abnormal bone histology and low-turnover bone disease was the predominant form of ROD. Characteristics associated with high bone turnover were worse renal function, lower serum calcium and higher intact parathyroid hormone and fibroblast growth factor-23 levels. Patients with low bone turnover, on the other hand, presented with higher sclerostin along with lower DKK1 and sRANKL levels. In the multivariable logistic regression analysis, sclerostin and DKK1 levels were independently associated with low-turnover bone disease. Conclusions Our results suggest that circulating levels of Wnt signalling inhibitors sclerostin and DKK1 are predictive of low-turnover bone disease in patients not yet on dialysis. Further research is needed to assess the performance of these bone turnover biomarkers, compared with histomorphometric analysis, in the diagnosis and treatment monitoring of ROD., Graphical Abstract Graphical Abstract

Vascular wall calcification (VC) is highly prevalent in patients with chronic kidney disease (CKD). In CKD, VC is more frequent and severe than in the general population and it is associated with increased cardiovascular mortality and morbidity. In the last years, laboratory and clinical evidence have drawn the attention to the relationship between bone disease and VC in CKD patients, leading to the concept of a bone-vessel or bone-vascular axis. It means that disorders of bone volume and bone turnover may influence the risk of VC and ultimately the high risk of cardiovascular mortality. In fact, a higher burden of VC has been associated to low bone volume and low bone turnover in hemodialysis (HD) patients with renal osteodystrophy characterized by histomorphometric evaluation of bone biopsies. The molecular mechanisms underlying the regulation of bone cells and vascular cells in CKD are poorly understood. In this review, we discuss relevant evidence linking bone disorders and VC in CKD and also rising molecular players involved in this bone-vascular axis. Indeed, accumulating data is available for two proposed systems: receptor activator for nuclear factor kB (RANK)/ RANK ligand (RANKL)/osteoprotegerin (OPG) system and inhibitors of Wnt signaling - mainly sclerostin. Although they are promising biochemical markers linking bone formation and bone reabsorption with VC, there is a long way to go as long evidence from laboratory studies is often divergent to the clinical data as will be discussed. Future prospective studies are needed in order to evaluate the role of these biochemical players as useful clinical markers for VC, bone volume and perhaps bone turnover.

Background The transition from chronic kidney disease stage 5 to initiation of hemodialysis has gained increased attention in recent years as this period is one of high risk for patients with an annual mortality rate exceeding 20%. Morbidity and mortality in incident hemodialysis patients are partially attributed to failure to attain guideline-based targets. This study focuses on improvements in six aspects of quality of dialysis care (adequacy, anemia, nutrition, chronic kidney disease-mineral bone disorder (CKD-MBD), blood pressure and vascular access) aligning with KDIGO guidelines, during the first 6 months of hemodialysis. Methods We analyzed patient demographics, practice patterns and laboratory data in all 3 462 patients (mean age 65.9 years, 41% females) on hemodialysis (incident n=603, prevalent ≥90 days on hemodialysis, mean 55 months, n=2 859) from all 56 DaVita centers in Poland (51 centers) and Portugal (5 centers). 80% of patients had hemodialysis and 20% hemodiafiltration. Statistical analyses included unpaired and paired Students t-test, Chi-2 analyses, McNemar test and logistic regression analysis. Results Incident patients had lower Kt/V (1.4 vs 1.7, pp=0.001), lower Hb (9.9 vs 11.0 g/dl, ppppp Improvements in quality of care was also analyzed in a subgroup of 258 incident patients who were followed prospectively for 6 months. We observed significant improvements in Kt/V (ppppp=0.005) and an increased use of AV fistula (p Conclusion This large real-world European multicenter analysis of representative incident hemodialysis patients indicates that the use of medical protocols and medical targets assures significant improvements in quality of care, which may correspond to better outcomes. A selection bias of survivors with less comorbidities in prevalent patients may have influenced the results.

© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/, Renin-angiotensin-aldosterone system inhibitors (RAASi) reduce morbidity and mortality in heart failure (HF) with reduced ejection fraction in a dose-dependent manner. They also have a positive impact in other cardiovascular diseases (CVDs). However, RAASi may induce hyperkalemia, a potentially life-threatening disorder. This risk is further increased in those with concomitant chronic kidney disease, diabetes mellitus, and/or in patients with hypertension. Current treatment guidelines recommend maximal RAASi dosing to improve clinical outcomes; however, this is often limited by the development of hyperkalemia. When this occurs, current guidelines recommend RAASi down-titration/interruption, which, while improving short-term prognosis, is associated with a negative long-term prognostic impact. At present, the European Society of Cardiology suggests the consideration of novel potassium binders (patiromer and sodium zirconium cyclosilicate) for the management of RAASi-associated hyperkalemia. Both drugs can reduce serum potassium levels and prevent recurrent hyperkalemia. Additionally, patiromer showed enabling of RAASi optimization in high-risk patients. Nevertheless, precise recommendations on the use of these drugs are lacking. Building upon current HF guideline recommendations, a multidisciplinary expert panel convened to design an algorithm providing practical guidance on the use of novel potassium binders/patiromer in patients with HF and/or other CVD. As a result of that effort, we present an evidence-based treatment algorithm for the management of hyperkalemia with novel potassium binders/patiromer in patients with HF and/or other CVD receiving RAASi, including the necessary monitoring to avoid induction of hypokalemia. This algorithm aims to maintain or up-titrate RAASi to optimized doses, while maintaining normokalemia, improved clinical outcomes, and long-term prognosis., This work was supported by Vifor Pharma, Portugal, via an educational grant.

Background Disordered bone and mineral metabolism are a common complication of chronic kidney disease (CKD). Phosphate binders are often prescribed in advanced CKD, when hyperphosphataemia develops. Little is known about the role of these drugs in earlier stages, when serum phosphorus levels are kept in the normal range by increased urinary excretion. Methods A retrospective, controlled observational study was conducted on a cohort of 78 pre-dialysis patients. Subjects had CKD Stage 3 or 4, normal serum phosphorus levels and increased urinary fractional excretion of phosphate. Thirty-eight patients receiving calcium carbonate for 24 months were compared with 40 patients under no phosphate binders, regarding mineral metabolism parameters and vascular calcification scores. Results Calcium carbonate decreased mean urinary fractional excretion of phosphate and median 24-h urine phosphorus, whereas no significant change was seen in the control group. Mean serum phosphorus and median serum intact parathyroid hormone (iPTH) remained stable in treated patients but increased in the control group. Vascular calcification, assessed by Kauppila and Adragão scores, worsened under calcium carbonate with no significant change in the control group. Conclusions Calcium carbonate reduced urinary phosphate excretion and prevented the rise in phosphorus and iPTH serum levels in a cohort of normophosphataemic pre-dialysis patients. However, treatment was associated with increased vascular calcification, suggesting that calcium-based phosphate binders are not a safe option for CKD patients.

BackgroundWomen of all ages and elderly patients of both genders comprise an increasing proportion of the haemodialysis population. Worldwide, significant differences in practice patterns and treatment results exist between genders and among younger versus older patients. Although efforts to mitigate sex-based differences have been attempted, significant disparities still exist.MethodsThis retrospective cohort study included all 1247 prevalent haemodialysis patients in DaVita units in Portugal (five dialysis centres, n = 730) and Poland (seven centres, n = 517). Demographic data, dialysis practice patterns, vascular access prevalence and the achievement of a variety of Kidney Disease: Improving Global Outcomes (KDIGO) treatment targets were evaluated in relation to gender and age groups.ResultsBody weight and the prescribed dialysis blood flow rate were lower in women (P 80 years of age.ConclusionsThis large, multicentre real-world analysis indicates that haemodialysis practices and treatment targets are similar for women and men, including the most elderly, in DaVita haemodialysis clinics in Europe.

Background The optimal treatment algorithm for iron therapy and the use of erythropoiesis-stimulating agents (ESA) in anemic hemodialysis (HD) patients has not been established. Hemoglobin (Hb) target levels can be achieved through more frequent intravenous (IV) iron use with lower ESA dose, or with less iron dosing but higher ESA. ESA therapy to correct anemia may result in severe arterial and venous thrombotic complications and the evidence base evaluating hard clinical outcomes related to the use of IV iron is sparse. Methods A total of 1247 maintenance HD patients from 12 dialysis centers in Portugal (n = 730) and Poland (n = 517) were considered. We assessed achievement of KDIGO renal anemia targets with focus on treatment strategies, which typically differ between countries. In Poland the use and dose of IV iron was 35–72% higher than that in Portugal (p 20 and > 50% were both significantly higher in patients in Poland (88.8 and 14.6%) than in Portugal (76.3 and 5.7% respectively, p 800 μg/L (35.6%) compared to Portugal (15.8%, p

Background Vascular calcification (VC) is a common finding in chronic kidney disease (CKD) patients and predicts subsequent cardiovascular morbidity and mortality in this population. Vascular calcification is linked to disordered mineral metabolism and has been associated with bone histomorphometry changes in CKD. However, data on predialysis patients is scarce. Methods A cross-sectional study was conducted on a cohort of 56 CKD patients not yet on dialysis, who underwent a transiliac bone biopsy for histomorphometric evaluation after double tetracycline labeling. Patients had no previous exposure to calcium salts, vitamin D agents, steroids or bisphosphonates. Vascular calcification was assessed at the time of biopsy, using Kauppila (plain X-ray of the lateral lumbar spine) and Adragão (plain X-ray of the pelvis and hands) scores. Results Vascular calcification was seen in two-thirds of the cohort. Subjects with VC were more likely to be male and have diabetes, and had significantly higher sclerostin and osteoprotegerin circulating levels than those without VC. The histomorphometric analysis showed that bone formation rate was significantly lower in VC compared to non-VC patients. In the multivariable logistic regression analysis, bone formation rate was independently associated with the presence of VC. Conclusions Vascular calcification is highly prevalent in predialysis patients, especially in those with diabetes. The independent association between bone formation rate and VC provides evidence of an important interaction between bone and vessel in CKD. Our results suggest that low bone turnover is a non-traditional risk factor for cardiovascular disease in predialysis patients.

Ao longo do seculo passado, enormes avancos cientificos permitiram melhor compreender a fisiopatologia da doenca mineral e ossea, na doenca renal cronica (DRC). De igual forma, o desenvolvimento de novas terapias farmacologicas, a par com alteracoes demograficas, contribuiu para a emergencia de novos padroes de doenca ossea. Atualmente, a doenca ossea na DRC esta incluida numa sindrome de amplo espectro, os disturbios minerais e osseos da DRC (DMO-DRC). Esta sindrome inclui alteracoes na morfologia ossea e nos marcadores do metabolismo mineral, mas tambem preve o aumento de calcificacao extra-esqueletica, nomeadamente a nivel vascular. Os pacientes idosos com DRC podem apresentar osteoporose relacionada com a idade e/ou osteodistrofia renal. Hoje em dia, os nefrologistas sao desafiados com a necessidade de prevenir fraturas em pacientes com DRC, onde a eficacia e a seguranca dos agentes farmacologicos usados para o tratamento da osteoporose na populacao geral nao foram estudadas. Durante decadas, o tratamento da osteodistrofia renal passou pelo controlo da secrecao da hormona paratiroideia (PTH) com calcitriol, analogos da vitamina D e agentes calcimimeticos. Contudo, a incidencia de fraturas da anca, ajustada a idade, tem aumentado e verifica-se um aumento da incidencia de fraturas com o envelhecimento em pacientes com DRC, sugerindo que estes pacientes apresentam fatores de risco identicos a populacao em geral, como a idade. Tem sido desenvolvidos novos farmacos para o tratamento da osteoporose, tais como o teriparatide, denosumab e romosozumab, dos quais os pacientes renais poderao beneficiar. Estes farmacos tem efeito direto na atividade das celulas osseas, osteoblastos e osteoclastos, e tem revelado potencial no tratamento da doenca ossea na DRC. Este artigo aborda os disturbios osseos na DRC, nos seus tres aspetos mais importantes, designadamente a remodelacao ossea, a mineralizacao e o volume. Uma breve revisao da fisiopatologia tambem sera incluida, particularmente os mecanismos moleculares do eixo osseo-vascular. Alem disso, serao abordadas estrategias de abordagem diagnostica, incluindo algoritmos de rastreio de risco de fratura, bem como a abordagem terapeutica com os novos agentes farmacologicos.

Background and Aims Patients with diabetes mellitus on hemodialysis (HD) are at increased risk of development and progression of vascular calcification, atherosclerosis and peripheral vascular disease (PVD). Presence of PVD constitute a major risk factor for the development of cardiovascular events, such as myocardial infarction, stroke, hospitalization or cardiovascular death. The presence of PVD is also associated with a reduced quality of life and disability. A significant proportion of patients with PVD are asymptomatic with no or few classical symptoms and early detection to prevent progressive disease is therefore very important. Both the ACC/AHA and KDIGO guidelines recommend screening of individuals who are at risk. Method We analyzed the frequency of foot complications following implementation of a standardized foot examination in 345 prevalent diabetic hemodialysis patients in 12 DaVita centers; 8 in Poland (n=177 patients) and 4 in Portugal (n=168 patients). The protocol includes: history of ulcers, amputation and examination of the pedal pulses (a dorsalis pedis and a tibialis posterior). Foot complications were classified according to Wagner (grade 0-5). PVD was classified by clinical pulse measurement (normal vs weak or missing). We analyzed associations between foot complications and peripheral pulses with risk of hospitalization and mortality using Cox proportional hazard models. Results The mean age in all diabetic HD patients (58% men) was 70.4 (14 SD) yrs. Charlson comorbidity index (CCI) was 8.8 (2.4), Kt/V 1.8 (0.4), s-albumin 39 (4) g/L, Hb 11.1 (1.3) g/dL. A normal pulse in both a dorsalis pedis and both a tibialis posterior was found in 18% and 10% of patients. All other patients had weak or absent pulses. The Wagner classification score was 0 in 79% of patients, 1-3 in 16 % patients and 4-5 in 5 %. All-cause mortality was 31% during the 2 year follow up and 71% of patients had at least one hospital stay In patients hospitalized during follow up, a dors ped was normal/abnormal in 12% and 88% respectively (p Conclusion Diabetic patients on HD have a high prevalence of PVD that warrant close clinical attention. Documentation of peripheral foot pulses for early detection of PVD is simple and suitable to identify patients at high risk of future complications and mortality. This standardized protocol could be the basis of a program to improve overall health outcomes in this vulnerable group of patients.

Background and Aims Vascular calcification (VC) is associated to morbidity and mortality in chronic kidney patients. However, it remains to clarify the relationship between VC and renal osteodystrophy (ROD) evaluated by bone biopsy in peritoneal dialysis (PD) patients. Method In order to characterize the relationship between VC and ROD in prevalent PD population, we performed tetracycline-labelled bone biopsies with histomorphometric analysis according KDIGO guidelines. Hands and pelvis x-ray were performed to evaluate VC and to calculate Adragão Score. Exclusion criteria: previous kidney transplant, hemodialysis, treatment with agents interfering in bone metabolism (for example bisphosphonates). All patients were treated with biocompatible PD solutions, with calcium concentration of 1.25 mmol/L. Results Thirty-one patients participated in the study. Mean age was 52.32±11.09 years, 16 male, 6 with diabetes mellitus (DM), 22 on manual PD, median time on PD was 12 (3-61) months. Mean calcium, phosphate and PTH were 9.2±0.5 mg/dL, 4.9±1.0 mg/dL and 486.0±230.5 pg/mL, respectively. Most frequent diagnosed ROD pattern was adynamic bone disease (44.4%) followed by hiperparathyroid bone disease (33.3%) and normal bone (14.8%). VC was detected in 29% of patients and mean Adragão score was 1.13. However, 100% of diabetics had VC on x-ray compared to 12% of non-diabetics. Clinical, analytical and histomorphometric essential data is represented in table 1: Also no significant differences were observed between the patients with or without VC in ROD patterns on bone biopsy, glucose load in PD solutions, prescribed phosphate binders namely calcium-based binders, active vitamin D or calcimimetics. In diabetic patients, bone volume tended to be lower (17.26% vs 22.54%; p=0.072) comparing to non-diabetics. Bone formation rate was similar in diabetics and non-diabetics (25.39 vs 27.71µm3/µm2/y) as mineralization lag time (18.7 vs 20.1 days). Conclusion ROD evaluated by bone biopsy and the proportion of PD patients with VC on x-ray were similar to previous reports. However, in the present study a striking difference in VC was detected in diabetics – all diabetic patients had VC demonstrated radiographically. This finding was not explained by differences in calcium, phosphate, PTH levels or other studied factors. So DM could be a strong risk factor to VC in this population. Also, patients with VC were older, with higher sedimentation rate and lower total KT/V. It is possible that diabetic patients represent a different subgroup, particularly prone to lower bone volume and specially VC. They might benefit from higher dialysis dose and aggressive approaches to prevent or retard VC. This remains to be proved in properly designed prospective studies. In conclusion, age, sedimentation rate, total KT/V and presence of diabetes were associated to VC in prevalent PD patients. Diabetics may be a subgroup of PD patients with very high risk of VC.

Secondary hyperparathyroidism (SHPT) is associated with increased bone turnover, risk of fractures, vascular calcifications, cardiovascular and all-cause mortality. The classical treatment for SHPT includes active vitamin D compounds and phosphate binders. However, achieving the optimal laboratory targets is often difficult because vitamin D sterols suppress PTH secretion, but also promote calcium and phosphate intestinal absorption. Calcimimetics increase the sensitivity of calcium sensing receptor so that even with lower levels of extracellular calcium a signal can still exist, leading to the decrease of the set-point for systemic calcium homeostasis. This enables a decrease in plasma PTH levels, and consequently of calcium levels. Cinacalcet was the first calcimimetic approved for clinical use. After more than 15 years from its approval, cinacalcet demonstrated that effectively reduces PTH and improves biochemical control of mineral and bone disorders in chronic kidney patients. Three randomized controlled trials analyzed cinacalcet treatment effects on hard clinical outcomes such as vascular calcification, bone histology and cardiovascular mortality and morbidity. However, a final conclusion on the effect of cinacalcet on hard outcomes remains elusive. Etelcalcetide is a new second generation intra-venously administered calcimimetic agent with a pharmacokinetic profile that allows thrice-weekly dosing at the time of hemodialysis. It was recently approved in Europe and is regarded as a second opportunity to improve outcomes optimizing the treatment for SHPT. Evocalcet is the newly developed oral calcimimetic agent with less gastrointestinal adverse effects than cinacalcet and may be an alternative option for the treatment of secondary hyperparathyroidism in dialysis patients. This chapter summarizes the impact of cinacalcet in biochemical and relevant clinical outcomes, discusses the possible implications of etelcalcetide in the quest for improving outcomes and review the available data of the new oral calcimimetic evocalcet.

© 2020 Sociedade Portuguesa de Cardiologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/)., Introduction and Objectives: Renin-angiotensin-aldosterone system inhibitors (RAASi) are the cornerstone of treatment of heart failure with reduced ejection fraction (HFrEF). RAASi optimization in real-life care is challenged by hyperkalemia, a potentially fatal adverse event, which can necessitate downtitration or discontinuation of RAASi and negatively impact survival in HFrEF. The literature on this problem is sparse. We performed a systematic review of studies on HFrEF to investigate the prevalence, incidence, and risk factors of hyperkalemia, RAASi prescription rates, frequency of RAASi downtitration or discontinuation due to hyperkalemia, and the potential negative effect of the latter on prognosis. Methods: We conducted a MEDLINE (PubMed) search including observational and interventional studies published between January 1987 and May 2018. Results: A total of 30 observational and 18 interventional studies were included in the review. The incidence of hyperkalemia reported was between 0% and 63% in observational studies and was between 0% and 30% in clinical trials. Risk factors for hyperkalemia included RAASi prescription, older age, diabetes, and chronic kidney disease. In real-life studies, RAASi were downtitrated or discontinued in 3-22% of HFrEF patients; hyperkalemia was the reported cause in 5% of cases. No reports were found on the impact on prognosis of RAASi downtitration or discontinuation due to hyperkalemia. Conclusions: Hyperkalemia and RAASi downtitration or discontinuation are frequent, particularly in real-life HFrEF studies. Further research is needed to clarify the role of RAASi downtitration or discontinuation due to hyperkalemia and to assess its long-term prognostic impact in HFrEF patients., This work was supported by OM Pharma (Amadora, Portugal) for the payment of medical writing support. OM Pharma had no role in the study design, or in the collection, analysis and interpretation of data, or in the writing of the manuscript, or the decision to submit the manuscript for publication. The views expressed in the manuscript are those of the authors and not necessarily those of OM Pharma.

Although magnesium has been shown to prevent vascular calcification in vitro , controlled in vivo studies in uremic animal models are limited. To determine whether dietary magnesium supplementation protects against the development of vascular calcification, 5/6 nephrectomized Wistar rats were fed diets with different magnesium content increasing from 0.1 to 1.1%. In one study we analyzed bone specimens from rats fed 0.1%, 0.3%, and 0.6% magnesium diets, and in another study we evaluated the effect of intraperitoneal magnesium on vascular calcification in 5/6 nephrectomized rats. The effects of magnesium on established vascular calcification were also evaluated in uremic rats fed on diets with either normal (0.1%) or moderately increased magnesium (0.6%) content. The increase in dietary magnesium resulted in a marked reduction in vascular calcification, together with improved mineral metabolism and renal function. Moderately elevated dietary magnesium (0.3%), but not high dietary magnesium (0.6%), improved bone homeostasis as compared to basal dietary magnesium (0.1%). Results of our study also suggested that the protective effect of magnesium on vascular calcification was not limited to its action as an intestinal phosphate binder since magnesium administered intraperitoneally also decreased vascular calcification. Oral magnesium supplementation also reduced blood pressure in uremic rats, and in vitro medium magnesium decreased BMP-2 and p65–NF-κB in TNF-α–treated human umbilical vein endothelial cells. Finally, in uremic rats with established vascular calcification, increasing dietary magnesium from 0.1% magnesium to 0.6% reduced the mortality rate from 52% to 28%, which was associated with reduced vascular calcification. Thus, increasing dietary magnesium reduced both vascular calcification and mortality in uremic rats.

Calcimimetics decrease parathyroid hormone (PTH) secretion in patients with secondary hyperparathyroidism. The decrease in PTH should cause a reduction in bone turnover; however, the direct effect of calcimimetics on bone cells, which express the calcium-sensing receptor (CaSR), has not been defined. In this study, we evaluated the direct bone effects of CaSR activation by a calcimimetic (AMG 641) in vitro and in vivo. To create a PTH "clamp," total parathyroidectomy was performed in rats with and without uremia induced by 5/6 nephrectomy, followed by a continuous subcutaneous infusion of PTH. Animals were then treated with either the calcimimetic or vehicle. Calcimimetic administration increased osteoblast number and osteoid volume in normal rats under a PTH clamp. In uremic rats, the elevated PTH concentration led to reduced bone volume and increased bone turnover, and calcimimetic administration decreased plasma PTH. In uremic rats exposed to PTH at 6-fold the usual replacement dose, calcimimetic administration increased osteoblast number, osteoid surface, and bone formation. A 9-fold higher dose of PTH caused an increase in bone turnover that was not altered by the administration of calcimimetic. In an osteosarcoma cell line, the calcimimetic induced Erk1/2 phosphorylation and the expression of osteoblast genes. The addition of a calcilytic resulted in the opposite effect. Moreover, the calcimimetic promoted the osteogenic differentiation and mineralization of human bone marrow mesenchymal stem cells in vitro. Thus, calcimimetic administration has a direct anabolic effect on bone that counteracts the decrease in PTH levels.

This study was designed to characterize cortical bone by histomorphometry in a predialysis population, to correlate turnover, mineralization, and volume between cortical and trabecular bone, and to compare the findings with those in patients treated with maintenance dialysis. We evaluated cortical bone by histomorphometry in 16 patients with stage 3 or stage 4 chronic kidney disease and in 16 dialysis patients. Dual-energy X-ray absorptiometry (DXA) of the distal end of the forearm was performed in seven predialysis patients, and the findings correlated with histologic parameters. Predialysis patients compared with dialysis patients showed increased cortical bone thickness (p = 0.027) and decreased osteonal bone formation rate (p = 0.020) and adjusted apposition rate (p = 0.018), mainly for external cortical bone. In this predialysis population, trabecular bone volume positively correlated with external cortical porosity (r = 0.723, p = 0.003), external cortical thickness (r = 0.569, p = 0.034), and external osteonal accumulation (osteonal osteoid thickness, r = 0.530, p = 0.05; osteonal osteoid volume to bone volume ratio, r = 0.921, p

Secondary hyperparathyroidism (SHPT) is associated with increased bone turnover, risk of fractures, vascular calcifications, and cardiovascular and all-cause mortality. The classical treatment for SHPT includes active vitamin D compounds and phosphate binders. However, achieving the optimal laboratory targets is often difficult because vitamin D sterols suppress parathyroid hormone (PTH) secretion, while also promoting calcium and phosphate intestinal absorption. Calcimimetics increase the sensitivity of the calcium-sensing receptor, so that even with lower levels of extracellular calcium a signal can still exist, leading to a decrease of the set-point for systemic calcium homeostasis. This enables a decrease in plasma PTH levels and, consequently, of calcium levels. Cinacalcet was the first calcimimetic to be approved for clinical use. More than 10 years since its approval, cinacalcet has been demonstrated to effectively reduce PTH and improve biochemical control of mineral and bone disorders in chronic kidney patients. Three randomized controlled trials have analysed the effects of treatment with cinacalcet on hard clinical outcomes such as vascular calcification, bone histology and cardiovascular mortality and morbidity. However, a final conclusion on the effect of cinacalcet on hard outcomes remains elusive. Etelcalcetide is a new second-generation calcimimetic with a pharmacokinetic profile that allows thrice-weekly dosing at the time of haemodialysis. It was recently approved in Europe, and is regarded as a second opportunity to improve outcomes by optimizing treatment for SHPT. In this review, we summarize the impact of cinacalcet with regard to biochemical and clinical outcomes. We also discuss the possible implications of the new calcimimetic etelcalcetide in the quest to improve outcomes. info:eu-repo/semantics/publishedVersion

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. ispartof: CLINICAL KIDNEY JOURNAL vol:12 issue:2 pages:269-280 ispartof: location:England status: published

Aim Post-transplant bone disease results from multiple factors, including previous bone and mineral metabolism disturbances and effects from transplant-related medications. Bone biopsy remains the gold-standard diagnostic tool. Methods We aimed to prospectively evaluate trabecular and cortical bone by histomorphometry after kidney transplantation. Seven patients, willing to perform follow-up bone biopsy, were included in the study. Dual-X-ray absorptiometry and trans-iliac bone biopsy were performed within the first 2 months after renal transplantation and repeated after 2-5 years of follow-up. Results Follow-up biopsy revealed a significant decrease in osteoblast surface/bone surface (0.91 ± 0.81 to 0.47 ± 0.12%, P = 0.036), osteoblasts number/bone surface (0.45 (0.23, 0.94) to 0.00/mm(2) , P = 0.018) and erosion surface/bone surface (3.75 ± 2.02 to 2.22 ± 1.38%, P = 0.044). A decrease in trabecular number (3.55 (1.81, 2.89) to 1.55/mm (1.24, 2.06), P = 0.018) and increase in trabecular separation (351.65 ± 135.04 to 541.79 ± 151.91 μm, P = 0.024) in follow-up biopsy suggest loss in bone quantity. We found no significant differences in cortical analysis, except a reduction in external cortical osteonal eroded surface (5.76 (2.94, 13.97) to 3.29% (0.00, 6.67), P = 0.043). Correlations between bone histomorphometric and dual-X-ray absorptiometry parameters gave inconsistent results. Conclusions The results show a reduction in bone activity, suggesting increased risk of adynamic bone and loss of bone volume. Cortical bone seems less affected by post-transplant biological changes in the first years after kidney transplantation.

BACKGROUND AND OBJECTIVES: In dialysis patients, there is an increasing evidence that altered bone metabolism is associated with cardiovascular calcifications. The main objective of this study was to analyse, in hemodialysis patients, the relationships between bone turnover, mineralization and volume, evaluated in bone biopsies, with a plain X-ray vascular calcification score. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: In a cross-sectional study, bone biopsies and evaluation of vascular calcifications were performed in fifty hemodialysis patients. Cancellous bone volume, mineralized bone volume, osteoid volume, activation frequency, bone formation rate/bone surface, osteoid thickness and mineralization lag time were determined by histomorphometry. Vascular calcifications were assessed by the simple vascular calcification score (SVCS) in plain X-Ray of pelvis and hands and, for comparison, by the Agatston score in Multi-Slice Computed Tomography (MSCT). RESULTS: SVCS≥3 was present in 20 patients (40%). Low and high bone turnover were present in 54% and 38% of patients, respectively. Low bone volume was present in 20% of patients. In multivariable analysis, higher age (p = 0.015) and longer hemodialysis duration (p = 0.017) were associated with SVCS≥3. Contrary to cancellous bone volume, the addition to this model of mineralized bone volume (OR = 0.863; 95%CI: 0.766, 0.971; p = 0.015), improved the performance of the model. For each increase of 1% in mineralized bone volume there was a 13.7% decrease in the odds of having SVCS≥3 (p = 0.015). An Agatston score>400 was observed in 80% of the patients with a SVCS≥3 versus 4% of patients with a SVCS

Chronic kidney disease (CKD) patients present specific bone and mineral metabolism disturbances, which account for important morbidity and mortality. The term renal osteodystrophy, classically used for the nomination of CKD-associated bone disorder, has been limited to the histologic description of bone lesions, requiring the use of bone biopsy. Biochemical markers and imaging tools do not adequately predict the complex bone changes that are observed in renal osteodystrophy. Parathyroid hormone, which is a universally used biomarker of bone turnover in clinical practice, lacks specificity and sensitivity. Therefore, tetracycline double-labelled transiliac bone biopsy, with bone histology and histomorphometric evaluation, remains the best clinical tool to discriminate bone turnover and to evaluate the other dimensions of renal osteodystrophy. This review will focus on the value of classic bone histomorphometric analysis of trabecular bone in CKD patients and unfold new perspectives of this diagnostic tool, including cortical bone evaluation and bone tissue immunohistochemistry.

AIMS To evaluate the relationship between the severity of secondary hyperparathyroidism (SHPT) - defined in terms of baseline plasma intact parathyroid hormone (iPTH) level - and the magnitude of response to cinacalcet. MATERIALS AND METHODS In this post hoc analysis, data were pooled from three randomized, placebo-controlled trials in which dialysis patients with iPTH ≥ 300 pg/ml were dose-titrated with cinacalcet or placebo in addition to conventional treatment to achieve iPTH ≤ 250 pg/ml. In 953 patients analyzed (cinacalcet, 545; placebo, 408), baseline iPTH levels were categorized in 100 pg/ml intervals (300 - ≥ 1,000 pg/ml), and the impact of baseline iPTH on changes in iPTH, phosphate (P), calcium (Ca) and calcium- phosphate product (Ca × P) was evaluated. RESULTS Cinacalcet reduced iPTH (47% reduction), P (9%), Ca (7%), and Ca × P (15%) across all subgroups. For patients receiving cinacalcet, the mean percentage reduction from baseline in iPTH varied from 35 to 55%, being consistently decreased across the severity subgroups. The mean absolute change in iPTH was more pronounced in patients with higher baseline iPTH levels, particularly in the ≥ 1,000 pg/ml subgroup vs. the other subgroups. However, as baseline iPTH levels increased, iPTH ≤ 250 pg/ml was achieved in fewer patients. A trend towards greater absolute change from baseline was observed for P in patients with more severe disease (iPTH ≥ 800 pg/ml) treated with cinacalcet compared with patients with less severe disease (iPTH 300 - < 800 pg/ml). CONCLUSIONS Cinacalcet lowers plasma iPTH and serum P, Ca and Ca × P levels in dialysis patients with SHPT, regardless of disease severity. Patients with more severe disease experienced greater reductions in PTH and P, but fewer achieved iPTH ≤ 250 pg/ml by the efficacy assessment phase. Use of cinacalcet when baseline PTH is lower may result in more stable control of SHPT and help to control bone and mineral alterations.

Disturbances in mineral metabolism play a central role in the development of renal bone disease. In a 54-wk, randomized, open-label study, 119 hemodialysis patients were enrolled to compare the effects of sevelamer hydrochloride and calcium carbonate on bone. Biopsy-proven adynamic bone disease was the most frequent bone abnormality at baseline (59%). Serum phosphorus, calcium, and intact parathyroid hormone were well controlled in both groups, although calcium was consistently lower and intact parathyroid hormone higher among patients who were randomly assigned to sevelamer. Compared with baseline values, there were no changes in mineralization lag time or measures of bone turnover (e.g., activation frequency) after 1 yr in either group. Osteoid thickness significantly increased in both groups, but there was no significant difference between them. Bone formation rate per bone surface, however, significantly increased from baseline only in the sevelamer group (P = 0.019). In addition, of those with abnormal microarchitecture at baseline (i.e., trabecular separation), seven of 10 in the sevelamer group normalized after 1 yr compared with zero of three in the calcium group. In summary, sevelamer resulted in no statistically significant changes in bone turnover or mineralization compared with calcium carbonate, but bone formation increased and trabecular architecture improved with sevelamer. Further studies are required to assess whether these changes affect clinical outcomes, such as rates of fracture.

Standard therapy for secondary hyperparathyroidism (SHPT) includes dietary calcium supplementation, active vitamin D, and phosphate binders; however, these are often insufficient to allow patients to achieve their serum parathyroid hormone (PTH), calcium and calcium-phosphorus product (Ca × P) targets. Recent preclinical studies have demonstrated that treatment with type II calcimimetics that increase the sensitivity of the calcium-sensing receptor (CaR) to calcium can reverse the alterations in CaR and vitamin D receptor expression and parathyroid cell proliferation that are associated with SHPT. These data suggest that calcimimetic treatment could stabilize disease progression and improve maintenance of treatment goals. In clinical trials involving SHPT patients, the calcimimetic cinacalcet has been shown to decrease PTH, calcium, phosphorus and Ca × P. Significant improvements were seen regardless of initial disease severity, and benefits were maintained over the course of long-term therapy (up to 4 years), indicating effective disease stabilization. In conclusion, preclinical and clinical data provide both theoretical and empirical support for the use of calcimimetics in moderate and advanced SHPT to effectively stabilize disease.

Calciphylaxis, or calcific uremic arteriolopathy, is a vascular ossification–calcification disease involving cutaneous or visceral arterioles, with ischemic damage of the surrounding tissues, usually in the setting of chronic kidney disease. Pathogenesis is still unclear and probably comprises the participation of vascular smooth muscle cells, endothelial cells and macrophages surrounded by a uremic and/or pro-calcifying environment. According to the original concept of calcific uremic arteriolopathy coined by Hans Selye, risk factors may be divided into sensitizers and challengers and their knowledge is useful in clinical practice to pre-emptively identify both uremic and non-uremic ‘at risk’ patients and guide treatment. Systemic calcific uremic arteriolopathy is a rarity. Cutaneous calcific uremic arteriolopathy is more frequent and clinically presents as a first phase of cutaneous hardening and erythema, followed by a second phase of ulcerations and scars; these two phases are probably associated with the initial development of arteriolar lesion and tissue ischemic damage, respectively. Clinical history, physical examination, laboratory analysis, histology and imaging are the main tools to exclude important differential diagnoses and obtain a definitive diagnosis. Treatment is generally unrewarding and consists of rigorous control of comorbid conditions, anti-oxidant, anti-inflammatory and antithrombotic strategies, avoidance of iatrogeny and wound and pain management. Prognosis remains poor in terms of morbidity and mortality. Efforts should be made towards a greater awareness of calcific uremic arteriolopathy, development of better therapies and improvement of clinical outcomes.

Background andobjectivesThecalcimimeticcinacalcet reduced therisk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older ($65 years, n=1005) and younger (,65 years, n=2878) patients. Design, setting, participants, & measurements Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified. ResultsOlderpatients hadhigher baselineprevalenceof diabetesmellitusandCV comorbidity. Annualizedrates of kidney transplantation and parathyroidectomy were .3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups. Conclusions In the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone. Clin J Am Soc Nephrol 10: ccc–ccc, 2015. doi: 10.2215/CJN.07730814

Calcimimetic agents: Review and perspectives. Background Recognition of the role of the extracellular calcium-sensing receptor (CaR) in mineral metabolism has greatly improved our understanding of calcium homeostasis. The activation of this receptor by small changes in the extracellular ionized calcium ( ec (Ca 2+ )) regulates PTH, calcitonin secretion, urinary calcium excretion, and, ultimately, bone turnover. Methods The cloning of the CaR and the discovery of mutations that make the receptor less or more sensitive to calcium have allowed a better understanding of several hereditary disorders characterized by either hyperparathyroidism or hypoparathyroidism. The CaR, able to amplify the sensitivity of the CaR to Ca ++ and suppress PTH levels with a resulting decrease in blood Ca ++ , became an ideal target for the development of compounds, the calcimimetics. Experience with the calcimimetic R-568 in patients with primary and secondary hyperparathyroidism and parathyroid carcinoma are summarized. Results The first clinical studies with the first-generation calcimimetic agents have demonstrated their efficacy in lowering plasma intact PTH concentration in uremic patients with secondary hyperparathyroidism. However, the low bioavailability of these first calcimimetics predicts a difficult clinical utilization. The second-generation calcimimetic, AMG 073, having a better pharmacokinetic profile, appears to be effective and safe for the treatment of secondary hyperparathyroidism, suppressing PTH levels while simultaneously reducing serum phosphorus levels and the calcium x phosphorus product. Conclusion The advantage of controlling PTH secretion without the complications related to hypercalcemia, hyperphosphatemia, and increased calcium x phosphorus product is very promising.

Most reports on the effectiveness and side effects of oral versus parenteral calcitriol or alfacalcidol in hemodialysis patients with secondary hyperparathyroidism show no advantage of parenteral treatment. The efficacy and safety of intravenous doxercalciferol (1αD 2 ) were studied in hemodialysis patients with secondary hyperparathyroidism (plasma intact parathyroid hormone [iPTH]: range, 266 to 3,644 pg/mL; median, 707 pg/mL). These results were compared with those of a previous trial using intermittent oral 1αD 2 ; the same 70 patients were entered onto both trials, and 64 patients completed both trials per protocol. Twelve weeks of open-label treatment in both trials were preceded by identical 8-week washout periods. Degrees of iPTH suppression from baseline were similar in the two trials, with iPTH level reductions less than 50% in 89% and 78% of patients during oral and intravenous treatment, respectively. Grouping patients according to entry iPTH levels ( 2 treatment, respectively ( P = not significant [NS]). Prevalences of serum calcium levels greater than 11.2 mg/dL during oral and intravenous treatment were 3.62% and 0.86% of calcium measurements, respectively ( P P = NS). The percentage of increments in serum phosphorus levels during oral treatment exceeded that during intravenous treatment during 5 of 12 treatment weeks. Thus, intermittent oral and intravenous therapy with 1αD 2 reduced iPTH levels effectively and similarly, hypercalcemia was less frequent, and serum phosphorus levels increased less during intravenous than oral 1αD 2 therapy, suggesting that intravenous 1αD 2 therapy may be advantageous in patients prone to hypercalcemia or hyperphosphatemia.

Hypercalcemia and hyperphosphatemia frequently necessitate vitamin D withdrawal in hemodialysis patients with secondary hyperparathyroidism. In short-term trials, doxercalciferol (1alpha-hydroxyvitamin D(2) [1alphaD(2)]) suppressed intact parathyroid hormone (iPTH) effectively with minimal increases in serum calcium and phosphorus (P) levels. This modified, double-blinded, controlled trial examined the efficacy and safety of 1alphaD(2) use in 138 hemodialysis patients with moderate to severe secondary hyperparathyroidism by using novel dose titration; 99 patients completed the study. Hemodialysis patients with secondary hyperparathyroidism were enrolled onto this study, consisting of washout (8 weeks), open-label 1alphaD(2) treatment (16 weeks), and randomized, double-blinded treatment with 1alphaD(2) or placebo (8 weeks). Oral 1alphaD(2) was administered at each hemodialysis session, with doses titrated to achieve target iPTH levels of 150 to 300 pg/mL. Baseline iPTH levels (897 +/- 52 [SE] pg/mL) decreased by 20% +/- 3.4% by week 1 (P:0.001) and by 55% +/- 2.9% at week 16; iPTH levels returned to baseline during placebo treatment but remained suppressed with 1alphaD(2) treatment. In 80% of the patients, iPTH level decreased by 70%, reaching the target level in 83% of the patients. Grouping patients by entry iPTH level (600, 600 to 1,200, and1,200 pg/mL) showed rapid iPTH suppression in the group with the lowest level; greater doses and longer treatment were required in the group with the highest level. During open-label treatment, serum calcium and P levels were 9.2 +/- 0.84 (SD) to 9.7 +/- 1.05 mg/dL and 5.4 +/- 1.10 to 5.9 +/- 1.55 mg/dL, respectively. During double-blinded treatment, serum calcium levels were slightly greater with 1alphaD(2) than placebo, but P levels did not differ. During double-blinded treatment, 3.26% and 0.46% of serum calcium measurements exceeded 11.2 mg/dL with 1alphaD(2) and placebo, respectively (P:0.01); median level was 11.6 mg/dL during hypercalcemia. Intermittent oral 1alphaD(2) therapy effectively suppresses iPTH in hemodialysis patients with secondary hyperparathyroidism, with acceptable mild hypercalcemia and hyperphosphatemia.

A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism. Background The calcimimetic agent R-568 lowers plasma parathyroid hormone (PTH) levels in hemodialysis patients with mild secondary hyperparathyroidism, but its efficacy in those with more severe secondary hyperparathyroidism has not been studied. Methods Twenty-one patients undergoing hemodialysis three times per week with plasma PTH levels between 300 and 1200 pg/mL were randomly assigned to 15 days of treatment with either 100 mg of R-568 ( N = 16) or placebo ( N = 5). Plasma PTH and blood ionized calcium levels were measured at intervals of up to 24 hours after oral doses on days 1, 2, 3, 5, 8, 11, 12, and 15. Results Pretreatment PTH levels were 599 ± 105 (mean ± SE) and 600 ± 90 pg/mL in subjects given R-568 or placebo, respectively, and values on the first day of treatment did not change in those given placebo. In contrast, PTH levels fell by 66 ± 5%, 78 ± 3%, and 70 ± 3% at one, two, and four hours, respectively, after initial doses of R-568, remaining below pretreatment values for 24 hours. Blood ionized calcium levels also decreased after the first dose of R-568 but did not change in patients given placebo. Despite lower ionized calcium concentrations on both the second and third days of treatment, predose PTH levels were 422 ± 70 and 443 ± 105 pg/mL, respectively, in patients given R-568, and values fell each day by more than 50% two hours after drug administration. Predose PTH levels declined progressively over the first nine days of treatment with R-568 and remained below pretreatment levels for the duration of study. Serum total and blood ionized calcium concentrations decreased from pretreatment levels in patients given R-568, whereas values were unchanged in those given placebo. Blood ionized calcium levels fell below 1.0 mmol/L in 7 of 16 patients receiving R-568; five patients withdrew from study after developing symptoms of hypocalcemia, whereas three completed treatment after the dose of R-568 was reduced. Conclusions The calcimimetic R-568 rapidly and markedly lowers plasma PTH levels in patients with secondary hyperparathyroidism caused by end-stage renal disease.

Calcium-sensing receptor and calcimimetic agents. Recognizing the role of the extracellular calcium-sensing receptor (CaR) in mineral metabolism greatly improves our understanding of calcium homeostasis. The biology of the low affinity, G-protein-coupled CaR and the effects of its activation in various tissues are reviewed. Physiological roles include regulation of parathyroid hormone (PTH) secretion by small changes in ionized calcium (Ca2+) and control of urinary calcium excretion with small changes in blood Ca2+. The CaR also affects the renal handling of sodium, magnesium and water. Mutations affecting the CaR that make it either less or more sensitive to Ca2+ cause various clinical disorders; heterozygotes of mutations causing the CaR to be less sensitive to extracellular Ca2+ cause familial hypocalciuric hypercalcemia, while the homozygous form results in severe infantile hyperparathyroidism. Mutations causing increased sensitivity of the CaR to extracellular Ca2+ produce hereditary forms of hypoparathyroidism. Disorders, such as primary and secondary hyperparathyroidism, may exhibit acquired abnormalities of the CaR. Calcimimetic drugs, which amplify the sensitivity of the CaR to Ca2+, can suppress PTH levels, leading to a fall in blood Ca2+. Experiences with this agent in patients with secondary and primary hyperparathyroidism and parathyroid carcinoma are summarized. In animals and humans with hyperparathyroidism, this agent produces a dose-dependant fall in PTH and blood Ca2+, with larger doses causing more sustained effects. The treatment has been short-term except for one patient followed for more than 600 days for parathyroid carcinoma; nonetheless the drug did not cause major side-effects and appears to be safe. Further long-term controlled studies are needed with calcimimetic agents of this type.

Calcitriol and alfacalcidol are useful in suppressing parathyroid hormone (PTH ) in haemodialysis patients, but hypercalcaemia and hyperphosphataemia are frequent. The vitamin D analogue, la-hydroxyvitamin D 2 (1αD 2 ), has a higher therapeutic index in animal models. Previously, 1αD 2 , 4μg/day or 4 μg/haemodialysis, lowered iPTH to the target range in 87.5% of 24 haemodialysis patients with moderate to severe secondary hyperparathyroidism (plasma iPTH, 359-1521 pg/ml). The incidences of hypercalcaemia (serum Ca>2.8mM) or hyperphosphataemia (serum P>2.23mM) were low. Later, 10 of these patients were re-treated with 1αD 2 , initial dose, 10 μg, thrice weekly with haemodialysis. The iPTH was suppressed as readily, and there was no greater incidence of hypercalcaemia and hyperphosphataemia. Based on these data, a large, multicentre study is ongoing in California and Tennessee/Mississippi, using 1αD 2 in haemodialysis patients with iPTH >400 pg/ml. In this and the earlier studies, only calcium-based phosphate binders were used to control serum phosphorus. The initial dose, 10 μg thrice weekly with haemodialysis, is adjusted to maintain a target iPTH within the range of 150-300 μg/ml; the final dose range is 2.5-20 μg per haemodialysis. The protocol includes 8 weeks of wash-out with no vitamin D, 16 weeks of open label treatment period with 1αD 2 , and finally 8 weeks of randomized double blinded treatment with either continued 1αD 2 or placebo. Forty two patients from California and 38 from Tennessee/Mississippi have completed 16 weeks of open label treatment. In California, iPTH declined from 832 ± 95 pg/ml at baseline to 222 ±71 pg/ml at the nadir and to 477 ± 117 pg/ml at week 16 of the treatment. In Tennessee/Mississippi, the iPTH declined from 977 ± 65 pg/ml to 286 ± 42 pg/ml at the lowest point and to 493 ± 79 at the end of the treatment. Plasma iPTH reached or fell below the target range in 84% of the 80 patients completing open treatment. Asymptomatic hypercalcaemia (serum Ca >2.8mM) increased from 0.3 episodes/100 weeks during wash-out to 3.6 episodes/100 treated weeks in California and from 0 to 3.7 episodes in Tennessee/Mississippi. In California and Tennessee, the episodes of hyperphosphataemia (serum P >2.2 mM) increased from 5.0 and 5.0 epiodes per 100 patient/week during wash-out to 10.1 and 10.9 episodes/100 treatment weeks, respectively, with 1αD 2 treatment. There were no adverse events in association with 1αD 2 treatment. Thus, oral 1αD 2 is safe and highly effective for the treatment of secondary hyperparathyroidism.

Fibroblast Growth Factor 23 (FGF-23) is a bone-derived hormone involved in the regulation of phosphate homeostasis. FGF-23 levels are extremely elevated in Chronic Kidney Disease (CKD) and there is evidence supporting the role of this hormone in the pathogenesis of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Furthermore, recent data associates FGF-23 with the pathogenesis of systemic complications of CKD-MBD. The increasing evidence that the consequences of abnormal mineral metabolism are not restricted to bone disease changed the approach to the pathophysiology and treatment of disturbed bone and mineral metabolism in CKD patients. FGF-23 has been proposed to be the initial adaptive response in early CKD to protect the organism from the adverse effects of phosphate retention. Increased levels of FGF-23 observed in CKD patients are associated with cardiovascular mortality risk and was shown to mediate direct, "off-target" toxicity to the heart. This report aims to review the relevant aspects of the physiology of FGF-23 in bone biology and mineral homeostasis and the role of FGF-23 in the pathophysiology of CKD-BMD and its clinical implications.

An elderly man with diabetes mellitus and end-stage renal disease managed with continuous ambulatory peritoneal dialysis (CAPD) was hospitalized with peripheral vascular insufficiency; he developed hypercalcemia and became mentally obtunded. Lowering dialysate Ca from 3.5 mEq/L to 2.5 mEq/L, stopping calcium acetate, and ultimately hemodialysis with calcium-free dialysate did not lead to reversal of the hypercalcemia or improvement of his symptoms. The intact parathyroid hormone PTH level was 187 pg/mL, a value rarely associated with significant osteitis fibrosa. A search for other causes of hypercalcemia was unrevealing, and a iliac crest bone biopsy was done. The latter showed osteitis fibrosa, and the patient underwent parathyroidectomy. The hypercalcemia reversed quickly, and his mental symptoms slowly improved. The discussion reviews the probable causes of hypercalcemia in diabetic patient undergoing CAPD with 3.5 mEq/L dialysate calcium and using calcium-containing phosphate binders, with hyperparathyroidism certainly not the usual cause. The reason for the occurrence of significant hyperparathyroidism in the face of only modest elevation of PTH is considered. The value of bone biopsy in resolution of this problem is apparent.

Background Elevated serum phosphorus (P) levels have been linked to increased morbidity and mortality in dialysis patients with secondary hyperparathyroidism (SHPT) but may be difficult to control if parathyroid hormone (PTH) is persistently elevated. We conducted a post hoc analysis of data from an earlier interventional study (OPTIMA) to explore the relationship between PTH control and serum P. Methods The OPTIMA study randomized dialysis patients with intact PTH (iPTH) 300–799 pg/mL to receive conventional care alone (vitamin D and/or phosphate binders [PB]; n = 184) or a cinacalcet-based regimen (n = 368). For patients randomized to conventional care, investigators were allowed flexibility in using a non-cinacalcet regimen (with no specific criteria for vitamin D analogue dosage) to attain KDOQI™ targets for iPTH, P, Ca and Ca x P. For those assigned to the cinacalcet-based regimen, dosages of cinacalcet, vitamin D sterols, and PB were optimized over the first 16 weeks of the study, using a predefined treatment algorithm. The present analysis examined achievement of serum P targets (≤4.5 and ≤5.5 mg/dL) in relation to achievement of iPTH ≤300 pg/mL during the efficacy assessment phase (EAP; weeks 17–23). Results Patients who achieved iPTH ≤ 300 pg/mL (or a reduction of ≥30% from baseline) were more likely to achieve serum P targets than those who did not, regardless of treatment group. Of those who did achieve iPTH ≤ 300 pg/mL, 43% achieved P ≤4.5 mg/dL and 70% achieved P ≤5.5 mg/dL, versus 21% and 46% of those who did not achieve iPTH ≤ 300 pg/mL. Doses of PB tended to be higher in patients not achieving serum P targets. Patients receiving cinacalcet were more likely to achieve iPTH ≤300 pg/mL than those receiving conventional care (73% vs 23% of patients). Logistic regression analysis identified lower baseline P, no PB use at baseline and cinacalcet treatment to be predictors of achieving P ≤4.5 mg/dL during EAP in patients above this threshold at baseline. Conclusions This post hoc analysis found that control of serum P in dialysis patients was better when serum PTH levels were lowered effectively, regardless of treatment received. Trial registration Clinicaltrials.gov identifier NCT00110890

Background and objectives: There is increasing evidence that altered bone metabolism is associated with cardiovascular calcifications in patients with stage 5 chronic kidney disease on hemodialysis (HD). This study was conducted to evaluate the association between bone volume, turnover, and coronary calcifications in HD patients. Design, setting, participants, & measurements: In a cross-sectional study, bone biopsies and multislice computed tomography were performed in 38 HD patients. Bone volume/total volume, activation frequency, and bone formation rate/bone surface were determined by histomorphometry and coronary calcifications were quantified by Agatston scores. Results: Prevalence of low bone turnover was 50% and of low bone volume was 16%. Among the studied traditional cardiovascular risk factors, only age was found to be associated with coronary calcifications. Lower bone volume was a significant risk factor for coronary calcifications during early years of HD, whereas this effect was not observed in patients with dialysis duration >6 yr. Histomorphometric parameters of bone turnover were not associated with coronary calcifications. Conclusions: Low bone volume is associated with increased coronary calcifications in patients on HD. Clin J Am Soc Nephrol 4: 450–455, 2009. doi: 10.2215/CJN.01870408

We evaluated the associations between dual energy X-ray absorptiometry (DXA) and histologically determined cancellous and cortical bone volume by controlling for vascular calcifications and demographic variables in hemodialysis (HD) patients. Femoral bone mineral density (f-BMD) was associated with cortical porosity.Assessment of bone mass in chronic kidney disease patients is of clinical importance because of the association between low bone volume, fractures, and vascular calcifications. DXA is used for noninvasive assessment of bone mass whereby vertebral results reflect mainly cancellous bone and femoral results reflect mainly cortical bone. Bone histology allows direct measurements of cancellous and cortical bone volume. The present study evaluates the association between DXA and histologically determined cancellous and cortical bone volumes in HD patients.In 38 HD patients, DXA was performed for assessment of bone mass, anterior iliac crest bone biopsies for bone volume, and multislice computed tomography for vascular calcifications.While lumbar bone mineral density (l-BMD) by DXA was not associated with histologically measured cancellous bone volume, coronary Agatson score showed a borderline statistically significant association (P = 0.055). When controlled for age and dialysis duration, f-BMD by DXA was associated with cortical porosity determined by histology (P = 0.005).The usefulness of l-BMD for predicting bone volume is limited most probably because of interference by soft tissue calcifications. In contrast, f-BMD shows significant association with cortical porosity.

In order to evaluate the persistence of antibodies against hepatitis C virus (HCV) in a chronic hemodialysis population, we studied 151 HBsAg-negative patients. Anti-HCV titers were evaluated every 3 months over 1 year, and the serum alanine aminotransferase/serum aspartate aminotransferase ratio monthly from the start of hemodialysis. The anti-HCV titers (ELISA C100-3) remained stable in 127 patients and fluctuated in 24, without an evident correlation with hepatic function. Using our criteria, we found 85 patients with non-A, non-B hepatitis, 57 of them with biochemical criteria of chronic hepatic disease. There was a strong correlation between antibodies to HCV and non-A, non-B hepatitis (chi 2; p0.05) which was more marked in those patients with biochemical criteria of chronic hepatic disease (chi 2; p0.001). We concluded that the anti-HCV titer is reliable as a long-term marker of hepatitis C virus infection.

The calcimimetic agents: Perspectives for treatment. Recognition of the role of the extracellular calcium sensing receptor (CaR) in mineral metabolism has greatly improved our understanding of calcium homeostasis. The biology of the low affinity, G-protein-coupled CaR and the effects of its activation in various tissues are reviewed. Physiological roles include regulation of parathyroid hormone (PTH) secretion by small changes in ionized calcium (Ca ++ ), and control of urinary calcium excretion with small changes in blood Ca ++ . The CaR also affects the renal handling of sodium, magnesium, and water. Mutations affecting the CaR that make it either less or more sensitive to Ca ++ cause various clinical disorders. Disorders, such as primary and secondary hyperparathyroidism, may exhibit acquired abnormalities of the CaR. Calcimimetic drugs, which amplify the sensitivity of the CaR to Ca ++ , can suppress PTH levels with a resultant fall in blood Ca ++ . Experiences with R-568 in patients with secondary and primary hyperparathyroidism and parathyroid carcinoma are summarized. In humans with hyperparathyroidism, these agents produce a dose-dependent fall in PTH and blood Ca ++ , with larger doses causing more sustained effects. The second generation calcimimetic, AMG 073, with a better pharmacokinetic profile appears to be an effective and safe treatment for secondary hyperparathyroidism, producing suppression of PTH levels with a simultaneous reduction in serum phosphorus levels and the calcium X phosphorus product. The advantage of controlling PTH secretion without the complications related to hypercalcemia, hyperphosphatemia, and increased calcium X phosphorus product is very promising. Treatment trials have been relatively short-term except for one patient treated with R-568 for more than 600 days for parathyroid carcinoma; nonetheless the drug had no major side effects and appeared to be safe. Further long-term controlled studies are underway to further confirm the effectiveness and safety of these compounds.