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BACKGROUND AND AIMS Anemia is a highly prevalent and modifiable comorbidity in patients with chronic kidney disease (CKD), which tends to aggravate as the disease progresses. The economic burden of anemia in CKD is high, and quality of life issues (e.g. fatigue, reduced productivity) is common in these patients. Data on the prevalence and treatment of anemia in CKD stages 3 and 4 (based on the estimated glomerular filtration rate according to KDIGO classification) in Portugal are lacking. The NEFROPOR study aimed to estimate the prevalence of anemia in patients with CKD stage 3 or 4 admitted to a Nephrology consultation between 1 January and 31 March 2017 and characterize anemia treatment in this patient population. METHODS NEFROPOR was a retrospective, multicentric study carried out in 10 Portuguese centers. All patients aged ≥18 years with stage 3 or 4 CKD admitted to a Nephrology consultation in one of those centers between 1 January and 31 March 2017 were invited to participate, and data for up to 24 months after admission were collected from patients’ clinical files. Retrieved data included age, body mass index (BMI), anemia status according to the World Health Organization (WHO) diagnostic criteria, and anemia treatment type and duration. Three assessments of the prevalence anemia were performed: at the time of the first Nephrology visit (presentation), at the first analytical results and the overall prevalence in the study cohort. Statistical analysis was performed in SPSS Statistics (v26) and a 0.05 significance level was adopted. RESULTS A total of 176 patients were included in this study, mostly (61.9%) male, with a median age of 76 years (range, 26–97) and a mean BMI indicative of pre-obesity (28.2; standard deviation, 4.2). CKD stage 3b was predominant (43.2%), followed by stage 4 (32.4%) and stage 3a (24.4%). The most frequent CKD etiologies in this cohort were diabetes (39.8%), followed by arterial hypertension (27.8%) and unknown cause (25.6%). Arterial hypertension was largely the most frequent comorbidity, present in 90.3% of patients, followed by diabetes (54.0%). Although less prevalent, coronary artery disease (18.2%) and congestive heart failure (14.8%) were also identified in this patient population. A total of 44.9% of patients [95% confidence interval (CI), 37.7%–52.3%] had anemia at presentation, which was significantly associated with CKD stage, diabetes, peripheral vascular disease and myocardial infarction comorbidities, and diabetes and unknown CKD etiology. The overall prevalence of anemia in the study cohort was 61.9% (95% CI 54.6%–68.9%), and it was significantly associated with diabetes and peripheral vascular disease comorbidities and with diabetes and primary glomerulonephritis as CKD etiologies. The prevalence of anemia at the first analytical results was 49.4% (95% CI 42.1%–56.8%), and it was significantly associated with CKD stage, diabetes, non-skin cancer, peripheral vascular disease and myocardial infarction comorbidities, and diabetes as CKD etiology. Figure 1 shows the evolution of anemia treatment in this cohort over 24 + months. CONCLUSION The three estimates of the prevalence of anemia in this study were consistent with each other, particularly those for the first visit and first analytical results. The latter were also consistent with evidence in the literature reporting a prevalence of anemia in the population of patients with CKD stages 3 and 4 between 40% and 60%. The overall prevalence of anemia in this study was 12%–15% higher than first visit and first analytical results estimates, in agreement with the fact that this refers to a cumulative prevalence. These data support the need for optimized and individualized treatment strategies for patients with CKD stages 3 and 4, maximizing the efficiency of health-care resource use.

BACKGROUND AND AIMS Intradialytic exercise (IDE) is recommended for HD patients. However, this recommendation is mostly based on research conducted under optimal instead of real-world conditions, limiting generalizability and its implementation into routine clinical care. This study aims to analyze implementation outcomes of IDE in real-world conditions at a large-scale, nationwide level. METHOD After a pilot experience in a single unit, all NephroCare Portugal dialysis clinics were invited to initiate an IDE program. A national coordinator was nominated, and a nurse and a doctor were selected in each unit as local coordinators. A simple exercise protocol was designed to be easily applied by current dialysis staff (though some units benefited from exercise science student internships). The IDE protocol includes a bout of aerobic exercise (cycle ergometer) and lower limb resistance exercises (ankle weights). The RE-AIM (reach, effectiveness, adoption, implementation and maintenance) framework was used to study clinical implementation over the first year. For each RE-AIM dimension, specific implementation outcomes were adapted to IDE. Effectiveness measures included safety (incidence of intradialytic adverse events over 1 year) and physical function at baseline and at 1 year (sit to stand 30, 8-foot up & go, handgrip strength, sit to stand 5 and single leg stance). For safety measures, IDE group was compared to a group of patients that refused IDE. Physical function measures were only applied to IDE patients, and so comparisons were made between low- and high-frequency exercise groups. RESULTS Adoption: 21 dialysis units (58.3%). Reach: 1270 eligible patients (55.8%). Main reasons for noneligibility were physical/cognitive incapacity (50.8%) and cardiovascular risk (34.9%). Eligible patients were younger (P CONCLUSION Large-scale implementation of IDE is a realistic and safe way to promote physical activity in HD patients with benefits on physical function. Yet, to optimize its generalizability, strategies to increase patients´ acceptability and long-term adherence are needed.

BACKGROUND AND AIMS Magnesium (Mg) deficiency is associated with altered bone metabolism, However, the relationship between Mg and the risk of fragility fractures haemodialysis (HD) patients is still unclear. The aim of this study was to evaluate the association between pre-dialysis Mg serum levels and the risk of incident bone fractures in a cohort of prevalent HD patients. METHOD We performed a prospective study of 206 prevalent HD patients followed from 2009 until 2021. Demographic, clinical and biochemical parameters were evaluated. RESULTS A total of 37 episodes of fragility fractures were identified with a median HD vintage of 42 months, which corresponds to an incidence rate of 29/1000 person-years. The mean age of the studied population was 68.3 ± 13.1 years, 121 (59%) were male and the median follow-up time on HD was 58 months. Patients with incident fractures showed significantly lower Mg levels compared with those without fractures (2.3 ± 0.3 versus 2.8 ± 0.4 mg/dL, P Patients with a Mg serum level CONCLUSION This study shows that the incidence of bone fragility fractures in HD patients is high and significantly associated with lower pre-dialysis Mg levels. Management of fracture risk in HD patients and assessment of its risk factors requires further study.

BACKGROUND AND AIMS Haemodialysis (HD) patients frequently experience reduced physical function, which is exacerbated throughout dialysis vintage, therefore compromising their quality of life. Despite recent studies highlighting improvements in physical function regardless of exercise modality, well-designed randomized controlled trials with progressive resistance exercise training protocols are scarce. Thus, this study investigated the effects of 12 weeks of intradialytic progressive resistance exercise (RE) and aerobic exercise (AE) training on physical function in HD patients. METHOD Fifty-six adult HD patients from three NephroCare Portugal SA clinics were included in this study. Following a 6-week run-in control period, participants were randomly allocated into either a supervised intradialytic AE [(n = 29, male: 66%, age: 66 ± 16 years)] or RE [(n = 27, male: 67%, age: 63 ± 14 years)] training protocol, 3 sessions per week for 12 weeks. Intradialytic RE training consisted of 2 sets of 12 repetitions of 8 different exercises for upper and lower body using free-weight dumbbells and a newly designed weight machine, while intradialytic AE training was performed on a cycle ergometer at 50–70 rpm for 30 min at a rating of perceived exertion (RPE) 12–14 (Borg scale). Physical function was assessed by completing the Sit to Stand 60 (STS-60) test, the Short Physical Performance Battery (SPPB), the Incremental Shuttle Walk Test (ISWT), the Timed Up and Go (TUG) test and isometric handgrip strength (HGS) on three occasions: before and after the 6-week run-in control, and after the 12-week exercise periods. The 6-week control period data were analyzed by paired sample t-tests or Wilcoxon rank test as this is prior to randomization. Training effects were examined using an ANOVA with mixed design (within- and between-subjects) for data with normal distribution or if data still with non-normal distribution after log transformation, Wilcoxon rank test (within subjects) and Mann–Whitney test (between subjects) were used with a significance value of P RESULTS There was no change in any variable when comparing before and after the 6-week control period (P > 0.05). AE and RE training significantly increased the number of repetitions performed on the STS-60 test compared to before the 12-week intervention, but had no effect on the SPPB scores. Additionally, despite no changes in the distance covered in ISWT in the AE group, AE training reduced the TUG time and an increase in HGS was observed. On the other hand, patients that performed RE training increased their walking distance in ISWT. However, no change in HGS was observed. Yet, and despite not impactful, a 0.1 s significant increase in the median time performed on the TUG test was also observed. Nevertheless, no changes between groups were observed after the 12-week exercise intervention (Table 1). CONCLUSION We conclude that 12 weeks of AE training seem to improve HGS, STS-60 and TUG test performance in HD patients, whereas progressive RE training only had an effect on the STS-60 and ISWT performance in these patients. This may suggest that HD patients can benefit from different exercise interventions which can improve their overall physical function. FUNDING Portuguese Foundation of Science and Technology (SFRH/BD/138 940/2018 and UID/04 045/2020). ACKNOWLEDGEMENTS We would like to acknowledge the support of NephroCare Portugal, the University of Maia staff, MSc students and all study participants for their collaboration.

BACKGROUND AND AIMS As high serum potassium levels can lead to adverse outcomes in haemodialysis (HD) patients, dietary potassium is frequently restricted in these patients. However, recent studies have questioned whether dietary potassium really affects serum potassium levels. Dietary approaches to stop hypertension (DASH) emphasizes the consumption of potassium rich foods, specially from plant sources, such as: fruits, vegetables, whole grains, nuts and seeds. The aim of this study was to analyze the association between the DASH dietary pattern and serum potassium levels. METHOD This was an observational cross-sectional multicentre study with 582 HD patients from 37 dialysis centers. Clinical and biochemical data were registered. Dietary intake was obtained using the Food Frequency Questionnaire. Adherence to DASH dietary pattern was obtained from Fung´s DASH index (8–40 points). For the statistical analysis, Fung´s DASH index was categorized into terciles and mean differences were analyzed with one-way ANOVA. Linear regression was used to analyze the relationship between serum potassium and adherence to the Dash dietary pattern. The multivariate model was adjusted to age, gender, presence of diabetes mellitus, energy intake, dietary potassium intake, residual diuresis, dialysis adequacy (Kt/V), dialysis vintage and intake of potassium binders. All statistical tests were performed using SPSS 26.0 software. A P-value lower than 0.05, was considered statistically significant. RESULTS Patients’ mean age was 67.8 ± 17.7 years and median HD vintage was 65 (43–104) months. Mean serum potassium was 5.3 ± 0.67 mEq/L, dietary potassium intake was 2465 ± 1005 mg/day and mean Fung´s Dash Index was 23.9 ± 3.9. Of the whole sample, 36.4% of the patients presented low adherence to the DASH dietary pattern (0–22 points), 39.0% presented a moderate adherence (23–26 points) whereas 24.6% a high adherence (≥27 points). Comparing to the lower adherence, patients with a higher adherence to the DASH dietary pattern were older (P CONCLUSION Most of the patients presented a moderate adherence to the DASH dietary pattern. Following this dietary pattern, which is rich in potassium, is not associated with increased serum potassium levels in HD patients. What is more, a higher adherence to the DASH dietary pattern predicts lower serum potassium levels. Therefore, tight dietary potassium restrictions may not be adequate, at least for those with a DASH diet plan as a more flexible diet, especially regarding plant-based foods rich in potassium, may promote other health benefits and reduce patient´s dietary plan limitations.

Background and Aims Chronic kidney disease-mineral and bone disorder (CKD-MBD) is frequent in end-stage renal disease (ESRD) patients, increasing morbid-mortality. The aim of this study was to determine the prevalence and phenotype of bone disease before transplantation; and to correlate FGF23, klotho and sclerostin serum levels with bone histomorphometric parameters and CV disease. The secondary aim was to correlate bone biopsies data with other bone related parameters, as PTH, bone alkaline phosphatase, 25-hidroxivitamin D3, calcitonin, calcium, phosphorus, and magnesium. Method We performed a prospective cohort study of a sample of ESRD patients listed for renal transplant. All patients were submitted to renal transplant and were followed for 12 months. Patient and graft survival were recorded. At inclusion, demographic and clinical data were collected, laboratorial evaluation; bone biopsy and X-ray of the pelvis and hands (Adragão score) were performed. Continuous variables are presented as medians and categorical variables as frequencies. Associations between variables were performed using Wilcoxon rank sum test, Fisher and Kruskal Wallis test. Multivariate analysis was performed using logistic regression. STATA software was used and p < 0.05 was considered statistically significant. Results We included 84 patients. Median age 53.5 (IQ range: 40.5 – 61.5) years, 59 men (70.2%), 65 caucasian (77.4%). The median left ventricular mass index was 108.5 (92 – 129) g/m2, with 32 patients presenting left ventricular hypertrophy and 19 valve calcifications. Median Adragão score was 1 (0 – 2). We diagnosed adynamic bone disease in 15 patients; hyperparathyroid bone disease in 19 patients; osteomalacia in 1 patient and mixed renal osteodystrophy in 3 patients. At the end of 12 months, 4 patients died, 5 had graft failure (non-primary function) and 4 had a cardiovascular event. Sclerostin was found to be a risk factor for low bone volume; whereas low phosphorus, low FGF23 and high bAP risk factors for abnormal mineralization. High turnover was mainly present in patients with high bAP and phosphorus and low sclerostin levels. The presence of valve calcifications was associated with low volume and with low or high turnover disorder. FGF23 appears as an important independent factor for vascular calcifications [as well age (p=0.009), BMI (p=0.02), presence of diabetes (p=0.01)], and for cardiovascular events. Sclerostin emerged as a risk factor for vascular calcifications and lower levels of sclerostin were associated with patient survival at the end of 12 months. Conclusion From the bone-derived hormones, sclerostin and FGF23 seem to act as risk factors for vascular calcifications and worse outcomes.

Background and Aims Successful renal transplant restores many physiologic abnormalities, including improvement of chronic kidney disease- mineral and bone disorder (CKD-MBD) syndrome. The primary aims of this study were: analyse the changes and evolution of the 3 components of CKD-MBD pre and 1 year post renal transplantation: the mineral abnormalities, the bone disorders and the vascular calcifications; and to correlate fibroblast grow factor 23 (FGF23), klotho and sclerostin serum levels with bone histomorphometric parameters and CV disease. The secondary aims were to study the evolution of other bone related parameters and correlate those with bone biopsies data, as well as to validate Adragão vascular calcification score in a population of renal transplant patients. Method We performed a prospective cohort study of a consecutive sample of de novo single renal transplanted patients in our unit. At inclusion, demographic, clinical and transplant-related data were collected, X-ray of the pelvis and hands (for Adragão score) and echocardiographic findings were recorded. All patients were submitted to a bone biopsy and laboratorial evaluation at baseline (time 0 – T0). Patients were followed for 12 months (time 1 – T1), after which performed laboratorial evaluation, a 2nd bone biopsy, echocardiogram, X-ray of pelvis and hands, bone densitometry and non-contrast cardiac CT (Agatston score). Continuous variables are presented as medians and categorical variables as frequencies. Differences between T0 and T1 were accessed by Wilcoxon matched-pairs test and paired McNemar test. Correlations between bone histomorphometric findings and severity of vascular calcifications with demographic and laboratorial parameters were obtained with Wilcoxon rank-sum test or Kruskall Wallis test. STATA software was used and p < 0.05 was considered statistically significant. Results We recruited 84 patients in a 28 month-period. At the end of 12 months, 69 patients performed a 2nd evaluation. Median age 53 years, 48 men, 53 caucasian, median dialysis vintage 55 months. We observe a significant reduction on phosphorus, magnesium, PTH, calcitonin, sclerostin, bone alkaline phosphatase and FGF23. Both calcium and alpha-klotho serum levels increase, with no significant changes in vitamin D levels. 68% of the patients presented renal osteodystrophy at the 2nd bone biopsy, and we observed a significant increase in the development of low turnover bone disorder, with no major changes in volume or mineralization. Changes in alpha-klotho, bAP and sclerostin (from T0 to T1) were important determinants of changes in turnover, mineralization and volume, respectively. Despite not being statistically significant, we were able to observe an improvement in the cortical bone porosity. Vascular calcifications and echocardiographic findings weren’t different comparing to the baseline (Median Adragão score was 1 in both evaluations, and valve calcifications were present in 22% and 23% of patients, with no changes in LVMI). The median Agatston score was 48.5, being the median adjusted percentile of 82%. FGF23 and sclerostin were found to be independent risk factors for extra-osseous calcifications, as well as low bone volume, cortical porosity and osteoid volume. Adragão score and valve calcifications correlated well with the increased severity of coronary calcifications determined by Agatston score (absolute and percentile). Conclusion In conclusion, renal transplantation improves two of the three components of CKD-MBD (biochemical and bone disorders), slowing the progression of vascular calcifications. FGF23, sclerostin and bAP seemed to be key parameters in understanding the bone changes observed in post transplant period, and these hormones also interfere with extra osseous calcification severity. Adragão score seems to be a good tool to access vascular calcifications in renal transplanted patients.

Background and Aims Renal transplant and associated immunosuppression can influence bone volume. The aim of this study was to analyze the relations between bone biopsy data and levels of bone-related molecules [phosphorus (Pi), Calcium (Ca), Magnesium (Mg), parathyroid hormone (PTH), bone alkaline phosphatase (bAP), calcitonin, vitamin D (vitD), alpha-klotho, fibroblast grow factor (FGF) 23, sclerostin], obtained 1-year after transplantation with bone densitometry findings in the same time point in renal transplanted patients. Method We performed a prospective cohort study of a consecutive sample of de novo single renal transplanted patients in our unit. At inclusion, demographic, clinical and transplant-related data were collected, X-ray of the pelvis and hands (Adragão score) and echocardiographic findings were recorded. All patients were submitted to a laboratorial evaluation and a bone biopsy at baseline. Patients were followed for 12 months, after which performed laboratorial evaluation, 2nd bone biopsy, echocardiogram, X-ray of pelvis and hands, bone densitometry (DXA) and non-contrast cardiac CT. For this report we use the information of the 2nd analysis: laboratorial information, bone histology information, as well the densitometry evaluation. Continuous variables were presented as medians and categorical variables as frequencies. Associations between variables were performed using Wilcoxon rank-sum test, Fisher exact test, Kruskal Wallis rank test or Spearman correlation test. Multivariate analysis was performed using linear regression models. STATA software was used and p < 0.05 was considered statistically significant. Results We recruited 84 patients and, at the end of 12 months, we performed a 2nd evaluation in 69 patients. Median age 53 years, 48 men, 53 caucasian (78.8%), median BMI 24.6, median dialysis vintage 55 months. Patients had a median cumulative steroid dose of 5692.5 mg. Analyzing bone biopsies, we found that 28 patients had adynamic bone disease; 6 had hyperparathyroid bone disease; 2 had osteomalacia and 3 other abnormal mineralization; 8 patients presented only with osteoporosis. There was no significant difference between bone volume / total volume pre transplant (18%) and 1 year after transplantation (19%). Using DXA technique, 14 patients were classified has having osteoporosis, and all those had low volume at the bone biopsy. Nevertheless, in 4 patients low bone turnover was also present. The positive predictive value dropped from 100% to 57%, if we add the other abnormalities of bone, in addiction to the volume. DXA exam wasn’t a good tool to detect a normal bone volume, as the negative predicted value dropped from 78% (normal volume, irrespective of turnover and mineralization) to 37% (normal bone biopsy). Nevertheless, overall bone volume assessed by a bone biopsy correlated well with densitometry findings. Conclusion DXA exam isn’t a good tool to identify the bone quality. Nevertheless, once osteoporosis is detected the probability of the patient having low bone volume is high, but we still need a bone biopsy in order to exclude mineralization or turnover deviations.

Background and Aims Bone fragility fractures (bone fractures) are extremely frequent in haemodialysis (HD) patients. Serum phosphate (P) has been suggested as a risk factor for bone fracture, nonetheless, evidence is poor. The aim of this study was to assess the association between incidence of bone fractures and serum phosphate (P), calcium (Ca) and parathyroid hormone (PTH) in patients from the COSMOS study. Method COSMOS is an observational, prospective, open cohort study with 3 years of follow-up including 6797 haemodialysis patients from 227 centres randomly selected from 20 European countries. At baseline, demographics, comorbidities, treatments, serum biochemical parameters of the previous six months and bone fractures of the previous 12 months were collected. Every 6 months, all these variables, outcomes, and incident bone fractures, were collected. Patients who had at least one bone fracture during follow-up were compared with those who had not. Multivariate binary logistic regression and Poisson regression were used to assess the association between incidence of bone fractures and serum P, Ca and PTH. Time to fracture (and possible re-fracture) was also evaluated using Cox regression and Cox regression for recurrent events. All the results were adjusted by 23 variables including Ca, P, PTH, albumin and haemoglobin (full adjusted model). Results Analysis included 6274 patients who had follow-up data and non-missing information regarding bone fractures at baseline and during follow-up; 252 patients (4.0%), suffered at least one incident bone fracture. The fractured patients were older (68.1±12.9 vs. 63.8±14.5 years, p Multivariate binary logistic regression showed that “well known risk factors for bone fracture”, such as a previous bone fracture (OR: 7.78[95%CI:4.83-12.55], p 800 pg/mL (OR: 1.60[95%CI: 1.01-2.55], p=0.047), were associated with a higher incidence of follow-up bone fractures. In addition to the “well known bone risk factors for fracture”, serum P > 6.1 mg/dL (OR: 1.50[95% CI: 1.07-2.11], p=0.02) and serum Ca > 9.7 mg/dL (OR: 1.42[95%CI: 1.01-2.03], p=0.043), were also associated with a higher incidence of bone fractures in the full-adjusted model. These findings were partly consistent with Poisson regression for serum P >6.1 mg/dL (IRR: 1.46[95% CI: 1.00-2.13], p=0.0085) and serum Ca > 9.7 mg/dL (IRR: 1.49[95%CI: 1.06-2.08], p=0.0047), but not for PTH. In addition, Cox regression analysis showed association between bone fractures and serum P >6.1 mg/dl (HR: 1.61 [95%CI: 1.16-2.24], p=0.0049) and 1.60 [95%CI: 1.14-2.24] (p=0.0066) for simple and recurrent events respectively, but no association was found with serum Ca and PTH in the 2 full-adjusted models for the Cox regression analyses. Conclusion In COSMOS, a large haemodialysis patient’s cohort with 3 years follow up, serum P was the only biochemical parameter that remained as a significant risk factor for bone fractures after 4 statistic approaches. Thus, for the first time, in a large scale well controlled study, high serum P has been identified as a new independent potential risk factor for incident bone fractures in haemodialysis patients.

Background and Aims Renal transplant and associated immunosuppression can influence bone volume. Presently, the data is conflicting with older studies showing bone loss after transplant, while recent ones didn’t conclude the same. The aim of this study was to analyse the relations between bone-related molecules [phosphorus (Pi), Calcium (Ca), Magnesium (Mg), parathyroid hormone (PTH), bone alkaline phosphatase (bAP), calcitonin, vitamin D (vitD), alpha-klotho, fibroblast grow factor (FGF) 23, sclerostin] and bone densitometry findings in renal transplanted patients. Method We performed a prospective cohort study of a consecutive sample of de novo single renal transplanted patients in our unit. At inclusion, demographic, clinical and transplant-related data were collected, X-ray of the pelvis and hands (Adragão score) and echocardiographic findings were recorded. All patients were submitted to a laboratorial evaluation and a bone biopsy at baseline (time 0). Patients were followed for 12 months, after which performed laboratorial evaluation, 2nd bone biopsy, echocardiogram, X-ray of pelvis and hands, bone densitometry (DXA) and non-contrast cardiac CT for Agatston score (time 1). Continuous variables are presented as medians and categorical variables as frequencies. Associations between variables were performed using Wilcoxon matched-pairs test and Spearman correlation test. STATA software was used and p < 0.05 was considered statistically significant. Results We recruited 85 patients from 1st October 2015 to 1st March 2018. At the end of 12 months, 6 patients refuse to perform the 2nd evaluation, 5 had primary non-function of the kidney graft, 1 had no 1st bone biopsy sample in time 0 and 4 patients died. We performed a 2nd evaluation in 69 patients and included those in this study. Mean age 50.2±12.4 years, 48 men, 53 caucasian (78.8%), median BMI 24.5 (22.7 – 27.8), median dialysis vintage 55 months (42 – 84). Patients had a median cumulative steroid dose of 5692.5 (5260 – 7250) mg. At 12 months, the median FRAX value for osteoporotic fracture was 3.5 (2.2 – 6.2) and for femoral neck fracture was 0.8 (0.2 – 2.7). The DXA findings are shown in Table 1. We found a negative correlation between vascular calcifications (Agatston Score and respective calcium percentile) and T and Z score of femoral neck (p=0.04), but not with the other DXA variables. Total femur variables (DMO, T-score, Z-score) were correlated with sclerostin values in time 1 (p Conclusion We found an inverse correlation between T and Z scores of femoral neck and coronary vascular calcifications. Regarding bone-derived hormones, Spine T and Z scores and FRAX values negatively correlated with alfa-klotho. Sclerostin seems to be associated with high mineral density.

Background and Aims Chronic kidney disease-mineral and bone disorder (CKD-MBD) is frequent in end-stage renal disease ESRD (ESRD) patients, increasing morbid-mortality. The aim of this study was to analyse the associations between the new CKD-MBD players [alpha-klotho, fibroblast grow factor (FGF) 23, sclerostin] and the usual markers of the disease [parathyroid hormone (PTH), bone alkaline phosphatase (bAP), vitamin D (vitD), phosphorus (Pi), Calcium (Ca) and Magnesium (Mg)], as well echocardiographic findings [left ventricular mass index (LVMI) measured by Devereux formula, valvular calcifications], vascular calcifications and patients outcomes. Method We performed a prospective cohort study of a sample of ESRD patients listed for renal transplant. All patients were submitted to renal transplant and were followed for 12 months. Patient and graft survival were recorded. At inclusion, demographic and clinical data were collected, laboratorial evaluation, bone biopsy and X-ray of the pelvis and hands (Adragão score) were performed. Continuous variables are presented as medians and categorical variables as frequencies. Associations between variables were performed using Wilcoxon rank sum test and Spearman correlation test. STATA software was used and p < 0.05 was considered statistically significant. Results We included 85 patients. Mean age 50.1±12.7 years, 59 men (69.4%), 66 caucasian (77.6%). The median LVMI was 108.5 (92 – 129) g/m2, with 32 patients presenting LVH and 19 valvular calcifications. Median Adragão score was 1 (0 – 2). At the end of 12 months, 4 patients died and 5 had graft failure (non-primary function). Alpha-klotho correlated with bAP (p=0.0006) and marginally with PTH and absence of valvular calcifications (p=0.05). FGF23 correlated with Pi (p Sclerostin correlated negatively with bAP (p=0.007) and PTH (p=0.04). The 3rd sclerostin tertile was associated with high scores of vascular calcifications (p=0.02). Lower levels of sclerostin were associated with patient survival at the end of 12 months (p=0.02). Conclusion From these 3 new bone-derived hormones, sclerostin, a bone formation inhibitor, seems to act as a risk factor for vascular calcifications and worse outcomes.

Background and Aims Body composition influences outcomes in hemodialysis (HD) patients. These patients need to follow specific nutritional recommendations and physical activity has been highly encouraged. The aim of this study was to evaluate if there are differences in body composition and in dietary patterns between physically active and no physically active HD patients. Method This was a multicenter observational cross-sectional study where 582 HD patients from 38 dialysis centers were enrolled. Clinical parameters were recorded and body composition analysis was performed with the Body Composition Monitor®. Dietary intake and physical activity were obtained respectively from the Food Frequency Questionnaire and from the International Physical Activity Questionnaire, both validated for the Portuguese population. For the analysis, patients were divided in 2 groups: physically active (PA), if they follow the World Health Organization recommendations, and no physically active (NPA). T-student and non-parametric tests were performed to compare means and medians respectively. A p Results Mean age was 67.8 ±17.7 years, 41.4% were female, 31.6 % had diabetes mellitus and median HD vintage was 65 (Interquartil range:43-104) months. PA patients were younger (p Conclusion These data shows that, after comparing PA patients with NPA, differences were observed in body composition and clinical parameters related to a better nutritional status. Moreover, the PA patients` dietary intake was more approximated to the existing recommendations for this population, namely for energy and protein daily intake.

Background and Aims Successful renal transplant restores many physiologic abnormalities, including improvement of chronic kidney disease-mineral and bone disorder (CKD-MBD) syndrome, and modifications of bone-related molecules in disease and health can help to understand pathophysiology of this syndrome. The aim of this study was to analyse the evolution of some of the new CKD-MBD players [alpha-klotho, fibroblast grow factor (FGF) 23, sclerostin] pre and post transplantation and the associations between those and the usual markers of the CKD-MBD disease [parathyroid hormone (PTH), bone alkaline phosphatase (bAP), calcitonin, vitamin D (vitD), phosphorus (Pi), Calcium (Ca) and Magnesium (Mg)] pre and post transplant. We also looked at the differences between values in the two time-points (delta). Method We performed a prospective cohort study of a consecutive sample of de novo single renal transplanted patients in our unit. At inclusion, demographic, clinical and transplant-related data were collected, X-ray of the pelvis and hands (for Adragão score) and echocardiographic findings were recorded. All patients were submitted to a bone biopsy and laboratorial evaluation at baseline (time 0). Patients were followed for 12 months (time 1), after which performed laboratorial evaluation, a second bone biopsy, echocardiogram, X-ray of pelvis and hands, bone densitometry and non-contrast cardiac CT (Agatston score). Continuous variables are presented as medians and categorical variables as frequencies. Associations between variables were performed using Wilcoxon matched-pairs test and Spearman correlation test. STATA software was used and p < 0.05 was considered statistically significant. Results We recruited 85 patients from 1st October 2015 to 1st March 2018. At the end of 12 months, 6 patients refuse to perform the 2nd evaluation, 5 had primary non-function of the kidney graft, 1 had no sample on bone biopsy in time 0 and 4 patients died. We performed a 2nd evaluation in 69 patients and included those in this study. Mean age 50.2±12.4 years, 48 men, 53 caucasian (78.8%), median BMI 24.5 (22.7 – 27.8), median dialysis vintage 55 (42 – 84). We observe a significant reduction on phosphorus (delta: -1.1 mg/dl), magnesium (delta: -0.5 mg/dl), PTH (delta: -297.7 pg/ml), Calcitonin (delta: -0.9 ng/L), sclerostin (delta: -1.1 ng/ml), bone alkaline phosphatase (delta: -11.5 U/L) and FGF23 (delta: -1656.5 RU/ml). Both calcium (delta: 0.7 mg/dl) and alpha-klotho (delta: 265.7 pg/ml) serum levels increase, with no significant changes in vitamin D levels. With restoring renal health (time 1) and comparing with time 0, PTH maintain the negative correlation with sclerostin (p=0.02) and the positive correlation with FGF23 (p=0.0002) as in time 0; modify the correlation with Pi, becoming a negative correlation instead of positive (p=0.001) and gain new correlations with Ca (p=0.001) and vitamin D levels (p=0.03). Also, PTH correlated with the delta FGF23 (rho=-0.4, p=0.003) and sclerostin correlated with delta PTH (p=0.01). FGF23 didn’t associate with delta PTH, neither PTH associated with delta sclerostin. FGF23 didn’t reveal statistical association with Pi or Ca levels after transplant, contrasting with positive associations in pre transplant (p=0.002, p Conclusion In conclusion, it seems that sclerostin influences PTH levels and that PTH is the stimulus for the increase or decrease of FGF23 serum levels (as we found a positive association between those two molecules in both time-points and a negative association between PTH and the difference of FGF23 pre and post transplant). Levels of Ca and Pi seemed to be directly influenced by the level of PTH in post transplant, and those minerals seemed to be key factors for sclerostin secretion.

Background and Aims Type 1 diabetes mellitus (DM1) is associated with an increased risk of coronary heart disease (CHD), which is generally more aggressive and frequently asymptomatic. This risk substantially increases for those with nephropathy. In selected patients, simultaneous pancreas-kidney transplantation (SPKT) is the renal and pancreatic replacement therapy of choice, as it increases longevity and stabilizes diabetic complications. Despite essential, universal screening protocols for silent CHD in this population are still debatable. As so, Gowdak recently developed a simple clinical risk score to determine the pre-test probability of significant CHD in single kidney transplant candidates. Our aim was to identify potential risk factors associated with the presence of significant lesions on pre-SPKT coronary angiography (CA) and test the utility of Gowdak score in SPKT candidates. Method 77 patients submitted to SPKT between 2011 and 2018 were retrospectively included in this study. All subjects underwent CA as screening method for CHD during the eligibility evaluation. Demographic, clinical, laboratory, therapeutic and imaging characteristics were studied. Continuous variables are presented as means or medians; categorical variables as frequencies. Univariate analysis (Qui2 or Fisher test) and multivariate analysis (logistic regression) were performed. Comparison between groups of patients with and without CA injury was performed using SPSS statistics version 23 and a p Results In the past 8 years, 99 SPKT were performed; 78% of these patients (N=77) were submitted to preoperative CA; mean age was 36±5.9 years and 64% were male. The mean duration of DM1 was 25 years and 97% had retinopathy, 43% neuropathy, 31% dysautonomia, 19% peripheral arterial disease and 7% cerebrovascular disease. We excluded 1 due to missing data. A minority of SPKT (3%, N=2) was preemptive. The mean time on dialysis was 37 months. Only one patient had angor, wh0 was excluded of Gowdak risk score assessment. Most patients (87%, N=67) were hypertensive; 56% (N=43) were on statin; 48% (N=37) had smoking habits, and 5% (N=4) had a BMI>30 kg/m2. CA identified at least one lesion in 48% (N = 37) of the patients, of which 30% (N=11; 14% of all CA) underwent intervention; none had complaints of angor. Based on Gowdak risk score, mean probability for CHD was 30.8% and 19 patients had a risk >40% - the recommended cut off to pursuit CA as screening method - but only 2 required intervention. In a univariate analysis, we found that the only distinguishing feature between the group of patients with and without CA lesions was smoking (p=0.005). DM1 with 20 or more years of evolution was found to have a significant association with coronary artery disease development (identifiable by any diagnostic test) (p=0.048). In our population of SPKT recipients Gowdak risk score did not predicted those with significant CHD. Conclusion In our study, CA was positive for lesion in almost half of the patients, all of them asymptomatic. Despite the fact that Gowdak probability score failed to identify those with significant CHD before CA (probably because all of our patients were diabetic), in our population for every seven patients submitted to CA, one needed coronary intervention. We highlight that asymptomatic patients with long-term DM and smokers should be carefully evaluated. The task of correctly ascertaining the presence of CAD can be more overwhelming when we take into account that there is a high prevalence of asymptomatic patients with extensive CAD. Facing the importance of an unmissed diagnosis we encourage the use of CA as an initial screening method, even if it is invasive. Further studies should be encouraged to create screening algorithm for SPKT candidates. Finally, medium- and long-term follow-up studies are needed to evaluate the effects of preoperative selection on posttransplant cardiac events and survival rates.

Background and Aims Chronic kidney disease – mineral and bone disorder (CKD-MBD) is a well-known syndrome in end stage renal disease. Vascular calcifications are one of its components. Renal transplantation seemed to halt the progression of vascular calcifications. The aim of this study was to analyse the progression of vascular calcifications in a cohort of renal transplanted patients, and the associations of those with the old and new bone-derived hormones. Method We performed a prospective cohort study of a consecutive sample of de novo single renal transplanted patients in our unit. All patients were submitted to a bone biopsy and laboratorial evaluation at baseline (time 0) including measurements of calcium (Ca), phosphorus (Pi), magnesium (Mg), vitamin D (vitD), calcitonin, parathyroid hormone (PTH), bone alkaline phosphatase (bAP) and total alkaline phosphatase (tAP), alpha-klotho, fibroblast grow-factor 23 (FGF23) and sclerostin. Patients were followed for 12 months, after which performed a second bone biopsy and laboratorial evaluation (time 1). At inclusion, demographic, clinical and transplant-related data were collected, X-ray of the pelvis and hands (Adragão score) and echocardiographic findings were recorded. At the end of the study, echocardiogram, X-ray of pelvis and hands, bone densitometry and non-contrast cardiac CT (Agatston score) were performed. Immunosuppression included induction therapy followed by tacrolimus, mycophenolate mofetil and prednisolone. Continuous variables are presented as medians and categorical variables as frequencies. Associations between variables were performed using Wilcoxon rank sum test and Spearman correlation test. STATA software was used and p < 0.05 was considered statistically significant. Results We recruited 85 patients from 1st October 2015 to 1st March 2018. Mean age 50.1±12.7 years, 59 men (69.4%), 66 caucasian (77.6%), median BMI 25.1±3.4. At the end of 12 months, 6 patients refuse to perform the 2nd evaluation, 5 had primary non-function of the kidney graft, 1 had no sample on bone biopsy in time 0 and 4 patients died. We performed a 2nd evaluation in 69 patients and included those in this study. The median baseline and 12 months Adragão score had no differences [1 (0 – 2)]. The median coronary artery calcium score was 48.5 (0 – 535) and median percentile was 80 (0 – 92.5). Valvular calcifications were present in 15 and 16 patients at baseline and after 1 year respectively, with no statistical difference between the two time points. Coronary artery calcium scores were correlated with age (p Conclusion In conclusion, vascular calcifications stabilize after renal transplant. Adragão score, that is a less expensive exam than cardiac CT, can assess vascular calcifications in renal transplanted patients. Only calcium and sclerostin correlated with both Agatston scores and coronary calcium percentiles.

Background and Aims Diabetes is the most common cause of chronic kidney disease (CKD) stage 5 and a relevant risk factor for mortality. The available CKD-MBD guidelines do not make differences between diabetics and non-diabetics regarding the optimal targets of the serum bone and mineral biochemical parameters. Thus, the objective of this analysis of COSMOS was to compare the association between the main serum bone and mineral biochemical parameters (calcium-Ca, phosphorus-P and parathyroid hormone-PTH) and mortality in diabetic and non-diabetic patients in haemodialysis. Method COSMOS is a 3-year, observational, prospective, open-cohort study that includes 6797 patients from 227 dialysis centres that were randomly selected from 20 European countries. Cox proportional hazard regression models with penalized splines smoothing were used to analyse the association between relative risk of mortality vs. Ca, P or PTH. Hazard ratios were adjusted by demographics, comorbidities, treatments and biochemical parameters. Interaction analysis was used to analyse if diabetes can influence the association between relative risk of mortality and Ca, P and PTH. Results The present analysis includes 6306 patients with follow-up data and accurate information on diabetes status. The mortality rate in COSMOS was 13.3 deaths per 100 patient-years (17.8 in diabetics and 11.4 in non-diabetics). At baseline, diabetic patients were older (66.7 ± 11.7 vs. 62.8 ± 15.3 years, p Conclusion These results suggest for the first time a differential effect of diabetes on the association between relative risk of mortality and serum PTH. High serum PTH predicts death only in diabetics. These findings could have relevant implications for the diagnosis and treatment of CKD-MBD in diabetic and non-diabetic patients in haemodialysis.

Purpose Using an institution-based view, this study aims to conceptualize how sub-national institutional characteristics are likely to explain location choice of multinationals’ research and development (R&D) subsidiaries. Design/methodology/approach In a conceptual paper, this study explores specific institutional facets of the regional environments within a country that are capable of explaining, at least in part, the location choices of multinational corporations’ R&D subsidiaries. Findings This study thus explores the more nuanced influences of the institutional environments at a subnational level and develops propositions to explain location choices based on the differences of the institutional environments. Originality/value This study contributes to international business theory by incorporating a location-specific analysis that contrasts to the usual country-level observation on the determinants of firms’ location decisions.

Background Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.Methods We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1.73 m(2) of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0.75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0.75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for >= 30 days) or end-stage kidney disease (eGFR = 90 days, chronic dialysis for >= 90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials. gov, number NCT01858532.Findings Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2.2 years (IQR 1.4-2.9). 79 (6.0%) of 1325 patients in the atrasentan group and 105 (7.9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0.65 [95% CI 0.49-0.88]; p=0.0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3.5%) of 1325 patients in the atrasentan group and 34 (2.6%) of 1323 patients in the placebo group (HR 1.33 [95% CI 0.85-2.07]; p=0.208). 58 (4.4%) patients in the atrasentan group and 52 (3.9%) in the placebo group died (HR 1.09 [95% CI 0.75-1.59]; p=0.65).Interpretation Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Institutional inefficiencies are likely to lead firms to approach ownership in cross-border acquisitions more carefully, possibly undertaking only a partial equity stake on the target firms. Howeve...