Bone pathology and cardiovascular disease in chronic kidney disease : new biomarkers and mediators of the bone-kidney-vessel axis

SUMMARY The studies included in this thesis contributed to clarify the role of some non-traditional cardiovascular risk factors, such as native vitamin D and serum magnesium, in hemodialysis patients. These biomarkers / mediators consolidate the existence of a strong interconnection between bone and cardiovascular disease in chronic kidney disease. Magnesium also appears to have an important role, until now underestimated, in the synthesis and metabolism of vitamin D. In some clinical situations, magnesium supplementation can reverse the resistance to therapy with native vitamin D, ensuring adequate levels of vitamin D, with a particularly positive impact on cardiovascular mortality. It is therefore essential to ensure adequate levels of magnesium in order to optimize the benefits of vitamin D supplementation in chronic kidney disease patients. We also proposed, for the first time, to evaluate the incidence of bone fractures in a large population of prevalent hemodialysis patients in Portugal and study their possible association with markers of bone disease and cardiovascular risk factors. Main results of the studies included in this thesis: - Deficiency of native vitamin D (calcidiol) and chronic kidney disease This study included 223 patients on hemodialysis who underwent two determinations, separated by 6 months of 25-hydroxyvitamin D 25(OH)D and 1,25-dihydroxyvitamin D 1,25(OH)2D. We found deficient levels (< 15 ng/mL) of 25(OH)D in 33.6% of the patients and insufficient levels (15 - 30 ng/mL) in 45.8% of the patients. We observed a positive association between 25(OH)D and 1,25(OH)2D levels and a negative association between 25(OH)D levels and age, diabetes mellitus, and markers of inflammation such as C-reactive protein. We also identified, for the first time, cardiovascular risk factors associated with insufficiency / deficiency in native vitamin D in hemodialysis patients. In the univariable analysis, serum 25(OH)D levels were negatively associated with brain natriuretic peptide (BNP) levels, with an elevated pulse pressure (≥ 65 mmHg) and with the presence of more vascular calcifications. In the multivariable analysis, low serum 25(OH)D levels were also independently associated with high BNP values, a pulse pressure ≥ 65 mmHg and a vascular calcification score ≥ 3. We demonstrated that baseline serum levels of 25(OH)D appear to be an excellent marker of global and cardiovascular morbidity and mortality in hemodialysis patients. In a 48-month prospective evaluation, we found that baseline serum levels of 25(OH)D were significantly lower in patients who died of all causes and in those who died of cardiovascular causes. Baseline serum 25(OH)D levels were also lower in patients who required hospitalization during the study. Considering these apparent protective effects of 25(OH)D on cardiovascular system dysfunction, we carried out a prospective study with a 5-year follow-up, on 97 hemodialysis patients, in which they were supplemented with oral cholecalciferol during hemodialysis sessions. Given the lack of specific recommendations regarding supplementation doses to be used in hemodialysis patients, we decided to transpose the proposals of the KDOQI guidelines for the pre-dialysis stage of chronic kidney disease to our population. We demonstrated a significant increase in serum 25(OH)D levels after 6 months (23.1 ± 13.2 vs. 39.9 ± 11.1 ng/mL; p 30 ng/mL) at the end of the study, compared to only 18% at the beginning of the study. Patients whose 25(OH)D levels did not increase were all diabetic and had hypomagnesemia (serum magnesium < 0.7 mmol/L). In clinical practice, we emphasize the importance of excluding magnesium deficiency in patients who, despite high doses, do not respond to native vitamin D supplementation. Serum levels of calcium, phosphorus and intact parathormone (iPTH) were significantly reduced with supplementation. On the contrary, there was an increase in serum magnesium. We also demonstrated a reduction in the number of patients treated with active vitamin D, a decrease in doses of erythropoiesis-stimulating agent, a reduction in C-reactive protein, and an increase in albuminemia. Finally, we found that supplementation with cholecalciferol was associated with a significant reduction in plasma BNP levels, pulse pressure, and left ventricular mass index. The supplementation was well tolerated, with no documented adverse effects (namely hypercalcemia greater than 10.5 mg/dL), and none of the patients achieved serum 25(OH)D levels considered toxic (> 100 ng/mL). These results demonstrated that long-term cholecalciferol supplementation in hemodialysis patients was safe, allowed correction of 25(OH)D deficiency, improved mineral metabolism control, attenuated the inflammatory state, and improved cardiac dysfunction. - Serum magnesium and chronic kidney disease In a 48-month prospective study, performed on 206 prevalent hemodialysis patients, we observed a mean pre-dialysis serum magnesium concentration of 1.36 ± 0.18 mmol/L and that none of the patients presented hypomagnesemia (magnesium < 0.7 mmol/L). In univariable analysis, pre-dialysis serum magnesium levels were negatively associated with age, diabetes mellitus, pulse pressure, left ventricular mass index and vascular calcifications. There was a positive association between serum magnesium and albumin. In multivariable analysis, lower magnesium concentrations were predictors of increased pulse pressure (≥ 65 mmHg) and left ventricular mass index (≥ 140 g/m2), and of a higher vascular calcification score (≥ 3). We also found that patients with serum magnesium < 1.15 mmol/L had lower survival at the end of the 48-month follow-up. Based on these results, we studied the effects of a phosphate binder with magnesium and low calcium concentration (calcium acetate / magnesium carbonate), for the treatment of hyperphosphatemia, whose effects on the cardiovascular system remain to be determined. We evaluated, in a 48-month prospective study, the relationship between calcium acetate / magnesium carbonate therapy and markers of cardiovascular risk, already validated in this population of hemodialysis patients, such as pulse pressure, left ventricular mass index and cardiac valve calcifications. Forty patients were on calcium acetate / magnesium carbonate therapy, 52 patients were on sevelamer and 114 were not taking phosphate binders. Patients taking calcium acetate / magnesium carbonate had higher serum magnesium levels compared to the other two groups. At the end of the study, we found that patients who were on calcium acetate / magnesium carbonate showed a reduction in pulse pressure, left ventricular mass index, and aortic and mitral valve calcifications compared to patients who were not taking phosphate binders. Compared to patients on sevelamer, patients on calcium acetate / magnesium carbonate had a reduction in pulse pressure, left ventricular mass index, and aortic valve calcifications. In multivariable analysis, therapy with calcium acetate / magnesium carbonate was inversely associated with the progression of left ventricular hypertrophy and aortic valve calcifications. In this 48-month prospective study, we observed for the first time that the use of calcium acetate / magnesium carbonate in the control of hyperphosphatemia in hemodialysis patients was associated with a reduction in pulse pressure and left ventricular mass index and stabilization of cardiac valvular calcifications. - Bone fractures: incidence and risk factors in chronic kidney disease We performed a retrospective analysis on 341 prevalent patients on hemodialysis since the beginning of the dialysis technique (median of 51 months). Fifty-seven episodes of fragility fractures were identified, with a median time on hemodialysis of 47 months, which corresponded to an incidence rate of 31 per 1,000 person-years. In univariable analysis, compared to patients without fractures, those who presented fractures were more frequently female and older patients, with longer hemodialysis vintage, diabetics, had a lower body mass index and lower albumin values. Patients who had fractures were less frequently receiving active vitamin D therapy and had a higher vascular calcification score. Therapy with phosphate binders or calcimimetics was not associated with the development of fractures. A significantly higher risk of fractures was also associated with higher bone alkaline phosphatase values and iPTH levels 800 pg/mL, compared to levels between 300 - 800 pg/mL. Analysis of long-term fracture-free survival demonstrated that patients with iPTH 800 pg/mL (HR: 3.48) had a significantly higher risk of fragility fractures. In multivariable analysis, age, female gender, longer time on dialysis, lower serum albumin levels and the presence of more vascular calcifications were independently associated with a higher risk of bone fractures. On the other hand, active vitamin D therapy was associated with a decreased risk. In this study, with a long follow-up, we observed that the incidence of fragility bone fractures in prevalent hemodialysis patients was high, and their risk appears to increase with age, female gender, presence of inflammation and more vascular calcifications. Bone disease associated with uremia also appeared to be an important factor in the development of fractures, as patients with lower or higher iPTH levels and increased bone alkaline phosphatase had a higher risk of fracture. On the other hand, active vitamin D therapy appeared to have a protective effect

Characterization of the bacterial population in water dams of the Sado watershed

As barragens são fundamentais para a gestão dos recursos hídricos. Estas infraestruturas permitem regular os caudais e aproveitar a água para diversas atividades como a agricultura, pecuária, captação para consumo humano e turismo (p.e. praias fluviais e despor tos aquáticos). Neste estudo, foi avaliada a flora bacteriana (planctónica e organizada em biofilmes) presente em 4 barragens da bacia hidrográfica do rio Sado. A caracterização da flora bacteriana presente para além de permitir a caracterização do ecossistema permite inferir sobre potenciais riscos para a saúde humana decorrentes dos diversos usos da água.Water dams are crucial for water management. These inf rastructures al low the control of water f lows and usage of water for acti vi ties such as agr iculture, li vestock, for human consumption and tour ism (e.g. beaches and aquatic spor ts). In this study, the bacter ial f lora present in four dams located at the hydrographic basin of Sado r i ver was evaluated (plank tonic and organized in biof ilms). The character ization of the bacter ial f lora al lows the character ization of the ecosystem and speculate about the potential r isks for human heal th caused by water usage for di f ferent applications.info:eu-repo/semantics/publishedVersio

Estado nutricional e hiperhidratación: ¿la bioimpedancia espectroscópica es válida en pacientes en hemodiálisis?

Background: Protein-energy wasting (PEW), associated with inflammation and overhydration, is common in haemodialysis (HD) patients and is associated with high morbidity and mortality. Objective: Assess the relationship between nutritional status, markers of inflammation and body composition through bioimpedance spectroscopy (BIS) in HD patients. Methods: This observational, cross-sectional, single centre study, carried out in an HD centre in Forte da Casa (Portugal), involved 75 patients on an HD programme. In all participating patients, the following laboratory tests were conducted: haemoglobin, albumin, C-reactive protein (CRP) and 25-hydroxyvitamin D3 [25(OH)D3]. The body mass index of all patients was calculated and a modified version of subjective global assessment (SGA) was produced for patients on dialysis. Intracellular water (ICW) and extracellular water (ECW) were measured by BIS (Body Composition Monitor®, Fresenius Medical Care®) after the HD session. In statistical analysis, Spearman’s correlation was used for the univariate analysis and linear regression for the multivariate analysis (SPSS 14.0). A P value of <.05 was considered statistically significant. Results: PEW, inversely assessed through the ICW/body weight (BW) ratio, was positively related to age (P<.001), presence of diabetes (P=.004), BMI (P=.01) and CRP (P=.008) and negatively related to albumin (p=.006) and 25(OH)D3 (P=.007). Overhydration, assessed directly through the ECW/BW ratio, was positively related with CRP (P=.009) and SGA (P=.03), and negatively with 25(OH)D3 (P=.006) and BMI (P=.01). In multivariate analysis, PEW was associated with older age (P<.001), the presence of diabetes (P=.003), lower 25(OH)D3 (P=.008), higher CRP (P=.001) and lower albumin levels (P=.004). Over-hydration was associated with higher CRP (P=.001) and lower levels of 25(OH)D3 (P=.003). Conclusions: Taking these results into account, the ICW/BW and ECW/BW ratios, assessed with BIS, have proven to be good markers of the nutritional and inflammatory status of HD patients. BIS may be a useful tool for regularly assessing the nutritional and hydration status in these patients and may allow nutritional advice to be improved and adjusted.RESUMEN - Antecedentes: El desgaste proteico-energético (DPE asociado a inflamación e hiperhidratación, es común en pacientes en hemodiálisis (HD) y se asocia a mayor morbilidad y mortalidad. Objetivo: Evaluar la relación entre el estado nutricional, los marcadores inflamatorios y la composición corporal a través de bioimpedancia espectroscópica (BIS) en pacientes en HD. Métodos: En este estudio observacional, transversal, unicéntrico, realizado en un centro de HD en Forte da Casa (Portugal), participaron 75 pacientes en programa de HD. En todos los participantes se hicieron las siguientes determinaciones analíticas: hemoglobina, albúmina, proteína C reactiva (PCR) y 25-hidroxivitamina D3 [25(OH)D3]. Se calculó el índice de masa corporal (IMC) de todos los pacientes y se aplicó una versión modificada de la valoración global subjetiva (VGS) para pacientes en diálisis. El agua intracelular (AIC) y extracelular (AEC) se midió con BIS (Body Composition Monitor®, Fresenius Medical Care®) después de la sesión de HD. En el análisis estadístico se utilizó la correlación de Spearman para el análisis univariante y la regresión lineal para el análisis multivariante (SPSS 14.0). Una p < 0,05 se consideró estadísticamente significativa. Resultados: El DPE, evaluado inversamente a través de la relación AIC/ peso corporal (PC), se relacionó positivamente con la edad (p < 0,001), la presencia de diabetes (p = 0,004), el IMC (p = 0,01) y la PCR (p = 0,008) y negativamente con la albúmina (p = 0,006) y la 25(OH)D3 (p = 0,007). La hiperhidratación, evaluada directamente a través de la relación AEC/PC, se relacionó positivamente con la PCR (p = 0,009) y con la VGS (p = 0,03), y negativamente con la 25(OH)D3 (p = 0,006) y el IMC (p = 0,01). En el análisis multivariante, el DPE se asoció a edad más elevada (p < 0,001), presencia de diabetes (p = 0,003), 25(OH)D3 más baja (p = 0,008), PCR más elevada (p = 0,001) y niveles de albúmina más bajos (p = 0,004). La hiperhidratación se asoció a PCR más elevada (p = 0,001) y niveles de 25(OH)D3 más bajos (p = 0,003). Conclusiones: Teniendo en cuenta estos resultados, las relaciones AIC/PC y AEC/PC, evaluadas con BIS, han demostrado ser buenos marcadores del estado nutricional e inflamatorio de pacientes en programa de HD. La BIS puede ser una herramienta útil para evaluar regularmente el estado nutricional y de hidratación en estos pacientes y puede permitir mejorar y adecuar el asesoramiento nutricional

Lower serum magnesium is associated with cardiovascular risk factors and mortality in haemodialysis patients

Publisher Copyright: © 2015 S. Karger AG, Basel.Background: Hypomagnesaemia is a cardiovascular (CV) risk factor in the general population. The aim of this study was to evaluate the relationship between pre-dialysis magnesium (Mg) and CV risk markers, [including pulse pressure (PP), left ventricular mass index (LVMI) and vascular calcifications (VC)], and mortality in haemodialysis (HD) patients. Methods: We performed a 48-month prospective study in 206 patients under pre-dilution haemodiafiltration with a dialysate Mg concentration of 1 mmol/l. Results: Lower Mg concentrations were predictors of an increased PP (≥65 mm Hg) (p = 0.002) and LVMI (≥140 g/m2) (p = 0.03) and of a higher VC score (≥3) (p = 0.01). Patients with Mg <1.15 mmol/l had a lower survival at the end of the study (p = 0.01). Serum Mg <1.15 mmol/l was an independent predictor of all-cause (p = 0.01) and CV mortality (p = 0.02) when adjusted for multiple CV risk factors. Conclusions: Lower Mg levels seem to be associated with increased CV risk markers, like PP, LVMI and VC, and with higher mortality in HD patients.publishersversionpublishe

Prevalence, awareness and control of diabetes in Portugal: results from the first National Health Examination Survey (INSEF 2015)

A Diabetes Mellitus é uma grande ameaça para a saúde pública em todo o mundo, continuando a aumentar em prevalência e significado. As estimativas da sua prevalência, conhecimento e controlo são essenciais para monitorizar as suas tendências de forma efetiva. Neste contexto, foi realizado o primeiro Inquérito Nacional de Saúde com Exame Físico (INSEF) à população residente em Portugal, com idade compreendida entre os 25 e os 74 anos, em 2015. O INSEF consistiu num estudo transversal de prevalência, que incluía a medição do nível de HbA1c no sangue, um exame físico e uma entrevista geral de saúde. A prevalência geral de diabetes foi estimada em 9,9% (IC95%: 8,4; 11,5), sendo mais elevada nos homens do que nas mulheres (12,1% vs 7,8%). A diabetes era mais prevalente entre os indivíduos que apresentavam baixa escolaridade e sem atividade profissional. A maioria dos indivíduos diabéticos estava ciente de sua condição (87,1%) e encontrava-se a tomar medicação antidiabética (79,7%). Destes, 63,2% apresentaram níveis de HbA1c inferiores a 7,0%. A prevalência de diabetes permanece mais elevada do que as estimativas globais e europeias, embora haja maior conscientização e melhor controlo dos objetivos clínicos relacionados com esta doença crónica.Diabetes Mellitus is a major public health threat around the world, continuing to increase both in prevalence and significance. Estimates of its prevalence, knowledge and control are essential to monitor its trends ef fectively. In this contex t, the first National Health Examination Sur vey (INSEF) was per formed on the resident population in Por tugal aged between 25 and 74 years old, in 2015. The INSEF consisted of a crosssectional prevalence study, which included the measurement of the HbA1c level in the blood, a physical examination and a general health inter view. The overall prevalence of diabetes was estimated at 9.9% (95% CI: 8.4, 11.5), being higher in men than in women (12.1% vs 7.8%). Diabetes was more prevalent among individuals with low education level and without professional activit y. The majorit y of diabetic individuals were aware of their condition (87.1%) and were taking antidiabetic medication (79.7%). Of these, 63.2% had HbA1c levels lower than 7.0%. The prevalence of diabetes in Por tugal remains higher than the global and European estimates, although there is greater awareness and bet ter control of the clinical objectives related to this chronic disease.info:eu-repo/semantics/publishedVersio

Fratura do processo coronoide da ulna: um caso raro identificado no sítio pré-histórico do Abrigo da Buraca da Moira (Boa Vista, Leiria)

In 2015, several disarticulated human skeletal remains were identified in the top layers of the prehistoric site of Buraca da Moira Rock Shelter (Boa Vista, Leiria), during the archaeological excavation carried out under the scope of the EcoPLis — Human Occupations in the Pleistocene Ecotones of the River Lis project. The recovery of chert, and quartzite blanks, a schist plate, as well as adornments in bone and shell indicates a Late Neolithic-Chalcolithic chronology. The disarticulated human assemblage, composed of a total of 129 bone and tooth fragments, allowed the estimation of a minimum number of six individuals. Among the remains recovered, an upper portion of an adult right ulna lacking the coronoid process was identified. Replacing it, a semi-oval groove with smooth contours and exposing some trabecular bone was observed. The location, type of bone change, and the observed signs of bone healing are consistent with an uncommon trauma: a fracture of the coronoid process. In the differential diagnosis, both postmortem changes and developmental disturbances were considered but later excluded. The mechanisms that underlie the bone changes are discussed in light of the clinical and paleopathological literature.No ano de 2015, durante a intervenção arqueológica afeta ao projeto EcoPLis: Ocupação Humana Plistocénica nos Ecótonos do Rio Lis foram identificados vestígios osteológicos humanos desarticulados à superfície e nas camadas iniciais do complexo cársico do Abrigo da Buraca da Moira (Boa Vista, Leiria). A recuperação de artefactos em quartzo e sílex, de uma placa de xisto, e de adornos em osso e concha sugerem como cronologia o Neolítico Final/Calcolítico. A análise paleobiológica preliminar dos fragmentos ósseos e peças dentárias recuperados (n=129) permitiu inferir que pertencerão a, pelo menos, seis indivíduos. De entre os elementos analisados macroscopicamente, destacou-se um segmento proximal de uma ulna direita pertencente a um indivíduo adulto. Este fragmento caracterizava-se pela ausência do processo coronóide, e pela presença de uma depressão óssea ovalada com contornos suaves, associada a uma ligeira exposição de osso trabecular. A localização, tipo de alteração e a presença de sinais de remodelação óssea são consistentes com uma lesão traumática incomum: a fratura do processo coronóide. No diagnóstico diferencial foram consideradas, e posteriormente excluídas, alterações de cariz tafonómico e problemas de desenvolvimento. Neste trabalho serão discutidos os mecanismos conducentes à lesão à luz da literatura clínica e paleopatológica

Prevalência, conhecimento, tratamento e controlo da diabetes em Portugal: resultados do primeiro Inquérito Nacional de Saúde com Exame Físico (INSEF 2015)

A Diabetes Mellitus constitui uma forte ameaça à saúde pública em todo o mundo, dadas as graves consequências que podem decorrer da progressão da doença. Neste contexto, as estimativas da prevalência, conhecimento, tratamento e controlo da diabetes são essenciais para monitorizar efetivamente as suas tendências, planear e avaliar intervenções. O último estudo de base populacional com o objetivo de estimar a prevalência da diabetes em Portugal utilizando dados de exame físico foi realizado em 2009 (PREVADIAB) (1).O Inquérito Nacional de Saúde com Exame Físico 2013-2016 (INSEF) desenvolvido como parte integrante do projeto “Improvement of epidemiological health information to support public health decision and management in Portugal. Towards reduced inequalities, improved health, and bilateral cooperation” beneficiou de um apoio financeiro de 1.500.000€ concedido pela Islândia, Liechtenstein e Noruega, através das EEA GrantsN/

Comparative Effectiveness of COVID-19 Vaccines in Preventing Infections and Disease Progression from SARS-CoV-2 Omicron BA.5 and BA.2, Portugal

We estimated comparative primary and booster vaccine effectiveness (VE) of SARS-CoV-2 Omicron BA.5 and BA.2 lineages against infection and disease progression. During April-June 2022, we implemented a case-case and cohort study and classified lineages using whole-genome sequencing or spike gene target failure. For the case-case study, we estimated the adjusted odds ratios (aORs) of vaccination using a logistic regression. For the cohort study, we estimated VE against disease progression using a penalized logistic regression. We observed no reduced VE for primary (aOR 1.07 [95% CI 0.93-1.23]) or booster (aOR 0.96 [95% CI 0.84-1.09]) vaccination against BA.5 infection. Among BA.5 case-patients, booster VE against progression to hospitalization was lower than that among BA.2 case-patients (VE 77% [95% CI 49%-90%] vs. VE 93% [95% CI 86%-97%]). Although booster vaccination is less effective against BA.5 than against BA.2, it offers substantial protection against progression from BA.5 infection to severe disease.The acquisition of sequencing equipment and reagents used in this study by the Instituto Nacional de Saúde Doutor Ricardo Jorge was partially funded by the HERA project (grant no. 2021/PHF/23776) supported by the European Commission through the European Centre for Disease Control, and also partially funded by the GenomePT project (grant no. POCI-01-0145-FEDER-022184), supported by COMPETE 2020–Operational Programme for Competitiveness and Internationalisation, Lisboa Portugal Regional Operational Programme, Algarve Portugal Regional Operational, under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund, and by the Portuguese Science and Technology Foundation. Algarve Biomedical Center Laboratory received public funding through the Project ALG-D2-2021-06 Variants Screen in Southern Portugal– Monitoring Variants of Concern in Southern Portugal and the Portuguese Science and Technology Foundation national support through the Comprehensive Health Research Center (grant no. UIDP/04923/2020)info:eu-repo/semantics/publishedVersio