Skeletal and cardiovascular consequences of a positive calcium balance during hemodialysis / Consequências esqueléticas e cardiovasculares de um balanço positivo de cálcio durante a hemodiálise

Abstract Patients on hemodialysis are exposed to calcium via the dialysate at least three times a week. Changes in serum calcium vary according to calcium mass transfer during dialysis, which is dependent on the gradient between serum and dialysate calcium concentration (d[Ca]) and the skeleton turnover status that alters the ability of bone to incorporate calcium. Although underappreciated, the d[Ca] can potentially cause positive calcium balance that leads to systemic organ damage, including associations with mortality, myocardial dysfunction, hemodynamic tolerability, vascular calcification, and arrhythmias. The pathophysiology of these adverse effects includes serum calcium changes, parathyroid hormone suppression, and vascular calcification through indirect and direct effects. Some organs are more susceptible to alterations in calcium homeostasis. In this review, we discuss the existing data and potential mechanisms linking the d[Ca] to calcium balance with consequent dysfunction of the skeleton, myocardium, and arteries.

Resumo Pacientes em hemodiálise são expostos ao cálcio, por meio do dialisato, pelo menos três vezes por semana. As alterações no cálcio sérico variam de acordo com a transferência de massa de cálcio durante a diálise, que é dependente do gradiente entre a concentração de cálcio no plasma e no dialisato (d [Ca]) e o estado de renovação do esqueleto que altera a capacidade do osso de incorporar cálcio. Embora subestimado, o d [Ca] pode potencialmente causar balanço positivo de cálcio que leva a danos em órgãos sistêmicos, incluindo associações com mortalidade, disfunção miocárdica, tolerabilidade hemodinâmica, calcificação vascular e arritmias. A fisiopatologia desses efeitos adversos inclui alterações do cálcio sérico, supressão do hormônio da paratireóide e calcificação vascular por meio de efeitos diretos e indiretos. Alguns órgãos são mais suscetíveis a alterações na homeostase do cálcio. Nesta revisão, discutimos os dados existentes e os mecanismos potenciais que ligam o d [Ca] ao equilíbrio do cálcio com a consequente disfunção no esqueleto, miocárdio e artérias.

Cardiovascular mortality in peritoneal dialysis: the impact of mineral disorders / Mortalidade cardiovascular em diálise peritoneal: o impacto dos distúrbios minerais

Abstract Introduction: Mineral and bone disorders (MBD) are associated with higher mortality in dialysis patients. The main guidelines related to the subject, Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease: Improving Global Outcomes (KDIGO), were elaborated based on published information from hemodialysis participants. The aim of our study was to evaluate the impact of calcium (Ca), phosphorus (P), and parathyroid hormone (PTH) (according to guideline ranges from KDOQI and KDIGO) on the cardiovascular mortality of peritoneal dialysis (PD) patients. Methods: We used the BRAZPDII database, an observational multi-centric prospective study, which assessed participants on PD between December 2004 and January 2011. Amongst 9,905 participants included in this database, we analyzed 4424 participants who were on PD for at least 6 months. The appropriate confounding variables were entered into the model. Serum levels of Ca, P, and PTH were the variables of interest for the purposes of the current study. Results: We found a significant association between high P serum levels, categorized by KDOQI and KDIGO (P above 5.5 mg/dL), and cardiovascular survival (p < 0.01). Likewise, a compelling association was found between lower levels of PTH, categorized by guidelines (KDOQI and KDIGO - PTH less than 150 pg/mL, p < 0.01), and cardiovascular survival. Conclusion: In conclusion, levels of P above and PTH below the values proposed by KDOQI and KDIGO were associated with cardiovascular mortality in PD patients.

Resumo Introdução: Os distúrbios minerais e ósseos (DMO) estão associados a maior mortalidade em pacientes de diálise. As principais diretrizes relacionadas ao assunto, Kidney Disease Outcomes Quality Initiative (KDOQI) e Kidney Disease: Improving Global Outcomes (KDIGO) foram elaboradas com base em informações publicadas de pacientes em hemodiálise. O objetivo do nosso estudo foi avaliar o impacto do cálcio (Ca), fósforo (P) e paratormônio (PTH) (de acordo com as faixas propostas pelas diretrizes do KDOQI e KDIGO) na mortalidade cardiovascular de pacientes em diálise peritoneal (DP). Métodos: Utilizamos o banco de dados BRAZPDII, um estudo prospectivo observacional multicêntrico, que avaliou participantes de DP entre dezembro de 2004 e janeiro de 2011. Entre os 9.905 participantes incluídos neste banco de dados, analisamos 4.424 que estavam em DP há pelo menos 6 meses. As variáveis de confusão apropriadas foram inseridas no modelo. Os níveis séricos de Ca, P e PTH foram as variáveis de interesse para os fins do presente estudo. Resultados: Encontramos uma associação significativa entre níveis séricos de P elevados, categorizados por KDOQI e KDIGO (P acima de 5,5 mg/dL), e sobrevivência cardiovascular (p < 0,01). Da mesma forma, foi encontrada uma associação convincente entre níveis mais baixos de PTH, categorizados por diretrizes (KDOQI e KDIGO - PTH inferior a 150 pg/mL, p < 0,01), e sobrevivência cardiovascular. Conclusão: Em conclusão, níveis de P acima e PTH abaixo dos valores propostos por KDOQI e KDIGO foram associados à mortalidade cardiovascular em pacientes de DP.

High prevalence of biochemical disturbances of chronic kidney disease - mineral and bone disorders (CKD-MBD) in a nation-wide peritoneal dialysis cohort: are guideline goals too hard to achieve? / Alta Prevalência de Distúrbios Bioquímicos Minerais e Ósseos na Doença Renal Crônica em uma coorte de diálise peritoneal nacional: as metas das diretrizes são muito difíceis de alcançar?

Abstract Introduction: Chronic kidney disease - mineral and bone disorders (CKD-MBD) are common in dialysis patients. Definition of targets for calcium (Ca), phosphorus (P), parathormone (iPTH), and alkaline phosphatase (ALP) and their treatment recommendations, are provided by international guidelines. There are few studies analyzing CKD-MBD in peritoneal dialysis (PD) patients and the impact of guidelines on mineral metabolism control. The aim of our study was to describe the prevalence of biomarkers for CKD-MBD in a large cohort of PD patients in Brazil. Methods: Data from the nation-wide prospective observational cohort BRAZPD II was used. Incident patients were followed between December 2004 and January 2011. According to KDOQI recommendations, reference ranges for total Ca were 8.4 to 9.5 mg/dL, for P, 3.5 to 5.5 mg/dL, for iPTH, 150-300 pg/mL, and for ALP, 120 U/L. Results: Mean age was 59.8 ± 16 years, 48% were male, and 43% had diabetes. In the beginning, Ca was 8.9 ± 0.9 mg/dL, and 48.3% were on the KODQI target. After 1 year, Ca increased to 9.1 ± 0.9 mg/dL and 50.4% were in the KDOQI preferred range. P at baseline was 5.2 ± 1.6 mg/dL, with 52.8% on target, declining to 4.9 ± 1.5 mg/dL after one year, when 54.7% were on target. Median iPTH at baseline was 238 (P25% 110 - P75% 426 pg/mL) and it remained stable throughout the first year; patients within target ranged from 26 to 28.5%. At the end of the study, 80% was in 3.5 meq/L Ca dialysate concentration, 66.9% of patients was taking any phosphate binder, and 25% was taking activated vitamin D. Conclusions: We observed a significant prevalence of biochemical disorders related to CKD-MBD in this dialysis population.

Resumo Introdução: Os distúrbios minerais e ósseos da doença renal crônica (DMO-DRC) são comuns em pacientes em diálise. A definição de metas para cálcio (Ca), fósforo (P), paratormônio (PTHi) e fosfatase alcalina (FA) e suas recomendações de tratamento são fornecidas por diretrizes internacionais. Há poucos estudos analisando o DMO-DRC em pacientes em diálise peritoneal (DP) e o impacto das diretrizes no controle do metabolismo mineral. O objetivo do nosso estudo foi descrever a prevalência de alterações nos marcadores para DMO-DRC em uma grande coorte de pacientes em DP no Brasil. Métodos: Foram utilizados dados da coorte observacional prospectiva nacional BRAZPD II. Pacientes incidentes foram acompanhados entre Dezembro de 2004 e Janeiro de 2011. De acordo com as recomendações do KDOQI, os intervalos de referência para Ca total foram de 8,4 a 9,5 mg/dL, para P, 3,5 a 5,5 mg/dL, para PTHi, 150-300 pg/mL, e para FA, 120 U/L. Resultados: A idade média foi de 59,8 ± 16 anos, 48% eram homens e 43% tinham diabetes. No início, o Ca era de 8,9 ± 0,9 mg/dL, e 48,3% estavam na meta do KODQI. Após 1 ano, o Ca aumentou para 9,1 ± 0,9 mg/dL e 50,4% estavam na faixa preferida do KDOQI. P basal era 5,2 ± 1,6 mg/dL, com 52,8% na meta, diminuindo para 4,9 ± 1,5 mg/dL após um ano, quando 54,7% estavam na meta. O PTHi basal mediano foi de 238 (P25% 110 - P75% 426 pg/mL) e permaneceu estável durante o primeiro ano; os pacientes dentro da meta variaram de 26 a 28,5%. No final do estudo, 80% estavam na concentração de 3,5 meq/L de Ca dialisato, 66,9% dos pacientes estavam tomando qualquer quelante de fosfato, e 25% estavam tomando vitamina D ativada. Conclusões: Observamos uma prevalência significativa de distúrbios bioquímicos relacionados ao DMO-DRC nesta população em diálise.

Racial differences in the relationship between high-normal 25-hydroxy vitamin d and parathyroid hormone levels in early stage chronic kidney disease / Diferenças raciais na relação entre níveis normais-elevados de 25-hidroxivitamina d e hormônio da paratireóide na doença renal crônica em estágio inicial

ABSTRACT Aim: Current guidelines do not address between-person variability in markers of bone and mineral metabolism across subgroups of patients, nor delineate treatment strategies based upon such factors. Methods: A cross sectional study was carried out to analyze data from 20,494 United States Veterans and verify the variability of Vitamin D (25(OH)D) and parathyroid hormone (PTH) levels across race and stage of chronic kidney disease. Results: PTH levels were higher in Black Americans (BA) than White Americans (WA) at all levels of 25(OH)D and across eGFR strata. There was a progressive decline in PTH levels from the lowest (25(OH)D < 20) to highest quartile (25(OH)D >=40) in both BA (134.4 v 90 pg/mL, respectively) and WA (112.5 v 71.62 pg/mL) (p<0.001 for all comparisons). Conclusion: In this analysis, higher than normal 25(OH)D levels were well tolerated and associated with lower parathyroid hormone values in both blacks and whites. Black Americans had higher PTH values at every level of eGFR and 25(OH)D levels suggesting a single PTH target is not appropriate.

RESUMO Objetivo: as diretrizes atuais não abordam a variabilidade entre as pessoas nos marcadores do metabolismo ósseo e mineral em subgrupos de pacientes, nem traçam estratégias de tratamento com base em tais fatores. Métodos: realizamos um estudo transversal para analisar dados de 20.494 veteranos de guerra dos Estados Unidos e verificar a variabilidade nos níveis de vitamina D (25 (OH) D) e hormônio da paratireóide (PTH) entre a raça e o estágio da doença renal crônica. Resultados: os níveis de PTH foram maiores em americanos negros (AN) do que em americanos brancos (AB) em todos os níveis de 25 (OH) D e em todos os estratos de TFGe. Houve um declínio progressivo nos níveis de PTH do quartil mais baixo (25 (OH) D <20) para o quartil mais alto (25 (OH) D> = 40) em AN (134,4 v 90 pg/mL, respectivamente) e AB (112,5 v 71,62 pg/mL) (p <0,001 para todas as comparações). Conclusão: Nesta análise, níveis de 25 (OH) D acima do normal foram bem tolerados e associados a valores mais baixos do hormônio da paratireóide em negros e brancos. Os americanos negros tinham valores de PTH mais altos em todos os níveis de TFGe e 25 (OH) D, sugerindo que uma única meta de PTH não é apropriado.

Digital radiography as an alternative method in the evaluation of bone density in uremic rats / Radiografia digital como método alternativo na avaliação da densidade óssea em ratos urêmicos

ABSTRACT Introduction: Digital radiography (DRx) may provide a suitable alternative to investigate mineral and bone disorder (MBD) and loss of bone density (BD) in rodent models of chronic kidney disease (CKD). The objective of this study was to use DRx to evaluate BD in CKD rats, and to evaluate the correlation between DRx findings and serum MBD markers and bone histomorphometry. Methods: Uremia was induced by feeding Wistar rats an adenine-enriched diet (0.75% for 4 weeks/0.10% for 3 weeks); outcomes were compared to a control group at experimental weeks 3, 4, and 7. The following biochemical markers were measured: creatinine clearance (CrC), phosphate (P), calcium (Ca), fractional excretion of P (FeP), alkaline phosphatase (ALP), fibroblast growth factor-23 (FGF-23), and parathyroid hormone (PTH). DRx imaging was performed and histomorphometry analysis was conducted using the left femur. Results: As expected, at week 7, uremic rats presented with reduced CrC and higher levels of P, FeP, and ALP compared to controls. DRx confirmed the lower BD in uremic animals (0.57±0.07 vs. 0.68 ± 0.06 a.u.; p = 0.016) compared to controls at the end of week 7, when MBD was more prominent. A severe form of high-turnover bone disease accompanied these biochemical changes. BD measured on DRx correlated to P (r=-0.81; p = 0.002), ALP (r = -0.69, p = 0.01), PTH (r = -0.83, p = 0.01), OS/BS (r = -0.70; p = 0.02), and ObS/BS (r = -0.70; p = 0.02). Conclusion: BD quantified by DRx was associated with the typical complications of MBD in CKD and showed to be viable in the evaluation of bone alterations in CKD.

RESUMO Introdução: A radiografia digital (RxD) pode representar uma alternativa adequada para investigar o distúrbio mineral e ósseo (DMO) e a perda de densidade óssea (DO) em modelos de roedores da doença renal crônica (DRC). O objetivo deste estudo foi utilizar a RxD para avaliar a DO em ratos com DRC, e avaliar a correlação entre os achados da RxD e marcadores séricos de DMO e histomorfometria óssea. Métodos: A uremia foi induzida pela alimentação de ratos Wistar com dieta enriquecida com adenina (0,75% por 4 semanas/0,10% por 3 semanas); os resultados foram comparados com um grupo controle nas semanas experimentais 3, 4 e 7. Os seguintes marcadores bioquímicos foram medidos: clearance de creatinina (CCr), fosfato (P), cálcio (Ca), fração excretada de P (FeP), fosfatase alcalina (ALP), fator de crescimento de fibroblastos-23 (FGF-23) e paratormônio (PTH). A imagem da RxD foi obtida e a análise histomorfométrica foi realizada com o fêmur esquerdo. Resultados: como esperado, na semana 7, os ratos urêmicos apresentaram redução do CCr e níveis mais altos de P, FeP e ALP em comparação aos controles. A RxD confirmou a menor DO em animais urêmicos (0,57 ± 0,07 vs. 0,68 ± 0,06 u.a.; p = 0,016) em comparação aos controles no final da semana 7, quando a DMO foi mais proeminente. Uma forma grave de doença óssea de alta renovação celular acompanhou essas mudanças bioquímicas. A DO, medida na RxD foi correlacionada a P (r = -0,81; p = 0,002), ALP (r = -0,69, p = 0,01), PTH (r = -0,83, p = 0,01), OS/BS (r = -0,70 p = 0,02) e Ob.S/BS (r = -0,70; p = 0,02). Conclusão: A DO quantificada por RxD esteve associada às complicações típicas da DMO na DRC e mostrou-se viável na avaliação de alterações ósseas na DRC.

Chronic kidney disease is a main confounding factor for 25-vitamin D measurement / A doença renal crônica é um importante fator de confusão para a dosagem de 25-hidroxivitamina D

Abstract Background: Current guidelines recommend assessment of 25-vitamin D status in patients with chronic kidney disease (CKD). Although significant differences among assays have been described, the impact of CKD on this variability has never been tested. Methods: We tested the variability between two 25-vitamin D assays in patients with CKD (eGFR < 60 mL/min/1.73m2) who had consecutive 25-vitamin D measurements in 2015 (Assay 1 - Diasorin LIASON 25 TOTAL - D assay®) and 2016 (Assay 2 - Beckman Coulter Unicel Xl 800®). The cohort consisted of 791 adult patients (122 with normal renal function and 669 with CKD - 33, 30, and 37% in stages 3, 4, and 5 on dialysis, respectively). Results: Levels of 25-vitamin D were lower and the prevalence of hypovitaminosis D using assay 1 was higher than using assay 2 in patients with CKD, regardless of similar levels of calcium, phosphate, and parathyroid hormone. As kidney function decreased, the percentage of disagreement between the assays increased. Conclusion: There is a noteworthy variability between assays in patients with CKD such that the diagnosis of hypovitaminosis D is modified. The mechanism behind this result is still unclear and might be due to a possible interference in the analytical process. However, the clinical significance is unquestionable, as the supplementation of vitamin D can be erroneously prescribed to these patients.

Resumo Antecedentes: As diretrizes atuais recomendam a avaliação do estado da 25-hidroxivitamina D em pacientes com doença renal crônica (DRC). Embora significativas diferenças entre os ensaios tenham sido descritas, o impacto da nesta variabilidade DRC nunca foi testado. Métodos: Testamos a variabilidade entre dois ensaios de 25-hidroxivitamina D em pacientes com DRC (TFGe < 60 mL/min/1,73 m2) que realizaram medidas consecutivas de 25-hidroxivitamina D em 2015 (Ensaio 1 - Diasorin LIASON 25 TOTAL - D assay® ) e 2016 (Ensaio 2 - Beckman Coulter Unicel Xl 800®). A coorte consistiu de 791 pacientes adultos (122 com função renal normal e 669 com DRC - 33, 30 e 37% nos estágios 3, 4 e 5 em diálise, respectivamente). Resultados: Os níveis de 25-hidroxivitamina D foram menores e a prevalência de hipovitaminose D foi maior utilizando o ensaio 1 do que com o ensaio 2 em pacientes com DRC, independentemente dos níveis similares de cálcio, fosfato e paratormônio. Quando a função renal diminuiu, a porcentagem de discordância entre os ensaios aumentou. Conclusão: Existe uma notável variabilidade entre os ensaios em pacientes com DRC, de modo a modificar o diagnóstico de hipovitaminose D. O mecanismo por trás desse resultado ainda não está claro e pode ser devido a uma possível interferência no processo analítico. Entretanto, o significado clínico é inquestionável, pois a suplementação de vitamina D pode ser erroneamente prescrita a esses pacientes.

Niveles de vitamina D en médicos: ¿son los anestesiólogos el único grupo de riesgo? / Vitamin D levels among anesthesiologists and other physicians

Background Sun exposure is the main source of 25-hydroxy-vitamin D. Since anesthesiologists work inside operating rooms, they are identified as a deficiency risk group. As medical activity in general occurs indoors, added to the work excess and sedentary lifestyle, physicians in general have low sun exposure. Aim To investigate the determinants of vitamin D levels in physicians. Material and Methods Anesthesiologists and physicians not working in operating rooms were included. A survey that comprised working hours, diet, skin color, sunscreen use and outdoor activities was also applied. Measurements of vitamin D and parathormone levels in blood were performed. Results We analyzed samples from 81 volunteers. Median vitamin D values of the whole sample were in the range of insufficiency (25.3 [interquartile range 12.4] ng/ml). Multiple linear regression analysis detected no differences between anesthesiologists and non-anesthesiologists. A higher body mass index was a risk factor for vitamin D deficiency, (p = 0.025). The only protective factor was the intake of a vitamin D supplement (p < 0.01). Conclusions Anesthesiologists and other specialists were both at risk for vitamin D deficiency. Obesity was a risk factor and the use of a vitamin D supplement was the only protective factor.

The impact of cinacalcet in the mineral metabolism markers of patients on dialysis with severe secondary hyperparathyroidism / Impacto de cinacalcete em marcadores do metabolismo mineral de pacientes em diálise portadores de hiperparatireoidismo secundário grave

Abstract Introduction: Treating secondary hyperparathyroidism (SHPT), a common condition associated with death in patients with chronic kidney disease, is a challenge for nephrologists. Calcimimetics have allowed the introduction of drug therapies no longer based on phosphate binders and active vitamin D. This study aimed to assess the safety and effectiveness of cinacalcet in managing chronic dialysis patients with severe SHPT. Methods: This retrospective study included 26 patients [age: 52 ± 12 years; 55% females; time on dialysis: 54 (4-236) months] on hemodialysis (N = 18) or peritoneal dialysis (N = 8) with severe SHPT (intact parathyroid hormone (iPTH) level > 600 pg/mL) and hyperphosphatemia and/or persistent hypercalcemia treated with cinacalcet. The patients were followed for 12 months. Their serum calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), and iPTH levels were measured at baseline and on days 30, 60, 90, 180, and 365. Results: Patients with hyperphosphatemia (57.7%), hypercalcemia (23%), or both (19.3%) with iPTH > 600 pg/mL were prescribed cinacalcet. At the end of the study, decreases were observed in iPTH (1348 ± 422 vs. 440 ± 210 pg/mL; p < 0.001), Ca (9.5 ± 1.0 vs. 9.1 ± 0.6 mg/dl; p = 0.004), P (6.0 ± 1.3 vs. 4.9 ± 1.1 mg/dl; p < 0.001), and ALP (202 ± 135 vs. 155 ± 109 IU/L; p = 0.006) levels. Adverse events included hypocalcemia (26%) and digestive problems (23%). At the end of the study, 73% of the patients were on active vitamin D and cinacalcet. Three (11.5%) patients on peritoneal dialysis did not respond to therapy with cinacalcet, and their iPTH levels were never below 800 pg/mL. Conclusion: Cinacalcet combined with traditional therapy proved safe and effective and helped manage the mineral metabolism of patients with severe SHPT.

Resumo Introdução: O tratamento do hiperparatireoidismo secundário (HPTs), patologia comum e associada à mortalidade na doença renal crônica, é um desafio para o nefrologista. Advento dos calcimiméticos propiciou terapêutica medicamentosa diferente da usual, baseada em quelantes de fósforo e vitamina D ativa. O objetivo deste estudo foi avaliar segurança e efetividade de cinacalcete no controle do HPTs grave de pacientes em diálise crônica. Métodos: Estudo retrospectivo 26 pacientes [idade: 52 ± 12 anos; 55% mulheres; tempo em diálise: 54 (4-236) meses], em hemodiálise (N = 18) ou diálise peritoneal (N = 8), com HPTs grave (nível de paratormônio intacto (PTHi) > 600 pg/mL), com hiperfosfatemia e/ou hipercalcemia persistentes, em tratamento com cinacalcete. Período de seguimento de 12 meses. Avaliados níveis séricos de cálcio (Ca), fósforo (P), fosfatase alcalina (FA) e PTHi no início do seguimento, 30, 60, 90, 180 e 365 dias. Resultados: Indicações para início do cinacalcete: hiperfosfatemia (57,7%), hipercalcemia (23%), ou ambos (19,3%) com PTH > 600 pg/mL. Ao final do seguimento, observada redução dos níveis PTHi (1348 ± 422 vs. 440 ± 210 pg/mL; p < 0,001), Ca (9,5 ± 1,0 vs. 9,1 ± 0,6 mg/dl; p = 0,004), P (6,0 ± 1,3 vs. 4,9 ± 1,1 mg/dl; p < 0,001) e FA (202 ± 135 vs. 155 ± 109 UI/L; p = 0,006). Eventos adversos: hipocalcemia (26%) e queixas digestivas (23%). No fim do estudo, 73% pacientes utilizavam vitamina D ativada associada ao cinacalcete. Três (11,5%) pacientes, todos em DP, não responderam ao cinacalcete, mantendo níveis PTHi > 800 pg/mL. Conclusão: Utilização de cinacalcete, associado à terapia tradicional, em pacientes com HPTs grave foi segura, eficiente e associada a melhor controle do metabolismo mineral.

The specific impact of uremic toxins upon cognitive domains: a review / O impacto específico de toxinas urêmicas em domínios cognitivos: uma revisão

ABSTRACT One of the mechanisms proposed for chronic kidney disease (CKD)-related cognitive impairment is the accumulation of uremic toxins due to the deterioration of the renal clearance function. Cognition can be categorized into five major domains according to its information processing functions: memory, attention, language, visual-spatial, and executive. We performed a review using the terms 'uric acid', 'indoxyl sulfate', 'p-cresyl sulfate', 'homocysteine', 'interleukins' and 'parathyroid hormone'. These are the compounds that were found to be strongly associated with cognitive impairment in CKD in the literature. The 26 selected articles point towards an association between higher levels of uric acid, homocysteine, and interleukin 6 with lower cognitive performance in executive, attentional, and memory domains. We also reviewed the hemodialysis effects on cognition. Hemodialysis seems to contribute to an amelioration of CKD-related encephalopathic dysfunction, although this improvement occurs more in some cognitive domains than in others.

RESUMO Um dos mecanismos propostos para explicar o comprometimento cognitivo relacionado à doença renal crônica (DRC) é o acúmulo de toxinas urêmicas devido à deterioração da função de depuração renal. A cognição pode ser categorizada em cinco domínios principais de acordo com suas funções de processamento de informações: memória, atenção, linguagem, visual-espacial e executiva. Realizamos uma revisão usando os termos "ácido úrico", "indoxil sulfato", "p-cresil sulfato", "homocisteína", "interleucinas" e "paratormônio". Estes são os compostos que se mostraram fortemente associados ao comprometimento cognitivo na DRC na literatura. Os 26 artigos selecionados apontam para uma associação entre níveis mais elevados de ácido úrico, homocisteína e interleucina-6 com menor desempenho cognitivo nos domínios executivo, atenção e de memória. Também revisamos os efeitos da hemodiálise na cognição. A hemodiálise parece contribuir para uma melhoria da disfunção encefalopática relacionada à DRC, embora essa melhora ocorra mais em alguns domínios cognitivos do que em outros.

Evaluation of prevalence, biochemical profile, and drugs associated with chronic kidney disease-mineral and bone disorder in 11 dialysis centers / Avaliação da prevalência, perfil bioquímico e drogas associadas ao distúrbio mineral ósseo-doença renal crônica em 11 centros de diálise

ABSTRACT Introduction: The diagnosis and treatment of mineral and bone disorder of chronic kidney disease (CKD-MBD) is a challenge for nephrologists and health managers. The aim of this study was to evaluate the prevalence, biochemical profile, and drugs associated with CKD-MBD. Methods: Cross-sectional study between July and November 2013, with 1134 patients on dialysis. Sociodemographic, clinical, and laboratory data were compared between groups based on levels of intact parathyroid hormone (iPTH) (< 150, 150-300, 301-600, 601-1000, and > 1001 pg/mL). Results: The mean age was 57.3 ± 14.4 years. The prevalence of iPTH < 150 pg/mL was 23.4% and iPTH > 601 pg/mL was 27.1%. The comparison between the groups showed that the level of iPTH decreased with increasing age. Diabetic patients had a higher prevalence of iPTH < 150 pg/mL (27.6%). Hyperphosphatemia (> 5.5 mg/dL) was observed in 35.8%. Calcium carbonate was used by 50.5%, sevelamer by 14.7%, 40% of patients had used some form of vitamin D and 3.5% used cinacalcet. Linear regression analysis showed a significant negative association between iPTH, age, and diabetes mellitus and a significant positive association between iPTH and dialysis time. Conclusion: The prevalence of patients outside the target for iPTH was 50.5%. There was a high prevalence of hyperphosphatemia (35.8%), and the minority of patients were using active vitamin D, vitamin D analogs, selective vitamin D receptor activators, and cinacalcet. These data indicate the need for better compliance with clinical guidelines and public policies on the supply of drugs associated with CKD-MBD.

RESUMO Introdução: O diagnóstico e tratamento do distúrbio mineral ósseo-doença renal crônica (DMO-DRC) é um desafio para os nefrologistas e gestores de saúde. O objetivo deste estudo foi avaliar a prevalência, perfil bioquímico, e drogas associadas a DMO-DRC. Métodos: Estudo transversal entre julho e novembro de 2013, em 11 centros com 1134 pacientes em diálise. Dados sociodemográficos, clínicos, e laboratoriais foram comparados entre os grupos, com base em níveis do paratormônio intacto (PTHi) (< 150,151-300, 301-600,601-1000, e > 1001 pg/mL). Resultados: A idade média foi de 57,3 ± 14,4 anos, 1071 pacientes estavam em hemodiálise, e 63 em diálise peritoneal. A prevalência de PTHi < 150 pg/mL foi 23,4% e PTHi > 601 pg/mL foi de 27,1%. A comparação dos grupos mostrou que o nível de PTHi diminuiu com o aumento da idade. Pacientes diabéticos apresentaram uma maior prevalência de PTHi < 150 pg/mL (27,6%). Carbonato de cálcio foi usado por 50,5%, Sevelamer por 14,7%, 40% dos pacientes utilizaram alguma forma de vitamina D, e 3,5% utilizaram cinacalcet. A hiperfosfatemia (> 5,5mg/dL) foi observada em 35,8%. A análise de regressão linear mostrou uma associação negativa significativa entre PTHi, idade, e diabetes mellitus e uma associação positiva significativa com o tempo em diálise. Conclusão: A prevalência de pacientes fora do alvo para PTHi foi de 50,5%. Houve uma alta prevalência de hiperfosfatemia e um baixo uso de vitamina D ativa, análogos da vitamina D, ativadores seletivos da vitamina D, e cinacalcet. Estes dados chamam a atenção para a necessidade de uma maior conformidade com as diretrizes e políticas públicas sobre o fornecimento de medicamentos associados à DMO-DRC.

The association of vitamin D levels and the frailty phenotype among non-geriatric dialysis patients: a cross-sectional study

OBJECTIVES: The aim of this study was to investigate the frequency of frailty and the association of vitamin D levels and the frailty phenotype among non-geriatric dialysis patients. METHOD: Seventy-four stable, chronic hemodialysis patients from the hemodialysis unit of the hospital were enrolled in the study. The patients' medical histories and laboratory findings were obtained from the medical records of the dialysis unit. Serum parathyroid hormone and 25-hydroxy vitamin D levels were determined using chemiluminometric immunoassays. Frailty was defined by Fried et al. as a phenotype; shrinking, weakness, self-reported exhaustion, decreased activity and slowed walking speed were evaluated. RESULTS: Forty-one (55%) of the patients were males. The patients were divided into 3 groups according to frailty scores: 39 (53%) patients were frail, 6 (8%) patients were intermediately frail, and 28 (39%) patients were normal. Significant differences were found for 25-hydroxy vitamin D and hemoglobin levels among the groups; however, no differences were observed in body mass index, comorbidities, sex, marital status, education, disease and dialysis durations, or parathyroid hormone, creatinine, serum calcium, phosphorus, and potassium levels. CONCLUSIONS: Weakness and slowness are serious outcomes of both vitamin D deficiency and frailty, and vitamin D deficiency has been associated with increased risks of decreased physical activity, falls, fractures and death in postmenopausal women and older men. Although studies on frailty have focused on older adults, growing evidence indicates that the frailty phenotype is becoming a factor associated with poor health outcomes in non-geriatric populations with chronic disease.

The association between periodontal conditions, inflammation, nutritional status and calcium-phosphate metabolism disorders in hemodialysis patients

Abstract Objectives To analyze the association between periodontal conditions and inflammation, nutritional status and calcium-phosphate metabolism disorders in hemodialysis (HD) patients. Material and Methods We analyzed 128 HD patients divided into two groups: dentate (n = 103) and edentulous (n=25). The following items were assessed: baseline characteristics, age at the start and duration of HD, biochemical data: C-reactive protein (CRP), serum albumin, calcium, phosphorus, alkaline phosphatase, parathormone. A single dentist performed a complete dental/periodontal examination, including parameters of oral hygiene and gingival bleeding. Results One person had healthy periodontium, 62.14% of the patients had gingivitis, and 36.9% had moderate or severe periodontitis. The age at HD onset had a positive impact on periodontal status and negatively correlated with the number of teeth. A positive correlation between age and CRP level and negative correlations between age and serum albumin and phosphorus were found. Pocket depth (PD) was negatively correlated with serum albumin. The number of teeth was negatively correlated with serum CRP. Conclusions High prevalence and severity of periodontal disease are observed in hemodialysis patients. There is a high probability that periodontal disease may be present at the early stages of chronic kidney disease (CKD) before the hemodialysis onset.

Osteoporose: seleção de medicamentos e avanços no manejo clínico / Osteoporosis: medication selection and advances in the clinical management

Osteoporose é um problema de saúde pública importante que acomete mais de metade das mulheres com idade superior a 50 anos. Doença com um enorme impacto sobre a saúde pública, através da morbidade e mortalidade aumentadas, com custos econômicos associados resultantes das fraturas. O objetivo é avaliar e identificar as pessoas de risco para desenvolver fraturas osteoporóticas de fragilidade que necessitam ser tratadas. A abordagem de mulheres com baixa massa óssea e aumento do risco de fraturas deve ser multidisciplinar. A farmacoterapia é apenas uma Steiner ML, Strufaldi R, Fernandes CE das possíveis intervenções. Aspectos como a nutrição orientada, fortalecimento muscular, prevenção de quedas, suplementos vitamínicos e minerais devem ser considerados. O tratamento farmacológico permite a prevenção da perda óssea, a prevenção primária e secundária de fragilidade óssea e deve ser baseado na avaliação do risco de fratura do indivíduo e na relação custo-benefício do medicamento escolhido.

Osteoporosis is a significant public health problem that affects more than half of women aged over 50. This disease has a huge impact on public health through morbidity and increased mortality, and economic costs associated with the resulting fractures. The goal is to assess and identify risk people to develop osteoporotic fragility fractures that need to be addressed. The approach of women with low bone mass and increased risk of fractures should be multidisciplinary. Pharmacotherapy is just one of the possible interventions. Aspects such as the guidance nutrition, muscle strengthening, prevention of falls, mineral and vitamin supplements should be considered. Pharmacological treatment allows preventing bone loss and primary and secondary prevention of osteoporosis and should be based on risk factors and pharmaceutical cost benefit analysis.

Alta prevalencia de deficiencia de vitamina D en niños con enfermedad renal crónica y trasplante renal / High prevalence of vitamin D deficiency among children with chronic kidney disease and kidney transplant

Introducción. la deficiencia de vitamina D (25OHD) es muy común en pacientes con enfermedad renal crónica (ERC). Los obj etivos de este trabajo fueron determinar la prevalencia del déficit de 25OHD en niños con ERC e identificar factores de riesgo. Se estableció la correlación entre 25OHD y paratohormona molécula intacta. Población y métodos. Estudio transversal realizado entre enero de 2013 y diciembre de 2015. Se incluyeron pacientes menores de 19 años con y sin ERC. Resultados. Se incluyeron 167 pacientes. Grupo 1 (controles sanos): 32 participantes; grupo 2 (ERC, estadios 2-4, filtrado glomerular entre 89 y 15 ml/min/1,73 m²): 34 pacientes; grupo 3 (estadio 5, en diálisis): 46 pacientes; y grupo 4 (trasplantados renales): 55 pacientes. Presentaron deficiencia de 25OHD 12,5% de los controles sanos y 32% de los pacientes con ERC (p= 0,025). El 23% de los pacientes del grupo 2, el 51% del grupo 3 y el 22% del grupo 4 presentaron deficiencia de 25OHD; el valor medio de 25OHD de los pacientes en diálisis fue significativamente menor que en el resto de los grupos. Los predictores de deficiencia de 25OHD fueron la hipoalbuminemia, ERC avanzada y la procedencia de la región Noroeste. La paratohormona molécula intacta fue significativamente más elevada en el grupo de pacientes con deficiencia y mostró una correlación inversa con los valores de 25OHD. Conclusión. El 32% de los pacientes con ERC presentó deficiencia de 25OHD; en el estadio 5 (diálisis), alcanzó el 51%. Los predictores de deficiencia fueron hipoalbuminemia, ERC avanzada y la procedencia del noroeste.

Introduction. Vitamin D (25(OH)D) deficiency is common among patients with chronic kidney disease (CKD). Our objective was to establish the prevalence of 25(OH)D deficiency among children with CKD and identify risk factors. A correlation was observed between 25(OH)D and parathormone intact molecule. Population and methods. Cross-sectional study conducted between January 2013 and December 2015. Patients younger than 19 years old with and without CKD were included. Results. One hundred and sixty-seven patients were included. Group 1 (healthy controls): 32 participants; group 2 (stage 2-4 CKD, glomerular filtration rate between 89 and 15 mL/min/1.73 m²): 34 patients; group 3 (stage 5 CKD, dialysis): 46 patients; and group 4 (kidney transplant recipients): 55 patients. Deficiency of 25(OH)D was detected in 12.5% of healthy controls and 32% of CKD patients (p= 0.025). Also, 23% of patients in group 2, 51% in group 3, and 22% in group 4 had 25(OH)D deficiency; the mean 25(OH)D level of dialysis patients was significantly lower than that of the rest of the groups. Predictors of 25(OH)D deficiency included hypoalbuminemia, advanced CKD, and place of origin from the Northwest region of Argentina. The parathormone intact molecule was significantly higher in the group of patients with deficiency and was inversely correlated with 25(OH)D levels. Conclusion. Among CKD patients, 32% had 25(OH)D deficiency, which reached 51% among those with stage 5 CKD (dialysis). Predictors of deficiency included hypoalbuminemia, advanced CKD, and place of origin from the Northwest region of Argentina.

Are PTH levels related to oxidative stress and inflammation in chronic kidney disease patients on hemodialysis? / Os níveis de PTH estão relacionados com estresse oxidativo e inflamação em pacientes renais crônicos em hemodiálise?

Abstract Introduction: Patients at end stage renal disease have higher levels of inflammation and oxidative stress than the general population. Many factors contribute to these issues, and the parathyroid hormone (PTH) is also implicated. Objective: The study was conducted in order to assess the relationship between PTH levels and inflammation and oxidative stress in hemodialysis patients. Methods: Cross-sectional study with patients of two hemodialysis facilities in Londrina, Brazil. Patients with other conditions known to generate oxidative stress and inflammation were excluded. Blood levels of PTH and biochemical parameters of inflammation (interleukins 1 and 6, tumor necrosis factor-alpha) and oxidative stress (total plasma antioxidant capacity, malonic dialdehyde, lipid hydroperoxidation, advanced oxidation protein products, quantification of nitric oxide metabolites, and 8-isoprostane) were measured before a dialysis session. Then, we made correlation analyses between PTH levels - either as the continuous variable or categorized into tertiles-, and inflammatory and oxidative stress biomarkers. Results: PTH did not show any correlation with the tested inflammation and oxidative stress parameters, nor as continuous variable neither as categorical variable. Conclusion: In this descriptive study, the results suggest that the inflammation and oxidative stress of hemodialysis patients probably arise from mechanisms other than secondary hyperparathyroidism.

Resumo Introdução: Pacientes com doença renal em estágio terminal têm níveis de inflamação e estresse oxidativo maiores do que a população geral. Muitos fatores contribuem para isso, e o hormônio paratireoidiano (PTH) é um deles. Objetivo: Estudo foi realizado para avaliar a relação entre os níveis de PTH e níveis de inflamação e estresse oxidativo em pacientes em hemodiálise. Métodos: estudo transversal com pacientes de duas unidades de hemodiálise de Londrina, Brasil. Pacientes com condições causadoras de inflamação e estresse oxidativo foram exclusos. Níveis plasmáticos de PTH e parâmetros bioquímicos de inflamação (interleucina 1 e 6, fator de necrose tumoral alfa) e estresse oxidativo (capacidade antioxidante plasmática total, dialdeído malônico, hidroperoxidação lipídica, produtos avançados da degradação proteica, quantificação de metabólitos de óxido nítrico e 8-isoprostano) foram dosados antes da sessão de hemodiálise. Realizou-se análise de correlação entre os níveis de PTH - tanto como variável continua como variável categórica em tercis - e os parâmetros de inflamação e estresse oxidativo. Resultados: Não houve correlação do PTH com nenhum dos parâmetros testados, nem como variável contínua, nem como categórica. Conclusão: Neste estudo descritivo, os resultados sugerem que a inflamação e o estresse oxidativo em pacientes em hemodiálise provavelmente tem origem em mecanismos que não incluem o hiperparatireoidismo secundário.

Differences in the prevalence of vitamin D deficiency and hip fractures in nursing home residents and independently living elderly

ABSTRACT Objective To compare the prevalence of vitamin D deficiency and fracture history in nursing home residents and community-dwelling elderly subjects and to explore the association of vitamin D levels with various characteristics. Materials and methods Sixty-six nursing home residents and 139 community-dwelling elderly subjects participated. Marital status, medical history, medication including vitamin D supplements, smoking, past fractures were assessed. Weight and height were measured and body mass index calculated. Serum 25-hydroxyvitamin D (25-OHD), PTH, Ca, phosphate, creatinine and eGFR were determined. Results In the nursing home residents 25-OHD was lower (17.8 nmol/l, [9.4-28.6] vs. 36.7 nmol/l, [26.9-50], p < 0.001), PTH was higher (5.6 pmol/l, [3.9-8.9] vs. 4.7 pmol/l [3.6-5.8], P = 0.003) and 25-OHD deficiency was more prevalent (65.2% [53.7-76.7] vs. 22.3% [15.4-29.2], p < 0.001) as was elevated PTH (23% [12.8-33] vs. 5.8% [2-10], p = 0.001). 25-OHD correlated negatively with PTH (institutionalized r = -0.28, p = 0.025 and community-dwelling r = -0.36, p < 0.001). Hip fractures were reported by 8% of the residents and 2% of the independent elderly. The only predictor for hip fracture was elevated PTH (OR = 7.6 (1.5-36.9), p = 0.013). Conclusion The prevalence of vitamin D deficiency and secondary hyperparathyroidism was high in the institutionalized subjects. Hip fracture risk was associated with elevated PTH and not directly with vitamin D levels or the residency status.

Hiperparatiroidismo secundario luego de trasplante renal Experiencia de un centro de trasplante / Secondary hyperparathyroidism after kidney transplant Experience of a transplant center

Introducción: la enfermedad renal crónica se asocia con alteraciones metabólicas severas que llevan a hiperparatiroidismo secundario (HPTS). El trasplante de riñón corrige las alteraciones fisiopatológicas que lo originan. Objetivo: describir cambios al año y a los tres años de seguimiento en los niveles séricos de hormona paratiroidea intacta (PTHi) y perfil fosfocálcico en pacientes llevados a trasplante renal con diagnóstico previo de HPTS. Metodología: se realizó un análisis descriptivo de todos los pacientes trasplantados entre 2005 y 2012, evaluando niveles de PTHi y perfil fosfocálcico antes del trasplante, al año y a los tres años de seguimiento. Resultados: en el pretrasplante el promedio de PTHi de los 175 pacientes fue 465.4 pg/dL; en 30.2% de los pacientes se encontraron niveles superiores a nueve veces el valor normal. Al año de seguimiento la tasa de filtración glomerular (TFG) promedio fue 65.4 mL/min/1.73 m². La PTH (114 pacientes), fue en promedio 118.7 pg/dL, con una disminución promedio de 339 pg/dL. Fue mayor la PTH en los que presentaban TFG menor a 40. Al tercer año de seguimiento los hallazgos se mantuvieron en todos los pacientes, con PTHi promedio de 100.4 pg/dL (un descenso de 396 pg/dL). Conclusiones: en este estudio se encontró que el HPTS mejora después del trasplante renal, con una disminución significativa de los niveles de PTHi al primero y tercer años de seguimiento

Introduction: chronic kidney disease is associated with severe metabolic abnormalities that lead to secondary hyperparathyroidism (SHPT). Kidney transplant corrects pathophysiological abnormalities that originate it. Objective: to describe changes at one year and at three years of follow- up of serum levels of intact parathyroid hormone (PTH) and calcium-phosphorus profile in patients undergoing renal transplantation with a previous diagnosis of SHPT. Methodology: a descriptive analysis of all patients transplanted between 2005 and 2012 was performed assessing levels of iPTH and calcium-phosphorus profile before transplantation, and after one year and three years of follow-up. Results: pre-transplant iPTH average of 175 patients was 465.4 pg / dL; in 30.2% of patients levels higher to nine times the normal value were found. At one year follow-up, glomerular filtration rate (GFR) average was 65.4 mL / min / 1.73 m². PTH (114 patients), averaged 118.7 pg / dL, with an average decrease of 339 pg / dL. PTH was greater in those with GFR less than 40. In the third year of follow-up findings were maintained in all patients with iPTH average of 100.4 pg / dL (a decrease of 396 pg / dL).

Responsividade paratireoideana à hipocalcemia após paratireoidectomia total com autoimplante em portadores de hiperparatireoidismo associado à doença renal crônica / Parathyroid responsiveness during hypocalcemia after total parathyroidectomy and autotransplantation in patients with renal hyperparathyroidism

Resumo Introdução: O hiperparatireoidismo é uma complicação frequente da doença renal crônica (DRC). A paratireoidectomia (PTX) total com autotransplante (AT) de tecido paratireoideano é uma opção terapêutica para os indivíduos que não respondem ao manejo clínico. Objetivo: Avaliar a resposta do tecido paratireoideano enxertado durante hipocalcemia induzida em pacientes portadores de DRC submetidos à PTX total com AT. Métodos: Dezoito pacientes portadores de hiperparatiroidismo associado à DRC foram submetidos à PTX total com AT de tecido paratireoideano selecionado por estereomicroscopia entre Abril e Outubro de 2008 em nosso serviço. Onze indivíduos (oito com transplante renal funcionante, 2 em diálise peritoneal e 1 em hemodiálise) apresentavam boa condição clínica e foram elegíveis para o teste. Induziu-se hipocalcemia por infusão de bicarbonato de sódio em 5 controles normais e nos pacientes 6-12 meses após a PTX. Resultados: A hipocalcemia determinou um aumento importante dos níveis de PTH intacto (iPTH) no grupo controle 4 minutos após a infusão de bicarbonato. Nos pacientes, houve uma redução significativa do cálcio ionizado [de 1,17 ± 0,12 para 1,09 ± 0,11 (media ± EP) mmol/L] no 4º minuto (p < 0,001) ilustrando o nadir do teste. No 10º minuto não houve elevação do cálcio ionizado comparado ao 4º minuto (p = 0,451). Os níveis de iPTH foram de 34,8 ± 18,6 para 34,1 ± 18,8 pg/mL (valor basal semelhante ao 4º minuto p = 0,087) e se mantiveram no 10º minuto (33,3 ± 19,6 pg/mL p = 0,693). Conclusão: Em pacientes portadores de DRC testados 6-12 meses depois da cirurgia, o enxerto de tecido paratireoideano revelou incapacidade de resposta à hipocalcemia induzida por bicarbonato sem mudança dos níveis de iPTH.

Abstract Introduction: Hyperparathyroidism is a frequent complication of chronic kidney disease (CKD). Total parathyroidectomy (PTX) with parathyroid tissue autotransplantation (AT) is a treatment option in those individuals that do not respond to clinical management. Objective: To evaluate grafted parathyroid tissue response during induced hypocalcemia among CKD patients who underwent total PTX with AT. Methods: Eighteen patients with renal hyperparathyroidism were submitted to total PTX with parathyroid AT selected by stereomicroscopy between April and October 2008. Eleven (eight with successful kidney transplantation, 2 in peritoneal dialysis and 1 in hemodialysis) were clinically stable and eligible for testing. Hypocalcemia was induced using sodium bicarbonate infusion in 5 healthy controls and in patients 6-12 months after surgery. Results: Among controls, hypocalcemia elicited a major rise in intact PTH (iPTH) levels 4 minutes after bicarbonate infusion. In patients, a significant decrease in ionized calcium concentration was observed [from 1.17 ± 0.12 to 1.09 ± 0.11 mean (± SE) mmol/L] in the 4th minute (p < 0.001) illustrating the nadir point. In the 10thminute, ionized calcium did not show a statistical increase compared to the 4th minute (p = 0.451). The iPTH levels ranged from 34.8 ± 18.6 to 34.1 ± 18.8 pg/mL (similar values between base line and 4thminute p = 0.087) and did not change in the 10th minute (33.3 ± 19,6 pg/ mL p = 0.693). Conclusion: Among CKD patients tested 6-12 months after surgery, grafted parathyroid tissue revealed a blunted secretory capacity during bicarbonate induced hypocalcemia with no changes in iPTH levels.