Objectives To evaluate patient experiences of specific aspects of haemodialysis care across several countries. Design Cross-sectional survey using the Choices for Healthy Outcomes in Caring for ...End-Stage Renal Disease (CHOICE) questionnaire. Setting Haemodialysis clinics within a single provider in Europe and South America. Participants 2748 adults treated in haemodialysis. Primary and secondary outcomes The primary outcome was patient satisfaction with overall care. Secondary outcomes included patient experiences of individual aspects of dialysis care. Results 2145 (78.1%) adults responded to the questionnaire. Fewer than half (46.5% (95% CI 44.5% to 48.6%)) rated their overall care as excellent. Global perceptions of care were uninfluenced by most respondent characteristics except age and depressive symptoms; older respondents were less critical of their care (adjusted OR for excellent rating 1.44 (1.01 to 2.04)) and those with depressive symptoms were less satisfied (0.56 (0.44 to 0.71)). Aspects of care that respondents most frequently ranked as excellent were staff attention to dialysis vascular access (54% (52% to 56%)); caring of nurses (53% (51% to 55%)); staff responsiveness to pain or discomfort (51% (49% to 53%)); caring, helpfulness and sensitivity of dialysis staff (50% (48% to 52%)); and ease of reaching dialysis staff by telephone (48% (46% to 50%)). The aspects of care least frequently ranked as excellent were information provided when choosing a dialysis modality (23% (21% to 25%)), ease of seeing a social worker (28% (24% to 32%)), information provided about dialysis (34% (32% to 36%)), accuracy of information from nephrologist (eg, about prognosis or likelihood of a kidney transplant; 37% (35% to 39%)) and accuracy of nephrologists’ instructions (39% (36% to 41%)). Conclusions Haemodialysis patients are least satisfied with the complex aspects of care. Patients’ expectations for accurate information, prognosis, the likelihood of kidney transplantation and their options when choosing dialysis treatment need to be considered when planning healthcare research and practices.
Periodontitis is associated with cardiovascular mortality in the general population and adults with chronic diseases. However, it is unclear whether periodontitis predicts survival in the setting of ...kidney failure.
ORAL-D was a propensity matched analysis in 3338 dentate adults with end-stage kidney disease treated in a hemodialysis network in Europe and South America designed to examine the association between periodontitis and all-cause and cardiovascular-related mortality in people on long-term hemodialysis. Participants were matched 1:1 on their propensity score for moderate to severe periodontitis assessed using the World Health Organization Community Periodontal Index. A random-effects Cox proportional hazards model was fitted with shared frailty to account for clustering of mortality risk within countries.
Among the 3338 dentate participants, 1355 (40.6%) had moderate to severe periodontitis at baseline. After using propensity score methods to generate a matched cohort of participants with periodontitis similar to those with none or mild periodontal disease, moderate to severe periodontitis was associated with a lower risk of all-cause (9.1 versus 13.0 per 100 person years, hazard ratio 0.74, 95% confidence interval 0.61 to 0.90) and cardiovascular (4.3 versus 6.9 per 100 person years, hazard ratio 0.67, 0.51 to 0.88) mortality. These associations were not changed substantially when participants were limited to those with 12 or more natural teeth and when accounting for competing causes of cardiovascular death.
In contrast to the general population, periodontitis does not appear to be associated with an increased risk of early death in adults treated with hemodialysis.
Introduction Adults with end-stage kidney disease (ESKD) treated with haemodialysis experience mortality of between 15% and 20% each year. Effective interventions that improve health outcomes for ...long-term dialysis patients remain unproven. Novel and testable determinants of health in dialysis are needed. Nutrition and dietary patterns are potential factors influencing health in other health settings that warrant exploration in multinational studies in men and women treated with dialysis. We report the protocol of the “DIETary intake, death and hospitalisation in adults with end-stage kidney disease treated with HaemoDialysis (DIET-HD) study,” a multinational prospective cohort study. DIET-HD will describe associations of nutrition and dietary patterns with major health outcomes for adults treated with dialysis in several countries. Methods and analysis DIET-HD will recruit approximately 10 000 adults who have ESKD treated by clinics administered by a single dialysis provider in Argentina, France, Germany, Hungary, Italy, Poland, Portugal, Romania, Spain, Sweden and Turkey. Recruitment will take place between March 2014 and June 2015. The study has currently recruited 8000 participants who have completed baseline data. Nutritional intake and dietary patterns will be measured using the Global Allergy and Asthma European Network (GA2LEN) food frequency questionnaire. The primary dietary exposures will be n-3 and n-6 polyunsaturated fatty acid consumption. The primary outcome will be cardiovascular mortality and secondary outcomes will be all-cause mortality, infection-related mortality and hospitalisation. Ethics and dissemination The study is approved by the relevant Ethics Committees in participating countries. All participants will provide written informed consent and be free to withdraw their data at any time. The findings of the study will be disseminated through peer-reviewed journals, conference presentations and to participants via regular newsletters. We expect that the DIET-HD study will inform large pragmatic trials of nutrition or dietary interventions in the setting of advanced kidney disease.
People with end-stage kidney disease treated with dialysis experience high rates of premature death that are at least 30-fold that of the general population, and have markedly impaired quality of ...life. Despite this, interventions that lower risk factors for mortality (including antiplatelet agents, epoetins, lipid lowering, vitamin D compounds, or dialysis dose) have not been shown to improve clinical outcomes for this population. Although mortality outcomes may be improving overall, additional modifiable determinants of health in people treated with dialysis need to be identified and evaluated. Oral disease is highly prevalent in the general population and represents a potential and preventable cause of poor health in dialysis patients. Oral disease may be increased in patients treated with dialysis due to their lower uptake of public dental services, as well as increased malnutrition and inflammation, although available exploratory data are limited by small sample sizes and few studies evaluating links between oral health and clinical outcomes for this group, including mortality and cardiovascular disease. Recent data suggest periodontitis may be associated with mortality in dialysis patients and well-designed, larger studies are now required.
The ORAL Diseases in hemodialysis (ORAL-D) study is a multinational, prospective (minimum follow-up 12 months) study. Participants comprise consecutive adults treated with long-term in-center hemodialysis. Between July 2010 and February 2012, we recruited 4500 dialysis patients from randomly selected outpatient dialysis clinics in Europe within a collaborative network of dialysis clinics administered by a dialysis provider, Diaverum, in Europe (France, Hungary, Italy, Poland, Portugal, and Spain) and South America (Argentina). At baseline, dental surgeons with training in periodontology systematically assessed the prevalence and characteristics of oral disease (dental, periodontal, mucosal, and salivary) in all participants. Oral hygiene habits and thirst were evaluated using self-administered questionnaires. Data for hospitalizations and mortality (total and cause-specific) according to baseline oral health status will be collected once a year until 2022.
This large study will estimate the prevalence, characteristics and correlations of oral disease and clinical outcomes (mortality and hospitalization) in adults treated with dialysis. We will further evaluate any association between periodontitis and risk of premature death in dialysis patients that has been suggested by existing research. The results from this study should provide powerful new data to guide strategies for future interventional studies for preventative and curative oral disease strategies in adults who have end-stage kidney disease.
Although scoring comorbidities for patients beginning chronic hemodialysis has proved significant and has led researchers to develop several indexes, none of them has been extensively accepted. The ...aim of this study was to: 1) develop a prognostic index for patients entering renal replacement therapy; and 2) identify which one of the available scores better predicts one-year survival.
Records from 5,360 incident dialysis-requiring ESRD individuals were studied and a novel comorbidity index (NI) was developed. The agreement of this NI with the Charlson age-comorbidity, Kahn-Wright, ACPI, and Hemmelgarn indexes was assessed to identify which one better predicts one-year survival. The Cox proportional hazard regression with time-dependent covariates was used to analyze survival and the area under the receiver operating characteristic (ROC) curve was calculated to assess the ability of this score to discriminate between prognoses and to compare this NI with indexes already in use.
16 of the original 19 predictor variables displayed hazard ratios =1.2. Although the area under the ROC curves for all the indexes compared were significantly different from 0.5, the NI showed better performance characteristics (0.74 vs. 0.70 for Charlson's, 0.68 for ACPI, 0.67 for Khan-Wright's and 0.63 for Hemmelgarn's). Compared with the Charlson score, the z statistic was 7.78 (p<0.001). One-year survival estimate for the high-risk group was 43% with the NI and ranged from 66% to 72% when assessed through other indexes.
We recommend the use of this NI because it better predicts the one-year survival probability of incident hemodialysis-requiring ESRD individuals.
Objetivo: Os objetivos deste trabalho foram: i) desenvolver modelo farmacocinético populacional (popPK) para descrever as concentrações livres teciduais de cefazolina (CFZ) em pacientes morbidamente ...obesos submetidos à cirurgia bariátrica buscando determinar a melhor dose para antibioticoprofilaxia, e ii) avaliar a possibilidade de translação dos desfechos clínicos usando modelo popPK e dados farmacocinéticos de modelo animal de obesidade. Métodos: Foi desenvolvido e validado método analítico para quantificação de CFZ no plasma e no microdialisado de tecido subcutâneo de animais e humanos por cromatografia líquida de alta eficiência (CLAE/UV). A etapa clínica do desenvolvimento do modelo popPK, foi realizada com dados de pacientes morbidamente obesas submetidas à cirurgia bariátrica após a dose única i.v. bolus de 2 e 3 g do fármaco. As concentrações livres de CFZ foram determinadas no tecido adiposo subcutâneo através de microdiálise (MD), sendo amostras de plasma foram coletadas simultaneamente nas pacientes durante a cirurgia. A análise farmacocinética não-compartimental (ANC) e a modelagem popPK dos dados obtidos foi realizada utilizando os softwares WinNonlin® e Monolix®, respectivamente. Utilizando o modelo popPK desenvolvido foram realizadas simulações de Monte Carlo para avaliação da eficácia profilática, tendo como alvo terapêutico a manutenção das concentrações livres teciduais acima da concentração inibitória mínima (CIM) durante todo o tempo de cirurgia (fT>CIM = 100%). Os resultados foram obtidos na forma de probabilidade de atingir o alvo (PTA), considerando bactérias com diferentes CIM e diferentes tempos de duração da cirurgia. Experimentos similares de MD foram realizados em ratos Wistar obesos induzidos por dieta, a fim de avaliar a possibilidade de utilização do modelo popPK de humanos para descrever a distribuição tecidual da CFZ em ratos obesos. Foram testadas doses de 30 e 45 mg/kg administradas via i.v. bolus, equivalentes às doses usadas em humanos. Os dados plasmáticos e teciduais foram avaliados por ANC e modelagem popPK e, com base em simulações de Monte Carlo, obtiveram-se os PTAs para os animais. A possibilidade de translação dos dados dos animais para humanos foi avaliada comparando-se diretamente os valores dos PTAs obtidos, e através de outras duas estratégias empregando escalonamento alométrico dos parâmetros farmacocinéticos populacionais, e comparando-se os desfechos na forma de PTAs. Resultados: O método analítico para quantificação de CFZ total e livre em plasma e em microdialisado de tecido foi validado e considerado adequado para a avaliação das amostras do estudo. A ANC dos dados plasmáticos e teciduais da CFZ nas pacientes obesas mórbidas mostrou que os parâmetros farmacocinética são dose independentes na faixa 2-3 g. Na modelagem populacional, os dados plasmáticos e teciduais foram descritos simultaneamente utilizando-se modelo de dois compartimentos que incluiu a saturação da ligação da CFZ às proteínas plasmáticas e teciduais. A simulação de Monte Carlo mostrou que a dose de 2 g é adequada para atingir o alvo terapêutico para bactérias com CIM ≤ 2 mg/L por até 4 h, geralmente suficiente para cirurgia bariátrica, não justificando o aumento de dose para 3 g. Para CIM ≤ 2 mg/L a dose de 3 g mantém efeito profilático por até 5 h, situação raramente encontrada na prática. Para bactérias com CIM de 4 mg/L, 3 g de CFZ são efetivas por 3 h, não adicionando vantagem significativa frente a dose de 2 g. Na etapa pré-clínica do trabalho houve a necessidade de ajustar o modelo popPK desenvolvido para humanos para uso em ratos, devido às diferenças observadas entre as duas espécies. Diferenças nas taxas de ligação às proteínas teciduais (Bmáx(t) de 622 mg/L e 160 mg/L em ratos e humanos, respectivamente) e a presença de um mecanismo adicional de eliminação hepática saturável da CFZ nos ratos foi incorporada no modelo. A estratégia de escalonamento alométrico de clearance e volume de distribuição de ratos para humanos e uso das taxas de ligação a proteínas de humanos no modelo popPK de ratos permitiu translação dos desfechos clínicos, com um percentual mínimo de concordância de 121.7%. Conclusões: A dose profilática de 2 g é capaz de garantir uma proteção contra infecções de sítio cirúrgico em cirurgias bariátricas por até 4 h para microrganismos com CIM ≤ 2 mg/L, equivalente à dose de 3 g, não havendo justificativa para aumento de dose em obesos. O uso de uma estratégia translacional permitiu a utilização do modelo popPK de ratos para previsão dos desfechos profiláticos da CFZ em pacientes obesos.
Objective: The aims of this work were: i) to develop a population pharmacokinetic model (popPK) to describe free tissue concentrations of cefazolin (CFZ) in morbidly obese patients submitted to bariatric surgery in order to determine the most appropriate dose for antibiotic prophylaxis, and ii) to evaluate the possibility of translating the clinical outcomes using popPK model and pharmacokinetic data from obese animal model. Methods: An analytical methodology was developed and validated for quantification of CFZ in plasma and microdialysate of subcutaneous tissue of humans and animals by high performance liquid chromatography (HPLC/UV). The clinical stage of the popPK model development was performed based on CFZ data from morbidly obese female patients undergoing bariatric surgery following administration of a single i.v. bolus dose of 2 g and 3 g. Free CFZ concentrations were determined in the subcutaneous adipose tissue using microdialysis (MD). The collection of plasma samples was performed simultaneously in the patients during the surgery. Non-compartmental pharmacokinetic analysis (NCA) and popPK modeling of data were performed using WinNonlin® and Monolix® software, respectively. Using the developed popPK model, Monte Carlo simulations were performed to evaluate the prophylactic efficacy of both doses, with the therapeutic target being the maintenance of free tissue concentrations above the minimum inhibitory concentration (MIC) for the entire duration of surgery (fT > MIC = 100%). The results were obtained as a probability of target attainment (PTA), considering bacteria with different MICs and diverse surgery durations. Similar microdialysis experiments were performed on diet-induced obese Wistar rats in order to evaluate the possibility of using the human’s popPK model to describe CFZ tissue distribution in obese rats. Two CFZ i.v. single bolus doses (30 and 45 mg/kg), equivalent to those used in humans, were investigated. Plasma and tissue data were evaluated by NCA and popPK modeling and, based on Monte Carlo simulations, the PTAs were obtained for the animals. The possibility of outcome translation from animals to humans was evaluated by comparing directly the values of the PTAs obtained, and trough other two strategies using allometric scaling of the populational pharmacokinetic parameters, and comparison of the outcomes given as PTAs. Results: The analytical method for quantification of total and free CFZ in plasma and tissue microdialysis was validated and considered suitable for the evaluation of the study samples. The NCA of CFZ plasma and tissue data from morbidly obese patients showed dose independency pharmacokinetic parameters in the 2-3 g dose range. For populational modeling, plasma and tissue data were simultaneously described using a two-compartment model with CFZ plasma and tissue protein binding saturation. Monte Carlo simulation showed that 2 g dose is adequate to reach the therapeutic target for bacteria with MIC ≤ 2 mg/L up to 4 h after administration, usually sufficient for bariatric surgery, not justifying dose increase to 3 g. For MIC ≤ 2 mg/L, 3 g dose sustains prophylactic effect up to 5 h, a situation rarely found in practice. For bacteria with MIC of 4 mg/L, 3 g dose is effective for up to 3 h, not adding a significant advantage over the 2 g dose. In the preclinical stage of the work the human popPK model had to be adjusted to accommodate differences between species. Differences in CFZ tissue protein binding rates (Bmax(t) of 622 mg/L and 160 mg/L in rats and humans, respectively) and the presence of an additional mechanism of saturated hepatic elimination in rats were incorporated into the popPK model. The strategy of allometrically scaling clearance and volume of distribution from rats to humans and the use of CFZ human’s protein binding in the popPK model allowed the translation of clinical outcomes, with a minimum percentage of equivalence of 121.7%. Conclusions: CFZ 2 g prophylactic dose guarantees protection against surgical site infections equivalent to 3 g dose up to 4 h for microorganisms with MIC ≤ 2 mg/L, not justifying the dose increase in obese patients. The use of a translational strategy allowed the use of rat’s popPK model to predict CFZ prophylactic outcomes in obese patients.
Classically, superoxide anion O
and reactive oxygen species ROS play a dual role. At the physiological balance level, they are a by-product of O
reduction, necessary for cell signalling, and at the ...pathological level they are considered harmful, as they can induce disease and apoptosis, necrosis, ferroptosis, pyroptosis and autophagic cell death. This revision focuses on understanding the main characteristics of the superoxide O
, its generation pathways, the biomolecules it oxidizes and how it may contribute to their modification and toxicity. The role of superoxide dismutase, the enzyme responsible for the removal of most of the superoxide produced in living organisms, is studied. At the same time, the toxicity induced by superoxide and derived radicals is beneficial in the oxidative death of microbial pathogens, which are subsequently engulfed by specialized immune cells, such as neutrophils or macrophages, during the activation of innate immunity. Ultimately, this review describes in some depth the chemistry related to O
and how it is harnessed by the innate immune system to produce lysis of microbial agents.
Living species are continuously subjected to all extrinsic forms of reactive oxidants and others that are produced endogenously. There is extensive literature on the generation and effects of ...reactive oxygen species (ROS) in biological processes, both in terms of alteration and their role in cellular signaling and regulatory pathways. Cells produce ROS as a controlled physiological process, but increasing ROS becomes pathological and leads to oxidative stress and disease. The induction of oxidative stress is an imbalance between the production of radical species and the antioxidant defense systems, which can cause damage to cellular biomolecules, including lipids, proteins and DNA. Cellular and biochemical experiments have been complemented in various ways to explain the biological chemistry of ROS oxidants. However, it is often unclear how this translates into chemical reactions involving redox changes. This review addresses this question and includes a robust mechanistic explanation of the chemical reactions of ROS and oxidative stress.
This review discusses the formation of hypochlorous acid HOCl and the role of reactive chlorinated species (RCS), which are catalysed by the enzyme myeloperoxidase MPO, mainly located in leukocytes ...and which in turn contribute to cellular oxidative stress. The reactions of RCS with various organic molecules such as amines, amino acids, proteins, lipids, carbohydrates, nucleic acids, and DNA are described, and an attempt is made to explain the chemical mechanisms of the formation of the various chlorinated derivatives and the data available so far on the effects of MPO, RCS and halogenative stress. Their presence in numerous pathologies such as atherosclerosis, arthritis, neurological and renal diseases, diabetes, and obesity is reviewed and were found to be a feature of debilitating diseases.
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