Prognostic factors of worse outcome for hospitalized COVID-19 patients, with emphasis on chest computed tomography data: a retrospective study

ABSTRACT Objective: To evaluate anthropometric and clinical data, muscle mass, subcutaneous fat, spine bone mineral density, extent of acute pulmonary disease related to COVID-19, quantification of pulmonary emphysema, coronary calcium, and hepatic steatosis using chest computed tomography of hospitalized patients with confirmed diagnosis of COVID-19 pneumonia and verify its association with disease severity. Methods: A total of 123 adults hospitalized due to COVID-19 pneumonia were enrolled in the present study, which evaluated the anthropometric, clinical and chest computed tomography data (pectoral and paravertebral muscle area and density, subcutaneous fat, thoracic vertebral bodies density, degree of pulmonary involvement by disease, coronary calcium quantification, liver attenuation measurement) and their association with poorer prognosis characterized through a combined outcome of intubation and mechanical ventilation, need of intensive care unit, and death. Results: Age (p=0.013), body mass index (p=0.009), lymphopenia (p=0.034), and degree of pulmonary involvement of COVID-19 pneumonia (p<0.001) were associated with poor prognosis. Extent of pulmonary involvement by COVID-19 pneumonia had an odds ratio of 1,329 for a poor prognosis and a cutoff value of 6.5 for increased risk, with a sensitivity of 64.9% and specificity of 67.1%. Conclusion: The present study found an association of high body mass index, older age, extent of pulmonary involvement by COVID-19, and lymphopenia with severity of COVID-19 pneumonia in hospitalized patients.

Intermittent hemodiafiltration as a down-step transition therapy in patients with acute kidney injury admitted to intensive care unit who initially underwent continuous venovenous hemodiafiltration.

BACKGROUND/AIMS: Continuous renal replacement therapies (CRRT) are initially employed in patients with acute kidney injury (AKI) in ICU setting. After the period of serious illness, hemodialysis is usually used as a mode of transition from CRRT. Intermittent hemodiafiltration (HDF) is not commonly applied in this scenario. OBJECTIVES: To evaluate the feasibility of using HDF as transition therapy after CVVHDF in critically patients with AKI. METHODS: An observational and prospective pilot study was conducted in ICU patients with dialysis-requiring AKI. Patients were initially treated with CVVHDF and, after medical improvement, those who still needed renal replacement therapy were switched to HDF treatment. RESULTS: Ten Patients underwent 53 HDF sessions (mean of 5.3 sessions/patient). The main cause of renal dysfunction was sepsis (N = 7; 70%). The APACHE II mean score was 27.6 ± 6.9. During HDF treatment, the urea reduction ratio was 64.5 ± 7.5%, for ß-2 microglobulin serum levels the percentage of decrease was 42.0 ± 7.8%, and for Cystatin C was 36.2 ± 6.9%. Five episodes of arterial hypotension occurred (9.4% of sessions). There were 20 episodes of electrolytic disturbance (37.7% of sessions), mainly hypophosphatemia. No pyrogenic or suggestive episode of bacteremia was observed. CONCLUSION: Hemodiafiltration was safe and efficient to treat critically ill patients with acute kidney injury during the transition phase from continuous to intermittent dialysis modality. Special attention should be paid regarding the occurrence of electrolytic disturbance, mainly hypophosphatemia.

Lipid profile and statin use in critical care setting: implications for kidney outcome / Perfil lipídico e uso de estatina em terapia intensiva: implicações no desfecho renal

ABSTRACT Objective: To determine whether pre-hospital statin use is associated with lower renal replacement therapy requirement and/or death during intensive care unit stay. Methods: Prospective cohort analysis. We analyzed 670 patients consecutively admitted to the intensive care unit of an academic tertiary-care hospital. Patients with ages ranging from 18 to 80 years admitted to the intensive care unit within the last 48 hours were included in the study. Results: Mean age was 66±16.1 years old, mean body mass index 26.6±4/9kg/m2 and mean abdominal circumference was of 97±22cm. The statin group comprised 18.2% of patients and had lower renal replacement therapy requirement and/or mortality (OR: 0.41; 95%CI: 0.18-0.93; p=0.03). The statin group also had lower risk of developing sepsis during intensive care unit stay (OR: 0.42; 95%CI: 0.22-0.77; p=0.006) and had a reduction in hospital length-of-stay (14.7±17.5 days versus 22.3±48 days; p=0.006). Statin therapy was associated with a protective role in critical care setting independently of confounding variables, such as gender, age, C-reactive protein, need of mechanical ventilation, use of pressor agents and presence of diabetes and/or coronary disease. Conclusion: Statin therapy prior to hospital admission was associated with lower mortality, lower renal replacement therapy requirement and sepsis rates.

RESUMO Objetivo: Determinar se o uso pré-admissão hospitalar de estatina está associado com menor necessidade de diálise e/ou óbito durante internação em unidade de terapia intensiva. Métodos: Análise de coorte prospectiva. Foram incluídos consecutivamente 670 pacientes admitidos na unidade de terapia intensiva de um hospital acadêmico de cuidados terciários. Os pacientes incluídos deveriam ter entre 18 e 80 anos e ter sido admitidos na unidade de terapia intensiva nas últimas 48 horas. Resultados: A média da idade dos pacientes foi de 66±16,1 anos. O índice de massa corporal foi de 26,6±4/9kg/m2 e a circunferência abdominal média foi de 97±22cm. O grupo que fez uso de estatina pré-admissão hospitalar (18,2% dos pacientes) necessitou menos de terapia de substituição renal e/ou evoluiu para óbito (OR: 0,41; IC95%: 0,18-0,93; p=0,03). O grupo que fez uso de estatina também apresentou menor risco de evoluir com sepse durante a internação na unidade de terapia intensiva (OR: 0,42; IC95%: 0,22-0,77; p=0,006) e teve menor duração da hospitalização (14,7±17,5 dias versus 22,3±48 dias; p=0,006). A terapia pré-admissão hospitalar com estatina foi associada a papel protetor no cenário da terapia intensiva independentemente de variáveis confundidoras, como sexo, idade, proteína C-reativa, necessidade de ventilação mecânica, uso de vasopressores e diagnóstico de diabetes e/ou coronariopatia. Conclusão: A terapia com estatina antes da admissão hospitalar foi associada a menor mortalidade, menor necessidade de terapia de substituição renal e taxa de ocorrência de sepse.

Serum Soluble-Fas, Inflammation, and Anemia in Acute Kidney Injury.

Anemia is a common feature in critically ill patients. Serum soluble-Fas (sFas) levels are associated with anemia in chronic kidney disease. It is possible that sFas levels are also associated with anemia in acute kidney injury (AKI) patients. The study aims to investigate the relationship between serum levels of sFas, erythropoietin (Epo), inflammatory cytokines, and hemoglobin (Hb) concentration in critically ill patients with AKI. We studied 72 critically ill patients with AKI (AKI group; n = 53) or without AKI (non-AKI group; n = 19), and 18 healthy volunteers. Serum sFas, Epo, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-10, iron status, and Hb concentration were analyzed in all groups. We also investigated the correlation between these variables in the AKI group. Critically ill patients (AKI and non-AKI groups) had higher serum levels of Epo than healthy volunteers. Hb concentration was lower in the AKI group than in the other groups. Serum sFas, IL-6, TNF-α, and ferritin levels were higher in the AKI group. Hb concentration correlated negatively with serum IL-6 (r = -0.37, P = 0.008), sFas (r = -0.35, P = 0.01), and Epo (r = -0.27, P = 0.04), while serum sFas correlated positively with iron levels (r = 0.36, P = 0.008) and IL-6 (r = 0.28, P = 0.04) in the AKI group. In multivariate analysis, after adjusting for markers of inflammation and iron stores, only serum sFas levels (P = 0.03) correlated negatively with Hb concentration in the AKI group. Serum Epo and inflammatory cytokine levels are elevated in critically ill patients with or without AKI. Serum levels of sFas are elevated and independently associated with anemia in critically ill patients with AKI.

The impact of continuous renal replacement therapy on renal outcomes in dialysis-requiring acute kidney injury may be related to the baseline kidney function.

BACKGROUND: Many controversies exist regarding the management of dialysis-requiring acute kidney injury (D-AKI). No clear evidence has shown that the choice of dialysis modality can change the survival rate or kidney function recovery of critically ill patients with D-AKI. METHODS: We conducted a retrospective study investigating patients (≥16 years old) admitted to an intensive care unit with D-AKI from 1999 to 2012. We analyzed D-AKI incidence, and outcomes, as well as the most commonly used dialysis modality over time. Outcomes were based on hospital mortality, renal function recovery (estimated glomerular filtration rate-eGFR), and the need for dialysis treatment at hospital discharge. RESULTS: In 1,493 patients with D-AKI, sepsis was the main cause of kidney injury (56.2%). The comparison between the three study periods, (1999-2003, 2004-2008, and 2009-2012) showed an increased in incidence of D-AKI (from 2.56 to 5.17%; p = 0.001), in the APACHE II score (from 20 to 26; p < 0.001), and in the use of continuous renal replacement therapy (CRRT) as initial dialysis modality choice (from 64.2 to 72.2%; p < 0.001). The mortality rate (53.9%) and dialysis dependence at hospital discharge (12.3%) remained unchanged over time. Individuals who recovered renal function (33.8%) showed that those who had initially undergone CRRT had a higher eGFR than those in the intermittent hemodialysis group (54.0 × 46.0 ml/min/1.73 m2, respectively; p = 0.014). In multivariate analysis, type of patient, sepsis-associated AKI and APACHE II score were associated to death. For each additional unit of the APACHE II score, the odds of death increased by 52%. The odds ratio of death for medical patients with sepsis-associated AKI was estimated to be 2.93 (1.81-4.75; p < 0.001). CONCLUSION: Our study showed that the incidence of D-AKI increased with illness severity, and the use of CRRT also increased over time. The improvement in renal outcomes observed in the CRRT group may be related to the better baseline kidney function, especially in the dialysis dependence patients at hospital discharge.

Outcomes from a cohort of patients with acute kidney injury subjected to continuous venovenous hemodiafiltration: The role of negative fluid balance.

BACKGROUND: Several factors influence the outcomes in acute kidney injury (AKI), especially in intensive care unit (ICU) patients. In this scenario, continuous renal replacement therapies (CRRT) are used to control metabolic derangements and blood volume. Knowing this fact, it may be possible to change the course of the disease and decrease the high mortality rate observed. Thus, we aimed to evaluate the main risk factors for death in AKI patients needing CRRT. RESULTS: This was a prospective, observational cohort study of ICU patients (N = 183) with AKI who underwent continuous venovenous hemodiafiltration (CVVHDF) as their initial dialysis modality choice. The patients were predominantly male (62.8%) and their median age was 65 (55-76) years. The most frequent comorbidities were cardiovascular disease (39.3%), hypertension (32.8%), diabetes (24%), and cirrhosis (20.7%). The main cause of AKI was sepsis (52.5%). At beginning of CVVHDF, 152 patients (83%) were using vasopressors. The median SAPS 3 and SOFA score at ICU admission was 61 (50-74) and 10 (7-12), respectively. The dialysis dose delivered was 33.2 (28.9-38.7) ml/kg/h. The median time between ICU admission and CVVHDF initiation was 2 (1-4) days. The median cumulative fluid balance during the CVVHDF period was -1838 (-5735 +2993) ml. The mortality rate up to90 days was 58%. The independent mortality risk factors in propensity score model were: chronic obstructive pulmonary disease (OR = 3.44[1.14-10.4; p = 0.028]), hematologic malignancy (OR = 5.14[1.66-15.95; p = 0.005]), oliguria (OR = 2.36[1.15-4.9; p = 0.02]), positive daily fluid balance during CVVHDF (OR = 4.55[2.75-13.1; p<0.001]), and total SOFA score on first dialysis day (OR = 1.27[1.12-1.45; p<0.001]). CONCLUSIONS: Dialysis-related factors may influence the outcomes. In our cohort, positive daily fluid balance during CRRT was associated with lower survival. Multicenter, randomized studies are needed to assess fluid balance as a primary outcome to define the best strategy in this patient population.

Synergistic effect of apoptosis and necroptosis inhibitors in cisplatin-induced nephrotoxicity.

Necroptosis is a nonapoptotic cell death pathway. We aim to study the effect of necrostatin-1 (a specific necroptosis inhibitor) in cisplatin-induced injury. We analyzed the effect of the combined use of inhibitors of apoptosis (z-vad) and necroptosis (necrostatin-1) in acute kidney injury by cisplatin in human proximal tubule cells. Our results showed moderate effectiveness in cytoprotection after treatment with z-vad. But the concomitant use of inhibitors (z-vad and necrostatin-1) presented synergistic and additive protection. The present study analyzed the caspase-3 activity and we observed a significant decrease in the group treated with z-vad and cisplatin. However we did not observe changes in the group treated with both inhibitors (z-vad and necrostatin-1) and cisplatin. Thus, demonstrating that necroptosis is a caspase-independent mechanism. We also analyzed the effect of necrostatin-1 in vivo model. C57BL/6 mice were treated with cisplatin and/or inhibitors. The concomitant use of inhibitors (z-vad and necrostatin-1) recovered renal function and decreased levels of urinary Ngal. Additionally, we analyzed the expression of RIP-1, a specific marker for necroptosis. In animals treated with cisplatin and z-VAD levels of RIP-1 were higher. This result reinforces that necroptosis occurs only in conditions where apoptosis was blocked. However, the use of both inhibitors (z-vad and necrostatin-1) provided additional protection. In conclusion, our study has a significant potential to show in vitro and in vivo protection obtained by necrostatin-1. Therefore, our results suggest that necroptosis may be an important mechanism of cell death after kidney injury.

Association of IL-6 polymorphism -174G/C and metabolic syndrome in hypertensive patients.

INTRODUCTION: Visceral obesity, the central core of metabolic syndrome (MetS), is conceived as the pathogenic basis of an increased cardiovascular burden and is related with changes in cytokines. We investigated whether IL-6-174G/C gene polymorphism is associated with MetS prevalence in hypertensive patients. METHOD: A population of hypertensive patients was included and stratified by the presence of MetS according to IDF criteria and evaluated by Framingham risk score. The IL-6-174G/C genotyping was performed by polymerase chain reaction and the prevalence of MetS was compared between "C" carrier and "non-C" carrier groups. RESULTS: From an original sample of 664 patients, 612 (34.2% men, age 57.3 ± 10.1, 30.4% diabetics) were included. MetS was diagnosed in 51.3% of total population and "C" carriers demonstrated high prevalence of MetS (P < 0.05) and each of its components. On binary logistic regression, it was observed that the IL-6 polymorphism was independently associated with occurrence of MetS, even after adjusting for covariates (OR 1.13-2.37, 95% CI, P < 0.05). CONCLUSION: The C allele at the -174 locus of IL-6 gene is independently associated with the occurrence of metabolic syndrome, emphasizing the importance of inflammatory genetic background in the pathogenesis of visceral obesity and related cardiovascular burden.

O nível sérico de Fas solúvel é preditor da necessidade de transfusão de hemácias em pacientes gravemente enfermos / Serum soluble-Fas is a predictor of red blood cell transfusion in critically ill patients

OBJETIVO: Investigar a relação entre a transfusão de hemácias e os níveis séricos de Fas solúvel, eritropoietina e citocinas inflamatórias em pacientes gravemente enfermos, com e sem insuficiência renal aguda. MÉTODOS: Os seguintes grupos foram estudados: pacientes gravemente enfermos com insuficiência renal aguda (n=30) e sem insuficiência renal aguda (n=13), pacientes portadores de doença renal crônica terminal em hemodiálise (n=25) e indivíduos saudáveis (n=21). Os níveis séricos de Fas solúvel, eritropoietina, interleucina 6, interleucina 10 e ferro, além da concentração de hemoglobina e de hematócrito, foram analisados em todos os grupos. A associação entre tais variáveis foram estudadas nos pacientes gravemente enfermos. RESULTADOS: Os níveis séricos de eritropoietina mostraram-se mais elevados nos pacientes gravemente enfermos do que nos dos demais grupos. Concentrações mais baixas de hemoglobina foram documentadas nos pacientes com insuficiência renal aguda em relação aos demais. Níveis séricos mais elevados de Fas solúvel foram observados nos pacientes com insuficiência renal aguda e doença renal crônica terminal. Pacientes gravemente enfermos transfundidos apresentaram níveis séricos mais elevados de Fas solúvel (5.906±2.047 e 1.920±1.060; p<0,001), interleucina 6 (518±537 e 255±502; p=0,02), interleucina 10 (35,8±30,7 e 18,5±10,9; p=0,02) e ferro, além de maior mortalidade em 28 dias. Os níveis séricos de Fas solúvel mostraram-se independentemente associados ao número de transfusões (p=0,02). O nível sérico de Fas solúvel foi um preditor independente da necessidade de transfusão de hemácias em pacientes gravemente enfermos (p=0,01). CONCLUSÃO: O nível sérico de Fas solúvel é um preditor independente da necessidade de transfusão de hemácias em pacientes gravemente enfermos, com ou sem insuficiência renal aguda. Mais estudos clínicos e laboratoriais são necessários para confirmar tal resultado.

OBJECTIVE: To investigate the relation between the need for red blood cell transfusion and serum levels of soluble-Fas, erythropoietin and inflammatory cytokines in critically ill patients with and without acute kidney injury. METHODS: We studied critically ill patients with acute kidney injury (n=30) and without acute kidney injury (n=13), end-stage renal disease patients on hemodialysis (n=25) and healthy subjects (n=21). Serum levels of soluble-Fas, erythropoietin, interleukin 6, interleukin 10, iron status, hemoglobin and hematocrit concentration were analyzed in all groups. The association between these variables in critically ill patients was investigated. RESULTS: Critically ill patients (acute kidney injury and non-acute kidney injury patients) had higher serum levels of erythropoietin than the other groups. Hemoglobin concentration was lower in the acute kidney injury patients than in other groups. Serum soluble-Fas levels were higher in acute kidney injury and end-stage renal disease patients. Critically ill patients requiring red blood cell transfusions had higher serum levels of soluble-Fas (5,906±2,047 and 1,920±1,060; p<0.001), interleukin 6 (518±537 and 255+502; p=0.02) and interleukin 10 (35.8±30.7 and 18.5±10.9; p=0.02), better iron status and higher mortality rates in the first 28 days in intensive care unit. Serum soluble-Fas levels were independently associated with the number of red blood cell units transfused (p=0.02). Serum soluble-Fas behaved as an independent predictor of the need for red blood cell transfusion in critically ill patients (p=0.01). CONCLUSIONS: Serum soluble-Fas level is an independent predictor of the need for red blood cell transfusion in critically ill patients with or without acute kidney injury. Further studies are warranted to reconfirm this finding.

Serum soluble-Fas is a predictor of red blood cell transfusion in critically ill patients.

OBJECTIVE: To investigate the relation between the need for red blood cell transfusion and serum levels of soluble-Fas, erythropoietin and inflammatory cytokines in critically ill patients with and without acute kidney injury. METHODS: We studied critically ill patients with acute kidney injury (n=30) and without acute kidney injury (n=13), end-stage renal disease patients on hemodialysis (n=25) and healthy subjects (n=21). Serum levels of soluble-Fas, erythropoietin, interleukin 6, interleukin 10, iron status, hemoglobin and hematocrit concentration were analyzed in all groups. The association between these variables in critically ill patients was investigated. RESULTS: Critically ill patients (acute kidney injury and non-acute kidney injury patients) had higher serum levels of erythropoietin than the other groups. Hemoglobin concentration was lower in the acute kidney injury patients than in other groups. Serum soluble-Fas levels were higher in acute kidney injury and end-stage renal disease patients. Critically ill patients requiring red blood cell transfusions had higher serum levels of soluble-Fas (5,906±2,047 and 1,920±1,060; p<0.001), interleukin 6 (518±537 and 255+502; p=0.02) and interleukin 10 (35.8±30.7 and 18.5±10.9; p=0.02), better iron status and higher mortality rates in the first 28 days in intensive care unit. Serum soluble-Fas levels were independently associated with the number of red blood cell units transfused (p=0.02). Serum soluble-Fas behaved as an independent predictor of the need for red blood cell transfusion in critically ill patients (p=0.01). CONCLUSIONS: Serum soluble-Fas level is an independent predictor of the need for red blood cell transfusion in critically ill patients with or without acute kidney injury. Further studies are warranted to reconfirm this finding.

Cystatin C at Admission in the Intensive Care Unit Predicts Mortality among Elderly Patients.

Introduction. Cystatin C has been used in the critical care setting to evaluate renal function. Nevertheless, it has also been found to correlate with mortality, but it is not clear whether this association is due to acute kidney injury (AKI) or to other mechanism. Objective. To evaluate whether serum cystatin C at intensive care unit (ICU) entry predicts AKI and mortality in elderly patients. Materials and Methods. It was a prospective study of ICU elderly patients without AKI at admission. We evaluated 400 patients based on normality for serum cystatin C at ICU entry, of whom 234 (58%) were selected and 45 (19%) developed AKI. Results. We observed that higher serum levels of cystatin C did not predict AKI (1.05 ± 0.48 versus 0.94 ± 0.36 mg/L; P = 0.1). However, it was an independent predictor of mortality, H.R. = 6.16 (95% CI 1.46-26.00; P = 0.01), in contrast with AKI, which was not associated with death. In the ROC curves, cystatin C also provided a moderate and significant area (0.67; P = 0.03) compared to AKI (0.47; P = 0.6) to detect death. Conclusion. We demonstrated that higher cystatin C levels are an independent predictor of mortality in ICU elderly patients and may be used as a marker of poor prognosis.

Estudo RFRIST (reserva de fluxo fracionada na quantificação funcional das estenoses em artérias de rins transplantados): racional e desenho do estudo / RFRIST study (fractional flow reserve in functional quantification of renal allograft artery stenosis): rationale and study design

INTRODUÇÃO: A estenose da artéria do enxerto renal é a complicação vascular mais prevalente após transplante renal. As limitações dos exames não-invasivos para seu diagnóstico são bem definidas e a angiografia permanece como padrão de referência para diagnóstico e definição terapêutica. A utilização da reserva de fluxo fracionada renal para melhor estratificação das estenoses de artéria renal nativa pode ajudar na adequada seleção de pacientes para tratamento percutâneo, porém tal método ainda não está padronizado em pacientes submetidos a transplante. O objetivo deste estudo será descrever e padronizar o protocolo de reserva de fluxo fracionada em pacientes com estenose da artéria do enxerto renal em um grupo de pacientes selecionados para intervenção renal percutânea, correlacionando o método com a angiografia. MÉTODOS: Estudo piloto, prospectivo, transversal, unicêntrico (Hospital São Paulo/Universidade Federal de São Paulo, São Paulo, SP, Brasil), em que serão selecionados 10 pacientes com quadro clínico compatível com estenose da artéria do enxerto renal, com angiografia do enxerto evidenciando estenose > 60%, admitidos para intervenção renal percutânea. Como avaliação da disfunção do enxerto serão realizadas dosagens de biomarcadores da função renal. CONCLUSÕES: No presente estudo, um protocolo original de reserva de fluxo fracionada para avaliação funcional de estenose da artéria do enxerto renal será padronizado, avaliando um método auxiliar na investigação funcional que possa identificar pacientes que realmente se beneficiem com a intervenção renal percutânea.

BACKGROUND: Renal allograft artery stenosis is the most prevalent vascular complication after renal transplantation. The diagnostic limitations of noninvasive tests are well defined and angiography remains the gold standard for diagnosis and therapeutic definition. The use of fractional flow reserve for a better stratification of native renal artery stenosis may be useful for an adequate selection of patients for percutaneous treatment, however this method has not yet been validated in patients undergoing transplantation. The objective of this study is to describe and standardize the fractional flow reserve protocol in patients with renal allograft artery stenosis in a group of patients selected for percutaneous renal intervention, correlating the method with angiography METHODS: Cross-sectional, single center pilot study (Hospital São Paulo/Universidade Federal de São Paulo, São Paulo, SP, Brazil), including 10 patients with a clinical picture compatible with renal allograft artery stenosis, with angiography showing graft stenosis > 60% and admitted for percutaneous renal intervention. Graft dysfunction assessment will include biomarkers of renal function. CONCLUSIONS: In this study, a fractional flow reserve protocol for the functional assessment of renal allograft artery stenosis will be standardized, evaluating an alternative method capable of identifying patients most likely to benefit from percutaneous renal intervention.

TNF-α modulates statin effects on secretion and expression of MCP-1, PAI-1 and adiponectin in 3T3-L1 differentiated adipocytes.

PURPOSE: Systemic inflammatory conditions, as seen in obesity and in the metabolic syndrome, are associated with high plasmatic levels of proatherogenic and prothromboticadipokines and low levels of adiponectin. Inhibitors of HMG-CoA reductase have beneficial effects in reducing cardiovascular events attributed predominantly to its lipid-lowering effects and recent studies suggest that these effects might be due to its anti-inflammatory properties. Based on the pleiotropic properties of simvastatin we studied the effects of this drug on the secretion and expression of adiponectin, PAI-1 and MCP-1 in mature adipocytes under baseline conditions and after an inflammatory stimulation. MATERIALS AND METHODS: The differentiated adipocytes were incubated with 10 µM simvastatin or vehicle and TNF-α 10 ng/mL or vehicle were added to treatment media. After 24h of incubation, the media was harvested and the proteins of interest were analyzed by Multiplex method. Gene expression was analyzed by real time-PCR. RESULTS: The addition of TNF-α increased the expression and secretion of MCP-1 and PAI-1. However, stimulation did not interfere with the secretion of adiponectin, despite having significantly reduced its expression. Our data also demonstrated that simvastatin reduced the expression and secretion of MCP-1, under baseline (770.4 ± 199.9 vs 312.7 ± 113.7 and 1.00 ± 0.14 vs 0.63 ± 0.13, p<0.05, respectively) and inflammatory conditions (14945 ± 228.7 vs 7837.6 ± 847.4 and 24.16 ± 5.49 vs 14.97 ± 2.67, p<0.05, p<0.05, respectively). Simvastatin also attenuated the increase in expression and secretion of PAI-1 induced by TNF-α (16898.6 ± 1663.3 vs 12922.1 ± 843.9 and 5.19 ± 3.12 vs 0.59 ± 0.16, respectively p<0.05), but under baseline conditions had no effect on the expression or secretion of PAI-1. The statin increased the expression of adiponectin under baseline conditions and inflammatory stimulation (1.03 ± 0.08 vs 4.0 ± 0.96 and 0.77 ± 0.19 vs 2.16 ± 0.23, respectively, p<0.05) and also increased the secretion of this adipokine but only with the inflammatory stimulus (5347.7 ± 1789.3 vs 7327.3 ± 753.6, p<0.05). CONCLUSIONS: Our findings suggested that simvastatin counteracted the stimulatory effect of TNF-α on secretion and expression of MCP-1, PAI-1 and adiponectin, implying a potential anti-atherogenic effect during the inflammatory process; these pleitropic effects were more pronounced with HMG-CoA reductase inhibitor.

Nec-1 protects against nonapoptotic cell death in cisplatin-induced kidney injury.

BACKGROUND/AIMS: Necrostatin-1 (Nec-1) inhibits necroptosis, a nonapoptotic cell death pathway. Acute kidney injury (AKI) is a clinical problem of high incidence and mortality. It involves several mechanisms of cell death. We aim to evaluate the effect of Nec-1 in the toxic kidney injury model by cisplatin. METHODS: We analyzed the effect of Nec-1 in AKI by cisplatin in human proximal tubule cells by flow cytometry. RESULTS: Our results show that Nec-1 has no effect on apoptosis in renal tubular epithelial cells (Nec-1 + Cis group 13.4 ± 1.7% vs. Cis group 14.6 ± 1.4%) (p > 0.05). But, in conditions in which apoptosis was blocked by benzyloxy-carbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD-fmk) the use of Nec-1 completely reversed cell viability (Nec-1 + Cis + z-VAD group 72.9 ± 6.3% vs. Cis group 35.5 ± 2.2%) (p < 0.05) suggesting that Nec-1 has effect on nonapoptotic cell death (necroptosis). CONCLUSION: Our findings suggest that the combined use of apoptosis and necroptosis inhibitors can provide additional cytoprotection in AKI. Furthermore, this is the first study to demonstrate that Nec-1 inhibits tubular kidney cell death and restores cell viability via a nonapoptotic mechanism.

Effects of simvastatin on cytokines secretion from mononuclear cells from critically ill patients with acute kidney injury.

PURPOSE: To assess the in vitro effects of simvastatin on IL-10 and TNF-α secretion from peripheral blood mononuclear cells (PBMC) of critically ill patients with and without acute kidney injury (AKI). METHODS: PBMC were collected from 63 patients admitted to the intensive care unit (ICU) and from 20 healthy controls. Patients were divided in 3 subgroups: with AKI, with sepsis and without AKI and with AKI and sepsis. After isolation by ficoll-gradient centrifugation cells were incubated in vitro with LPS 1 ng/mL, simvastatin (10(-8)M) and with LPS plus simvastatin for 24h. TNF-α and IL-10 concentrations on cells surnatant were determined by ELISA. RESULTS: Cells isolated from critically ill patients showed a decreased spontaneous production of TNF-α and IL-10 compared to healthy controls (6.7 (0.2-12) vs 103 (64-257) pg/mL and (20 (13-58) vs 315 (105-510) pg/mL, respectively, p<0.05). Under LPS-stimulus, IL-10 production remains lower in patients compared to healthy control (451 (176-850) vs 1150 (874-1521) pg/mL, p<0.05) but TNF-α production was higher (641 (609-841) vs 406 (201-841) pg/mL, p<0.05). The simultaneous incubation with LPS and simvastatin caused decreased IL-10 production in cells from patients compared to control (337 (135-626) vs 540 (345-871) pg/mL, p<0.05) and increased TNF-α release (711 (619-832) vs 324 (155-355) pg/mL, p<0.05). Comparison between subgroups showed that the results observed in TNF-α and IL-10 production by PBMC from critically ill patients was independent of AKI occurrence. CONCLUSIONS: The PBMC treatment with simvastatin resulted in attenuation on pro-inflammatory cytokine spontaneous production that was no longer observed when these cells were submitted to a second inflammatory stimulus. Our study shows an imbalance between pro and anti-inflammatory cytokine production in PBMC from critically ill patients regardless the presence of AKI.

A new spectrophotometric method to detect residual amounts of peroxide after reprocessing hemodialysis filters / Um novo método espectrofotométrico para detectar níveis residuais de peróxido após o reprocessamento de filtros de hemodiálise

ABSTRACT Objective: Reuse of hemodialysis filters is a standard practice and the sterilizing chemical most often employed is peracetic acid. Before starting the dialysis session, filters and lines are checked for residual levels of peracetic acid by means of a non-quantitative colorimetric test that is visually interpreted. The objective of this study was to investigate a new quantitative spectrophotometric test for detection of peracetic acid residues. Methods: Peracetic acid solutions were prepared in concentrations ranging from 0.01 to 10 ppm. A reagent (potassium-titanium oxide + sulfuric acid) was added to each sample in proportions varying from 0.08 to 2.00 drops/mL of solution. Optical densities were determined in a spectrophotometer using a 405-nm filter and subjected to visual qualitative test by different observers. Results: A relation between peroxide concentrations and respective optical densities was observed and it was linear with R2 > 0.90 for all reagent/substrate proportions. The peak optical densities were obtained with the reagent/substrate ratio of 0.33 drops/mL, which was later standardized for all further experiments. Both qualitative and quantitative tests yielded a specificity of 100%. The quantitative test was more sensitive than the qualitative test and resulted in higher positive and negative predictive values. There was a difference between observers in the qualitative test and some samples with significant amounts of peroxide were not detected. Conclusion: A quantitative spectrophotometric test may improve detection of residues of peracetic acid when compared to the standard visual qualitative test. This innovation may contribute to the development of safer standards for reuse of hemodialysis filters.

RESUMO Objetivo: A reutilização de filtros de hemodiálise é uma prática disseminada e a substância química esterilizante mais empregada é o ácido peracético. Antes de iniciar a sessão de diálise, os filtros e as linhas são verificados em relação a níveis residuais de ácido peracético por meio de teste colorimétrico não quantitativo, com interpretação visual. O objetivo deste trabalho foi investigar um novo teste espectrofotométrico quantitativo para detecção de resíduos de ácido peracético. Métodos: As soluções de ácido peracético foram preparadas em concentrações que variam de 0,01 a 10 ppm. O reagente (óxido de potássio-titânio + ácido sulfúrico) foi acrescentado a cada amostra em proporções que variaram de 0,08 a 2,00 gotas/mL de solução. As densidades ópticas foram determinadas em um espectrofotômetro com filtro de 405 nm e submetidas a um teste visual qualitativo por diferentes observadores. Resultados: Observou-se a relação linear entre as concentrações de peróxido e as respectivas densidades ópticas com R2 > 0,90 para todas as proporções de reagente/substrato. As maiores densidades ópticas foram obtidas com a proporção reagente/substrato de 0,33 gotas/mL, que foi padronizada para todos os experimentos posteriores. Os testes qualitativos e quantitativos apresentaram especificidade de 100%. O teste quantitativo foi mais sensível do que o qualitativo e apresentou maiores valores preditivos positivos e negativos. Houve uma diferença entre os observadores no teste qualitativo e algumas amostras com quantidade significativa de peróxido não foram detectadas. Conclusão: O teste espectrofotométrico quantitativo pode melhorar a detecção de resíduos de ácido peracético em comparação ao teste visual qualitativo padrão. Essa inovação pode contribuir para o desenvolvimento de padrões mais seguros na reutilização de filtros de hemodiálise.

Tratamento MARS (Molecular Adsorbent Recirculating System) em pacientes com cirrose biliar primária: relato da primeira expectativa ambulatorial no Brasil / The MARS (Molecular Adsorbent Recirculating System): patient with primary biliary cirrhosis: first experience report in Brazil

O tratamento MARS (Molecular Adsorbent Recirculating System) permite a remoção de toxinas hepáticas ligadas à albumina. Dentre estas substâncias estão os ácidos biliares, que têm importante papel no prurido nas síndromes colestáticas. Relato do Caso: Descrição da primeira experiência brasileira ambulatorial de diálise MARS em paciente de 39 anos, sexo feminino, com diagnóstico de cirrose biliar primária e prurido recorrente após transplante de fígado e refratário às medidas clínicas, havendo também importante comprometimento na qualidade de vida. Após a realização de 2 sessões consecutivas do tratamento MARS, houve controle do prurido por pelo menos 7 meses. Procedimento bem tolerado e sem intercorrências Conclusão: O tratamento MARS é uma opção para pacientes com prurido intratável secundário a síndromes colestáticas e está associado à reduzida taxa de complicações

Expressão de canais de potássio ATP- sensível em ratos com cirrose: correlação com atividade simpática e função renal / Expression of adenosine triphosphate-sensitive potassium channels in rats with cirrhosis: correlationship with sympathetic activity and renal function

O objetivo deste trabalho foi realizar uma análise direta da expressão de RNAm de KATP por RT-PCR em rim e aorta isolados de ratos com cirrose (induzida por tetracloreto de carbono) e de controles. O presente trabalho também estudou as relações entre a cirrose induzida e a excreção urinária de sódio e a atividade simpática em ratos cirróticos. Os ratos foram colocados em gaiolas metabólicas com acesso livre a comida e água. A cirrose foi induzida por repetidas doses de tetracloreto de carbono por gavage gástrica. Depois de algumas semanas, o rim e a aorta foram dissecados e foi feita a extração de RNA. A dosagem de letrólitos foi feita no sangue e na urina. A função renal foi estimada elo “clearance” de creatinina e a excreção urinária de sódio. As catecolaminas séricas foram medidas por análise de HPLC. Em primeiro lugar, a análise do RNAm de KATP expressou-se em fígados com cirrose e fibrose vigorosa, mas não com fibrose moderada. Posteriormente, a análise de RT-PCR revelou que a expressão de RNAm e KATP foi detectada somente na aorta dissecada de ratos com cirrose. Finalmente, uma reabsorção aumentada de sódio, sem falência renal, sugeriu que um potencial mediador aumente a atividade do sistema simpático. Conclusão: Estes resultados sugerem que o RNAm de KATP seja expresso em ratos cirróticos com ativação simpática e disfunção renal. Este canal pode estar envolvido em outra via, onde o tônus vascular pode ser modulado na cirrose.

hipertensão arterial / hypertension

A hipertensão (pressão sistólica >= 140 mmhg ou díastólíca >= 90 mmhg) tem alta prevalência em países desenvolvidos. Ocorre em um a cada quatro indivíduos em determinada comunidade e indivíduos normotensos'com mais de 50 anos tem 90por cento de chance de desenvolver um aumento da pressão arterial durante os próximos 25 anos. A prevalêncía é maior entre negros e idosos, especialmente mulheres idosas. O risco cardiovascular da hipertensão sistálica se inicia em 115 mmhg e o risco da hipertensão diastólica começa em 75 mmhg. O JNC 7 Report demonstrou que o peso/risco da hipertensão (ataque cardíaco, doença cardíaca, derrame, doença renal) pode ser atenuado com a diminuição da pressão arterial através de um novo nível objetivado de 120/80 mmhg. A medida exata da pressão arterial e a verificação da pressão elevada sobre múltiplas ocasiões há muito tempo são importantes. A pressão arterial que está elevada onde a duração medida em uma visita ao consultório, mas que é, por outro lado, normal (hipertensão do avental branco), pre- sente em 20 por cento dos pacientes com pressão arterial elevada, pode ser um precursor de hipertensão sancionada e, por essa razão, garantia de advertência. A avaliação poderia identificar sinais cardiovascular, cerebrovascular ou doença vascular periférica, bem como outros fatores de risco cardiovascular comumente presentes com hipertensão. Análise urinária, contagem completa de hemácías, 12-lead eletrocardíografia, testes químicos sanguíneos (creatinina, sódio, potássio, fasting glucose, colesteroi total e lipoproteína de alta densidade) são rotineiramente indicados. A maior parte dos casos de hipertensão pode ser prevenida e controlada, mas isso requer entrega de tarefas. O objetivo primário do tratamento é prevenir a doença cardiovascular e a morte. Intervenções no estilo de vida seriam defendídas como a primeira linha de tratamento em todos os casos.

Dislipidemias / Diagnosis and management of lipoprotein abnormalities

Anormalidades do perfil lipídico säo definidas:valores de LDL-colesterol>=160mg/dl(4,1 mmol/L),HDL-colesterol<40 mg/dL (1,0 mmol/dL),triglicerídes>= 150mg/dL (1,7 mmol/L) e lipoproteína (a)[lP(A)]>= 30mgmd/dL. Os valores acima descritos aumentam o risco de doença coronariana(DAC).As III Diretrizes Brasileira de Dislipidemia e III Programa Educacional em Colesterol (NCEP) ainda enfocam a otimizaçäo dos valores de LDL-colesterol como objetivo primário, estabelecendo como alvo valores abaixo de 100mg/dL, especialmente para pacientes com DAC, pacientes diabéticos e aqueles com risco de DAC maior que 20(por cento) em 10 anos. Com este intuito, dietas restritas em ácidos graxos saturados (maior que 7( por cento) do total de calorias) e colesterol (maior que 20mg/dia) assim como o uso dos inibidores da hidroximetilglutaril-CoA(estatinas) säo os pilares do tratamento da dislipidedmia, visando a reduçäo na incidência de DAC. A hipertrigliceeridemia severa (maior que 1.000 mg/dL ou 11,0 mmol/L) aumenta o risco de pancreatite e deve ser tratada com restriçäo na ingesta de gordura, controle da glicemia e uso dos fibratos. A niacina é a droga mais efetivana reduçäo das concecntraçöes dee Lp(a) e aumento dos níveis dee HDL-colesterol.(au)