Tasa de filtración glomerular como estimador de la hipertensión en enfermedades renales y cardiovasculares / Glomerular filtration rate as an estimator of renal and cardiovascular diseases such as hypertension

Introducción: Las fórmulas para la estimación de la tasa de filtración glomerular son fundamentales para estimar el curso de enfermedades renales; incluso ha sido de gran ayuda para obtener datos de prevalencia. Las ecuaciones comparadas con otros métodos son una forma económica y rápida para dar una estimación de la función renal. Objetivo: Describir la utilización de diferentes fórmulas para calcular la tasa de filtración glomerular relacionada con la hipertensión arterial y otras patologías renales y cardiovasculares. Metodología: Se realizó la búsqueda de artículos de investigación en bases de datos como PubMed, Science-Direct, Embase y otras, se estableció un tiempo de publicación entre los años 2018-2022 y se seleccionaron 42 artículos científicos relacionados con el tema. Resultados: La hipertensión arterial es una situación que incrementa el riesgo tanto de enfermedad cardiovascular como de deterioro de la función renal, por lo que en los pacientes hipertensos se espera una relación estrecha en la expresión de ambas patologías. Existen factores que alteran los valores de la creatinina sérica como la dieta, el ejercicio, la edad, el género, la masa muscular, enfermedades musculares y medicamentos. El impacto de la hipertensión en la función renal está descrito además de la relación entre el deterioro de la función renal y el incremento del riesgo cardiovascular; es por esto que en los últimos años la estimación de la función renal se ha incorporado como un marcador de morbilidad y mortalidad cardiovascular. Conclusiones: La estimación de la tasa de filtración glomerular es importante en varios contextos clínicos, en especial en aquellos pacientes con enfermedades que afectan la función glomerular, la creatinina es el biomarcador más usado a pesar de sus evidentes limitaciones.

Introduction: Formulas for estimating glomerular fil-tration rate are fundamental for estimating the course of renal diseases; they have even been of great help in obtaining prevalence data. Equations compared with other methods are an economical and fast way to give an estimation of renal function. Objective: Describe the use of different formulas to calculate the glomerular filtration rate related to high blood pressure and other kidney or cardiovascular pa-thologies. Methodology: Research articles were searched in da-tabases such as PubMed, Science-Direct, Embase and others, a publication time was established between the years 2018-2022 and 42 scientific articles related to the topic were selected. Results: Arterial hypertension is a situation that in-creases the risk of both cardiovascular disease and re-nal function deterioration, so in hypertensive patients a close relationship in the expression of both pathologies is expected. There are factors that alter serum creati-nine values such as diet, exercise, age, gender, muscle mass, muscle diseases and medications. The impact of hypertension on renal function has been described in addition to the relationship between the deterioration of renal function and the increase in cardiovascular risk; this is why in recent years the estimation of renal func-tion has been incorporated as a marker of cardiovascu-lar morbidity and mortality. Conclusions: The estimation of glomerular filtration rate is important in several clinical contexts, especia-lly in those patients with diseases that affect glomerular function; creatinine is the most widely used biomarker despite its obvious limitations

Benefits of water intake on kidney function in older adults: protocol for a randomized controlled trial / Benefícios da ingestão de água na função renal de idosos: protocolo para um estudo clínico randomizado controlado

Objective: The goal of this study is to evaluate the benefits of an increase in water intake guided by a mathematical formula (per kg of body weight) on kidney function in older adults. Methods: Older adults (≥ 65 years old) cared for at the Internal Medicine Unit of a tertiary hospital will be randomized to receive or not guidance on water intake (30 mL/kg per day) after initial assessment of kidney function. After 14 days, participants will be reevaluated through clinical and laboratory examinations. Patients with uncompensated disease will be excluded. The main outcomes will be glomerular filtration rate and laboratory measures such as serum and urinary osmolality, sodium, urea, 24-h urine volume and serum creatinine, uric acid, and copeptin. The Mini Nutritional Assessment (MNA) questionnaire will be applied to participants at each visit. Categorical variables will be described as numbers of cases (%) and compared using the χ2 test whereas continuous variables will be analyzed with Student's t-test in relation to baseline measures. The Generalized Estimating Equations (GEE) method will be performed to assess differences over time and between groups. This study was approved by the Institution's Research Ethics Committee (grant number 16-0153) and is in accordance with the Declaration of Helsinki. Expected Results:By increasing water intake (ml/Kg) we expect to provide an improvement in kidney function in older population assessed by serum creatinine and cystatin-c applied to eGFR formulas. Relevance:Many conditions, both organic and behavioral, can contribute to chronic dehydration states in older adults. To mention, decreased ability to concentrate urine, reduced kidney mass, blood flow, and glomerular filtration rate (GFR) along with changes in sensitivity to hormones such as renin, vasopressin and natriuretic peptide can generate water imbalance, leading to dehydration. For being simple and inexpensive, this strategy may be broadly used and bring several health benefits to older adults.

Objetivo: O objetivo deste estudo é avaliar os benefícios de um aumento da ingestão de água guiado por uma fórmula matemática (por kg de massa corporal) na função renal de idosos. Metodologia:Idosos (≥ 65 anos) atendidos pelo Serviço de Clínica Médica de um hospital terciário foram randomizados para receber ou não orientação sobre o consumo de água (30 mL/kg por dia) após uma avaliação inicial da função renal. Após 14 dias, os participantes serão reavaliados através de exames clínicos e laboratoriais. Pacientes com doença descompensada serão excluídos. Os desfechos principais são a taxa de filtração glomerular e medidas laboratoriais como osmolaridade, sódio e ureia séricos e urinários, volume de urina de 24 horas e creatinina, ácido úrico e copeptina séricos. A Mini Avaliação Nutricional (MNA) será aplicada aos participantes a cada consulta. Variáveis categóricas serão descritas como números de casos (%) e comparadas usando o teste χ2 , enquanto variáveis contínuas serão analisadas com o teste t de Student em relação às medidas iniciais. O método de Equações de Estimativas Generalizadas (GEE) será usado para avaliar diferenças ao longo do tempo e entre grupos. Este estudo foi aprovado pelo Comitê de Ética em Pesquisa da nossa Instituição (processo número 16-0153) e está de acordo com a Declaração de Helsinki. Resultados esperados:Ao aumentar a ingestão de água (ml/Kg) esperamos proporcionar uma melhora na função renal na população idosa avaliada pela creatinina sérica e cistatina-c aplicada às fórmulas de eGFR. Relevância:Muitas condições, tanto orgânicas quanto comportamentais, podem contribuir para estados de desidratação crônica em idosos. Vale mencionar que a diminuição da capacidade de concentração da urina, redução da massa renal, fluxo sanguíneo e taxa de filtração glomerular (TFG) juntamente com alterações na sensibilidade a hormônios como renina, vasopressina e peptídeo natriurético podem gerar desequilíbrio hídrico, levando à desidratação. Por ser simples e de baixo custo, essa estratégia pode ser amplamente utilizada e trazer diversos benefícios à saúde dos idosos.

Verificación y transferencia de intervalos de referencia de variables bioquímicas de rutina / Verification and transfer of reference intervals of routine biochemical variables

Introducción. El correcto análisis en la interpretación de los resultados de cualquier analito biológico es esencial para la salud del paciente y está fuertemente ligado a contrastar dichos resultados con los intervalos biológicos referenciales que estén acorde a la población que está siendo analizada diariamente. El objetivo de este artículo, fue establecer intervalos referenciales (IR) en adultos para glicemia, urea, creatinina, ácido úrico, colesterol total y triglicéridos en un laboratorio clínico y comparar los valores obtenidos con los incluidos en los insertos para ese rango de edad. Metodología. La población fue de 561 adultos de ambos sexos, aparentemente sanos, que acudieron a Biomasterclin Laboratorio en Valencia, Venezuela, y cuyas edades fueron de 57,1±18,1 años. Resultados. Los IR obtenidos fueron glicemia 63,0-108,8 mg/dL, urea 17,7-54,9 mg/dL, creatinina 0,60-1,41 mg/dL, ácido úrico 0,89-7,26 mg/dL, colesterol total 78,5-251,1 mg/dL y triglicéridos 39,5-176,0 mg/dL. Los IR propuestos por la casa comercial empleada para la determinación de la glicemia y la creatinina pudieron ser transferidos a la población evaluada, mientras que el resto de los IR no. Conclusión. Debido a las diferencias que se presentan entre los IR en los estuches comerciales comparados con los de la población de individuos que acuden a los laboratorios clínicos, se hace necesario establecer IR para ser empleados en cada laboratorio clínico

The correct analysis in the interpretation of the results of any biological analyte is essential for the health of the patient and it is strongly linked to comparing those results with reference ranges that are in accordance with the population that is being analyzed on a daily basis. The objective of this study was to establish reference ranges in adults for glycemia, urea, creatinine, uric acid, total cholesterol and triglycerides in a clinical laboratory and compare the values obtained with those included in the inserts for the corresponding age group. Methodology. The population consisted of 561 apparently healthy adults of both sexes that attended Biomasterclin Laboratorio in Valencia, Venezuela, whose ages were 57.1±18.1 years. Results. The reference ranges obtained for glycemia were 63.0- 108.8 mg/dL, urea 17.7-54.9 mg/dL, creatinine 0.60-1.41 mg/dL, uric acid 0.89- 726 mg/dL, total cholesterol 78.5-251.1 mg/dL and triglycerides 39.5-176.0 mg/ dL. The reference ranges proposed by the commercial kits used for the determination of glycemia and creatinine could be transferred to the evaluated population, while the rest of the reference ranges could not. Conclusion. Due to the differences that occur between the reference ranges in commercial kits compared to those of the population of individuals who attend clinical laboratories, it is necessary to establish reference values in each clinical laboratory

Marcadores hematológicos y bioquímicos para el diagnóstico precoz de bacteriemiascausadas por Enterobacteriaceae resistentes a los carbapenémicos / Haematological and biochemical markers for the early diagnosis of bacteremias caused bycarbapenem-resistant Enterobacteriaceae

INTRODUCCIÓN. Las bacteriemias causadas por Enterobacteriaceae resistentes a carbapenémicos se asocian con altas tasas de mortalidad a diferencia de las bacteriemias causadas por Enterobacteriaceae sensibles a carbapenémicos. Los hallazgos clínicos y de laboratorio son importantes para determinar los esquemas terapéuticos y su pronóstico; su diagnóstico precoz resulta esencial para un manejo adecuado. OBJETIVO. Relacionar valores de marcadores sanguíneos y bioquímicos en bacteriemias causadas por Enterobacteriaceae resistentes a carbapenémicos. MATERIALES Y MÉTODOS. Estudio analítico transversal. Población de 427 y muestra de 224 datos de hemocultivos positivos para Enterobacteriaceae de pacientes atendidos en el Hospital de Especialidades Carlos Andrade Marín en el periodo mayo 2016 a julio 2018. Criterios de inclusión: i) al menos un hemocultivo positivo; ii) recuperación del aislado de CRE o CSE y iii) recolección simultanea de muestras de sangre y pruebas de laboratorio. Criterios de exclusión: i) bacteriemias polimicrobianas; ii) valores fuera de rango y iii) reportes sin valores numéricos. El análisis de datos se realizó mediante el programa estadístico International Business Machines Statistical Package for the Social Sciences versión 24.0. RESULTADOS. Se demostró que el recuento de leucocitos [OR 1,21 (95% IC: 1,03-1,43)], el recuento de plaquetas [OR 1,65 (95% IC: 1,37-1,98)] y el tiempo parcial de tromboplastina [OR 1,29 (95% IC: 1,04-1,60)] fueron buenas variables predictoras independientes, mediante análisis de regresión logística multivariante. CONCLUSIÓN. La trombocitopenia y el tiempo parcial de tromboplastina prolongado se asociaron con bacteremia causada por Enterobacteriaceae resistentes a carbapenémicos.

INTRODUCTION. Bacteremias caused by carbapenem-resistant Enterobacteriaceae are associated with high mortality rates in contrast to bacteremias caused by carbapenem-sensitive Enterobacteriaceae. Clinical and laboratory findings are important in determining therapeutic regimens and prognosis; early diagnosis is essential for appropriate management. OBJECTIVE. To relate blood and biochemical marker values in bacteremia caused by carbapenem-resistant Enterobacteriaceae. MATERIALS AND METHODS. Cross-sectional analytical study. Population of 427 and sample of 224 blood culture data positive for Enterobacteriaceae from patients attended at the Carlos Andrade Marín Specialties Hospital in the period May 2016 to July 2018. Inclusion criteria: i) at least one positive blood culture; ii) recovery of CRE or CSE isolate and iii) simultaneous collection of blood samples and laboratory tests. Exclusion criteria: i) polymicrobial bacteremia; ii) out-of-range values and iii) reports without numerical values. Data analysis was performed using the statistical program International Business Machines Statistical Package for the Social Sciences version 24.0. RESULTS. Leukocyte count [OR 1.21 (95% CI: 1.03-1.43)], platelet count [OR 1.65 (95% CI: 1.37- 1.98)] and partial thromboplastin time [OR 1.29 (95% CI: 1.04-1.60)] were shown to be good independent predictor variables, by multivariate logistic regression analysis. CONCLUSION. Thrombocytopenia and prolonged partial thromboplastin time were associated with bacteremia caused by carbapenem-resistant Enterobacteriaceae.

An Assessment of the Accuracy of Creatinine Measurements in Guyana

ABSTRACT Background: The incidence of chronic kidney disease (CKD) is relatively high in Guyana. Estimated glomerular filtration rate (eGFR) reporting allows for early-stage CKD identification when therapeutic interventions can prevent CKD progression. Accurate creatinine measurements are essential for valid eGFR calculations. Objective: This study was undertaken to assess the accuracy of creatinine measurements in Guyana prior to implementing routine eGFR reporting. Methods: Sixteen Guyanese laboratories participated in this study. Each laboratory received a common set of blinded human serum samples (n = 3) containing clinically relevant creatinine concentrations, assigned by an international reference method (ID-GCMS). Laboratories performed repeated measurements of creatinine in each sample. These data were used to calculate bias, precision and total error (TE) for each creatinine method. Linear regression was used to compare measured creatinine results to assigned reference sample values and to post-analytically correct calibration bias, a priori, for recent patient results from each laboratory. Patient eGFR profiles were compared before and after bias correction. Results: The mean across samples CV and bias for all labs were 9% (range 2.5%-39.3%) and 11% positive (range 0.4%-29.1%), respectively. The mean TE was 28.6%. If the mean TE from a subset of the better performing laboratories (CV < 7%) was to apply nationally, an 'all stage' eGFR misclassification rate of 36% would result. Conclusion: There is a pressing need to improve the accuracy of creatinine measurements in Guyana as, at this time, routine reporting of eGFR by Guyanese laboratories cannot be recommended based on the accuracy data presented in this study.

Avaliação dos níveis de creatinina em pacientes submetidos à tomografia contrastada: uma metanálise / Creatinine level variation in patients subjected to contrast-enhanced tomography: a meta-analysis

Resumo A variação do valor encontrado nos exames de creatinina em pacientes submetidos à tomografia computadorizada (TC) contrastada tem sido utilizada como método prático para a avaliação de possíveis lesões renais causadas pelo uso do contraste. Entre os critérios, considera-se o aumento absoluto de creatinina sérica ≥ 0,5 mg/dL ou relativo em ≥ 25% para possíveis distúrbios renais, como a nefropatia induzida por contraste (NIC). Nosso objetivo foi analisar a incidência de NIC através de uma metanálise envolvendo nove artigos relacionados à incidência de lesão renal por contraste, sendo calculado o odds ratio (OR) e o intervalo de confiança (IC95%) por meio do programa RStudio. A incidência de NIC em pacientes submetidos a TC foi de 11,29%, sendo o OR de 1,38 (IC95% 0,88-2,16). Contrastes não iônicos apresentam maior segurança em seu uso que outros tipos de contraste, e o volume maior que 115 mL pode estar relacionado a NIC. A doença renal prévia apresentou significado estatístico em agravar a NIC.

Abstract Variation in the creatinine levels of patients who have undergone contrast-enhanced computed tomography (CT) has been adopted as a practical method for assessment of possible kidney damage caused by the contrast. Criteria employed include an absolute increase in serum creatinine ≥ 0.5 mg/dL or a relative increase ≥ 25% as indicative of possible renal disorders, such as contrast-induced nephropathy (CIN). Our objective was to analyze the incidence of CIN by means of a meta-analysis of nine articles related to incidence of kidney damage caused by contrast, calculating odds ratios (OR) and confidence intervals (95%CI) using RStudio. The overall incidence of CIN in patients who had CT scans was 11.29%, with an OR of 1.38 (95%CI 0.88-2.16). Non-ionic contrasts are safer than other types of contrast, and volumes exceeding 115 mL may be associated with CIN. Preexisting kidney disease had a statistically significant relationship with worse CIN rates.

Sarcoidose como diagnóstico diferencial de mieloma múltiplo / Sarcoidosis as a differential diagnosis of multiple myeloma

A sarcoidose caracteriza-se como doença granulomatosa que acomete diferentes órgãos humanos, especialmente os pulmões, sendo sua patogênese pouco conhecida. No caso em questão, a paciente iniciou com sintomas inespecíficos, como fraqueza, perda ponderal e tosse seca esporádica, sendo internada para extensão da propedêutica. Sugeriu-se como hipótese diagnóstica inicial possível quadro de mieloma múltiplo, tendo em vista a anemia, a disfunção renal, a hipercalcemia e, sobretudo, as lesões osteolíticas apresentadas pela paciente. Todavia, o diagnóstico de sarcoidose foi selado a partir das biópsias de medula óssea e de linfonodo inguinal, que evidenciaram mielite e linfadenite granulomatosas, respectivamente. A terapêutica instituída baseou-se na administração de corticosteroides e em medidas de redução da calcemia. A paciente recebeu alta, com melhora do quadro clínico, para acompanhamento ambulatorial da doença. Conclui-se que a sarcoidose não possui tratamento curativo, mas a terapêutica imunossupressora é eficaz no controle da progressão da enfermidade, fazendo com que o paciente tenha um prognóstico favorável.

Sarcoidosis is characterized as a granulomatous disease that affects different human organs, especially the lungs, and its pathogenesis is little known. In this case, the patient started with nonspecific symptoms, such as weakness, weight loss, and sporadic dry cough, being hospitalized for extension of the propaedeutics. The initial diagnostic hypothesis suggested was a possible case of multiple myeloma, based on the anemia, renal dysfunction, hypercalcemia and, above all, the osteolytic lesions presented by the patient. However, the diagnosis of sarcoidosis was made after bone marrow and inguinal lymph node biopsies that showed granulomatous myelitis and lymphadenitis, respectively. The therapy instituted was based on the administration of corticosteroids and on measures to reduce the level of calcium. The patient was discharged, with clinical improvement, for outpatient follow-up of the disease. It is concluded that sarcoidosis has no curative treatment, but immunosuppressive therapy is effective in controlling the progression of the disease, giving the patient a favorable prognosis.

Redução de hemoglobina: risco para lesão renal aguda após revascularização do miocárdio / Hemoglobin decrease: risk for acute kidney injury after myocardial revascularization / Reducción de la hemoglobina: riesgo de lesión renal aguda después de la revascularización miocárdica

Objetivo: verificar se a redução da taxa de hemoglobina no pós-operatório de revascularização do miocárdio interfere na função renal dos pacientes. Método: estudo observacional e prospectivo, desenvolvido entre fevereiro e junho de 2016, com 51 pacientes que realizaram cirurgia de revascularização do miocárdio em um hospital especializado em cardiologia do Distrito Federal. Os dados foram coletados por meio de um instrumento estruturado. O teste exato de Fisher, Qui-quadrado e Kruskal Wallis foram empregados para análise estatística. Considerou-se significativo resultados com p≤0,05. Projeto de pesquisa aprovado pelo Comitê de Ética, protocolo 44999215.9.0000.0026. Resultados: entre os pacientes, 45 (78,9%) evoluíram com lesão renal aguda após revascularização do miocárdio. Idade mais elevada (64±9 anos, p=0,05), tempo de circulação extracorpórea (p=0,05), índice de massa corporal (p=0,02), uso de antibióticos (p=0,03) e redução da taxa de hemoglobina (p=0,04), contribuíram para lesão renal aguda. Conclusão: a redução da taxa de hemoglobina foi associada estatisticamente à lesão renal aguda após revascularização do miocárdio.

Objective: to determine whether decreased hemoglobin rate after myocardial revascularization surgery interferes with patients' renal function. Method: this prospective, observational study was conducted between February and June 2016 with 51 patients who underwent myocardial revascularization surgery at a specialist cardiology hospital specializing in the Federal District. Data were collected using a structured instrument. The Fisher's exact, Chi-square and Kruskal-Wallis tests were used for statistical analysis. Results were considered significant at p ≤ 0.05. The research project was approved by the research ethics committee (Protocol 44999215.9.0000.0026). Results: it was observed that 45 patients (78.9%) developed acute kidney injury after myocardial revascularization. Oldest age (64 ± 9 years, p = 0.05), cardiopulmonary bypass time (p = 0.05), body mass index (p = 0.02), use of antibiotics (p = 0.03), and decreased hemoglobin rate (p = 0.04) contributed to acute kidney injury. Conclusion: decreased hemoglobin rate was statistically associated with acute kidney injury following myocardial revascularization.

Objetivo: verificar si la reduciendo la tasa de hemoglobina en el postoperatorio de revascularización miocárdica interfiere con la función renal de los pacientes. Método: estudio observacional prospectivo realizado entre febrero y junio de 2016 con 51 pacientes que se sometieron a una cirugía de revascularización miocárdica en un hospital especializado en cardiología en el Distrito Federal. Los datos fueron recolectados utilizando un instrumento estructurado. La prueba exacta de Fisher, Chicuadrado y Kruskal-Wallis se utilizaron para el análisis estadístico. Los resultados se consideraron significativos con p≤0.05. Proyecto de investigación aprobado por el Comité de Ética, protocolo 44999215.9.0000.0026. Resultados: se observó que 45 (78,9%) pacientes desarrollaron lesión renal aguda después de la revascularización miocárdica. Edad avanzada (64 ± 9 años, p = 0.05), tiempo de circulación corporal extra (p = 0.05), índice de masa corporal (p = 0.02), uso de antibióticos (p = 0.03) y tasa de hemoglobina reducida (p = 0.04), contribuyó a lesión renal aguda. Conclusión: reduciendo la tasa de hemoglobina contribuyó a lesión renal aguda después de la revascularización miocárdica.

Acetaminophen induces alterations to the renal tubular ultrastructure in a rat model of acute nephrotoxicity protected by resveratrol and quercetin / El acetaminofeno induce alteraciones en la ultraestructura tubular renal en un modelo de rata con nefrotoxicidad aguda protegida por resveratrol y quercetina

Acetaminophen (also called paracetamol, or APAP) induced nephrotoxicity is reported after accidental or intentional ingestion of an overdose of the drug. Renal tubular ultrastructural alterations induced by APAP overdose associated with the induction of biomarkers of kidney injury have not been investigated before. Also, we investigated whether the combined polyphenolic anti-inflammatory and antioxidants agents, resveratrol (RES) and quercetin (QUR) can protect against APAP-induced acute kidney injury. The model group of rats received a single dose of APAP (2 g/kg), whereas the protective group of rats was pre-treated for 7 days with combined doses of RES (30 mg/kg) and QUR (50 mg/kg) before being given a single dose of APAP. All rats were then sacrificed one day post APAP ingestion. Harvested kidney tissues were prepared for transmission electron microscopy (TEM) staining and blood samples were assayed for urea, creatinine, and biomarkers of inflammation and oxidative stress. TEM images and blood chemistry analysis showed that APAP overdose induced kidney damage as demonstrated by substantial alterations to the proximal convoluted tubule ultrastructure, and a significant (p<0.05) increase in urea, creatinine, tumor necrosis factor-alpha (TNF-a), and malondialdehyde (MDA) blood levels, which were protected by RES+QUR. These findings indicate that APAP induces alterations to the renal tubular ultrastructure, which is inhibited by resveratrol plus quercetin, which also decreases blood levels of kidney injury biomarkers.

El objetivo de este trabajo fue estudiar la nefrotoxicidad inducida por acetaminofeno (también llamado paracetamol o APAP) después de la ingestión accidental o intencional de una sobredosis de la droga. Las alteraciones ultraestructurales tubulares renales inducidas por sobredosis de APAP asociadas con la inducción de biomarcadores de daño renal no se han investigado. Además, estudiamos si los agentes combinados antiinflamatorios y antioxidantes polifenólicos, el resveratrol (RES) y la quercetina (QUR) pueden proteger contra la lesión renal aguda inducida por APAP. El grupo modelo de ratas recibió una dosis única de APAP (2 g / kg), mientras que el grupo protector de ratas se trató previamente durante 7 días con dosis combinadas de RES (30 mg / kg) y QUR (50 mg / kg) antes de recibir una dosis única de APAP. Todas las ratas se sacrificaron un día después de la ingestión de APAP. Los tejidos renales fueron preparados para el análisis a través de la microscopía electrónica de transmisión (MET). En las muestras de sangre se determinaron la urea, creatinina y los biomarcadores de inflamación y estrés oxidativo. Las imágenes MET y el análisis químico de la sangre mostraron que la sobredosis de APAP inducía daño renal, como lo demuestran las alteraciones sustanciales en la ultraestructura del túbulo contorneado proximal, y además, de un aumento significativo (p <0,05) de la urea, creatinina, factor de necrosis tumoral alfa y niveles sanguíneos de malondialdehído, protegidos por RES + QUR. Estos hallazgos indican que APAP induce alteraciones en la ultraestructura tubular renal, inhibida por el resveratrol más quercetina, que también disminuye los niveles sanguíneos de biomarcadores de daño renal.

Mast cells in the kidney biopsies of pediatric patients with lupus nephritis / Mastócitos em biópsias renais de pacientes pediátricos com nefrite lúpica

ABSTRACT Introduction: Mast cells may be involved in inflammation and contribute to the onset of fibrosis in lupus nephritis (LN). Objective: This study aimed to correlate the presence of mast cells in kidney biopsy specimens of pediatric patients with LN with activity (AI) and chronicity (CI) indices and assess how effectively mast cells may be used as a prognostic factor. Method: The study included 40 patients aged 6-18 years diagnosed with LN at the Renal Disease Service of the Federal University of Triângulo Mineiro between 1996 and 2015. Workup and epidemiological data were evaluated vis-à-vis AI, CI, and mast cell counts (MCC). Results: Significant positive correlations were found between mast cell counts (MCC) and AI (p = 0.003; r: 0.66) and MCC and CI (p = 0.048; r: 0.48). The ROC curve showed that mast cells were highly sensitive and specific in the differentiation of patients with an AI > 12 from individuals with an AI ≤ 12. Serum creatinine levels were higher in individuals with class IV LN than in patients with class V disease [1.50 (0.40-20.90) vs. 0.70 (0.62-0.90), p = 0.04]. Blood urea nitrogen had a positive significant correlation with MCC (p = 0.002; r: 0.75). A trend toward a negative correlation was observed between MCC and serum albumin (p = 0.06; r: -0.5459). Kidney biopsies of patients with nephrotic syndrome had higher MCC [2.12 (0.41-5.140) vs. 0.53 (0.0-3.94), p = 0.07]. Conclusion: Inflammatory cell infiltration and morphological differences between cell types in the inflammatory infiltrate are relevant factors in the assessment of the LN. Mast cell analysis and AI/CI assessment may be relevant prognostic indicators for pediatric patients with LN.

RESUMO Introdução: Mastócitos podem participar da inflamação e contribuir para fibrose na nefrite lúpica (NL). Objetivo: Correlacionar mastócitos em biópsias renais (BR) de pacientes pediátricos com NL com índices de atividade (IA) e cronicidade (IC), avaliando sua efetividade como fator prognóstico. Metodologia: Foram estudados 40 pacientes, entre 6 e 18 anos, diagnosticados com NL pelo Serviço de Nefropatologia da UFTM entre 1996 e 2015. Dados laboratoriais e epidemiológicos foram correlacionados com IA, IC e contagem de mastócitos (CM). Resultados: Encontramos correlação positiva e significativa entre contagem de mastócitos (CM) e IA (p = 0,003; r: 0,66) e entre CM e IC (p = 0,048; r: 0,48). Conforme a curva Roc, os mastócitos têm alta sensibilidade e especificidade na diferenciação de pacientes com IA menor ou maior do que 12. A creatinina sérica foi mais elevada na classe IV em relação à classe V [1,50 (0,40 - 20,90) versus 0,70 (0,62 - 0,90), p = 0,04]. Ureia sérica apresentou correlação positiva e significativa com CM (p = 0,002; r: 0,75). Observou-se tendência à correlação negativa entre CM e albumina sérica (p = 0,06; r: -0,5459). BR de pacientes com síndrome nefrótica apresentaram maior CM [2,12 (0,41 - 5,140) versus 0,53 (0,0 - 3,94), p = 0,07]. Conclusão: Não apenas o infiltrado inflamatório como também a diferenciação morfológica dos tipos celulares que o constituem são importantes para a avaliação da NL. Isso indica que a análise dos mastócitos, juntamente com a dos IA e IC, pode ajudar os nefrologistas a definirem o prognóstico de pacientes pediátricos.

Urine microscopy as a biomarker of Acute Kidney Injury following cardiac surgery with cardiopulmonary bypass / Microscopia urinária como biomarcador de lesão renal aguda após cirurgia cardíaca com circulação extracorpórea

Abstract Introduction: Acute kidney injury (AKI) occurs in about 22% of the patients undergoing cardiac surgery and 2.3% requires renal replacement therapy (RRT). The current diagnostic criteria for AKI by increased serum creatinine levels have limitations and new biomarkers are being tested. Urine sediment may be considered a biomarker and it can help to differentiate pre-renal (functional) from renal (intrinsic) AKI. Aims: To investigate the microscopic urinalysis in the AKI diagnosis in patients undergoing cardiac surgery with cardiopulmonary bypass. Methods: One hundred and fourteen patients, mean age 62.3 years, 67.5 % male, with creatinine 0.91 mg/dL (SD 0.22) had a urine sample examined in the first 24 h after the surgery. We looked for renal tubular epithelial cells (RTEC) and granular casts (GC) and associated the results with AKI development as defined by KDIGO criteria. Results: Twenty three patients (20.17 %) developed AKI according to the serum creatinine criterion and 76 (66.67 %) by the urine output criterion. Four patients required RRT. Mortality was 3.51 %. The use of urine creatinine criterion to predict AKI showed a sensitivity of 34.78 % and specificity of 86.81 %, positive likelihood ratio of 2.64 and negative likelihood ratio of 0.75, AUC-ROC of 0.584 (95%CI: 0.445-0.723). For the urine output criterion sensitivity was 23.68 % and specificity 92.11 %, AUC-ROC was 0.573 (95%CI: 0.465-0.680). Conclusion: RTEC and GC in urine sample detected by microscopy is a highly specific biomarker for early AKI diagnosis after cardiac surgery.

Resumo Introdução: Lesão renal aguda (LRA) ocorre em cerca de 22% dos pacientes submetidos a cirurgia cardíaca e 2,3% necessitam de terapia renal substitutiva (TRS). Os atuais critérios diagnósticos para LRA fundamentados no aumento dos níveis de creatinina sérica apresentam limitações e novos biomarcadores estão sendo testados. O sedimento urinário é um biomarcador que pode ajudar a diferenciar a LRA pré-renal (funcional) da LRA renal (intrínseca). Objetivos: Investigar a urinálise microscópica no diagnóstico de LRA em pacientes submetidos a cirurgia cardíaca com circulação extracorpórea. Métodos: Um total de 114 pacientes com idade média de 62,3 anos, 67,5% do sexo masculino e níveis médios de creatinina de 0,91 mg/dL (DP 0,22) tiveram amostras de urina examinadas nas primeiras 24 horas após a cirurgia. A identificação de células epiteliais tubulares renais (CETR) e cilindros granulares (CG) foi associada a desfechos de desenvolvimento de LRA conforme os critérios do KDIGO. Resultados: Vinte e três pacientes (20,17%) desenvolveram LRA pelo critério de creatinina sérica e 76 (66,67%) pelo critério de diurese. Quatro pacientes necessitaram de TRS. A mortalidade foi de 3,51%. O uso da creatinina urinária como critério preditivo para LRA mostrou sensibilidade de 34,78% e especificidade de 86,81%; razão de verossimilhança positiva de 2,64 e razão de verossimilhança negativa de 0,75; e ASC-COR de 0,584 (IC 95%: 0,445-0,723). Para o critério de diurese, a sensibilidade foi de 23,68% e a especificidade 92,11%; a ASC-COR foi 0,573 (IC 95%: 0,465-0,680). Conclusão: A identificação de CETR e CG em amostras de urina por microscopia representa um biomarcador altamente específico para o diagnóstico precoce de LRA após cirurgia cardíaca.

Treatment of chronic hepatitis C in patients with chronic kidney disease with Sofosbuvir-basead regimes

ABSTRACT Background: To analyze the effectiveness and the safety of Sofosbuvir-based regimens to treat patients with chronic hepatitis C virus (HCV) infection and chronic kidney disease (CKD). Methods: A retrospective, observational study in patients with chronic HCV infection and CKD treated with Sofosbuvir-based regimens was performed. Liver fibrosis, comorbidities, HCV genotype and sustained virological resposnse (SVR) at 12th week post-treatment were evaluated. Kidney function was accessed by serum creatinine and glomerular filtration rate (GFR). The assumed level of significance was 5 %. Results: Thirty-five patients were treated. The mean age was 52.1 ± 10.9 years, 19 (54.3 %) were women, 32 (91.4 %) were already kidney transplanted and 3 (8.6 %) were on hemodialysis. The SVR by intention to treat was 88.6 %. The mean GFR was 65.8 ± 28.6 and 63.7 ± 28.3 ml/min pre- and post-treatment respectively (p > 0.05). Treatment was interrupted in 1 (2.85 %) patient due to anemia and in 2 (5.7 %) due to loss of kidney function. Conclusion: Sofosbuvir-based regimens are effective to treat HCV in patients with CKD. In patients with mild CKD this type of therapy seems to be safe.

Renal changes and acute kidney injury in covid-19: a systematic review

SUMMARY OBJECTIVE We aimed to present a review of renal changes in patients with COVID-19. METHODS We performed a systematic review of the literature to identify original articles regarding clinical, laboratory, and anatomopathological kidney changes in patients infected with SARS-CoV-2 published until May 7, 2020. The search was carried out across PubMed, Scopus, and Embase using the keywords "COVID-19", "coronavirus", "SARS-CoV-2", "kidney injury" and "kidney disease". Fifteen studies presented clinical and laboratory renal changes in patients with COVID-19, and three addressed anatomopathological changes. DISCUSSION Acute kidney injury (AKI) was a relevant finding in patients with COVID-19. There were also significant changes in laboratory tests that indicated kidney injury, such as increased serum creatinine and blood urea nitrogen (BUN), proteinuria, and hematuria. The presence of laboratory abnormalities and AKI were significant in severely ill patients. There was a considerable prevalence of AKI among groups of patients who died of COVID-19. Histopathological analysis of the kidney tissue of patients infected with SARS-CoV-2 suggested that the virus may directly affect the kidneys. CONCLUSION Although COVID-19 affects mainly the lungs, it can also impact the kidneys. Increased serum creatinine and BUN, hematuria, proteinuria, and AKI were frequent findings in patients with severe COVID-19 and were related to an increased mortality rate. Further studies focusing on renal changes and their implications for the clinical condition of patients infected with the novel coronavirus are needed.

RESUMO OBJETIVO Apresentar uma revisão sobre as alterações renais nos pacientes com COVID-19. MÉTODOS Foi realizada uma revisão sistemática de literatura para buscar estudos referentes a pacientes com alterações renais clínicas, laboratoriais e anatomopatológicas durante a infecção por SARS-CoV-2. A busca foi realizada nas bases de dados eletrônicos PubMed, Scopus e Embase, com as palavras-chaves: "COVID-19", "coronavirus", "Sars-CoV-2", "kidney injury" e "kidney disease", para identificar artigos originais publicados na literatura até 07 de maio de 2020. Quinze estudos trouxeram alterações renais clínicas e laboratoriais dos pacientes com COVID-19, e três abordaram análises anatomopatológicas. DISCUSSÃO A Lesão renal aguda (LRA) foi um achado relevante nos pacientes com COVID-19. Houve também alterações significativas nos exames laboratoriais que indicam lesão renal, como o nível de creatinina e ureia séricas, proteinúria e hematúria. As alterações laboratoriais e a LRA foram importantes nos pacientes que desenvolveram o quadro grave da doença. Há considerável prevalência de LRA nos grupos de pacientes que vieram a óbito. Na análise histopatológica de pacientes com SARS-CoV-2 foram encontrados achados renais sugestivos que o vírus poderia ter efeitos diretos sobre o rim. CONCLUSÃO A COVID-19 é uma doença que, apesar de acometer principalmente os pulmões, também acomete os rins. Aumento das escórias nitrogenadas, hematúria, proteinúria e LRA foram achados frequentes em pacientes com quadros graves da COVID-19. Esses achados foram relacionados a maior mortalidade. É necessária a realização de mais estudos com enfoque nas alterações renais e suas implicações no quadro clínico causadas pelo novo coronavírus.

Kidney transplantation with donors in severe acute kidney injury. Should we use these organs? Retrospective Case Series / Transplante renal com doadores em lesão renal aguda severa. Devemos utilizar esses órgãos? Série de casos retrospectiva

ABSTRACT Introduction: The number of incident and prevalent patients on dialysis has increased, as well as the number of candidates for renal transplantation in Brazil, without a proportional increase in the number of organ donors. The use of expanded kidneys, as to renal function, may be an alternative to increase the supply of organs. Objective: to discuss the feasibility of using expanded kidneys for renal function, which are in severe acute renal injury. Methods: All cases of renal transplantation of deceased donors performed at the Hospital das Clínicas de Botucatu of UNESP, from January 2010 to June 2018, totaling 732 cases were evaluated. Cases with final donor creatinine greater than 6 mg/dL were selected. Results: four patients were selected, of whom all donors were in severe acute kidney injury (AKI). These donors presented rhabdomyolysis as a probable cause of severe AKI, were young, with no comorbidities and had decreased urinary volume in the last 24 hours. The clinical evolution of all the recipients was satisfactory, with a glomerular filtration rate after transplantation ranging from 48 to 98 mL/min/1.73 m2. Conclusion: this series of cases shows the possibility of using renal donors in severe AKI, provided the following are respected: donor age, rhabdomyolysis as the cause of AKI, and implantation-favorable biopsy findings. Additional studies with better designs, larger numbers of patients and longer follow-up times are needed.

RESUMO Introdução: O número de pacientes incidentes e prevalentes em diálise tem aumentado, assim como o número de candidatos ao transplante renal no Brasil, sem um aumento proporcional do número de doadores de órgãos. O uso de rins expandidos, quanto à função renal, pode ser uma alternativa para aumentar a oferta de órgãos. Objetivo: discutir a viabilidade do uso de rins expandidos quanto à função renal, que estejam em lesão renal aguda severa. Métodos: foram avaliados todos os casos de transplante renal de doador falecido realizados no Hospital das Clínicas de Botucatu da UNESP, de janeiro de 2010 a junho de 2018, totalizando 732 casos. Selecionou-se os casos com creatinina final do doador maior do que 6 mg/dL. Resultados: quatro pacientes foram selecionados, dos quais todos os doadores estavam em lesão renal aguda (LRA) severa. Esses doadores apresentavam rabdomiólise como provável causa de LRA severa, eram jovens, sem comorbidades e apresentavam diminuição de volume urinário nas últimas 24 horas. A evolução clínica de todos os receptores foi satisfatória, com taxa de filtração glomerular após o transplante variando entre 48 a 98 mL/min/1,73m2. Conclusão: essa série de casos mostra a possibilidade de utilização de doadores renais em LRA severa, desde que respeitadas as condições seguintes: idade do doador, rabdomiólise como causa de LRA e achados de biópsia favoráveis à implantação. Estudos adicionais com melhores desenhos, maior número de pacientes e maiores tempos de seguimento são necessários.

Zinc alpha 2 glycoprotein as an early biomarker of diabetic nephropathy in patients with type 2 diabetes mellitus / Zinco-alfa2-glicoproteina (ZAG) como biomarcador precoce de nefropatia diabética em pacientes com diabetes mellitus tipo 2

Abstract Introduction: Although microalbuminuria remains the gold standard for early detection of diabetic nephropathy (DN), it is not a sufficiently accurate predictor of DN risk. Thus, new biomarkers that would help to predict DN risk earlier and possibly prevent the occurrence of end-stage kidney disease are being investigated. Objective: To investigate the role of zinc-alpha-2-glycoprotein (ZAG) as an early marker of DN in type 2 diabetic (T2DM) patients. Methods: 88 persons were included and classified into 4 groups: Control group (group I), composed of normal healthy volunteers, and three patient groups with type 2 diabetes mellitus divided into: normo-albuminuria group (group II), subdivided into normal eGFR subgroup and increased eGFR subgroup > 120 mL/min/1.73m2), microalbuminuria group (group III), and macroalbuminuria group (group IV). All subjects were submitted to urine analysis, blood glucose levels, HbA1c, liver function tests, serum creatinine, uric acid, lipid profile and calculation of eGFR, urinary albumin creatinine ratio (UACR), and measurement of urinary and serum ZAG. Results: The levels of serum and urine ZAG were higher in patients with T2DM compared to control subjects and a statistically significant difference among studied groups regarding serum and urinary ZAG was found. Urine ZAG levels were positively correlated with UACR. Both ZAG levels were negatively correlated with eGFR. Urine ZAG levels in the eGFR ˃ 120 mL/min/1.73m2 subgroup were higher than that in the normal eGFR subgroup. Conclusion: These findings suggest that urine and serum ZAG might be useful as early biomarkers for detection of DN in T2DM patients, detectable earlier than microalbuminuria.

Resumo Introdução: Embora a microalbuminúria continue sendo o padrão ouro para a detecção precoce da nefropatia diabética (ND), ela não é um preditor suficientemente preciso do risco de ND. Assim, novos biomarcadores para prever mais precocemente o risco de ND e possivelmente evitar a ocorrência de doença renal terminal estão sendo investigados. Objetivo: Investigar a zinco-alfa2-glicoproteína (ZAG) como marcador precoce de ND em pacientes com debates mellitus tipo 2 (DM2). Métodos: Os 88 indivíduos incluídos foram divididos em quatro grupos: grupo controle (Grupo I), composto por voluntários saudáveis normais; e três grupos de pacientes com DM2 assim divididos: grupo normoalbuminúria (Grupo II), subdivididos em TFG normal e TFG > 120 mL/min/1,73 m2), grupo microalbuminúria (Grupo III) e grupo macroalbuminúria (Grupo IV). Todos foram submetidos a urinálise e exames para determinar glicemia, HbA1c, função hepática, creatinina sérica, ácido úrico, perfil lipídico, cálculo da TFG, relação albumina/creatinina (RAC) e dosagem urinária e sérica de ZAG. Resultados: Os níveis séricos e urinários de ZAG foram mais elevados nos pacientes com DM2 em comparação aos controles. Foi identificada diferença estatisticamente significativa entre os grupos estudados em relação aos níveis séricos e urinários de ZAG. Os níveis urinários de ZAG foram positivamente correlacionados com a RAC. Ambos os níveis de ZAG foram negativamente correlacionados com TFG. Os níveis urinários de ZAG no subgrupo com TFG ˃ 120 mL/min/1,73m2 foram maiores do que no subgrupo com TFG normal. Conclusão: Constatamos que a ZAG sérica e urinária pode ser um útil biomarcador precoce para detecção de ND em pacientes com DM2, sendo detectável mais precocemente que microalbuminúria.

Correlación anátomo-clínica entre clases y subclases roliferativas de nefritis lúpica en biopsias renales: experiencia de un centro único / Clinicopathological correlation among proliferative classes and subclasses of lupus nephritis in renal biopsies

Background Lupus nephritis (LN) is a complication of systemic lupus erythematosus that requires renal biopsy (RB). Proliferative classes III, IV-S, IV-G have especial clinical and pathological characteristics. Aim To determine the association between pathological features in RB with serum creatinine and urine protein levels. Material and Methods We analyzed 186 RB performed in adults aged 18 to 73 years, from a renal pathology reference center. Histopathological variables such as class and subclass of proliferative LN, endocapillary and extracapillary proliferation, activity and chronicity indexes, and vascular sclerosis were correlated with serum creatinine and urine protein levels, at the time of diagnosis. Results As compared with LN III, all the morphological and laboratory values were significantly more deteriorated in LN IV, with special focus on vascular sclerosis. Serum creatinine was the only variable that significantly differentiated LN IV-S from LN IV-G. Proteinuria was non-significantly higher in LN IV-G compared to LN IV-S. However, the difference became significant when proteinuria was compared between LN IV-G and LN III. Conclusions The significant difference in serum creatinine between LN IV-S and LN IV-G supports the concept that they are different subclasses. Proteinuria is a variable that differentiates classes III from IV-G, being significantly higher in the second. Severe arteriosclerosis is a constant and significant finding that differentiates LN III from LN IV. Thus, we propose its usefulness for distinguishing LN classes, and eventually, to be considered in the chronicity index.

Reserva funcional renal: concepto y aplicabilidad potencial en la práctica clínica / Renal functional reserve: concept and potential application in clinical practice

Renal functional reserve (RFR) is the capacity of the kidney to increase its glomerular filtration rate (GFR) in response to physiological or pathological stimuli. The most commonly used stimuli to assess this reserve are an oral load of proteins of animal origin, amino acid infusions, dopamine, glucagon or combinations of them. RFR is calculated as the difference between stimulated and baseline GFR. Vegetarians have lower baseline GFR than the general population and an increased RFR. Subjects with only one kidney and those suffering from chronic nephropathies usually have a reduced or absent RFR despite having normal basal GFR. Quantification of RFR may be useful to detect subclinical renal damage, physiological conditions that reduce baseline GFR, evaluation of potential donors for kidney transplantation, suspected hyperfiltration, detection of renal lability against acute injuries or pregnancy and the evaluation after an acute renal injury when renal function seems to be recovered and residual subclinical damage is suspected.

Mortalidad y fracaso renal agudo en pacientes con ventilación no invasiva / Mortality and acute kidney injury in patients with noninvasive ventilation

Se efectuó un estudio prospectivo observacional, obteniendo datos clínicos y analíticos de pacientes ingresados en la unidad de cuidados intensivos del Hospital Reina Sofía, que precisaron de ventilación mecánica no invasiva. El estudio se llevó a cabo desde el 1 de enero 2013 al 31 de diciembre de 2015. El objetivo principal fue determinar la mortalidad a los 90 días en pacientes ingresados con estas características en dicho periodo. Se definió como fracaso renal agudo al incremento de creatinina sérica > 0.3 mg/dl a las 48 horas con respecto al basal. Los pacientes fueron seguidos durante 90 días. Se analizaron 221 pacientes, 65 (29.4%) presentaron fracaso renal agudo y 156 (70.6%) función renal normal. La mortalidad global a los 90 días fue de 44 (19.9%); en el grupo del fracaso renal agudo fue de 33 (51.6%), y de 11 (7.1%) en los pacientes sin fracaso renal agudo (RR 7.340; IC 95%: 3.974-13.559. p < 0.001). La estancia hospitalaria fue de 24.2 ± 24.1 días en aquellos con fracaso renal agudo vs. 21.5 ± 20.7 días en el segundo grupo; p = 0.429), la estancia en la unidad de cuidados intensivos: 10.9 ± 14.4 con fracaso renal agudo vs. 7.3 ± 9.6; p = 0.357, sin dicha condición, y los días de ventilación mecánica no invasiva: 3.4 ± 3.0 con fracaso renal agudo vs. 2.7 ± 1.9; p = 0.569, en los que no se vieron afectados por la presencia del fracaso renal agudo. Como conclusión, la presencia de fracaso renal agudo es un factor independiente de mortalidad en los pacientes que presentan insuficiencia respiratoria aguda con necesidad de ventilación mecánica no invasiva.

We developed a prospective observational study, obtaining clinical and analytical data of patients admitted to the intensive care unit of the Hospital Reina Sofía, who required noninvasive ventilation, from January 1, 2013 to December 31, 2015. The main objective was to determine the 90-day mortality in these patients and conditions, who required noninvasive ventilation as treatment for acute respiratory failure and who developed acute kidney injury. Acute renal failure was defined as an increase in serum creatinine > 0.3 mg/dl at 48 hours with respect to the baseline. The patients were followed for 90 days. We analyzed 221 patients, 65 (29.4%) presented acute kidney injury and 156 (70.6%) normal renal function. Overall mortality at 90 days was 44 (19.9%). In the group of acute kidneys injury, it was 33 (51.6%), being 11 (7.1%) in patients without acute kidney injury (RR 7.340, 95% CI: 3.974-13.559, p < 0.001). Hospital stay in days was 24.2 ± 24.1 with acute kidney injury vs. 21.5 ± 0.7, p = 0.429; stay in the intensive care unit in days was 10.9 ± 14.4 with acute kidney injury vs. 7.3 ± 9.6, p = 0.357, and days of non-invasive ventilation 3.4 ± 3.0 with acute kidney injury vs. 2.7 ± 1.9, p = 0.569, in those patients not affected by the presence of acute kidney injury. In conclusion, the presence of acute kidney injury is an independent factor of mortality in patients with acute respiratory failure requiring noninvasive ventilation.