RESUMO
Clinical trials investigating the potential of mesenchymal stromal cells (MSCs) for the treatment of inflammatory diseases, such as acute respiratory distress syndrome (ARDS), have been disappointing, with less than 50% of patients responding to treatment. Licensed MSCs show enhanced therapeutic efficacy in response to cytokine-mediated activation signals. There are two distinct sub-phenotypes of ARDS: hypo- and hyper-inflammatory. We hypothesized that pre-licensing MSCs in a hyper-inflammatory ARDS environment would enhance their therapeutic efficacy in acute lung inflammation (ALI). Serum samples from patients with ARDS were segregated into hypo- and hyper-inflammatory categories based on interleukin (IL)-6 levels. MSCs were licensed with pooled serum from patients with hypo- or hyper-inflammatory ARDS or healthy serum controls. Our findings show that hyper-inflammatory ARDS pre-licensed MSC conditioned medium (MSC-CMHyper) led to a significant enrichment in tight junction expression and enhanced barrier integrity in lung epithelial cells in vitro and in vivo in a vascular endothelial growth factor (VEGF)-dependent manner. Importantly, while both MSC-CMHypo and MSC-CMHyper significantly reduced IL-6 and tumor necrosis factor alpha (TNF-α) levels in the bronchoalveolar lavage fluid (BALF) of lipopolysaccharide (LPS)-induced ALI mice, only MSC-CMHyper significantly reduced lung permeability and overall clinical outcomes including weight loss and clinical score. Thus, the hypo- and hyper-inflammatory ARDS environments may differentially influence MSC cytoprotective and immunomodulatory functions.
RESUMO
PURPOSE OF REVIEW: Deciphering the effect of acute kidney injury (AKI) during critical illness on long-term quality of life versus the impact of conditions that brought on critical illness is difficult. RECENT FINDINGS: Reports on patient-centred outcomes such as health-related quality of life (HRQOL) have provided insight into the long-lasting impact of critical illness complicated by AKI. However, these data stem from observational studies and randomized controlled trials, which have been heterogeneous in their patient population, timing, instruments used for assessment and reporting. Recent studies have corroborated these findings including lack of effect of renal replacement therapy compared to severe AKI on outcomes and worse physical compared to cognitive dysfunction. SUMMARY: In adults, more deficits in physical than mental health domains are found in survivors of AKI in critical care, whereas memory deficits and learning impairments have been noted in children. Further study is needed to understand and develop interventions that preserve or enhance the quality of life for individual patients who survive AKI following critical illness, across all ages.
Assuntos
Injúria Renal Aguda , Qualidade de Vida , Adulto , Criança , Humanos , Qualidade de Vida/psicologia , Estado Terminal , Injúria Renal Aguda/terapia , Injúria Renal Aguda/complicações , Terapia de Substituição Renal , Cuidados CríticosRESUMO
BACKGROUND: Acute kidney injury (AKI) is a frequent and severe complication of both COVID-19-related acute respiratory distress syndrome (ARDS) and non-COVID-19-related ARDS. The COVID-19 Critical Care Consortium (CCCC) has generated a global data set on the demographics, management and outcomes of critically ill COVID-19 patients. The LUNG-SAFE study was an international prospective cohort study of patients with severe respiratory failure, including ARDS, which pre-dated the pandemic. METHODS: The incidence, demographic profile, management and outcomes of early AKI in patients undergoing invasive mechanical ventilation for COVID-19-related ARDS were described and compared with AKI in a non-COVID-19-related ARDS cohort. RESULTS: Of 18,964 patients in the CCCC data set, 1699 patients with COVID-19-related ARDS required invasive ventilation and had relevant outcome data. Of these, 110 (6.5%) had stage 1, 94 (5.5%) had stage 2, 151 (8.9%) had stage 3 AKI, while 1214 (79.1%) had no AKI within 48 h of initiating invasive mechanical ventilation. Patients developing AKI were older and more likely to have hypertension or chronic cardiac disease. There were geo-economic differences in the incidence of AKI, with lower incidence of stage 3 AKI in European high-income countries and a higher incidence in patients from middle-income countries. Both 28-day and 90-day mortality risk was increased for patients with stage 2 (HR 2.00, p < 0.001) and stage 3 AKI (HR 1.95, p < 0.001). Compared to non-COVID-19 ARDS, the incidence of shock was reduced with lower cardiovascular SOFA score across all patient groups, while hospital mortality was worse in all groups [no AKI (30 vs 50%), Stage 1 (38 vs 58%), Stage 2 (56 vs 74%), and Stage 3 (52 vs 72%), p < 0.001]. The time profile of onset of AKI also differed, with 56% of all AKI occurring in the first 48 h in patients with COVID-19 ARDS compared to 89% in the non-COVID-19 ARDS population. CONCLUSION: AKI is a common and serious complication of COVID-19, with a high mortality rate, which differs by geo-economic location. Important differences exist in the profile of AKI in COVID-19 versus non-COVID-19 ARDS in terms of their haemodynamic profile, time of onset and clinical outcomes.
Assuntos
Injúria Renal Aguda , COVID-19 , Síndrome do Desconforto Respiratório , Humanos , COVID-19/complicações , COVID-19/epidemiologia , COVID-19/terapia , Estudos Prospectivos , Fatores de Risco , Síndrome do Desconforto Respiratório/epidemiologia , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/terapia , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Estudos Retrospectivos , Unidades de Terapia Intensiva , Mortalidade HospitalarRESUMO
There is significant interest in the potential for nebulised unfractionated heparin (UFH), as a novel therapy for patients with COVID-19 induced acute hypoxaemic respiratory failure requiring invasive ventilation. The scientific and biological rationale for nebulised heparin stems from the evidence for extensive activation of coagulation resulting in pulmonary microvascular thrombosis in COVID-19 pneumonia. Nebulised delivery of heparin to the lung may limit alveolar fibrin deposition and thereby limit progression of lung injury. Importantly, laboratory studies show that heparin can directly inactivate the SARS-CoV-2 virus, thereby prevent its entry into and infection of mammalian cells. UFH has additional anti-inflammatory and mucolytic properties that may be useful in this context. METHODS AND INTERVENTION: The Can nebulised HepArin Reduce morTality and time to Extubation in Patients with COVID-19 Requiring invasive ventilation Meta-Trial (CHARTER-MT) is a collaborative prospective individual patient data analysis of on-going randomised controlled clinical trials across several countries in five continents, examining the effects of inhaled heparin in patients with COVID-19 requiring invasive ventilation on various endpoints. Each constituent study will randomise patients with COVID-19 induced respiratory failure requiring invasive ventilation. Patients are randomised to receive nebulised heparin or standard care (open label studies) or placebo (blinded placebo-controlled studies) while under invasive ventilation. Each participating study collect a pre-defined minimum dataset. The primary outcome for the meta-trial is the number of ventilator-free days up to day 28 day, defined as days alive and free from invasive ventilation.
Assuntos
Tratamento Farmacológico da COVID-19 , Ventilação não Invasiva , Insuficiência Respiratória , Extubação , Heparina , Humanos , Pulmão , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Respiratória/induzido quimicamente , SARS-CoV-2 , Resultado do TratamentoRESUMO
BACKGROUND: Awake prone positioning (APP) improves oxygenation in coronavirus disease (COVID-19) patients and, when successful, may decrease the risk of intubation. However, factors associated with APP success remain unknown. In this secondary analysis, we aimed to assess whether APP can reduce intubation rate in patients with COVID-19 and to focus on the factors associated with success. METHODS: In this multicenter randomized controlled trial, conducted in three high-acuity units, we randomly assigned patients with COVID-19-induced acute hypoxemic respiratory failure (AHRF) requiring high-flow nasal cannula (HFNC) oxygen to APP or standard care. Primary outcome was intubation rate at 28 days. Multivariate analyses were performed to identify the predictors associated to treatment success (survival without intubation). RESULTS: Among 430 patients randomized, 216 were assigned to APP and 214 to standard care. The APP group had a lower intubation rate (30% vs 43%, relative risk [RR] 0.70; CI95 0.54-0.90, P = 0.006) and shorter hospital length of stay (11 interquartile range [IQR, 9-14] vs 13 [IQR, 10-17] days, P = 0.001). A respiratory rate ≤ 25 bpm at enrollment, an increase in ROX index > 1.25 after first APP session, APP duration > 8 h/day, and a decrease in lung ultrasound score ≥ 2 within the first 3 days were significantly associated with treatment success for APP. CONCLUSION: In patients with COVID-19-induced AHRF treated by HFNC, APP reduced intubation rate and improved treatment success. A longer APP duration is associated with APP success, while the increase in ROX index and decrease in lung ultrasound score after APP can also help identify patients most likely to benefit. TRIAL REGISTRATION: This study was retrospectively registered in ClinicalTrials.gov at July 20, 2021. Identification number NCT04477655. https://clinicaltrials.gov/ct2/show/NCT04477655?term=PRO-CARF&draw=2&rank=1.
Assuntos
COVID-19 , Insuficiência Respiratória , COVID-19/complicações , COVID-19/terapia , Cânula , Humanos , Decúbito Ventral , Insuficiência Respiratória/complicações , Insuficiência Respiratória/terapia , VigíliaRESUMO
The definition of acute respiratory distress syndrome (ARDS), has evolved since it was first described in 1967 by Ashbaugh and Petty to the current "Berlin" definition of ARDS developed in 2012 by an expert panel, that provided clarification on the definition of "acute," and on the cardiac failure criteria. It expanded the definition to include patients receiving non-invasive ventilation, and removed the term "acute lung injury" and added a requirement of patients to be receiving a minimum 5 cmH2O expiratory pressure.Since 2012, a series of observational cohort studies have generated insights into the utility and robustness of this definition. This review will examine novel insights into the epidemiology of ARDS, failures in ARDS diagnosis, the role of lung imaging in ARDS, the novel ARDS cohort that is not invasively ventilated, lung compliance profiles in patients with ARDS, sex differences that exist in ARDS management and outcomes, the progression of ARDS following initial diagnosis, and the clinical profile and outcomes of confirmed versus resolved ARDS. Furthermore, we will discuss studies that challenge the utility of distinguishing ARDS from other causes of acute hypoxemic respiratory failure (AHRF) and identify issues that may need to be addressed in a revised definition.
Assuntos
Lesão Pulmonar Aguda , Síndrome do Desconforto Respiratório , Insuficiência Respiratória , Feminino , Humanos , Masculino , Estudos Observacionais como Assunto , Estudos Prospectivos , Respiração Artificial/métodos , Síndrome do Desconforto Respiratório/diagnósticoRESUMO
The novel coronavirus, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), is the causative agent of the 2020 worldwide coronavirus pandemic. Antibody testing is useful for diagnosing historic infections of a disease in a population. These tests are also a helpful epidemiological tool for predicting how the virus spreads in a community, relating antibody levels to immunity and for assessing herd immunity. In the present study, SARS-CoV-2 viral proteins were recombinantly produced and used to analyse serum from individuals previously exposed, or not, to SARS-CoV-2. The nucleocapsid (Npro) and spike subunit 2 (S2Frag) proteins were identified as highly immunogenic, although responses to the former were generally greater. These two proteins were used to develop two quantitative enzyme-linked immunosorbent assays (ELISAs) that when used in combination resulted in a highly reliable diagnostic test. Npro and S2Frag-ELISAs could detect at least 10% more true positive coronavirus disease-2019 (COVID-19) cases than the commercially available ARCHITECT test (Abbott). Moreover, our quantitative ELISAs also show that specific antibodies to SARS-CoV-2 proteins tend to wane rapidly even in patients who had developed severe disease. As antibody tests complement COVID-19 diagnosis and determine population-level surveillance during this pandemic, the alternative diagnostic we present in this study could play a role in controlling the spread of the virus.
Assuntos
Teste Sorológico para COVID-19/métodos , COVID-19/diagnóstico , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , SARS-CoV-2/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto , Idoso , Anticorpos Antivirais/sangue , Proteínas do Nucleocapsídeo de Coronavírus/genética , Proteínas do Nucleocapsídeo de Coronavírus/isolamento & purificação , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/sangue , Cinética , Masculino , Pessoa de Meia-Idade , Fosfoproteínas/genética , Fosfoproteínas/imunologia , Fosfoproteínas/isolamento & purificação , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/isolamento & purificação , SARS-CoV-2/imunologia , Sensibilidade e Especificidade , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/isolamento & purificaçãoRESUMO
BACKGROUND: To determine the frequency of, and factors associated with, death in hospital following ICU discharge to the ward. METHODS: The Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE study was an international, multicenter, prospective cohort study of patients with severe respiratory failure, conducted across 459 ICUs from 50 countries globally. This study aimed to understand the frequency and factors associated with death in hospital in patients who survived their ICU stay. We examined outcomes in the subpopulation discharged with no limitations of life sustaining treatments ('treatment limitations'), and the subpopulations with treatment limitations. RESULTS: 2186 (94%) patients with no treatment limitations discharged from ICU survived, while 142 (6%) died in hospital. 118 (61%) of patients with treatment limitations survived while 77 (39%) patients died in hospital. Patients without treatment limitations that died in hospital after ICU discharge were older, more likely to have COPD, immunocompromise or chronic renal failure, less likely to have trauma as a risk factor for ARDS. Patients that died post ICU discharge were less likely to receive neuromuscular blockade, or to receive any adjunctive measure, and had a higher pre- ICU discharge non-pulmonary SOFA score. A similar pattern was seen in patients with treatment limitations that died in hospital following ICU discharge. CONCLUSIONS: A significant proportion of patients die in hospital following discharge from ICU, with higher mortality in patients with limitations of life-sustaining treatments in place. Non-survivors had higher systemic illness severity scores at ICU discharge than survivors. TRIAL REGISTRATION: ClinicalTrials.gov NCT02010073 .
Assuntos
Mortalidade/tendências , Alta do Paciente/estatística & dados numéricos , Insuficiência Respiratória/mortalidade , Adulto , Idoso , Feminino , Humanos , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Insuficiência Respiratória/epidemiologia , Fatores de RiscoRESUMO
BACKGROUND: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. METHODS: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). RESULTS: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). CONCLUSIONS: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. TRIAL REGISTRATION: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073.
Assuntos
Oxigenoterapia Hiperbárica , Oxigênio/uso terapêutico , Respiração Artificial , Síndrome do Desconforto Respiratório/terapia , Humanos , Unidades de Terapia Intensiva , Prevalência , Síndrome do Desconforto Respiratório/mortalidadeRESUMO
RATIONALE: We wished to determine the influence of sex on the management and outcomes in acute respiratory distress syndrome (ARDS) patients in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE). METHODS: We assessed the effect of sex on mortality, intensive care unit and hospital length of stay, and duration of invasive mechanical ventilation (IMV) in patients with ARDS who underwent IMV, adjusting for plausible clinical and geographic confounders. FINDINGS: Of 2377 patients with ARDS, 905 (38%) were female and 1472 (62%) were male. There were no sex differences in clinician recognition of ARDS or critical illness severity profile. Females received higher tidal volumes (8.2±2.1 versus 7.2±1.6â mL·kg-1; p<0.0001) and higher plateau and driving pressures compared with males. Lower tidal volume ventilation was received by 50% of females compared with 74% of males (p<0.0001). In shorter patients (height ≤1.69â m), females were significantly less likely to receive lower tidal volumes. Surviving females had a shorter duration of IMV and reduced length of stay compared with males. Overall hospital mortality was similar in females (40.2%) versus males (40.2%). However, female sex was associated with higher mortality in patients with severe confirmed ARDS (OR for sex (male versus female) 0.35, 95% CI 0.14-0.83). CONCLUSIONS: Shorter females with ARDS are less likely to receive lower tidal volume ventilation, while females with severe confirmed ARDS have a higher mortality risk. These data highlight the need for better ventilatory management in females to improve their outcomes from ARDS.
Assuntos
Mortalidade Hospitalar , Tempo de Internação/estatística & dados numéricos , Respiração Artificial/métodos , Síndrome do Desconforto Respiratório/terapia , Adulto , Idoso , Estatura , Estudos de Coortes , Duração da Terapia , Feminino , Humanos , Peso Corporal Ideal , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Mortalidade , Pneumonia/epidemiologia , Estudos Prospectivos , Respiração Artificial/estatística & dados numéricos , Aspiração Respiratória de Conteúdos Gástricos/epidemiologia , Síndrome do Desconforto Respiratório/epidemiologia , Síndrome do Desconforto Respiratório/mortalidade , Sepse/epidemiologia , Índice de Gravidade de Doença , Fatores Sexuais , Volume de Ventilação Pulmonar , Resultado do TratamentoRESUMO
OBJECTIVES: To understand the impact of mild-moderate and severe acute kidney injury in patients with acute respiratory distress syndrome. DESIGN: Secondary analysis of the "Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure", an international prospective cohort study of patients with severe respiratory failure. SETTING: Four-hundred fifty-nine ICUs from 50 countries across five continents. SUBJECTS: Patients with a glomerular filtration rate greater than 60 mL/min/1.73 m prior to admission who fulfilled criteria of acute respiratory distress syndrome on day 1 and day 2 of acute hypoxemic respiratory failure. INTERVENTIONS: Patients were categorized based on worst serum creatinine or urine output into: 1) no acute kidney injury (serum creatinine < 132 µmol/L or urine output ≥ 0.5 mL/kg/hr), 2) mild-moderate acute kidney injury (serum creatinine 132-354 µmol/L or minimum urine output between 0.3 and 0.5mL/kg/hr), or 3) severe acute kidney injury (serum creatinine > 354 µmol/L or renal replacement therapy or minimum urine output < 0.3 mL/kg/hr). MEASUREMENTS AND MAIN RESULTS: The primary outcome was hospital mortality, whereas secondary outcomes included prevalence of acute kidney injury and characterization of acute respiratory distress syndrome risk factors and illness severity patterns, in patients with acute kidney injury versus no acute kidney injury. One-thousand nine-hundred seventy-four patients met inclusion criteria: 1,209 (61%) with no acute kidney injury, 468 (24%) with mild-moderate acute kidney injury, and 297 (15%) with severe acute kidney injury. The impact of acute kidney injury on the ventilatory management of patients with acute respiratory distress syndrome was relatively limited, with no differences in arterial CO2 tension or in tidal or minute ventilation between the groups. Hospital mortality increased from 31% in acute respiratory distress syndrome patients with no acute kidney injury to 50% in mild-moderate acute kidney injury (p ≤ 0.001 vs no acute kidney injury) and 58% in severe acute kidney injury (p ≤ 0.001 vs no acute kidney injury and mild-moderate acute kidney injury). In multivariate analyses, both mild-moderate (odds ratio, 1.61; 95% CI, 1.24-2.09; p < 0.001) and severe (odds ratio, 2.13; 95% CI, 1.55-2.94; p < 0.001) acute kidney injury were independently associated with mortality. CONCLUSIONS: The development of acute kidney injury, even when mild-moderate in severity, is associated with a substantial increase in mortality in patients with acute respiratory distress syndrome.
Assuntos
Injúria Renal Aguda/epidemiologia , Mortalidade Hospitalar/tendências , Unidades de Terapia Intensiva/estatística & dados numéricos , Síndrome do Desconforto Respiratório/epidemiologia , Síndrome do Desconforto Respiratório/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Dióxido de Carbono/sangue , Comorbidade , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Prospectivos , Respiração Artificial/métodos , Síndrome do Desconforto Respiratório/mortalidade , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
PURPOSE OF REVIEW: Recent advances in our understanding of the epidemiology of ARDS has generated key insights into the incidence, risk factors, demographics, management and outcomes from this devastating clinical syndrome. RECENT FINDINGS: ARDS occurs in 10% of all ICU patients, in 23% of all mechanically ventilated patients, with 5.5 cases per ICU bed each year. Although some regional variation exists regarding ARDS incidence, this may be less than previously thought. Subphenotypes are increasingly identified within the ARDS cohort, with studies identifying a 'hyperinflammatory' or 'reactive' subgroup that has a higher mortality, and may respond differently to therapeutic interventions. Demographic factors, such as race, may also affect the therapeutic response. Although mortality in ARDS is decreasing in clinical trials, it remains unchanged at approximately 40% in major observational studies. Modifiable ventilatory management factors, including PEEP, airway pressures, and respiratory rate are associated with mortality in ARDS. Hospital and ICU organizational factors play a role in outcome, whereas socioeconomic status is independently associated with survival in patients with ARDS. The Kigali adaptation of the Berlin ARDS definition may provide useful insights into the burden of ARDS in the developing world. SUMMARY: ARDS exerts a substantial disease burden, with 40% of patients dying in hospital. Diverse factors, including patient-related factors such as age and illness severity, country level socioeconomic status, and ventilator management and ICU organizational factors each contribute to outcome from ARDS. Addressing these issues provides opportunities to improve outcome in patients with ARDS.
Assuntos
Cuidados Críticos , Unidades de Terapia Intensiva/organização & administração , Respiração Artificial/normas , Síndrome do Desconforto Respiratório/epidemiologia , Síndrome do Desconforto Respiratório/terapia , Cuidados Críticos/economia , Cuidados Críticos/organização & administração , Cuidados Críticos/normas , Países em Desenvolvimento/estatística & dados numéricos , Medicina Baseada em Evidências , Mortalidade Hospitalar , Humanos , Incidência , Unidades de Terapia Intensiva/economia , Respiração Artificial/economia , Síndrome do Desconforto Respiratório/economia , Síndrome do Desconforto Respiratório/mortalidade , Fatores de Risco , Índice de Gravidade de Doença , Fatores SocioeconômicosRESUMO
Parietal epithelial cell (PEC) response to glomerular injury may underlie a common pathway driving fibrogenesis following podocyte loss that typifies several glomerular disorders. Although the mammalian target of rapamycin (mTOR) pathway is important in cell homeostasis, little is known of the biological role or impact of reducing mTOR activity on PEC response following podocyte depletion, nor in the aging kidney. The purpose of these studies was to determine the impact on PECs of reducing mTOR activity following abrupt experimental depletion in podocyte number, as well as in a model of chronic podocyte loss and sclerosis associated with aging. Podocyte depletion was induced by an anti-podocyte antibody and rapamycin started at day 5 until death at day 14 Reducing mTOR did not lead to a greater reduction in podocyte density, despite greater glomerulosclerosis. However, mTOR inhibition lead to an increase in PEC density and PEC-derived crescent formation. Additionally, markers of epithelial-to-mesenchymal transition (platelet-derived growth factor receptor-ß, α-smooth muscle actin, Notch-3) and PEC activation (CD44, collagen IV) were further increased by mTOR reduction. Aged mice treated with rapamycin for 1, 2, and 10 wk before death at 26.5 mo (≈75-yr-old human age) had increased the number of glomeruli with a crescentic appearance. mTOR inhibition at either a high or low level lead to changes in PEC phenotype, indicating PEC morphology is sensitive to changes mediated by global mTOR inhibition.
Assuntos
Envelhecimento/metabolismo , Células Epiteliais/metabolismo , Glomerulosclerose Segmentar e Focal/metabolismo , Rim/metabolismo , Podócitos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Envelhecimento/patologia , Animais , Contagem de Células , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal , Feminino , Glomerulosclerose Segmentar e Focal/patologia , Rim/efeitos dos fármacos , Rim/patologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Masculino , Camundongos , Podócitos/efeitos dos fármacos , Podócitos/patologia , Sirolimo/farmacologiaRESUMO
Kidney aging is accompanied by characteristic changes in the glomerulus, but little is known about the effect of aging on glomerular parietal epithelial cells (PECs), nor if the characteristic glomerular changes in humans and rats also occur in very old mice. Accordingly, a descriptive analysis was undertaken in 27-mo-old C57B6 mice, considered advanced age. PEC density was significantly lower in older mice compared with young mice (aged 3 mo), and the decrease was more pronounced in juxtamedullary glomeruli compared with outer cortical glomeruli. In addition to segmental and global glomerulosclerosis in older mice, staining for matrix proteins collagen type IV and heparan sulfate proteoglycan were markedly increased in Bowman's capsules of older mouse glomeruli, consistent with increased extracellular matrix production by PECs. De novo staining for CD44, a marker of activated and profibrotic PECs, was significantly increased in aged glomeruli. CD44 staining was more pronounced in the juxtamedullary region and colocalized with phosphorylated ERK. Additionally, a subset of aged PECs de novo expressed the epithelial-to-mesenchymal transition markers α-smooth muscle and vimentin, with no changes in epithelial-to-mesenchymal transition markers E-cadherin and ß-catenin. The mural cell markers neural/glial antigen 2, PDGF receptor-ß, and CD146 as well as Notch 3 were also substantially increased in aged PECs. These data show that mice can be used to better understand the aging kidney and that PECs undergo substantial changes, especially in juxtamedullary glomeruli, that may participate in the overall decline in glomerular structure and function with advancing age.
Assuntos
Envelhecimento/patologia , Células Epiteliais/patologia , Glomérulos Renais/patologia , Envelhecimento/metabolismo , Animais , Biomarcadores/metabolismo , Cápsula Glomerular/metabolismo , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal , Proteínas da Matriz Extracelular/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Receptores de Hialuronatos/metabolismo , Glomérulos Renais/metabolismo , Camundongos Endogâmicos C57BL , Pericitos/metabolismo , Fosforilação , Podócitos , Receptor Notch3 , Receptores Notch/metabolismoRESUMO
Collapsing glomerulopathy predominantly afflicts patients of African ancestry, often first presenting after the immune system is engaged by another disorder. Nichols et al. now show that collateral induction of pathogenic APOL1 allelic variants in podocytes by the ongoing immune response may be the long-sought-after explanation for the development of collapsing glomerulopathy in these patients.