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Acute kidney injury (AKI) is a frequent and challenging clinical condition associated with high morbidity and mortality and represents a common complication in critically ill patients with COVID-19. In AKI, renal tubular epithelial cells (TECs) are a primary site of damage, and recovery from AKI depends on TEC plasticity. However, the molecular mechanisms underlying adaptation and maladaptation of TECs in AKI remain largely unclear. Here, our study of an autopsy cohort of patients with COVID-19 provided evidence that injury of TECs by myoglobin, released as a consequence of rhabdomyolysis, is a major pathophysiological mechanism for AKI in severe COVID-19. Analyses of human kidney biopsies, mouse models of myoglobinuric and gentamicin-induced AKI, and mouse kidney tubuloids showed that TEC injury resulted in activation of the glucocorticoid receptor by endogenous glucocorticoids, which aggravated tubular damage. The detrimental effect of endogenous glucocorticoids on injured TECs was exacerbated by the administration of a widely clinically used synthetic glucocorticoid, dexamethasone, as indicated by experiments in mouse models of myoglobinuric- and folic acid–induced AKI, human and mouse kidney tubuloids, and human kidney slice cultures. Mechanistically, studies in mouse models of AKI, mouse tubuloids, and human kidney slice cultures demonstrated that glucocorticoid receptor signaling in injured TECs orchestrated a maladaptive transcriptional program to hinder DNA repair, amplify injury-induced DNA double-strand break formation, and dampen mTOR activity and mitochondrial bioenergetics. This study identifies glucocorticoid receptor activation as a mechanism of epithelial maladaptation, which is functionally important for AKI. Editor's summary: Acute kidney injury (AKI) is a complication of critically ill patients with COVID-19. Dexamethasone is a synthetic glucocorticoid used to treat severe COVID-19. Zhou et al. combined data from patients who died in association with COVID-19, human tissue, and mouse models of AKI and found that renal tubular epithelial cell (TEC) damage from myoglobinuria resulted in glucocorticoid receptor activation and worse injury. Mice given myoglobinuric injury and dexamethasone treatment had exacerbated TEC damage. Human kidney slices and TEC organoids from both humans and mice corroborated this exacerbated damage. Inhibiting endogenous glucocorticoid production or inactivating the glucocorticoid receptor ameliorated TEC damage in these models. TEC damage was linked to DNA damage and mitochondrial impairment. These data suggest that glucocorticoid receptor activation aggravates renal injury. —Brandon Berry [ABSTRACT FROM AUTHOR]

Introduction: The proportion of very elderly patients in the intensive care unit (ICU) is expected to rise. Furthermore, patients are likely more prone to suffer a cardiac arrest (CA) event within the ICU. The occurrence of intensive care unit cardiac arrest (ICU-CA) is associated with high mortality. To date, the incidence of ICU-CA and its clinical impact on outcome in the very old (≥ 90 years) patients treated is unknown. Methods: Retrospective analysis of all consecutive critically ill patients ≥ 90 years admitted to the ICU of a tertiary care university hospital in Hamburg (Germany). All patients suffering ICU-CA were included and CA characteristics and functional outcome was assessed. Clinical course and outcome were assessed and compared between the subgroups of patients with and without ICU-CA. Results: 1,108 critically ill patients aged ≥ 90 years were admitted during the study period. The median age was 92.3 (91.0–94.2) years and 67% (n = 747) were female. 2% (n = 25) of this cohort suffered ICU-CA after a median duration 0.5 (0.2–3.2) days of ICU admission. The presumed cause of ICU-CA was cardiac in 64% (n = 16). The median resuscitation time was 10 (2–15) minutes and the initial rhythm was shockable in 20% (n = 5). Return of spontaneous circulation (ROSC) could be achieved in 68% (n = 17). The cause of ICU admission was primarily medical in the total cohort (ICU-CA: 48% vs. No ICU-CA: 34%, p = 0.13), surgical - planned (ICU-CA: 32% vs. No ICU-CA: 37%, p = 0.61) and surgical - unplanned/emergency (ICU-CA: 43% vs. No ICU-CA: 28%, p = 0.34). The median Charlson Comorbidity Index (CCI) was 2 (1–3) points for patients with ICU-CA and 1 (0–2) for patients without ICU-CA (p = 0.54). Patients with ICU-CA had a higher disease severity according to SAPS II (ICU-CA: 54 vs. No ICU-CA: 36 points, p < 0.001). Patients with ICU-CA had a higher rate of mechanically ventilation (ICU-CA: 64% vs. No ICU-CA: 34%, p < 0.01) and required vasopressor therapy more often (ICU-CA: 88% vs. No ICU-CA: 41%, p < 0.001). The ICU and in-hospital mortality was 88% (n = 22) and 100% (n = 25) in patients with ICU-CA compared to 17% (n = 179) and 28% (n = 306) in patients without ICU-CA. The mortality rate for patients with ICU-CA was observed to be 88% (n = 22) in the ICU and 100% (n = 25) in-hospital. In contrast, patients without ICU-CA had an in-ICU mortality rate of 17% (n = 179) and an in-hospital mortality rate of 28% (n = 306) (both p < 0.001). Conclusion: The occurrence of ICU-CA in very elderly patients is rare but associated with high mortality. Providing CPR in this cohort did not lead to long-term survival at our centre. Very elderly patients admitted to the ICU likely benefit from supportive care only and should probably not be resuscitated due to poor chance of survival and ethical considerations. Providing personalized assurances that care will remain appropriate and in accordance with the patient's and family's wishes can optimise compassionate care while avoiding futile life-sustaining interventions. [ABSTRACT FROM AUTHOR]

Introduction: Hypoxic liver injury (HLI) is a frequent and life-threatening complication occurring in up to 10% of critically ill patients. Heart failure and age were previously identified as risk factors for occurrence of HLI. However, there is lack of data on incidence of HLI and its clinical implications on outcome in very old (≥90 years) patients. The aim of this study was to investigate occurrence, clinical characteristics, and outcome of HLI in critically ill patients ≥90 years. Methods: This is a retrospective analysis of all consecutive critically ill patients ≥90 years admitted to the intensive care unit (ICU) of a tertiary care university hospital in Hamburg, Germany. Clinical course and laboratory data were analyzed for all patients. HLI was defined according to established criteria as elevation of aminotransferase levels (>20-fold upper limit of normal). Predictors of HLI occurrence, clinical course, and outcome were assessed and compared to those of patients without HLI. Results: In total, 1,065 critically ill patients ≥90 years were included. During the ICU stay, 3% (n = 35) developed HLI. Main causes of HLI were cardiogenic shock (51%, n = 18), septic shock (23%, n = 8), and cardiac arrest (20%, n = 7). Presenting characteristics including age, gender, and BMI were comparable between patients with and without HLI. The admission cause was primary medical (HLI: 49% vs. No-HLI: 34%, p = 0.07), surgical – planned (9% vs. 38%, p < 0.001), and surgical – emergency (43% vs. 28%, p = 0.06). The median Charlson Comorbidity Index (CCI) and the median updated CCI were 2 (1–3) and 2 (1–2) points in patients with HLI and 1 (0–2) and 1 (0–2) in patients without HLI (p < 0.01 and p = 0.08). Patients with HLI presented with higher SAPS II (55 vs. 36 points p < 0.001) score on admission and required mechanical ventilation (66% vs. 34%, p < 0.001), vasopressor therapy (91% vs. 40%, p < 0.001), renal replacement therapy (20% vs. 2%, p < 0.001), and parenteral nutrition (29% vs. 7%, p < 0.001). The ICU mortality and hospital mortality in patients with HLI were 66% (n = 23) and 83% (n = 29) compared with 17% (n = 170) and 28% (n = 292) in patients without HLI, respectively (both p < 0.001). Regression analysis identified SAPS II (OR 1.05, 95% CI: [1.02–1.07]; p < 0.001) and vasopressor therapy (OR 9.21, 95% CI: [2.58–32.86]; p < 0.01) as factors significantly associated with new onset of HLI. Occurrence of HLI was independently associated with mortality (HR 2.23, 95% CI: [1.50–3.30]; p < 0.001). Conclusion: HLI is an uncommon but not rare condition in critically ill patients aged ≥90 years. Occurrence of HLI is associated with high mortality and is mainly caused by cardiogenic or septic shock. HLI may serve as early prognostic marker in critically ill patients aged ≥90 years. [ABSTRACT FROM AUTHOR]