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Acute kidney injury (AKI) is now recognized as a heterogeneous syndrome that not only affects acute morbidity and mortality, but also a patient’s long-term prognosis. In this narrative review, an update on various aspects of AKI in critically ill patients will be provided. Focus will be on prediction and early detection of AKI (e.g., the role of biomarkers to identify high-risk patients and the use of machine learning to predict AKI), aspects of pathophysiology and progress in the recognition of different phenotypes of AKI, as well as an update on nephrotoxicity and organ cross-talk. In addition, prevention of AKI (focusing on fluid management, kidney perfusion pressure, and the choice of vasopressor) and supportive treatment of AKI is discussed. Finally, post-AKI risk of long-term sequelae including incident or progression of chronic kidney disease, cardiovascular events and mortality, will be addressed.

The World Health Organization defines overweight and obesity as the condition where excess or abnormal fat accumulation increases risks to health. The prevalence of obesity is increasing worldwide and is around 20% in ICU patients. Adipose tissue is highly metabolically active, and especially visceral adipose tissue has a deleterious adipocyte secretory profile resulting in insulin resistance and a chronic low-grade inflammatory and procoagulant state. Obesity is strongly linked with chronic diseases such as type 2 diabetes, hypertension, cardiovascular diseases, dyslipidemia, non-alcoholic fatty liver disease, chronic kidney disease, obstructive sleep apnea and hypoventilation syndrome, mood disorders and physical disabilities. In hospitalized and ICU patients and in patients with chronic illnesses, a J-shaped relationship between BMI and mortality has been demonstrated, with overweight and moderate obesity being protective compared with a normal BMI or more severe obesity (the still debated and incompletely understood “obesity paradox”). Despite this protective effect regarding mortality, in the setting of critical illness morbidity is adversely affected with increased risk of respiratory and cardiovascular complications, requiring adapted management. Obesity is associated with increased risk of AKI and infection, may require adapted drug dosing and nutrition and is associated with diagnostic and logistic challenges. In addition, negative attitudes toward obese patients (the social stigma of obesity) affect both health care workers and patients.

Background The CytoSorb hemoadsorption device has been demonstrated to be capable of clearing inflammatory cytokines, but has not yet been shown to attenuate plasma cytokine concentrations. We investigated the effects of CytoSorb hemoperfusion on plasma levels of various cytokines using the repeated human experimental endotoxemia model, a highly standardized and reproducible human in vivo model of systemic inflammation and immunological tolerance induced by administration of bacterial lipopolysaccharide (LPS). Methods Twenty-four healthy male volunteers (age 18–35) were intravenously challenged with LPS (a bolus of 1 ng/kg followed by continuous infusion of 0.5 ng/kg/hr for three hours) twice: on day 0 to quantify the initial cytokine response and on day 7 to quantify the degree of endotoxin tolerance. Subjects either received CytoSorb hemoperfusion during the first LPS challenge (CytoSorb group), or no intervention (control group). Plasma cytokine concentrations and clearance rates were determined serially. This study was registered at ClinicalTrials.gov (NCT04643639, date of registration November 24th 2020). Results LPS administration led to a profound increase in plasma cytokine concentrations during both LPS challenge days. Compared to the control group, significantly lower plasma levels of tumor necrosis factor (TNF, − 58%, p  < 0.0001), interleukin (IL)-6 ( − 71%, p  = 0.003), IL-8 ( − 48%, p  = 0.02) and IL-10 ( − 26%, p  = 0.03) were observed in the CytoSorb group during the first LPS challenge. No differences in cytokine responses were observed during the second LPS challenge. Conclusions CytoSorb hemoperfusion effectively attenuates circulating cytokine concentrations during systemic inflammation in humans in vivo, whereas it does not affect long-term immune function. Therefore, CytoSorb therapy may be of benefit in conditions characterized by excessive cytokine release.

Background The sepsis-induced immunodepression contributes to impaired clinical outcomes of various stress conditions. This syndrome is well documented and characterized by attenuated function of innate and adaptive immune cells. Several pharmacological interventions aimed to restore the immune response are emerging of which interferon-gamma (IFNγ) is one. It is of paramount relevance to obtain clinical information on optimal timing of the IFNγ-treatment, −tolerance, −effectiveness and outcome before performing a RCT. We describe the effects of IFNγ in a cohort of 18 adult and 2 pediatric sepsis patients. Methods In this open-label prospective multi-center case-series, IFNγ treatment was initiated in patients selected on clinical and immunological criteria early (< 4 days) or late (> 7 days) following the onset of sepsis. The data collected in 18 adults and 2 liver transplanted pediatric patients were: clinical scores, monocyte expression of HLA-DR (flow cytometry), lymphocyte immune-phenotyping (flow cytometry), IL-6 and IL-10 plasma levels (ELISA), bacterial cultures, disease severity, and mortality. Results In 15 out of 18 patients IFNγ treatment was associated with an increase of median HLA-DR expression from 2666 [IQ 1547; 4991] to 12,451 [IQ 4166; 19,707], while the absolute number of lymphocyte subpopulations were not affected, except for the decrease number of NK cells 94.5 [23; 136] to 32.5 [13; 90.8] (0.0625)]. Plasma levels of IL-6 464 [201–770] to 108 (89–140) ng/mL ( p  = 0.04) and IL-10 from IL-10 from 29 [12–59] to 9 [1–15] pg/mL decreased significantly. Three patients who received IFNγ early after ICU admission (<4 days) died. The other patients had a rapid clinical improvement assessed by the SOFA score and bacterial cultures that were repeatedly positive became negative. The 2 pediatric cases improved rapidly, but 1 died for hemorrhagic complication. Conclusion Guided by clinical and immunological monitoring, adjunctive immunotherapy with IFNγ appears well-tolerated in our cases and improves immune host defense in sepsis induced immuno suppression. Randomized clinical studies to assess its potential clinical benefit are warranted.

Background Decreased monocytic (m)HLA-DR expression is the most studied biomarker of sepsis-induced immunosuppression. To date, little is known about the relationship between sepsis characteristics, such as the site of infection, causative pathogen, or severity of disease, and mHLA-DR expression kinetics. Methods We evaluated mHLA-DR expression kinetics in 241 septic shock patients with different primary sites of infection and pathogens. Furthermore, we used unsupervised clustering analysis to identify mHLA-DR trajectories and evaluated their association with outcome parameters. Results No differences in mHLA-DR expression kinetics were found between groups of patients with different sites of infection (abdominal vs. respiratory, p  = 0.13; abdominal vs. urinary tract, p  = 0.53) and between pathogen categories (Gram-positive vs. Gram-negative, p  = 0.54; Gram-positive vs. negative cultures, p  = 0.84). The mHLA-DR expression kinetics differed between survivors and non-survivors ( p  < 0.001), with an increase over time in survivors only. Furthermore, we identified three mHLA-DR trajectories (‘early improvers’, ‘delayed or non-improvers’ and ‘decliners’). The probability for adverse outcome (secondary infection or death) was higher in the delayed or non-improvers and decliners vs. the early improvers (delayed or non-improvers log-rank p  = 0.03, adjusted hazard ratio 2.0 [95% CI 1.0–4.0], p  = 0.057 and decliners log-rank p  = 0.01, adjusted hazard ratio 2.8 [95% CI 1.1–7.1], p  = 0.03). Conclusion Sites of primary infection or causative pathogens are not associated with mHLA-DR expression kinetics in septic shock patients. However, patients showing delayed or no improvement in or a declining mHLA-DR expression have a higher risk for adverse outcome compared with patients exhibiting a swift increase in mHLA-DR expression. Our study signifies that changes in mHLA-DR expression over time, and not absolute values or static measurements, are of clinical importance in septic shock patients.

Decades of sepsis research into a specific immune system-targeting adjunctive therapy have not resulted in the discovery of an effective compound. Apart from antibiotics, source control, resuscitation and organ support, not a single adjunctive treatment is used in current clinical practice. The inability to determine the prevailing immunological phenotype of patients and the related large heterogeneity of study populations are regarded by many as the most important factors behind the disappointing results of past clinical trials. While the therapeutic focus has long been on immunosuppressive strategies, increased appreciation of the importance of sepsis-induced immunoparalysis in causing morbidity and mortality in sepsis patients has resulted in a paradigm shift in the sepsis research field towards strategies aimed at enhancing the immune response. However, similar to immunosuppressive therapies, precision medicine is imperative for future trials with immunostimulatory compounds to succeed. As such, identifying those patients with a severely suppressed or hyperactive immune system who will most likely benefit from either immunostimulatory or immunosuppressive therapy, and accurate monitoring of both the immune and treatment response is crucial. This review provides an overview of the challenges lying ahead on the path towards precision immunotherapy for patients suffering from sepsis.

Background Acute kidney injury (AKI) is a common complication of critical illness and is associated with worse outcomes. However, the influence of deterioration or improvement in renal function on clinical outcomes is unclear. Using a large international database, we evaluated the prevalence and evolution of AKI over a 7-day period and its effects on clinical outcomes in septic and non-septic critically ill patients worldwide. Methods From the 10,069 adult intensive care unit (ICU) patients in the Intensive Care Over Nations database, all those with creatinine and urine output data were included in this substudy. Patients who developed sepsis during the ICU stay (≥ 2 days after admission) were excluded. AKI was evaluated within 72 hours after admission and before discharge/death up to day 7 according to the Acute Kidney Injury Network (AKIN) criteria. Results A total of 7970 patients were included, 59% of whom met AKIN criteria for AKI within the first 72 hours of the ICU stay. Twenty-four per cent of patients had sepsis on admission, of whom 68% had AKI, compared to 57% of those without sepsis on admission ( p < 0.001). AKIN stage 3 (40% vs 24%, p < 0.001) and use of renal replacement therapy (20% vs 5%, p < 0.0001) were more prevalent in patients with sepsis. Patients with sepsis and AKIN stage 3 were less likely to improve to a lower stage during the 7-day follow-up period than non-septic patients with AKIN stage 3 (21% vs 32%, p < 0.0001). In-hospital mortality was related to severity of AKI and was reduced in patients in whom AKI improved compared to those who remained stable or deteriorated, but remained higher than in patients without AKI, even if there was apparent full recovery at day 7. Conclusion These findings illustrate the different kinetics of AKI in septic and non-septic ICU patients and emphasize the important impact of AKI on mortality rates even when there is apparent full renal recovery at day 7 .

While adrecizumab only partially inhibits ADM signaling, the strong concentration increase of ADM (complexed with adrecizumab) in the circulation is thought to result in an overall “net” increase of ADM activity on endothelial cells, augmenting endothelial barrier stabilizing effects, while decreased concentrations of ADM in the interstitium reduce vasodilatory effects on vascular smooth muscle cells. P. Pickkers received travel reimbursements and consultancy fees from Adrenomed AG. P. Pickkers’s institution received a research grant from Adrenomed AG. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Sepsis is the leading cause of death in the intensive care unit and ranks in the top 10 causes of death in general worldwide. Proinflammatory mediators are related to symptoms observed early in patients with sepsis, such as fever and hemodynamic instability. However, in recent years it has become clear that most septic patients do not die from an overwhelming proinflammatory immune response but in an immunosuppressive state, which can last for days or even weeks, and that results in increased susceptibility to secondary (opportunistic) infections. Although infection control and supportive therapies will remain the cornerstone of treatment, especially in the early phase of sepsis, the identification of this so-called \"immunoparalysis\" is currently causing a paradigm shift in the adjunctive treatment of sepsis from therapies that suppress the immune system toward immunostimulation. In this Critical Care Perspective we give an overview of the pathophysiology of sepsis, with a focus on immunosuppressive mechanisms that play an important role in outcome. In addition, we present an appraisal of the recent advances in immunotherapy as an adjunctive treatment for sepsis.

Sepsis is poorly understood, largely untreatable and frequently fatal. Netea and colleagues assess both mouse sepsis and human sepsis to demonstrate that its late phase is characterized by immunoparalysis and broad metabolic alterations in cells of the immune system. The acute phase of sepsis is characterized by a strong inflammatory reaction. At later stages in some patients, immunoparalysis may be encountered, which is associated with a poor outcome. By transcriptional and metabolic profiling of human patients with sepsis, we found that a shift from oxidative phosphorylation to aerobic glycolysis was an important component of initial activation of host defense. Blocking metabolic pathways with metformin diminished cytokine production and increased mortality in systemic fungal infection in mice. In contrast, in leukocytes rendered tolerant by exposure to lipopolysaccharide or after isolation from patients with sepsis and immunoparalysis, a generalized metabolic defect at the level of both glycolysis and oxidative metabolism was apparent, which was restored after recovery of the patients. Finally, the immunometabolic defects in humans were partially restored by therapy with recombinant interferon-γ, which suggested that metabolic processes might represent a therapeutic target in sepsis.