Sepsis-induced acute kidney injury Gómez, Hernando; Kellum, John A
Current opinion in critical care,
12/2016, Letnik:
22, Številka:
6
Journal Article
Odprti dostop
Sepsis is a common and frequently fatal condition in which mortality has been consistently linked to increasing organ dysfunction. For example, acute kidney injury (AKI) occurs in 40-50% of septic ...patients and increases mortality six to eight-fold. However, the mechanisms by which sepsis causes organ dysfunction are not well understood and hence current therapy remains reactive and nonspecific.
Recent studies have challenged the previous notion that organ dysfunction is solely secondary to hypoperfusion, by showing, for example, that AKI occurs in the setting of normal or increased renal blood flow; and that it is characterized not by acute tubular necrosis or apoptosis, but rather by heterogeneous areas of colocalized sluggish peritubular blood flow and tubular epithelial cell oxidative stress. Evidence has also shown that microvascular dysfunction, inflammation, and the metabolic response to inflammatory injury are fundamental pathophysiologic mechanisms that may explain the development of sepsis-induced AKI.
The implications of these findings are significant because in the context of decades of negative clinical trials in the field, the recognition that other mechanisms are at play opens the possibility to better understand the processes of injury and repair, and provides an invaluable opportunity to design mechanism-targeted therapeutic interventions.
Reactive oxygen species- (ROS-) induced lipid peroxidation plays a critical role in cell death including apoptosis, autophagy, and ferroptosis. This fundamental and conserved mechanism is based on an ...excess of ROS which attacks biomembranes, propagates lipid peroxidation chain reactions, and subsequently induces different types of cell death. A highly evolved sophisticated antioxidant system exists that acts to protect the cells from oxidative damage. In this review, we discussed how ROS propagate lipid peroxidation chain reactions and how the products of lipid peroxidation initiate apoptosis and autophagy in current models. We also discussed the mechanism of lipid peroxidation during ferroptosis, and we summarized lipid peroxidation in pathological conditions of critical illness. We aim to bring a more global and integrative sight to know how different ROS-induced lipid peroxidation occurs among apoptosis, autophagy, and ferroptosis.
IMPORTANCE: Sepsis is a heterogeneous syndrome. Identification of distinct clinical phenotypes may allow more precise therapy and improve care. OBJECTIVE: To derive sepsis phenotypes from clinical ...data, determine their reproducibility and correlation with host-response biomarkers and clinical outcomes, and assess the potential causal relationship with results from randomized clinical trials (RCTs). DESIGN, SETTINGS, AND PARTICIPANTS: Retrospective analysis of data sets using statistical, machine learning, and simulation tools. Phenotypes were derived among 20 189 total patients (16 552 unique patients) who met Sepsis-3 criteria within 6 hours of hospital presentation at 12 Pennsylvania hospitals (2010-2012) using consensus k means clustering applied to 29 variables. Reproducibility and correlation with biological parameters and clinical outcomes were assessed in a second database (2013-2014; n = 43 086 total patients and n = 31 160 unique patients), in a prospective cohort study of sepsis due to pneumonia (n = 583), and in 3 sepsis RCTs (n = 4737). EXPOSURES: All clinical and laboratory variables in the electronic health record. MAIN OUTCOMES AND MEASURES: Derived phenotype (α, β, γ, and δ) frequency, host-response biomarkers, 28-day and 365-day mortality, and RCT simulation outputs. RESULTS: The derivation cohort included 20 189 patients with sepsis (mean age, 64 SD, 17 years; 10 022 50% male; mean maximum 24-hour Sequential Organ Failure Assessment SOFA score, 3.9 SD, 2.4). The validation cohort included 43 086 patients (mean age, 67 SD, 17 years; 21 993 51% male; mean maximum 24-hour SOFA score, 3.6 SD, 2.0). Of the 4 derived phenotypes, the α phenotype was the most common (n = 6625; 33%) and included patients with the lowest administration of a vasopressor; in the β phenotype (n = 5512; 27%), patients were older and had more chronic illness and renal dysfunction; in the γ phenotype (n = 5385; 27%), patients had more inflammation and pulmonary dysfunction; and in the δ phenotype (n = 2667; 13%), patients had more liver dysfunction and septic shock. Phenotype distributions were similar in the validation cohort. There were consistent differences in biomarker patterns by phenotype. In the derivation cohort, cumulative 28-day mortality was 287 deaths of 5691 unique patients (5%) for the α phenotype; 561 of 4420 (13%) for the β phenotype; 1031 of 4318 (24%) for the γ phenotype; and 897 of 2223 (40%) for the δ phenotype. Across all cohorts and trials, 28-day and 365-day mortality were highest among the δ phenotype vs the other 3 phenotypes (P < .001). In simulation models, the proportion of RCTs reporting benefit, harm, or no effect changed considerably (eg, varying the phenotype frequencies within an RCT of early goal-directed therapy changed the results from >33% chance of benefit to >60% chance of harm). CONCLUSIONS AND RELEVANCE: In this retrospective analysis of data sets from patients with sepsis, 4 clinical phenotypes were identified that correlated with host-response patterns and clinical outcomes, and simulations suggested these phenotypes may help in understanding heterogeneity of treatment effects. Further research is needed to determine the utility of these phenotypes in clinical care and for informing trial design and interpretation.
Sepsis-associated acute kidney injury (SA-AKI) is common in critically ill patients and is strongly associated with adverse outcomes, including an increased risk of chronic kidney disease, ...cardiovascular events and death. The pathophysiology of SA-AKI remains elusive, although microcirculatory dysfunction, cellular metabolic reprogramming and dysregulated inflammatory responses have been implicated in preclinical studies. SA-AKI is best defined as the occurrence of AKI within 7 days of sepsis onset (diagnosed according to Kidney Disease Improving Global Outcome criteria and Sepsis 3 criteria, respectively). Improving outcomes in SA-AKI is challenging, as patients can present with either clinical or subclinical AKI. Early identification of patients at risk of AKI, or at risk of progressing to severe and/or persistent AKI, is crucial to the timely initiation of adequate supportive measures, including limiting further insults to the kidney. Accordingly, the discovery of biomarkers associated with AKI that can aid in early diagnosis is an area of intensive investigation. Additionally, high-quality evidence on best-practice care of patients with AKI, sepsis and SA-AKI has continued to accrue. Although specific therapeutic options are limited, several clinical trials have evaluated the use of care bundles and extracorporeal techniques as potential therapeutic approaches. Here we provide graded recommendations for managing SA-AKI and highlight priorities for future research.
Extracorporeal membrane oxygenation is a life-sustaining therapy for severe respiratory failure. Extracorporeal membrane oxygenation circuits require systemic anticoagulation that creates a delicate ...balance between circuit-related thrombosis and bleeding-related complications. Although unfractionated heparin is most widely used anticoagulant, alternative agents such as bivalirudin have been used. We sought to compare extracorporeal membrane oxygenation circuit thrombosis and bleeding-related outcomes in respiratory failure patients receiving either unfractionated heparin or bivalirudin for anticoagulation on venovenous extracorporeal membrane oxygenation support.
Retrospective cohort study.
Single-center, cardiothoracic ICU.
Consecutive patients requiring venovenous extracorporeal membrane oxygenation who were maintained on anticoagulation between 2013 and 2020.
IV bivalirudin or IV unfractionated heparin.
Primary outcomes were the presence of extracorporeal membrane oxygenation in-circuit-related thrombotic complications and volume of blood products administered during extracorporeal membrane oxygenation duration. One hundred sixty-two patients receiving unfractionated heparin were compared with 133 patients receiving bivalirudin for anticoagulation on venovenous extracorporeal membrane oxygenation. In patients receiving bivalirudin, there was an overall decrease in the number of extracorporeal membrane oxygenation circuit thrombotic complications (p < 0.005) and a significant increase in time to circuit thrombosis (p = 0.007). Multivariable Cox regression found that heparin was associated with a significant increase in risk of clots (ExpB = 2.31, p = 0.001). Patients who received bivalirudin received significantly less volume of packed RBCs, fresh frozen plasma, and platelet transfusion (p < 0.001 for each). There was a significant decrease in the number major bleeding events in patients receiving bivalirudin, 40.7% versus 11.7%, p < 0.001.
Patients receiving bivalirudin for systemic anticoagulation on venovenous extracorporeal membrane oxygenation experienced a decrease in the number of extracorporeal membrane oxygenation circuit-related thrombotic events as well as a significant decrease in volume of blood products administered.
All of medicine aspires to be precise, where a greater understanding of individual data will lead to personalized treatment and improved outcomes. Prompted by specific examples in oncology, the field ...of critical care may be tempted to envision that complex, acute syndromes could bend to a similar reductionist philosophy-where single mutations could identify and target our critically ill patients for treatment. However, precision medicine faces many challenges in critical care. These include confusion about terminology, uncertainty about how to divide patients into discrete groups, the challenges of multi-morbidity, scale, and the need for timely interventions. This review addresses these challenges and provides a translational roadmap spanning preclinical work to identify putative treatment targets, novel designs for clinical trials, and the integration of the electronic health record to implement precision critical care for all.
The recognition that sepsis induces acute kidney injury (AKI) in the absence of overt necrosis or apoptosis and even in the presence of increased renal blood flow has led to the consideration that ...kidney tubular epithelial cells (TECs) may deploy defense mechanisms to survive the insult.
This concept dovetails well with the notion that the defense against infection not only depends on the capacity of the immune system to limit the microbial burden or resistance capacity but also on the capacity of the host to limit tissue injury, collectively known as tolerance. To sustain the high energy requirement that ion transport mandates, kidney TECs use fatty acid oxidation (FAO) as one of the preferred sources of energy. Inflammatory processes like endotoxemia and sepsis decrease mitochondrial FAO and hinder mitochondrial respiration. Impaired FAO is associated with TEC de-differentiation, loss of kidney function, and TEC injury through lipotoxicity and oxidative stress in the acute setting, and with maladaptive repair and fibrosis after AKI in the latter stages. AMP-activated protein kinase (AMPK) is a master regulator of energy and promoter of FAO that can be activated pharmacologically to protect against AKI and death during experimental sepsis, operating through a tolerance mechanism.
Organ dysfunction during sepsis is the expression of tissue injury and adaptive defense mechanisms operating through resistance or tolerance that prioritize cell survival over organ function. Metabolic reprogramming away from FAO/oxidative phosphorylation seems to be a common pathological denominator throughout the AKI continuum that may be targeted through the activation of AMPK.
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