Sodium-Glucose Transport Protein 2 Inhibitor Use for Type 2 Diabetes and the Incidence of Acute Kidney Injury in Taiwan.
JAMA network open
Importance:The association between sodium-glucose transport protein 2 inhibitor (SGLT2i) use and the incidence of acute kidney injury (AKI) remains controversial. The benefits of SGLT2i use in patients to reduce AKI requiring dialysis (AKI-D) and concomitant diseases with AKI as well as improve AKI prognosis have not yet been established. Objective:To investigate the association between SGLT2i use and AKI incidence in patients with type 2 diabetes (T2D). Design, Setting, and Participants:This nationwide retrospective cohort study used the National Health Insurance Research Database in Taiwan. The study analyzed a propensity score-matched population of 104 462 patients with T2D treated with SGLT2is or dipeptidyl peptidase 4 inhibitors (DPP4is) between May 2016 and December 2018. All participants were followed up from the index date until the occurrence of outcomes of interest, death, or the end of the study, whichever was earliest. Analysis was conducted between October 15, 2021, and January 30, 2022. Main Outcomes and Measures:The primary outcome was the incidence of AKI and AKI-D during the study period. AKI was diagnosed using International Classification of Diseases diagnostic codes, and AKI-D was determined using the diagnostic codes and dialysis treatment during the same hospitalization. Conditional Cox proportional hazard models assessed the associations between SGLT2i use and the risks of AKI and AKI-D. The concomitant diseases with AKI and its 90-day prognosis, ie, the occurrence of advanced chronic kidney disease (CKD stage 4 and 5), end-stage kidney disease, or death, were considered when exploring the outcomes of SGLT2i use. Results:In a total of 104 462 patients, 46 065 (44.1%) were female patients, and the mean (SD) age was 58 (12) years. After a follow-up of approximately 2.50 years, 856 participants (0.8%) had AKI and 102 (<0.1%) had AKI-D. SGLT2i users had a 0.66-fold risk for AKI (95% CI, 0.57-0.75; P < .001) and 0.56-fold risk of AKI-D (95% CI, 0.37-0.84; P = .005) compared with DPP4i users. The numbers of patients with AKI with heart disease, sepsis, respiratory failure, and shock were 80 (22.73%), 83 (23.58%), 23 (6.53%), and 10 (2.84%), respectively. SGLT2i use was associated with lower risk of AKI with respiratory failure (hazard ratio [HR], 0.42; 95% CI, 0.26-0.69; P < .001) and shock (HR, 0.48; 95% CI, 0.23-0.99; P = .048) but not AKI with heart disease (HR, 0.79; 95% CI, 0.58-1.07; P = .13) and sepsis (HR, 0.77; 95% CI, 0.58-1.03; P = .08). The 90-day AKI prognosis for the risk of advanced CKD indicated a 6.53% (23 of 352 patients) lower incidence in SGLT2i users than in DPP4i users (P = .045). Conclusions and Relevance:The study findings suggest that patients with T2D who receive SGLT2i may have lower risk of AKI and AKI-D compared with those who receive DPP4i.
10.1001/jamanetworkopen.2023.0453
TREM2 resident macrophages protect the septic heart by maintaining cardiomyocyte homeostasis.
Nature metabolism
Sepsis-induced cardiomyopathy (SICM) is common in septic patients with a high mortality and is characterized by an abnormal immune response. Owing to cellular heterogeneity, understanding the roles of immune cell subsets in SICM has been challenging. Here we identify a unique subpopulation of cardiac-resident macrophages termed CD163RETNLA (Mac1), which undergoes self-renewal during sepsis and can be targeted to prevent SICM. By combining single-cell RNA sequencing with fate mapping in a mouse model of sepsis, we demonstrate that the Mac1 subpopulation has distinct transcriptomic signatures enriched in endocytosis and displays high expression of TREM2 (TREM2). TREM2 Mac1 cells actively scavenge cardiomyocyte-ejected dysfunctional mitochondria. Trem2 deficiency in macrophages impairs the self-renewal capability of the Mac1 subpopulation and consequently results in defective elimination of damaged mitochondria, excessive inflammatory response in cardiac tissue, exacerbated cardiac dysfunction and decreased survival. Notably, intrapericardial administration of TREM2 Mac1 cells prevents SICM. Our findings suggest that the modulation of TREM2 Mac1 cells could serve as a therapeutic strategy for SICM.
10.1038/s42255-022-00715-5
Sepsis take-out: Inhibiting bacterial deliveries.
Christgen Shelbi,Kanneganti Thirumala-Devi
Immunity
Sepsis remains a deadly disease with limited treatment options. In this issue of Immunity, Tang et al. propose that heparin provides protection during gram-negative sepsis by dampening harmful CASP11-dependent signaling through inhibition of HMGB1- and heparanase-mediated cytosolic delivery of LPS.
10.1016/j.immuni.2021.02.010
Current challenges in the management of sepsis in ICUs in resource-poor settings and suggestions for the future.
Schultz Marcus J,Dunser Martin W,Dondorp Arjen M,Adhikari Neill K J,Iyer Shivakumar,Kwizera Arthur,Lubell Yoel,Papali Alfred,Pisani Luigi,Riviello Beth D,Angus Derek C,Azevedo Luciano C,Baker Tim,Diaz Janet V,Festic Emir,Haniffa Rashan,Jawa Randeep,Jacob Shevin T,Kissoon Niranjan,Lodha Rakesh,Martin-Loeches Ignacio,Lundeg Ganbold,Misango David,Mer Mervyn,Mohanty Sanjib,Murthy Srinivas,Musa Ndidiamaka,Nakibuuka Jane,Serpa Neto Ary,Nguyen Thi Hoang Mai,Nguyen Thien Binh,Pattnaik Rajyabardhan,Phua Jason,Preller Jacobus,Povoa Pedro,Ranjit Suchitra,Talmor Daniel,Thevanayagam Jonarthan,Thwaites C Louise,
Intensive care medicine
BACKGROUND:Sepsis is a major reason for intensive care unit (ICU) admission, also in resource-poor settings. ICUs in low- and middle-income countries (LMICs) face many challenges that could affect patient outcome. AIM:To describe differences between resource-poor and resource-rich settings regarding the epidemiology, pathophysiology, economics and research aspects of sepsis. We restricted this manuscript to the ICU setting even knowing that many sepsis patients in LMICs are treated outside an ICU. FINDINGS:Although many bacterial pathogens causing sepsis in LMICs are similar to those in high-income countries, resistance patterns to antimicrobial drugs can be very different; in addition, causes of sepsis in LMICs often include tropical diseases in which direct damaging effects of pathogens and their products can sometimes be more important than the response of the host. There are substantial and persisting differences in ICU capacities around the world; not surprisingly the lowest capacities are found in LMICs, but with important heterogeneity within individual LMICs. Although many aspects of sepsis management developed in rich countries are applicable in LMICs, implementation requires strong consideration of cost implications and the important differences in resources. CONCLUSIONS:Addressing both disease-specific and setting-specific factors is important to improve performance of ICUs in LMICs. Although critical care for severe sepsis is likely cost-effective in LMIC setting, more detailed evaluation at both at a macro- and micro-economy level is necessary. Sepsis management in resource-limited settings is a largely unexplored frontier with important opportunities for research, training, and other initiatives for improvement.
10.1007/s00134-017-4750-z
Sepsis and septic shock.
Hotchkiss Richard S,Moldawer Lyle L,Opal Steven M,Reinhart Konrad,Turnbull Isaiah R,Vincent Jean-Louis
Nature reviews. Disease primers
For more than two decades, sepsis was defined as a microbial infection that produces fever (or hypothermia), tachycardia, tachypnoea and blood leukocyte changes. Sepsis is now increasingly being considered a dysregulated systemic inflammatory and immune response to microbial invasion that produces organ injury for which mortality rates are declining to 15-25%. Septic shock remains defined as sepsis with hyperlactataemia and concurrent hypotension requiring vasopressor therapy, with in-hospital mortality rates approaching 30-50%. With earlier recognition and more compliance to best practices, sepsis has become less of an immediate life-threatening disorder and more of a long-term chronic critical illness, often associated with prolonged inflammation, immune suppression, organ injury and lean tissue wasting. Furthermore, patients who survive sepsis have continuing risk of mortality after discharge, as well as long-term cognitive and functional deficits. Earlier recognition and improved implementation of best practices have reduced in-hospital mortality, but results from the use of immunomodulatory agents to date have been disappointing. Similarly, no biomarker can definitely diagnose sepsis or predict its clinical outcome. Because of its complexity, improvements in sepsis outcomes are likely to continue to be slow and incremental.
10.1038/nrdp.2016.45
Surviving sepsis campaign: research priorities for sepsis and septic shock.
Coopersmith Craig M,De Backer Daniel,Deutschman Clifford S,Ferrer Ricard,Lat Ishaq,Machado Flavia R,Martin Greg S,Martin-Loeches Ignacio,Nunnally Mark E,Antonelli Massimo,Evans Laura E,Hellman Judith,Jog Sameer,Kesecioglu Jozef,Levy Mitchell M,Rhodes Andrew
Intensive care medicine
OBJECTIVE:To identify research priorities in the management, epidemiology, outcome and underlying causes of sepsis and septic shock. DESIGN:A consensus committee of 16 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine was convened at the annual meetings of both societies. Subgroups had teleconference and electronic-based discussion. The entire committee iteratively developed the entire document and recommendations. METHODS:Each committee member independently gave their top five priorities for sepsis research. A total of 88 suggestions (ESM 1 - supplemental table 1) were grouped into categories by the committee co-chairs, leading to the formation of seven subgroups: infection, fluids and vasoactive agents, adjunctive therapy, administration/epidemiology, scoring/identification, post-intensive care unit, and basic/translational science. Each subgroup had teleconferences to go over each priority followed by formal voting within each subgroup. The entire committee also voted on top priorities across all subgroups except for basic/translational science. RESULTS:The Surviving Sepsis Research Committee provides 26 priorities for sepsis and septic shock. Of these, the top six clinical priorities were identified and include the following questions: (1) can targeted/personalized/precision medicine approaches determine which therapies will work for which patients at which times?; (2) what are ideal endpoints for volume resuscitation and how should volume resuscitation be titrated?; (3) should rapid diagnostic tests be implemented in clinical practice?; (4) should empiric antibiotic combination therapy be used in sepsis or septic shock?; (5) what are the predictors of sepsis long-term morbidity and mortality?; and (6) what information identifies organ dysfunction? CONCLUSIONS:While the Surviving Sepsis Campaign guidelines give multiple recommendations on the treatment of sepsis, significant knowledge gaps remain, both in bedside issues directly applicable to clinicians, as well as understanding the fundamental mechanisms underlying the development and progression of sepsis. The priorities identified represent a roadmap for research in sepsis and septic shock.
10.1007/s00134-018-5175-z
Advances in the understanding and treatment of sepsis-induced immunosuppression.
Venet Fabienne,Monneret Guillaume
Nature reviews. Nephrology
Sepsis is defined as a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. Sepsis can induce acute kidney injury and multiple organ failures and represents the most common cause of death in the intensive care unit. Sepsis initiates a complex immune response that varies over time, with the concomitant occurrence of both pro-inflammatory and anti-inflammatory mechanisms. As a result, most patients with sepsis rapidly display signs of profound immunosuppression, which is associated with deleterious consequences. Scientific advances have highlighted the role of metabolic failure, epigenetic reprogramming, myeloid-derived suppressor cells, immature suppressive neutrophils and immune alterations in primary lymphoid organs (the thymus and bone marrow) in sepsis. An improved understanding of the mechanisms underlying this immunosuppression as well as of the similarities between sepsis-induced immunosuppression and immune defects in cancer or immunosenescence has led to novel therapeutic strategies aimed at stimulating immune function in patients with sepsis. Trials assessing the therapeutic benefit of IL-7, granulocyte-macrophage colony-stimulating factor (GM-CSF) and antibodies against programmed cell death protein 1 (PD1) and programmed cell death 1 ligand 1 (PDL1) for the treatment of sepsis are in progress. The reappraisal of sepsis pathophysiology has also resulted in a novel approach to the design of clinical trials evaluating sepsis treatments, based on an evaluation of the immune status and biomarker-based stratification of patients.
10.1038/nrneph.2017.165
Mechanisms and treatment of organ failure in sepsis.
Lelubre Christophe,Vincent Jean-Louis
Nature reviews. Nephrology
Sepsis is a dysregulated immune response to an infection that leads to organ dysfunction. Knowledge of the pathophysiology of organ failure in sepsis is crucial for optimizing the management and treatment of patients and for the development of potential new therapies. In clinical practice, six major organ systems - the cardiovascular (including the microcirculation), respiratory, renal, neurological, haematological and hepatic systems - can be assessed and monitored, whereas others, such as the gut, are less accessible. Over the past 2 decades, considerable amounts of new data have helped improve our understanding of sepsis pathophysiology, including the regulation of inflammatory pathways and the role played by immune suppression during sepsis. The effects of impaired cellular function, including mitochondrial dysfunction and altered cell death mechanisms, on the development of organ dysfunction are also being unravelled. Insights have been gained into interactions between key organs (such as the kidneys and the gut) and organ-organ crosstalk during sepsis. The important role of the microcirculation in sepsis is increasingly apparent, and new techniques have been developed that make it possible to visualize the microcirculation at the bedside, although these techniques are only research tools at present.
10.1038/s41581-018-0005-7
Current gaps in sepsis immunology: new opportunities for translational research.
Rubio Ignacio,Osuchowski Marcin F,Shankar-Hari Manu,Skirecki Tomasz,Winkler Martin Sebastian,Lachmann Gunnar,La Rosée Paul,Monneret Guillaume,Venet Fabienne,Bauer Michael,Brunkhorst Frank M,Kox Matthijs,Cavaillon Jean-Marc,Uhle Florian,Weigand Markus A,Flohé Stefanie B,Wiersinga W Joost,Martin-Fernandez Marta,Almansa Raquel,Martin-Loeches Ignacio,Torres Antoni,Giamarellos-Bourboulis Evangelos J,Girardis Massimo,Cossarizza Andrea,Netea Mihai G,van der Poll Tom,Scherag André,Meisel Christian,Schefold Joerg C,Bermejo-Martín Jesús F
The Lancet. Infectious diseases
Increasing evidence supports a central role of the immune system in sepsis, but the current view of how sepsis affects immunity, and vice versa, is still rudimentary. The European Group on Immunology of Sepsis has identified major gaps that should be addressed with high priority, such as understanding how immunological alterations predispose to sepsis, key aspects of the immunopathological events during sepsis, and the long-term consequences of sepsis on patient's immunity. We discuss major unmet topics in those three categories, including the role of key immune cells, the cause of lymphopenia, organ-specific immunology, the dynamics of sepsis-associated immunological alterations, the role of the microbiome, the standardisation of immunological tests, the development of better animal models, and the opportunities offered by immunotherapy. Addressing these gaps should help us to better understand sepsis physiopathology, offering translational opportunities to improve its prevention, diagnosis, and care.
10.1016/S1473-3099(19)30567-5