The pathophysiology of sepsis and precision-medicine-based immunotherapy

Nature Immunology, Journal Year: 2024, Volume and Issue: 25(1), P. 19 - 28

Published: Jan. 1, 2024

Language: Английский

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Sepsis-associated acute kidney injury in the intensive care unit: incidence, patient characteristics, timing, trajectory, treatment, and associated outcomes. A multicenter, observational study

Intensive Care Medicine, Journal Year: 2023, Volume and Issue: 49(9), P. 1079 - 1089

Published: July 11, 2023

The Acute Disease Quality Initiative (ADQI) Workgroup recently released a consensus definition of sepsis-associated acute kidney injury (SA-AKI), combining Sepsis-3 and Kidney Improving Global Outcomes (KDIGO) AKI criteria. This study aims to describe the epidemiology SA-AKI.This is retrospective cohort carried out in 12 intensive care units (ICUs) from 2015 2021. We studied incidence, patient characteristics, timing, trajectory, treatment, associated outcomes SA-AKI based on ADQI definition.Out 84,528 admissions, 13,451 met criteria with its incidence peaking at 18% patients were typically admitted home via emergency department (ED) median time diagnosis 1 day (interquartile range (IQR) 1-1) ICU admission. At diagnosis, most (54%) had stage AKI, mostly due low urinary output (UO) criterion only (65%). Compared by creatinine alone, or both UO criteria, diagnosed alone lower renal replacement therapy (RRT) requirements (2.8% vs 50%; p < 0.001), which was consistent across all stages AKI. hospital mortality independently increased mortality. In SA-AKI, only, compared an odds ratio 0.34 (95% confidence interval (CI) 0.32-0.36) for mortality.SA-AKI occurs 6 patients, carries significant morbidity risk ED. However, UO, much than other

Language: Английский

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Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Dec. 10, 2023

Abstract Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other modes, plays pivotal role in regulating tumorigenesis offers new opportunity for modulating anticancer drug resistance. Aberrant epigenetic modifications posttranslational (PTMs) promote resistance, cancer progression, metastasis. Accumulating studies indicate that can transcriptionally translationally determine vulnerability to ferroptosis functions as driver nervous system diseases (NSDs), cardiovascular (CVDs), liver diseases, lung kidney diseases. In this review, we first summarize the core molecular mechanisms ferroptosis. Then, roles processes, including histone PTMs, DNA methylation, noncoding RNA regulation such phosphorylation, ubiquitination, SUMOylation, acetylation, ADP-ribosylation, are concisely discussed. The PTMs genesis cancers, NSD, CVDs, well application PTM modulators therapy these then discussed detail. Elucidating mediated by will facilitate development promising combination therapeutic regimens containing or PTM-targeting agents inducers be used overcome chemotherapeutic resistance could prevent addition, highlight potential approaches chemoresistance halt

Language: Английский

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Phase-3 trial of recombinant human alkaline phosphatase for patients with sepsis-associated acute kidney injury (REVIVAL)

Intensive Care Medicine, Journal Year: 2024, Volume and Issue: 50(1), P. 68 - 78

Published: Jan. 1, 2024

Ilofotase alfa is a human recombinant alkaline phosphatase with reno-protective effects that showed improved survival and reduced Major Adverse Kidney Events by 90 days (MAKE90) in sepsis-associated acute kidney injury (SA-AKI) patients. REVIVAL, was phase-3 trial conducted to confirm its efficacy safety. In this international double-blinded randomized-controlled trial, SA-AKI patients were enrolled < 72 h on vasopressor 24 of AKI. The primary endpoint 28-day all-cause mortality. main secondary MAKE90, other endpoints (i) alive free organ support through day 28, (ii) out the intensive care unit (ICU) (iii) time death 90. Prior unblinding, statistical analysis plan amended, including an updated MAKE90 definition. Six hundred fifty treated analyzed for safety; 649 data (ilofotase n = 330; placebo 319). observed mortality rates ilofotase groups 27.9% at 28 days, 33.9% 34.8% days. stopped futility endpoint. proportion MAKE90A MAKE90B 56.7% 37.4% group vs. 64.6% 42.8% group. Median [interquartile range (IQR)] 17 [0–24] 14 [0–24], number discharged from ICU 15 [0–22] 10 groups, respectively. events reported 67.9% 75% Among critically ill SA-AKI, did not improve survival. There may, however, be events. No safety concerns identified.

Language: Английский

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Sepsis-Associated Acute Kidney Injury: Where Are We Now?

Medicina, Journal Year: 2024, Volume and Issue: 60(3), P. 434 - 434

Published: March 6, 2024

Worldwide, sepsis is a well-recognized cause of death. Acute kidney injury (AKI) may be related to in up 70% AKI cases. Sepsis-associated (SA-AKI) defined as the presence according Kidney Disease: Improving Global Outcomes criteria context sepsis. SA-AKI categorized into early, which presents during first 48 h sepsis, and late, presenting between 7 days associated with worse prognosis among patients However, there are different phenotypes well pathophysiological pathways SA-AKI. The aim this review provide an updated synopsis pathogenetic mechanisms underlying development analyze its prognosis. In addition, potential novel diagnostic prognostic biomarkers therapeutic approaches discussed. A plethora implicated pathogenesis SA-AKI, including inflammation metabolic reprogramming sepsis; various types cell death such apoptosis, necroptosis, pyroptosis ferroptosis; autophagy efferocytosis; hemodynamic changes (macrovascular microvascular dysfunction). Apart from urine output serum creatinine levels, have been incorporated definition AKI, several urinary also developed, comprising, others, interleukins 6, 8 18, osteoprotegerin, galectin-3, presepsin, cystatin C, NGAL, proenkephalin A, CCL-14, TIMP-2 L-FABP stemming multi-omics technologies machine learning algorithms. Interestingly, long non-coding RNAs (lncRNAs) microRNAs (miRNAs), PlncRNA-1, miR-22-3p, miR-526b, LncRNA NKILA, miR-140-5p miR-214, serve targets. combination omics represents innovative holistic approach toward providing more integrated view molecular physiological events for deciphering unique specific phenotypes. Although evidence still necessary, it expected that incorporation integrative useful not only early diagnosis risk but targets could revolutionize management personalized manner.

Language: Английский

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Sepsis-associated acute kidney injury: recent advances in enrichment strategies, sub-phenotyping and clinical trials

Critical Care, Journal Year: 2024, Volume and Issue: 28(1)

Published: March 21, 2024

Abstract Acute kidney injury (AKI) often complicates sepsis and is associated with high morbidity mortality. In recent years, several important clinical trials have improved our understanding of sepsis-associated AKI (SA-AKI) impacted care. Advances in sub-phenotyping trial design offer unprecedented opportunities to fill gaps knowledge generate better evidence for improving the outcome critically ill patients SA-AKI. this manuscript, we review literature focus on studies that explore SA-AKI as a primary or secondary outcome. We discuss lessons learned potential improve actionable future research. specifically role enrichment strategies target populations are most likely derive benefit importance patient-centered endpoints appropriate designs aim provide guidance designing trials.

Language: Английский

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Acute Kidney Injury in Sepsis

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(11), P. 5924 - 5924

Published: May 29, 2024

Sepsis-associated kidney injury is common in critically ill patients and significantly increases morbidity mortality rates. Several complex pathophysiological factors contribute to its presentation perpetuation, including macrocirculatory microcirculatory changes, mitochondrial dysfunction, metabolic reprogramming. Recovery from acute (AKI) relies on the evolution towards adaptive mechanisms such as endothelial repair tubular cell regeneration, while maladaptive risk of progression chronic disease. Fundamental management strategies include early sepsis recognition prompt treatment, through administration adequate antimicrobial agents, fluid resuscitation, vasoactive agents needed. In septic patients, organ-specific support often required, particularly renal replacement therapy (RRT) setting severe AKI, although ongoing debates persist regarding ideal timing initiation dosing RRT. A comprehensive approach integrating recognition, targeted interventions, close monitoring essential mitigate burden SA-AKI improve patient outcomes critical care settings.

Language: Английский

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Acute kidney injury

The Lancet, Journal Year: 2025, Volume and Issue: 405(10474), P. 241 - 256

Published: Jan. 1, 2025

Language: Английский

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The role of phospholipid transfer protein in sepsis-associated acute kidney injury

Critical Care, Journal Year: 2025, Volume and Issue: 29(1)

Published: Jan. 20, 2025

Language: Английский

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Sepsis-associated acute kidney injury—treatment standard

Nephrology Dialysis Transplantation, Journal Year: 2023, Volume and Issue: 39(1), P. 26 - 35

Published: July 3, 2023

ABSTRACT Sepsis is a host's deleterious response to infection, which could lead life-threatening organ dysfunction. Sepsis-associated acute kidney injury (SA-AKI) the most frequent dysfunction and associated with increased morbidity mortality. contributes ≈50% of all AKI in critically ill adult patients. A growing body evidence has unveiled key aspects clinical risk factors, pathobiology, treatment elements renal recovery that have advanced our ability detect, prevent treat SA-AKI. Despite these advancements, SA-AKI remains critical condition major health burden, further studies are needed diminish short long-term consequences We review current standards discuss novel developments pathophysiology, diagnosis, outcome prediction management

Language: Английский

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