Molecular Phenotyping of Sepsis and Differential Response to Fluid Resuscitation.

Biological heterogeneity in critical illness syndromes, such as sepsis and acute kidney injury (AKI), has hindered development of effective therapies. In sepsis-associated AKI, two molecular subphenotypes (SP1 and SP2) have been identified with differing characteristics, outcomes, and response to vasopressor treatment. It is unknown if these subphenotypes extend to all patients with sepsis and whether they respond differently to fluid resuscitation strategy.

Biological subphenotypes in patients hospitalized with suspected infection in Thailand: a secondary analysis of a prospective observational study.

Background: Subphenotypes of infected patients have been reported in Europe and North America, but few studies have investigated populations in Southeast Asia. We sought to identify and differentiate subphenotypes of patients hospitalized with suspected infection in rural Thailand using biological markers implicated in the dysregulated host response.

Methods: In a cohort of prospectively enrolled patients hospitalized with suspected infection in northeastern Thailand, we measured 15 circulating biomarkers from a random selection of 585 subjects and developed latent profile models to identify subphenotypes.

Proteomic Analyses in COVID-19-Associated Secondary Hemophagocytic Lymphohistiocytosis.

Context: COVID-19 has been associated with features of a cytokine storm syndrome with some patients sharing features with the hyperinflammatory disorder, secondary hemophagocytic lymphohistiocytosis (sHLH).

Hypothesis: We hypothesized that proteins associated with sHLH from other causes will be associated with COVID-sHLH and that subjects with fatal COVID-sHLH would have defects in immune-related pathways.

Methods And Models: We identified two cohorts of adult patients presenting with COVID-19 at two tertiary care hospitals in Seattle, Washington in 2020 and 2021.

Urinary proteomics identifies distinct immunological profiles of sepsis associated AKI sub-phenotypes.

Background: Patients with sepsis-induced AKI can be classified into two distinct sub-phenotypes (AKI-SP1, AKI-SP2) that differ in clinical outcomes and response to treatment. The biologic mechanisms underlying these sub-phenotypes remains unknown. Our objective was to understand the underlying biology that differentiates AKI sub-phenotypes and associations with kidney outcomes.

Plasma proteomics of acute tubular injury.

The kidney tubules constitute two-thirds of the cells of the kidney and account for the majority of the organ's metabolic energy expenditure. Acute tubular injury (ATI) is observed across various types of kidney diseases and may significantly contribute to progression to kidney failure. Non-invasive biomarkers of ATI may allow for early detection and drug development.

Identification of biomarkers for COVID-19 associated secondary hemophagocytic lymphohistiocytosis.

Objectives: We aimed to define and validate novel biomarkers that could identify individuals with COVID-19 associated secondary hemophagocytic lymphohistiocytosis (sHLH) and to test whether fatalities due to COVID-19 in the presence of sHLH were associated with specific defects in the immune system.

Design: In two cohorts of adult patients presenting with COVID-19 in 2020 and 2021, clinical lab values and serum proteomics were assessed. Subjects identified as having sHLH were compared to those with COVID-19 without sHLH.

Mediators of monocyte chemotaxis and matrix remodeling are associated with mortality and pulmonary fibroproliferation in patients with severe COVID-19.

Acute respiratory distress syndrome (ARDS) has a fibroproliferative phase that may be followed by pulmonary fibrosis. Pulmonary fibrosis following COVID-19 pneumonia has been described at autopsy and following lung transplantation. We hypothesized that protein mediators of tissue remodeling and monocyte chemotaxis are elevated in the plasma and endotracheal aspirates of critically ill patients with COVID-19 who subsequently develop features of pulmonary fibroproliferation.

Acute kidney injury genetic risks: taking it 1 SNP at a time.

This commentary addresses some of the strengths, shortcomings, and challenges of the genome-wide association study of acute kidney injury (AKI) report in this issue. This AKI genome-wide association study is well executed and provides significant progress in finding 2 genome-wide significant loci. However, significant interpretive challenges remain, where advancements in methods are needed because of the clinical heterogeneity of the AKI phenotype, plus possible bias due to genetic correlation between index hospitalization risk and AKI risk.

PD-L1 and PD-1 Are Associated with Clinical Outcomes and Alveolar Immune Cell Activation in Acute Respiratory Distress Syndrome.

The relationship between the PD-L1 (Programmed Death-Ligand 1)/PD-1 pathway, lung inflammation, and clinical outcomes in acute respiratory distress syndrome (ARDS) is poorly understood. We sought to determine whether PD-L1/PD-1 in the lung or blood is associated with ARDS and associated severity. We measured soluble PD-L1 (sPD-L1) in plasma and lower respiratory tract samples (ARDS1 [ = 59] and ARDS2 [ = 78]) or plasma samples alone (ARDS3 [ = 149]) collected from subjects with ARDS and tested for associations with mortality using multiple regression.

Kidney Outcomes and Trajectories of Tubular Injury and Function in Critically Ill Patients With and Without COVID-19.

Importance: COVID-19 may injure the kidney tubules via activation of inflammatory host responses and/or direct viral infiltration. Most studies of kidney injury in COVID-19 lacked contemporaneous controls or measured kidney biomarkers at a single time point.

Objectives: To better understand mechanisms of acute kidney injury in COVID-19, we compared kidney outcomes and trajectories of tubular injury, viability, and function in prospectively enrolled critically ill adults with and without COVID-19.

The Road to Precision Medicine for Acute Kidney Injury.

Objectives: Acute kidney injury (AKI) is a common form of organ dysfunction in the ICU. AKI is associated with adverse short- and long-term outcomes, including high mortality rates, which have not measurably improved over the past decade. This review summarizes the available literature examining the evidence of the need for precision medicine in AKI in critical illness, highlights the current evidence for heterogeneity in the field of AKI, discusses the progress made in advancing precision in AKI, and provides a roadmap for studying precision-guided care in AKI.

Acute Kidney Injury, Systemic Inflammation, and Long-Term Cognitive Function: ASSESS-AKI.

Key Points: This study highlights that AKI is associated with long-term cognitive decline. Soluble TNF receptor 1 concentrations seem to mediate a significant proportion of the risk of long-term cognitive impairment after AKI.

Background: Cognitive dysfunction is a well-known complication of CKD, but it is less known whether cognitive decline occurs in survivors after AKI.

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

Acute kidney injury (AKI) often complicates sepsis and is associated with high morbidity and mortality. In recent years, several important clinical trials have improved our understanding of sepsis-associated AKI (SA-AKI) and impacted clinical care. Advances in sub-phenotyping of sepsis and AKI and clinical trial design offer unprecedented opportunities to fill gaps in knowledge and generate better evidence for improving the outcome of critically ill patients with SA-AKI.

Kidney Outcomes and Trajectories of Tubular Injury and Function in Critically Ill Persons with and without Coronavirus-2019.

Background: Coronavirus disease-2019 (COVID-19) may injure the kidney tubules via activation of inflammatory host responses and/or direct viral infiltration. Most studies of kidney injury in COVID-19 lacked contemporaneous controls or measured kidney biomarkers at a single time point. To better understand mechanisms of AKI in COVID-19, we compared kidney outcomes and trajectories of tubular injury, viability, and function in prospectively enrolled critically ill adults with and without COVID-19.

Inflammation, endothelial injury, and the acute respiratory distress syndrome after out-of-hospital cardiac arrest.

Background: Acute respiratory distress syndrome (ARDS) is often seen in patients resuscitated from out-of-hospital cardiac arrest (OHCA). We aim to test whether inflammatory or endothelial injury markers are associated with the development of ARDS in patients hospitalized after OHCA.

Methods: We conducted a prospective, cohort, pilot study at an urban academic medical center in 2019 that included a convenience sample of adults with non-traumatic OHCA.

Clonal hematopoiesis of indeterminate potential is associated with acute kidney injury.

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown. Clonal hematopoiesis of indeterminate potential (CHIP) confers increased risk for several chronic diseases associated with aging. Here we sought to test whether CHIP increases the risk of AKI.

Development and External Validation of Models to Predict Persistent Hypoxemic Respiratory Failure for Clinical Trial Enrichment.

Objectives: Improving the efficiency of clinical trials in acute hypoxemic respiratory failure (HRF) depends on enrichment strategies that minimize enrollment of patients who quickly resolve with existing care and focus on patients at high risk for persistent HRF. We aimed to develop parsimonious models predicting risk of persistent HRF using routine data from ICU admission and select research immune biomarkers.

Design: Prospective cohorts for derivation ( n = 630) and external validation ( n = 511).

Identification of prognostic biomarkers for antibiotic associated nephrotoxicity in cystic fibrosis.

Background: Our objective was to discover novel urinary biomarkers of antibiotic-associated nephrotoxicity using an ex-vivo human microphysiological system (MPS) and to translate these findings to a prospectively enrolled cystic fibrosis (CF) population receiving aminoglycosides and/or polymyxin E (colistin) for a pulmonary exacerbation.

Methods: We populated the MPS with primary human kidney proximal tubule epithelial cells (PTECs) from three donors and modeled nephrotoxin injury through exposure to 50 µg/mL polymyxin E for 72 h. We analyzed gene transcriptional responses by RNAseq and tested MPS effluents.