Publications by authors named "Susanna Kosamo"

12 Publications

  • Page 1 of 1

Characterization of nucleic acids from extracellular vesicle-enriched human sweat.

BMC Genomics 2021 Jun 9;22(1):425. Epub 2021 Jun 9.

Faculty of Biochemistry and Molecular Medicine, Disease Networks Research Unit, Laboratory of Developmental Biology, Kvantum Institute, Infotech Oulu, University of Oulu, 90014 University of Oulu, Oulu, Finland.

Background: The human sweat is a mixture of secretions from three types of glands: eccrine, apocrine, and sebaceous. Eccrine glands open directly on the skin surface and produce high amounts of water-based fluid in response to heat, emotion, and physical activity, whereas the other glands produce oily fluids and waxy sebum. While most body fluids have been shown to contain nucleic acids, both as ribonucleoprotein complexes and associated with extracellular vesicles (EVs), these have not been investigated in sweat. In this study we aimed to explore and characterize the nucleic acids associated with sweat particles.

Results: We used next generation sequencing (NGS) to characterize DNA and RNA in pooled and individual samples of EV-enriched sweat collected from volunteers performing rigorous exercise. In all sequenced samples, we identified DNA originating from all human chromosomes, but only the mitochondrial chromosome was highly represented with 100% coverage. Most of the DNA mapped to unannotated regions of the human genome with some regions highly represented in all samples. Approximately 5 % of the reads were found to map to other genomes: including bacteria (83%), archaea (3%), and virus (13%), identified bacteria species were consistent with those commonly colonizing the human upper body and arm skin. Small RNA-seq from EV-enriched pooled sweat RNA resulted in 74% of the trimmed reads mapped to the human genome, with 29% corresponding to unannotated regions. Over 70% of the RNA reads mapping to an annotated region were tRNA, while misc. RNA (18,5%), protein coding RNA (5%) and miRNA (1,85%) were much less represented. RNA-seq from individually processed EV-enriched sweat collection generally resulted in fewer percentage of reads mapping to the human genome (7-45%), with 50-60% of those reads mapping to unannotated region of the genome and 30-55% being tRNAs, and lower percentage of reads being rRNA, LincRNA, misc. RNA, and protein coding RNA.

Conclusions: Our data demonstrates that sweat, as all other body fluids, contains a wealth of nucleic acids, including DNA and RNA of human and microbial origin, opening a possibility to investigate sweat as a source for biomarkers for specific health parameters.
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http://dx.doi.org/10.1186/s12864-021-07733-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188706PMC
June 2021

Alveolar CCN1 is associated with mechanical stretch and acute respiratory distress syndrome severity.

Am J Physiol Lung Cell Mol Physiol 2020 11 16;319(5):L825-L832. Epub 2020 Sep 16.

Division of Pulmonary, Critical Care, and Sleep Medicine, University of Washington, Seattle, Washington.

The cellular communication network factor 1 (CCN1) is a matricellular protein that can modulate multiple tissue responses, including inflammation and repair. We have previously shown that adenoviral overexpression of is sufficient to cause acute lung injury in mice. We hypothesized that CCN1 is present in the airspaces of lungs during the acute phase of lung injury, and higher concentrations are associated with acute respiratory distress syndrome (ARDS) severity. We tested this hypothesis by measuring ) CCN1 in bronchoalveolar lavage fluid (BALF) and lung homogenates from mice subjected to ventilation-induced lung injury (VILI), ) gene expression and protein levels in MLE-12 cells (alveolar epithelial cell line) subjected to mechanical stretch, and ) CCN1 in BALF from mechanically ventilated humans with and without ARDS. BALF CCN1 concentrations and whole lung CCN1 protein levels were significantly increased in mice with VILI ( = 6) versus noninjured controls ( = 6). gene expression and CCN1 protein levels were increased in MLE-12 cells cultured under stretch conditions. Subjects with ARDS ( = 77) had higher BALF CCN1 levels compared with mechanically ventilated subjects without ARDS ( = 45) ( < 0.05). In subjects with ARDS, BALF CCN1 concentrations were associated with higher total protein, sRAGE, and worse [Formula: see text]/[Formula: see text] ratios (all < 0.05). CCN1 is present in the lungs of mice and humans during the acute inflammatory phase of lung injury, and concentrations are higher in patients with increased markers of severity. Alveolar epithelial cells may be an important source of CCN1 under mechanical stretch conditions.
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http://dx.doi.org/10.1152/ajplung.00073.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789974PMC
November 2020

Genetic variation implicates plasma angiopoietin-2 in the development of acute kidney injury sub-phenotypes.

BMC Nephrol 2020 07 17;21(1):284. Epub 2020 Jul 17.

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, 325 9th Avenue, Seattle, WA, 98104, USA.

Background: We previously identified two acute kidney injury (AKI) sub-phenotypes (AKI-SP1 and AKI-SP2) with different risk of poor clinical outcomes and response to vasopressor therapy. Plasma biomarkers of endothelial dysfunction (tumor necrosis factor receptor-1, angiopoietin-1 and 2) differentiated the AKI sub-phenotypes. However, it is unknown whether these biomarkers are simply markers or causal mediators in the development of AKI sub-phenotypes.

Methods: We tested for associations between single-nucleotide polymorphisms within the Angiopoietin-1, Angiopoietin-2, and Tumor Necrosis Factor Receptor 1A genes and AKI- SP2 in 421 critically ill subjects of European ancestry. Top performing single-nucleotide polymorphisms (FDR < 0.05) were tested for cis-biomarker expression and whether genetic risk for AKI-SP2 is mediated through circulating biomarkers. We also completed in vitro studies using human kidney microvascular endothelial cells. Finally, we calculated the renal clearance of plasma biomarkers using 20 different timed urine collections.

Results: A genetic variant, rs2920656C > T, near ANGPT2 was associated with reduced risk of AKI-SP2 (odds ratio, 0.45; 95% CI, 0.31-0.66; adjusted FDR = 0.003) and decreased plasma angiopoietin-2 (p = 0.002). Causal inference analysis showed that for each minor allele (T) the risk of developing AKI-SP2 decreases by 16%. Plasma angiopoietin-2 mediated 41.5% of the rs2920656 related risk for AKI-SP2. Human kidney microvascular endothelial cells carrying the T allele of rs2920656 produced numerically lower levels of angiopoietin-2 although this was not statistically significant (p = 0.07). Finally, analyses demonstrated that angiopoietin-2 is minimally renally cleared in critically ill subjects.

Conclusion: Genetic mediation analysis provides supportive evidence that angiopoietin-2 plays a causal role in risk for AKI-SP2.
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http://dx.doi.org/10.1186/s12882-020-01935-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368773PMC
July 2020

sTREM-1 predicts mortality in hospitalized patients with infection in a tropical, middle-income country.

BMC Med 2020 07 1;18(1):159. Epub 2020 Jul 1.

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, 98195, USA.

Background: Few studies of biomarkers as predictors of outcome in infection have been performed in tropical, low- and middle-income countries where the burden of sepsis is highest. We evaluated whether selected biomarkers could predict 28-day mortality in infected patients in rural Thailand.

Methods: Four thousand nine hundred eighty-nine adult patients admitted with suspected infection to a referral hospital in northeast Thailand were prospectively enrolled within 24 h of admission. In a secondary analysis of 760 patients, interleukin-8 (IL-8), soluble tumor necrosis factor receptor 1 (sTNFR-1), angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and soluble triggering receptor expressed by myeloid cells 1 (sTREM-1) were measured in the plasma. Association with 28-day mortality was evaluated using regression; a parsimonious biomarker model was selected using the least absolute shrinkage and selection operator (LASSO) method. Discrimination of mortality was assessed by receiver operating characteristic curve analysis and verified by multiple methods.

Results: IL-8, sTNFR-1, Ang-2, and sTREM-1 concentrations were strongly associated with death. LASSO identified a three-biomarker model of sTREM-1, Ang-2, and IL-8, but sTREM-1 alone provided comparable mortality discrimination (p = 0.07). sTREM-1 alone was comparable to a model of clinical variables (area under receiver operating characteristic curve [AUC] 0.81, 95% confidence interval [CI] 0.77-0.85 vs AUC 0.79, 95% CI 0.74-0.84; p = 0.43). The combination of sTREM-1 and clinical variables yielded greater mortality discrimination than clinical variables alone (AUC 0.83, 95% CI 0.79-0.87; p = 0.004).

Conclusions: sTREM-1 predicts mortality from infection in a tropical, middle-income country comparably to a model derived from clinical variables and, when combined with clinical variables, can further augment mortality prediction.

Trial Registration: The Ubon-sepsis study was registered on ClinicalTrials.gov ( NCT02217592 ), 2014.
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http://dx.doi.org/10.1186/s12916-020-01627-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329452PMC
July 2020

Alveolar MMP28 is associated with clinical outcomes and measures of lung injury in acute respiratory distress syndrome.

Crit Care 2020 04 8;24(1):141. Epub 2020 Apr 8.

Division of Pulmonary, Critical Care, and Sleep Medicine, Center for Lung Biology, University of Washington, 850 Republican St, Seattle, WA, 98109, USA.

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http://dx.doi.org/10.1186/s13054-020-02847-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144344PMC
April 2020

Endothelial Activation, Innate Immune Activation, and Inflammation Are Associated With Postbronchodilator Airflow Limitation and Obstruction Among Adolescents Living With HIV.

J Acquir Immune Defic Syndr 2020 03;83(3):267-277

Department of Medicine, University of Washington, Seattle, WA.

Background: Chronic inflammation, innate immune activation, T-cell imbalance and endothelial activation have been linked with lung diseases. We sought to determine whether markers of these pathophysiologic pathways were associated with spirometry and chest computed tomography (CT) abnormalities among adolescents living with HIV (ALWH).

Setting: Coptic Hope Center for Infectious Diseases in Nairobi, Kenya.

Methods: We performed a cross-sectional study of ALWH (10-19 years old). Participants underwent chest CT, spirometry, and venipuncture for serum biomarkers. We also collected demographic, anthropometric, T-cell subset, antiretroviral therapy, and exposure data. We compared characteristics and biomarkers by airflow obstruction [postbronchodilator FEV1/FVC z-score (zFEV1/FVC) < -1.64]. We used multivariable linear regression to determine associations of log10-transformed biomarkers and chest CT abnormalities with lower postbronchodilator zFEV1/FVC (airflow limitation). We performed exploratory principal components analysis on biomarkers, and determined associations of factors with postbronchodilator zFEV1/FVC and chest CT abnormalities.

Results: Of 47 participants with acceptable quality spirometry, 21 (45%) were female, median age was 13 years and 96% had perinatally-acquired HIV. Median CD4 was 672 cells/µL. Overall, 28% had airflow obstruction and 78% had a chest CT abnormality; airflow obstruction was associated with mosaic attenuation (P = 0.001). Higher endothelial activation (sVCAM-1, sICAM-1), inflammation and innate immune activation (serum amyloid-A, sTREM-1, sCD163), and T-cell imbalance (lower CD4/CD8) markers were associated with airflow limitation. Factors comprising endothelial and innate immune activation were associated with airflow limitation.

Conclusions: Endothelial activation, innate immune activation, T-cell imbalance, and chronic inflammation are associated with airflow limitation and obstruction, providing insights into chronic lung disease pathophysiology among ALWH.
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http://dx.doi.org/10.1097/QAI.0000000000002255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735385PMC
March 2020

Strong toll-like receptor responses in cystic fibrosis patients are associated with higher lung function.

J Cyst Fibros 2020 07 5;19(4):608-613. Epub 2019 Dec 5.

University of Washington, Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Seattle, WA, United States. Electronic address:

Background: Cystic fibrosis (CF) airways disease varies widely among patients with identical cystic fibrosis transmembrane conductance regulator (CFTR) genotypes. Robust airway inflammation is thought to be deleterious in CF; inter-individual variation in Toll-like receptor (TLR)-mediated innate immune inflammatory responses (TMIIR) might account for a portion of the phenotypic variation. We tested if TMIIR in people with CF are different than those of healthy controls, and whether higher TMIIR in people with CF are associated with reduced lung function.

Methods: We cultured whole blood from clinically stable subjects with CF (n = 76) and healthy controls (n = 45) with TLR agonists, and measured cytokine production and expression of TLR-associated genes. We tested for differences in TLR-stimulated cytokine levels between subjects with CF and healthy subjects, and for associations between cytokine and gene expression levels with baseline lung function (forced expiratory volume in one second percent predicted (FEV%)) and decline in FEV% over time.

Results: TMIIR in blood from subjects with CF were lower than in healthy controls. Expression of TLR regulators SARM1, TOLLIP, and AKT1 were downregulated in CF. In subjects with CF we found that lower TLR4-agonist-induced IL-8 was associated with lower FEV% at enrollment (p<0.001) and with greater five year FEV% decline (p<0.001).

Conclusions: TMIIR were lower in people with CF relative to healthy controls; however, unexpectedly, greater whole blood TMIIR were positively associated with lung function in people with CF. These findings suggest a complex interaction between inflammation and disease in people with CF.
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http://dx.doi.org/10.1016/j.jcf.2019.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272272PMC
July 2020

Interleukin-6 improves infection identification when added to physician judgment during evaluation of potentially septic patients.

Am J Emerg Med 2020 05 25;38(5):947-952. Epub 2019 Jul 25.

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, United States of America.

Background: Identifying infection is critical in early sepsis screening. This study assessed whether biomarkers of endothelial activation and/or inflammation could improve identification of infection among Emergency Department (ED) patients with organ dysfunction.

Methods: We performed a prospective, observational study at two urban, academic EDs, between June 2016 and December 2017. We included admitted adults with 1) two systemic inflammatory response syndrome criteria and organ dysfunction, 2) systolic blood pressure < 90 mmHg, or 3) lactate ≥4.0 mmol/L. We excluded patients with trauma, transferred for intracranial hemorrhage, or without available blood samples. Treating ED physicians reported presence of infection (yes/no) at inpatient admission. Assays for angiopoietin-1, angiopoietin-2, soluble tumor necrosis factor receptor-1, interleukin-6, and interleukin-8 were performed using ED blood samples. The primary outcome was infection, adjudicated by paired physician review. Using logistic regression, we compared the performance of physician judgment, biomarkers, and physician judgment-biomarkers combination to predict infection. Area under the curve (AUC) and AUC 95% confidence intervals were estimated by bootstrap procedure.

Results: Of 421 patients enrolled, 306 patients met final study criteria. Of these, 154(50.3%) patients had infectious etiologies. Physicians correctly discriminated infectious from non-infectious etiologies in 239 (78.1%). Physician judgment performed moderately when discriminating infection (AUC 0.78, 95% CI: 0.74-0.82) and outperformed the best biomarker model, interleukin-6 alone, (AUC 0.71, 0.66-0.76). Physician judgment improved when including interleukin-6 (AUC 0.84, 0.79-0.87), with modest AUC improvement: 0.06 (0.03-0.08).

Conclusions: In ED patients with organ dysfunction, plasma interleukin-6 may improve infection discrimination when added to physician judgment.
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http://dx.doi.org/10.1016/j.ajem.2019.158361DOI Listing
May 2020

Physician Judgment and Circulating Biomarkers Predict 28-Day Mortality in Emergency Department Patients.

Crit Care Med 2019 11;47(11):1513-1521

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA.

Objectives: To determine whether biomarkers of endothelial activation and inflammation provide added value for prediction of in-hospital mortality within 28 days when combined with physician judgment in critically ill emergency department patients.

Design: Prospective, observational study.

Setting: Two urban, academic emergency departments, with ≈80,000 combined annual visits, between June 2016 and December 2017.

Patients: Admitted patients, greater than 17 years old, with two systemic inflammatory response syndrome criteria and organ dysfunction, systolic blood pressure less than 90 mm Hg, or lactate greater than 4.0 mmol/L. Patients with trauma, intracranial hemorrhage known prior to arrival, or without available blood samples were excluded.

Interventions: Emergency department physicians reported likelihood of in-hospital mortality (0-100%) by survey at hospital admission. Remnant EDTA blood samples, drawn during the emergency department stay, were used to measure angiopoietin-1, angiopoietin-2, tumor necrosis factor receptor-1, interleukin-6, and interleukin-8.

Measurements And Main Results: We screened 421 patients and enrolled 314. The primary outcome of in-hospital mortality within 28 days occurred in 31 (9.9%). When predicting the primary outcome, the best biomarker model included angiopoietin-2 and interleukin-6 and performed moderately well (area under the curve, 0.72; 95% CI, 0.69-0.75), as did physician judgment (area under the curve, 0.78; 95% CI, 0.74-0.82). Combining physician judgment and biomarker models improved performance (area under the curve, 0.85; 95% CI, 0.82-0.87), with area under the curve change of 0.06 (95% CI, 0.04-0.09; p < 0.01) compared with physician judgment alone.

Conclusions: Predicting in-hospital mortality within 28 days among critically ill emergency department patients may be improved by including biomarkers of endothelial activation and inflammation in combination with emergency department physician judgment.
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http://dx.doi.org/10.1097/CCM.0000000000003899DOI Listing
November 2019

Flagellin-independent effects of a Toll-like receptor 5 polymorphism in the inflammatory response to Burkholderia pseudomallei.

PLoS Negl Trop Dis 2019 05 8;13(5):e0007354. Epub 2019 May 8.

Department of Medicine, University of Washington, Seattle, Washington, United States of America.

Background: Toll-like receptors (TLRs) are sentinel receptors of the innate immune system. TLR4 detects bacterial lipopolysaccharide (LPS) and TLR5 detects bacterial flagellin. A common human nonsense polymorphism, TLR5:c.1174C>T, results in a non-functional TLR5 protein. Individuals carrying this variant have decreased mortality from melioidosis, infection caused by the flagellated Gram-negative bacterium Burkholderia pseudomallei. Although impaired flagellin-dependent signaling in carriers of TLR5:c.1174C>T is well established, this study tested the hypothesis that a functional effect of TLR5:c.1174C>T is flagellin-independent and involves LPS-TLR4 pathways.

Methodology/principal Findings: Whole blood from two independent cohorts of individuals genotyped at TLR5:c.1174C>T was stimulated with wild type or aflagellated B. pseudomallei or purified bacterial motifs followed by plasma cytokine measurements. Blood from individuals carrying the TLR5:c.1174C>T variant produced less IL-6 and IL-10 in response to an aflagellated B. pseudomallei mutant and less IL-8 in response to purified B. pseudomallei LPS than blood from individuals without the variant. TLR5 expression in THP1 cells was silenced using siRNA; these cells were stimulated with LPS before cytokine levels in cell supernatants were quantified by ELISA. In these cells following LPS stimulation, silencing of TLR5 with siRNA reduced both TNF-α and IL-8 levels. These effects were not explained by differences in TLR4 mRNA expression or NF-κB or IRF activation.

Conclusions/significance: The effects of the common nonsense TLR5:c.1174C>T polymorphism on the host inflammatory response to B. pseudomallei may not be restricted to flagellin-driven pathways. Moreover, TLR5 may modulate TLR4-dependent cytokine production. While these results may have broader implications for the role of TLR5 in the innate immune response in melioidosis and other conditions, further studies of the mechanisms underlying these observations are required.
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http://dx.doi.org/10.1371/journal.pntd.0007354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527242PMC
May 2019

A Prediction Model for Severe AKI in Critically Ill Adults That Incorporates Clinical and Biomarker Data.

Clin J Am Soc Nephrol 2019 04 27;14(4):506-514. Epub 2019 Mar 27.

Division of Pulmonary and Critical Care Medicine, Department of Medicine.

Background And Objectives: Critically ill patients with worsening AKI are at high risk for poor outcomes. Predicting which patients will experience progression of AKI remains elusive. We sought to develop and validate a risk model for predicting severe AKI within 72 hours after intensive care unit admission.

Design, Setting, Participants, & Measurements: We applied least absolute shrinkage and selection operator regression methodology to two prospectively enrolled, critically ill cohorts of patients who met criteria for the systemic inflammatory response syndrome, enrolled within 24-48 hours after hospital admission. The risk models were derived and internally validated in 1075 patients and externally validated in 262 patients. Demographics and laboratory and plasma biomarkers of inflammation or endothelial dysfunction were used in the prediction models. Severe AKI was defined as Kidney Disease Improving Global Outcomes (KDIGO) stage 2 or 3.

Results: Severe AKI developed in 62 (8%) patients in the derivation, 26 (8%) patients in the internal validation, and 15 (6%) patients in the external validation cohorts. In the derivation cohort, a three-variable model (age, cirrhosis, and soluble TNF receptor-1 concentrations [ACT]) had a c-statistic of 0.95 (95% confidence interval [95% CI], 0.91 to 0.97). The ACT model performed well in the internal (c-statistic, 0.90; 95% CI, 0.82 to 0.96) and external (c-statistic, 0.93; 95% CI, 0.89 to 0.97) validation cohorts. The ACT model had moderate positive predictive values (0.50-0.95) and high negative predictive values (0.94-0.95) for severe AKI in all three cohorts.

Conclusions: ACT is a simple, robust model that could be applied to improve risk prognostication and better target clinical trial enrollment in critically ill patients with AKI.
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http://dx.doi.org/10.2215/CJN.04100318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450340PMC
April 2019

Identification of Acute Kidney Injury Subphenotypes with Differing Molecular Signatures and Responses to Vasopressin Therapy.

Am J Respir Crit Care Med 2019 04;199(7):863-872

1 Division of Pulmonary, Critical Care, and Sleep Medicine.

Rationale: Currently, no safe and effective pharmacologic interventions exist for acute kidney injury (AKI). One reason may be that heterogeneity exists within the AKI population, thereby hampering the identification of specific pathophysiologic pathways and therapeutic targets.

Objective: The aim of this study was to identify and test whether AKI subphenotypes have prognostic and therapeutic implications.

Methods: First, latent class analysis methodology was applied independently in two critically ill populations (discovery [n = 794] and replication [n = 425]) with AKI. Second, a parsimonious classification model was developed to identify AKI subphenotypes. Third, the classification model was applied to patients with AKI in VASST (Vasopressin and Septic Shock Trial; n = 271), and differences in treatment response were determined. In all three populations, AKI was defined using serum creatinine and urine output.

Measurements And Main Results: A two-subphenotype latent class analysis model had the best fit in both the discovery (P = 0.004) and replication (P = 0.004) AKI groups. The risk of 7-day renal nonrecovery and 28-day mortality was greater with AKI subphenotype 2 (AKI-SP2) relative to AKI subphenotype 1 (AKI-SP1). The AKI subphenotypes discriminated risk for poor clinical outcomes better than the Kidney Disease: Improving Global Outcomes stages of AKI. A three-variable model that included markers of endothelial dysfunction and inflammation accurately determined subphenotype membership (C-statistic 0.92). In VASST, vasopressin compared with norepinephrine was associated with improved 90-day mortality in AKI-SP1 (27% vs. 46%, respectively; P = 0.02), but no significant difference was observed in AKI-SP2 (45% vs. 49%, respectively; P = 0.99) and the P value for interaction was 0.05.

Conclusions: This analysis identified two molecularly distinct AKI subphenotypes with different clinical outcomes and responses to vasopressin therapy. Identification of AKI subphenotypes could improve risk prognostication and may be useful for predictive enrichment in clinical trials.
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http://dx.doi.org/10.1164/rccm.201807-1346OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444649PMC
April 2019
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