Angela J. Frank

Body mass index and acute kidney injury in the acute respiratory distress syndrome.

Objectives:Obesity is increasingly encountered in intensive care units but the relationship between obesity and acute kidney injury is unclear. We aimed to evaluate whether body mass index was associated with acute kidney injury in the acute respiratory distress syndrome and to examine the association between acute kidney injury and mortality in patients with and without obesity. Design:Retrospective study. Setting:Massachusetts General Hospital and Beth Israel Deaconess Medical Center. Patients:Seven hundred fifty-one patients with acute respiratory distress syndrome. Interventions:None. Measurements and Main Results:Acute kidney injury was defined as meeting the “Risk” category according to modified Risk, Injury, Failure, Loss, End-stage criteria based on creatinine and glomerular filtration rate because urine output was only available on the day of intensive care unit admission. Body mass index was calculated from height and weight at intensive care unit admission. The prevalence of acute kidney injury increased significantly with increasing weight (p = .01). The odds of acute kidney injury were twice in obese and severely obese patients compared to patients with normal body mass index, after adjusting for predictors of acute kidney injury (age, diabetes, Acute Physiology and Chronic Health Evaluation III, aspiration, vasopressor use, and thrombocytopenia [platelets ⩽ 80,000/mm3]). After adjusting for the same predictors, body mass index was significantly associated with acute kidney injury (odds ratioadj 1.20 per 5 kg/m2 increase in body mass index, 95% confidence interval 1.07–1.33). On multivariate analysis, acute kidney injury was associated with increased acute respiratory distress syndrome mortality (odds ratioadj 2.76, 95% confidence interval 1.72–4.42) whereas body mass index was associated with decreased mortality (odds ratioadj 0.81 per 5 kg/m2 increase in body mass index, 95% confidence interval 0.71–0.93) after adjusting for mortality predictors. Conclusions:In acute respiratory distress syndrome patients, obesity is associated with increased development of acute kidney injury, which is not completely explained by severity of illness or shock. Although increased body mass index is associated with decreased mortality, acute kidney injury remained associated with higher mortality even after adjusting for body mass index.

Pharmacological treatments for acute respiratory distress syndrome.

Purpose of review Studies of the pharmacologic management of acute respiratory distress syndrome (ARDS) have yielded conflicting results. The purpose of this review is to discuss recent pharmacologic trials in ARDS, using the conceptual framework of ARDS as a heterogeneous disease. Recent findings Whereas most drug trials in ARDS have been negative, some studies suggest that targeting therapies at subgroups of patients may be successful. Proposed subgroups include early versus late-phase ARDS, direct versus indirect lung injury, and patients with altered coagulation. Corticosteroids have beneficial short-term effects when given at low or moderate doses sooner than 2 weeks but appear to be harmful if initiated later and are of unclear benefit if lung protective ventilation is also used. Surfactant may be helpful in patients with direct lung injury. Anticoagulants and vasodilators may have a greater chance for success in the subset of patients with vascular disease and a high dead-space fraction may identify such a population. Summary ARDS is a heterogeneous syndrome. Failure to target subgroups more likely to benefit from specific therapies may be one explanation for largely disappointing trial results so far.

Distinct and replicable genetic risk factors for acute respiratory distress syndrome of pulmonary or extrapulmonary origin

Background The role of genetics in the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) from direct or indirect lung injury has not been specifically investigated. The aim of this study was to identify genetic variants contributing to ALI/ARDS from pulmonary or extrapulmonary causes. Methods We conducted a multistage genetic association study. We first performed a large-scale genotyping (50K ITMAT-Broad_CARe Chip) in 1717 critically ill Caucasian patients with either pulmonary or extrapulmonary injury, to identify single nucleotide polymorphisms (SNPs) associated with the development of ARDS from direct or indirect insults to the lung. Identified SNPs (p≤0.0005) were validated in two separated populations (Stage II), with trauma (Population I; n=765) and pneumonia/pulmonary sepsis (Population II; n=838), as causes for ALI/ARDS. Genetic variants replicating their association with trauma related-ALI in Stage II were validated in a second trauma-associated ALI population (n=224, Stage III). Results In Stage I, non-overlapping SNPs were significantly associated with ARDS from direct/indirect lung injury, respectively. The association between rs1190286 (POPDC3) and reduced risk of ARDS from pulmonary injury was validated in Stage II (p<0.003). SNP rs324420 (FAAH) was consistently associated with increased risk of ARDS from extrapulmonary causes in two independent ALI-trauma populations (p<0.006, Stage II; p<0.05, Stage III). Meta-analysis confirmed these associations. Conclusions Different genetic variants may influence ARDS susceptibility depending on direct versus indirect insults. Functional SNPs in POPDC3 and FAAH genes may be driving the association with direct and indirect ALI/ARDS, respectively.

BCL2 Genetic Variants Are Associated With Acute Kidney Injury in Septic Shock

Objective:Acute kidney injury frequently complicates septic shock and independently predicts mortality in this population. Clinical factors alone do not entirely account for differences in risk of acute kidney injury between patients. Genetic variants are likely to explain this differential susceptibility. To identify genetic variants linked to acute kidney injury susceptibility, we conducted a high-density genotyping association study in a large population of patients with septic shock. Design:Retrospective study. Setting:Tertiary academic medical center. Patients:One thousand two hundred and sixty-four patients with septic shock were analyzed to elucidate clinical risk factors associated with the development of acute kidney injury. Among them, 887 Caucasian patients were randomly split into discovery and validation cohorts and genotyped using the Illumina Human-CVD BeadChip (Illumina, San Diego, CA). Interventions:None. Measurements and Main Results:Six hundred and twenty-seven of the 1,264 patients with septic shock and 441 of the 887 patients with genotyping data developed acute kidney injury within the first 72 hrs of intensive care unit admission. Five single nucleotide polymorphisms were associated with acute kidney injury in both the discovery and validation cohorts. Two of these were in the BCL2 gene and both were associated with a decreased risk of acute kidney injury (rs8094315: odds ratio 0.61, p = .0002; rs12457893: odds ratio 0.67, p = .0002, both for combined data). Bcl-2 is involved in the apoptosis pathway, which has previously been implicated in acute kidney injury. Another single nucleotide polymorphism was in the SERPINA4 gene, whose protein product, kallistatin, has been linked to apoptosis in the kidney. Conclusions:Large-scale genotyping reveals two single nucleotide polymorphisms in the BCL2 gene and a single nucleotide polymorphism in the SERPINA4 gene associated with a decreased risk of developing acute kidney injury, supporting the putative role of apoptosis in the pathogenesis of acute kidney injury.