Additional file 2: Table S1. of Angiotensin converting enzyme inhibition increases ADMA concentration in patients on maintenance hemodialysis – a randomized cross-over study

Baseline characteristics of patients with no history of CKD. (DOCX 14 kb

Perioperative Intravenous Acetaminophen Attenuates Lipid Peroxidation in Adults Undergoing Cardiopulmonary Bypass: A Randomized Clinical Trial

<div><p>Background</p><p>Cardiopulmonary bypass (CPB) lyses erythrocytes and induces lipid peroxidation, indicated by increasing plasma concentrations of free hemoglobin, F₂-isoprostanes, and isofurans. Acetaminophen attenuates hemeprotein-mediated lipid peroxidation, reduces plasma and urine concentrations of F₂-isoprostanes, and preserves kidney function in an animal model of rhabdomyolysis. Acetaminophen also attenuates plasma concentrations of isofurans in children undergoing CPB. The effect of acetaminophen on lipid peroxidation in adults has not been studied. This was a pilot study designed to test the hypothesis that acetaminophen attenuates lipid peroxidation in adults undergoing CPB and to generate data for a clinical trial aimed to reduce acute kidney injury following cardiac surgery.</p><p>Methods and Results</p><p>In a prospective double-blind placebo-controlled clinical trial, sixty adult patients were randomized to receive intravenous acetaminophen or placebo starting prior to initiation of CPB and for every 6 hours for 4 doses. Acetaminophen concentrations measured 30 min into CPB and post-CPB were 11.9±0.6 μg/mL (78.9±3.9 μM) and 8.7±0.3 μg/mL (57.6±2.0 μM), respectively. Plasma free hemoglobin increased more than 15-fold during CPB, and haptoglobin decreased 73%, indicating hemolysis. Plasma and urinary markers of lipid peroxidation also increased during CPB but returned to baseline by the first postoperative day. Acetaminophen reduced plasma isofuran concentrations over the duration of the study (P = 0.05), and the intraoperative plasma isofuran concentrations that corresponded to peak hemolysis were attenuated in those subjects randomized to acetaminophen (P = 0.03). Perioperative acetaminophen did not affect plasma concentrations of F₂-isoprostanes or urinary markers of lipid peroxidation.</p><p>Conclusions</p><p>Intravenous acetaminophen attenuates the increase in intraoperative plasma isofuran concentrations that occurs during CPB, while urinary markers were unaffected.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01366976" target="_blank">NCT01366976</a></p></div

Plasma free hemoglobin (A) and creatinine (B) concentrations in subjects that developed acute kidney injury (AKI) compared to subjects that did not.

<p>base, baseline; 30min, 30min of CPB; 60min, 60min of CPB; post, post-bypass; ICU, intensive care unit; and POD, postoperative day.</p

Preoperative Patient Characteristics.

<p>Continuous data are reported as mean± SEM or median (25^th, 75^th percentile). PVD, peripheral vascular disease; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; AST, aspartate aminotransferase; CKD EPI eGFR, chronic kidney disease epidemiology collaboration estimated glomerular filtration rate.[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117625#pone.0117625.ref027" target="_blank">27</a>]</p><p>^a Mann Whitney U test;</p><p>^b t-test;</p><p>^c Fischer Exact test,</p><p>^d Pearson Chi-Square test</p><p>Preoperative Patient Characteristics.</p

Postoperative Outcomes.

<p>Continuous data are reported as mean± SEM or median (25^th, 75^th percentile).CK, creatine kinase; AST, aspartate aminotransferase; POD, postoperative day; NGAL, neutrophil gelatinase-associated lipocalin; †Acute kidney injury was defined as an increase in subject serum creatinine concentration of 50% or 0.3 mg/dL within 72 hours of surgery.</p><p>^a Mann Whitney U test;</p><p>^b t-test;</p><p>^c Fischer Exact test</p><p>Postoperative Outcomes.</p

Effect of study drug on plasma and urine markers of lipid peroxidation.; isoF, isofurans; F₂isoP, F₂-isoprostanes; base, baseline; 30min, 30min of CPB; 60min, 60min of CPB; post, post-bypass; ICU, intensive care unit; and POD1, postoperative day 1.

<p>Effect of study drug on plasma and urine markers of lipid peroxidation.; isoF, isofurans; F₂isoP, F₂-isoprostanes; base, baseline; 30min, 30min of CPB; 60min, 60min of CPB; post, post-bypass; ICU, intensive care unit; and POD1, postoperative day 1.</p

Free hemoglobin (A) and haptoglobin (B) concentrations.

<p>CPB was associated with an increase in free hemoglobin concentrations and a decrease in haptoglobin concentrations with no significant difference between the acetaminophen and placebo group. base, baseline; 30min, 30min of CPB; 60min, 60min of CPB; post, post-bypass; ICU, intensive care unit; and POD1, postoperative day 1.</p

A comparison of previously identified significant SNPs from literature to African Americans from Vanderbilt AF cohort.

<p>The case/control sample size for the previously published studies are: Ellinor et. al n = 14,179 (11); Kaab et. al. n = 36,196 (9); Benjamin et. al. n = 46,736 (10); and Gudbjartsson et al. n = 39,014 (50). AA =  Subjects with self-reported African American race.</p

SNPs associated with atrial fibrillation in African Americans.

<p>SNP, location (NCBI.36), coded allele, odds ratios, 95% confidence intervals, and p-value are shown for significant associations (p<0.05) after adjusting for age, BMI, history of CAD, history of CHF, history of diabetes, and history of hypertension.</p

Study Population Characteristics.

<p>Mean (± standard errors) or proportions are given for each variable among cases and controls. A chi-square test or a Student's t-test was performed to test for differences between cases and controls, where appropriate.</p