Midregional Proadrenomedullin Concentrations Research Articles

Postmortem study of adrenomedullin and cortisol in femoral serum and pericardial fluid related to acute pulmonary edema.

Currently, various tools aid in determining the cause of death and the circumstances surrounding it. Thanatochemistry is one such method that provides insights into the physiopathological mechanisms of death and the behavior of specific biomarkers in different body fluids postmortem. Certain biomarkers, characterized by their stability and specificity to vital tissues like the lungs, are associated with mechanisms contributing to death, such as acute pulmonary edema (APE). This study aims to analyze the behavior of midregional pro-adrenomedullin (MR-proADM) and cortisol levels, measured in pericardial fluid and femoral serum, in relation to the severity of APE, categorized according to specific criteria. Samples were collected from a total of 92 corpses (77 males, 15 females) with a mean age of 56.7 ± 15.2 years. The severity of APE associated with the deaths was classified into three groups: slight or absent (n = 7; 8.6%), medium or moderate (n = 16; 19.8%), and intense (n = 58;71.6%).The determination of MR-proADM and cortisol levels was conducted using ELISA kits and an Immunoassay Analyzer, respectively. Our results reveal a significant increase in MR-proADM concentration with the severity of APE. Furthermore, a correlation was established between cortisol and MR-proADM concentrations in both pericardial fluid and femoral serum samples. This indicates that the severity of APE influences the production of ADM, regardless of the specific underlying pathophysiological mechanisms. Cortisol values were also found to be higher in the intense APE group compared to the moderate group.This study contributes to our understanding of the relationship between MR-proADM and cortisol, and the severity of APE, shedding light on potential applications in postmortem investigations.

MR-proADM as Prognostic Factor of Outcome in COVID-19 Patients.

Serum mid-regional proadrenomedullin (MR-proADM) has emerged as a marker of organ failure (mainly lungs and kidneys) and poor prognosis in patients admitted to intensive care (IC); some reports also suggest it and other markers, such as Krebs von den Lungen-6 (KL-6) and interleukin-6 (IL-6), as a prognostic biomarker of COVID-19. The aim of the study was to evaluate the performance MR-proADM in hospitalized COVID-19 patients for predicting in-hospital mortality and need for non-invasive or invasive respiratory support. We enrolled 74 patients hospitalized in the COVID Unit of Siena Hospital from March to May 2020, for whom serum samples were available on admission for assay of MR-proADM, KL-6 and IL-6. Demographic data, comorbidities, medical history and clinical laboratory data on days 1-3 of admission and Simplified Acute Physiology Score and Simplified Organ Failure Assessment scores calculated at day 1 were collected retrospectively, as well as mortality and IC admission data. 12 patients died in hospital (16%) and 14 patients were admitted to IC (19%). Serum concentrations of MR-proADM on admission and on day 1 were higher among non-survivors than among survivors (p = 0.015 and p = 0.045, respectively), while those on day 3 were not significantly different. Patients needing respiratory support had higher MR-proADM concentrations on admission than the others (p = 0.046), and those requiring invasive mechanical ventilation had higher MR-proADM on day 1 (p = 0.017). Serum concentrations of KL-6 and IL-6 were significantly higher in non-survivors (p = 0.03 and p = 0.004, respectively). ROC curve analysis showed that serum MR-proADM on day 1 had the best accuracy in predicting death and/or IC admission (AUC = 0.9583, p = 0.0006); the combination of all three biomarkers further improved the accuracy of prediction of death or IC admission (AUC = 0.9793; p = 0.00004). Our data sustain the potential of serum MR-proADM as a reliable prognostic biomarker of hospitalized COVID-19 patients and confirms the utility of the three markers in the management and risk stratification of hospitalized patients. The markers are collected mini-invasively and are quick to analyze and cost-effective.

Comparative performances of soluble urokinase plasminogen activator receptor and Mid-regional proADM to predict composite death and new heart failure rehospitalisation in acutely breathless patients

Abstract Background Soluble urokinase plasminogen activator receptor (suPAR) is a pleotropic receptor, capable of orchestrating plaque vulnerability and vascular immune dysfunction. Mid-regional pro-adrenomedullin (MR-proADM) is the stable peptide precursor of adrenomedullin, with concentrations reflective of vasodilation and cardiac remodelling. We compared the prognostic performances of suPAR and MR-proADM for the composite clinical endpoint of death and new heart failure (HF) in patients with undifferentiated breathlessness. Methods Patients presenting to hospital with the primary complaint of acute dyspnoea were recruited in New Zealand (n=612) and in Singapore (n=483)]. Baseline plasma measurements were undertaken for suPAR (ViroGates) and MR-proADM (Thermo Scientific). Cardiac biomarker levels of NT-proBNP (Roche) was available on all patients. Statistical assessment was made using SPSS v28 (IBM), with all biomarkers treated as continuous variables and presented as median [interquartile range (IQR)]. Prognostic performance of suPAR, MR-proADM and NT-proBNP to predict the composite clinical endpoint of death/new HF at 90-days and 1-yr were assessed using receiver operator curve (ROC) area under the curve (AUC) analysis (Z-scores) and Cox hazard regression analysis (per doubling of biomarker concentrations) after adjustment for traditional risk factors. P-value <0.05 was considered statistically significant. Results In the entire acutely breathless cohort [median age: 65 years (IQR: 52.9–76.0), 63.1% males], 343/1095 of patients had the final adjudication of ADHF. suPAR and MR-proADM concentrations were higher with increasing age (Spearmans rho, r>0.46, P<0.0001), lower eGFR (r>0.58, P<0.0001) and in those with ADHF (r>0.40, P<0.0001). During the follow-up period, 122 patients were categorised with death/new HF by 90-days, rising to 281 at 1-year. suPAR and MR-proADM were able to predict death/new HF at 90-days (both ROC-AUC >0.77) and at 1-year (both ROC-AUC ≥0.78) (Table 1). All markers were however less accurate in predicting this endpoint in the presence of ADHF (ROC-AUC <0.71). After adjustment in Cox-regression modelling, suPAR obtained HR >1.35 per doubling of suPAR concentrations (P=0.001) for outcomes at 90-days and at 1-year (Table 2), achieving the highest prognostic performance for this clinical endpoint, followed by NT-proBNP (HR >1.29) (Table 2), whilst MR-proADM was not an independent predictor of death/HF in this cohort. suPAR was also an independent predictor of death/HF for patients with ADHF, obtaining HR >1.35 per doubling of concentrations. Above a cut-off concentration of 3.6 ng/mL, suPAR was associated with a HR of 2.1 (95% CI: 1.55–2.91) for death/HF at 1-year for acutely dyspnoeic patients. Conclusion suPAR concentrations is superior than MR-proADM in predicting the clinical end-point of death/HF at 1-year in this cohort. It may aid in risk-stratification strategies for the management of acutely breathless patients. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): National Heart Foundation of New ZealandHealth Research Council of New Zealand

Mid-Regional Pro-Adrenomedullin as a Prognostic Factor for Severe COVID-19 ARDS.

Mid-regional proadrenomedullin (MR-proADM) protects against endothelial permeability and has been associated with prognosis in bacterial sepsis. As endothelial dysfunction is central in the pathophysiology of severe SARS-CoV-2 infection, we sought to evaluate MR-proADM both as a prognostic biomarker and as a marker of bacterial superinfection. Consecutive patients admitted to the ICU for severe SARS-CoV-2 pneumonia were prospectively included and serum was bio-banked on days 1, 3, and 7. MR-proADM levels were measured blindly from clinical outcomes in batches at the end of follow-up. Among the 135 patients included between April 2020 and May 2021, 46 (34.1%) had died at day 60. MR-proADM levels on days 1, 3, and 7 were significantly higher in day-60 non-survivors. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve (0.744, p < 0.001) of day-1 MR-proADM compared favorably with the AUC ROC curve of day-1 procalcitonin (0.691, p < 0.001). Serial MR-proADM measurements on days 3 and 7 may add prognostic information. After adjusting for CRP, LDH, and lymphocyte values, day-1 MR-proADM remained significantly associated with day-60 mortality. MR-proADM concentrations were significantly higher in patients with respiratory superinfections (on days 3 and 7) and bloodstream infections (on days 1, 3, and 7) than in patients without infection. Our results suggest that MR-proADM is a good predictor of outcome in severe SARS-CoV-2 infection and could be a useful tool to assess bacterial superinfection in COVID-19 patients.

Nitric oxide metabolites: associations with cardiovascular biomarkers and clinical parameters in patients with HFpEF.

Heart failure with preserved ejection fraction (HFpEF) is one of the most rapidly growing cardiovascular health burden worldwide, but there is still a lack of understanding about the HFpEF pathophysiology. The nitric oxide (NO) signalling pathway has been identified as a potential key element. The aim of our study was to investigate markers of NO metabolism [l-arginine (l-Arg), homoarginine (hArg), and asymmetric and symmetric dimethylarginine (ADMA and SDMA)], additional biomarkers [N-terminal pro-B-type natriuretic peptide (NT-proBNP), endothelin-1 (ET-1), mid-regional pro-adrenomedullin (MR-proADM), copeptin, and high-sensitivity C-reactive protein (hsCRP)], and the endothelial function in an integrated approach focusing on associations with clinical characteristics in patients with HFpEF. Seventy-three patients, prospectively enrolled in the 'German HFpEF Registry', were analysed. Inclusion criteria were left ventricular ejection fraction (LVEF)≥50%; New York Heart Association functional class≥II; elevated levels of NT-proBNP>125pg/mL; and at least one additional criterion for structural heart disease or diastolic dysfunction. All patients underwent transthoracic echocardiography, cardiopulmonary exercise testing, and pulse amplitude tonometry (EndoPAT™). Patients were categorized in two groups based on their retrospectively calculated HFA-PEFF score. Serum concentrations of l-Arg, hArg, ADMA, SDMA, NT-proBNP, ET-1, MR-proADM, copeptin, and hsCRP were determined. Patients had a median age of 74years, 47% were female, and median LVEF was 57%. Fifty-two patients (71%) had an HFA-PEFF score≥5 (definitive HFpEF), and 21 patients (29%) a score of 3 to 4 (risk for HFpEF). Overall biomarker concentrations were 126±32μmol/L for l-Arg, 1.67±0.55μmol/L for hArg, 0.74 (0.60;0.85) μmol/L for SDMA, and 0.61±0.10μmol/L for ADMA. The median reactive hyperaemia index (RHI) was 1.55 (1.38;1.87). SDMA correlated with NT-proBNP (r=0.291; P=0.013), ET-1 (r=0.233; P=0.047), and copeptin (r=0.381; P=0.001). ADMA correlated with ET-1 (r=0.250; P=0.033) and hsCRP (r=0.303; P=0.009). SDMA was associated with the left atrial volume index (β=0.332; P=0.004), also after adjustment for age, sex, and comorbidities. Biomarkers were non-associated with the RHI. A principal component analysis revealed two contrary clusters of biomarkers. Our findings suggest an impaired NO metabolism as one possible key pathogenic determinant in at least a subgroup of patients with HFpEF. We argue for further evaluation of NO-based therapies. Upcoming studies should clarify whether subgroups of HFpEF patients can take more benefit from therapies that are targeting NO metabolism and pathway.

The kinetic profiles of copeptin and mid regional proadrenomedullin (MR-proADM) in pediatric lower respiratory tract infections.

Kinetics of copeptin and mid regional proadrenomedullin (MR-proADM) during febrile pediatric lower respiratory tract infections (LRTI) are unknown. We aimed to analyze kinetic profiles of copeptin and MR-proADM and the impact of clinical and laboratory factors on those biomarkers. This is a retrospective post-hoc analysis of a randomized controlled trial, evaluating procalcitonin guidance for antibiotic treatment of LRTI (ProPAED-study). In 175 pediatric patients presenting to the emergency department plasma copeptin and MR-proADM concentrations were determined on day 1, 3, and 5. Their association with clinical characteristics and other inflammatory biomarkers were tested by non-linear mixed effect modelling. Median copeptin and MR-proADM values were elevated on day 1 and decreased during on day 3 and 5 (-26%; -34%, respectively). The initial concentrations of MR-proADM at inclusion were higher in patients receiving antibiotics intravenously compared to oral administration (difference 0.62 pmol/L, 95%CI 0.44;1.42, p<0.001). Intensive care unit (ICU) admission was associated with a daily increase of MR-proADM (increase/day 1.03 pmol/L, 95%CI 0.43;1.50, p<0.001). Positive blood culture in patients with antibiotic treatment and negative results on nasopharyngeal aspirates, or negative blood culture were associated with a decreasing MR-proADM (decrease/day -0.85 pmol/L, 95%CI -0.45;-1.44), p<0.001). Elevated MR-proADM and increases thereof were associated with ICU admission suggesting the potential as a prognostic factor for severe pediatric LRTI. MR-proADM might only bear limited value for decision making on stopping antibiotics due to its slow decrease. Copeptin had no added value in our setting.

The Role of Mid-Regional Proadrenomedullin in the Differential Diagnosis between Culture-Negative and Culture-Positive Sepsis at Emergency Department Admission.

Background: The host response in culture-negative sepsis (CnS) has been marginally explored upon emergency department (ED) admission. It would be of paramount importance to create a clinical prediction rule to support the emergency department physician in identifying septic patients who can be treated with antibiotics immediately without waiting time to draw cultures if they are unlikely to provide useful diagnostic information. Methods: A multivariable logistic regression analysis was applied to identify the independent clinical variables and serum biomarkers of the culture-negative status among 773 undifferentiated septic patients. Those predictors were combined to build a nomogram predictive of CnS. Results: The serum concentrations of six biomarkers, among the eight biomarkers assayed in this study, were significantly lower in the patients with CnS (449) than in those with culture-positive sepsis (324). After correction for co-variates, only mid-regional proadrenomedullin (MR-proADM) was found to be independently correlated with culture-negative status. Absence of diabetes, hemoglobin concentrations, and respiratory source of infection were the other independent clinical variables integrated into the nomogram—its sensitivity and specificity for CnS were 0.80 and 0.79, respectively. Conclusions: Low concentrations of MR-proADM were independently associated with culture-negative sepsis. Our nomogram, based on the MR-proADM levels, did not predict culture-negative status with reasonable certainty in patients with a definitive diagnosis of sepsis at ED admission.

Mid-regional proadrenomedullin (MR-proADM), C-reactive protein (CRP) and other biomarkers in the early identification of disease progression in patients with COVID-19 in the acute NHS setting

AimsThere is a lack of biomarkers validated for assessing clinical deterioration in patients with COVID-19 on presentation to secondary or tertiary care. This evaluation looked at the potential clinical application...

Activity of the adrenomedullin system to personalise post-discharge diuretic treatment in acute heart failure

BackgroundQuantifying the activity of the adrenomedullin system might help to monitor and guide treatment in acute heart failure (AHF) patients. The aims were to (1) identify AHF patients with marked benefit or harm from specific treatments at hospital discharge and (2) predict mortality by quantifying the adrenomedullin system activity.MethodsThis was a prospective multicentre study. AHF diagnosis and phenotype were centrally adjudicated by two independent cardiologists among patients presenting to the emergency department with acute dyspnoea. Adrenomedullin system activity was quantified using the biologically active component, bioactive adrenomedullin (bio-ADM), and a prohormone fragment, midregional proadrenomedullin (MR-proADM). Bio-ADM and MR-proADM concentrations were measured in a blinded fashion at presentation and at discharge. Interaction with specific treatments at discharge and the utility of these biomarkers on predicting outcomes during 365-day follow-up were assessed.ResultsAmong 1886 patients with adjudicated AHF, 514 patients (27.3%) died during 365-day follow-up. After adjusting for age, creatinine, and treatment at discharge, patients with bio-ADM plasma concentrations above the median (> 44.6 pg/mL) derived disproportional benefit if treated with diuretics (interaction p values < 0.001). These findings were confirmed when quantifying adrenomedullin system activity using MR-proADM (n = 764) (interaction p values < 0.001). Patients with bio-ADM plasma concentrations above the median were at increased risk of death (hazard ratio 1.87, 95% CI 1.57–2.24; p < 0.001). For predicting 365-day all-cause mortality, both biomarkers performed well, with MR-proADM presenting an even higher predictive accuracy compared to bio-ADM (p < 0.001).ConclusionsQuantifying the adrenomedullin’s system activity may help to personalise post-discharge diuretic treatment and enable accurate risk-prediction in AHF.

Inflammation and neurohormonal activation is increased at hospital admission in patients with ST-elevation myocardial infarction with diabetes compared to non-diabetic patients

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Rigshospitalets Forskningsfond. The Lundbeck Foundation. Background Patients with diabetes have an increased risk of coronary artery disease (CAD). In patients with myocardial infarction (MI), diabetes is associated with a poor outcome. Inflammation and neurohormonal activation have previously been shown to be associated with poor outcomes in patients with ST-elevation MI (STEMI). We therefore sought to assess whether STEMI-patients with diabetes (DM) had increased levels of inflammation and neurohormonal activation upon hospital admission. Methods In 1892 consecutive STEMI-patients from two danish tertiary heart centres, biomarkers reflecting neurohormonal activation (pro-atrial natriuretic peptide (proANP) and mid-regional pro-adrenomedullin (MRproADM)) and inflammation (soluble suppression of tumorigenicity 2 (sST2) and C-reactive peptide (CRP)) were measured upon admission before angiography. Patients were stratified according to DM or not. Results In total, 245 (13%) patients had DM. DM patients were older (mean (SD) 66 (11) vs 63 (13) years old, p = 0.0002), had more comorbidities (hypertension, previous stroke/TIA, ischemic heart disease (IHD), chronic kidney dysfunction (CKD)), and higher body mass index (BMI). In addition, DM patients had a longer time from symptom debut to angiography and more often multivessel disease (MVD). We found no difference in admission troponin plasma concentrations. Upon hospital admission, DM patients had higher concentrations of MRproADM (median (IQR) 0.88 (0.64-1.20) vs. 0.71 (0.58-0.90) nmol/L, p &amp;lt; 0.0001), sST2 (41 (64-31) vs. 39 (55-28) ng/ml, p = 0.01), and CRP (4.5 (1.9-12.1) vs. 3.4 (1.4-8.3) mg/L, p = 0.001) but not proANP (figure). When adjusted for age, BMI, CKD, IHD, time from symptom debut to angiography, and MVD, DM remained associated with increased MRproADM (OR (95% CI) 1.35 (1.05; 1.74), p = 0.02) and sST2 (1.20 (1.02; 1.41), p = 0.03), but no longer with CRP. Patients with DM had a higher one-year all-cause mortality rate (12% vs. 9.4%, p = 0.03). Conclusion STEMI patients with diabetes have increased neurohormonal activation and inflammation at hospital admission compared to patients without diabetes. This may play a role in the increased mortality in STEMI patients with diabetes. Abstract Figure.

Midregional Proadrenomedullin (MRproADM) Serum Levels in Critically Ill Patients Are Associated with Short-Term and Overall Mortality during a Two-Year Follow-Up.

Adrenomedullin (ADM) is a peptide with pleiotropic effects in systemic inflammation. Its more stable precursor protein midregional proadrenomedullin (MRproADM) can be measured more reliably compared to ADM. Our objective was to investigate the potential role of MRproADM as a diagnostic and prognostic biomarker in critically ill patients at the intensive care unit (ICU). We therefore measured MRproADM in 203 ICU patients and 66 healthy controls. We found that MRproADM levels are significantly increased in critically ill patients as compared to healthy controls. MRproADM levels are significantly increased in patients with sepsis, but its diagnostic value for identifying sepsis is numerically lower than that of established markers (e.g., interleukin-6, C-reactive protein, and procalcitonin). MRproADM levels are closely correlated to endothelial and organ dysfunction, inflammation, and established clinical scores (APACHE II, SOFA, and SAPS2). MRproADM concentrations correlate with vasopressor use but not fluid balance. Increased MRproADM levels (cut − off > 1.4 nmol/L) in critically ill patients are independent predictors of ICU and overall mortality during a follow-up of up to 26 months (OR 3.15 for ICU mortality, 95% CI 1.08-9.20, p = 0.036; OR for overall mortality 2.4, 95% CI 1.12-5.34, p = 0.026). Our study demonstrates the potential of MRproADM serum levels as a prognostic biomarker in critical illness for ICU mortality and long-term survival during follow-up.

Mortality in cardiogenic shock is stronger associated to clinical factors than contemporary biomarkers reflecting neurohormonal stress and inflammatory activation

Purpose To validate the IABP-SHOCK II risk score in a Danish cohort and assess the association between the IABP-SHOCK II risk score and admission concentration of biomarkers reflecting neurohormonal – (Copeptin, Pro-atrial natriuretic peptide (proANP), Mid-regional pro-adrenomedullin (MRproADM)) and inflammatory (ST2) activation in patients with CS complicating ST segment elevation myocardial infarction (STEMI). Methods A total of 137 consecutive patients admitted with STEMI and CS at two tertiary heart centres were stratified according to the IABP-SHOCK II risk score (0–2; 3/4; 5–9), and had blood sampled upon admission. Results Plasma concentrations of Copeptin (median (pmol/L) score 0–2: 313; score 3/4: 682; score 5–9: 632 p < 0.0001), proANP (pmol/L) (1459; 2225; 2876 p = 0.0009) and MRproADM (nmol/L) (0.86; 1.2; 1.4 p = 0.04) were significantly associated with the risk score, whereas ST2 (ng/mL) was not (44; 60; 45 p = 0.23). The IABP-SHOCK II risk score predicted 30-day mortality (score 0–2: 22%; score 4/3: 51%; score 5–9: 72%, area under the curve (AUC): 0.73, plogrank < 0.0001), while the tested biomarkers did not (AUC: 0.51<plogrank < 0.57). Conclusion Plasma concentrations of Copeptin, MRproADM and proANP were associated with the IABP-SHOCK II risk score in STEMI patients admitted with CS. The risk score predicted 30-day mortality, with no improvement in prediction when concentrations of the assessed biomarkers were added.

Midregional Proadrenomedullin Can Reflect the Accumulation of Visceral Adipose Tissue-A Key to Explaining the Obesity Paradox.

Background: The aim of this study was to investigate whether plasma midregional proadrenomedullin (MR-proADM) reflected body composition, such as body mass index (BMI), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), VAT/SAT ratio, body fat mass (BFM), and skeletal muscle mass (SMM). Methods: A total of 2244 individuals (727 men and 1517 women) were included in the study. Multiple regression analysis was performed to assess the combined influence of variables: age, daily alcohol consumption, Brinkman index, sleeping time, metabolic equivalents, anamnesis for hypertension, dyslipidemia, diabetes, and body composition of MR-proADM, by using a stepwise forward selection method. Results: MR-proADM was significantly related to all anthropometric indices (BMI, VAT, SAT, VAT/SAT ratio, BFM, and SMM) in men and women. On the basis of a stepwise forward selection method, VAT (men: beta = 0.184, p < 0.001, women: beta = 0.203, p < 0.001) and BFM (beta = 0.181, p < 0.001) in women, were found to be significantly associated with MR-proADM. Conclusion: This study suggests that plasma MR-proADM concentration is a more reliable indicator of VAT for fat distribution, and thus, MR-proADM may help better understand the obesity paradox. Changes in circulating levels of MR-proADM could possibly reflect changes in body composition, endocrine, and metabolic milieu.

Early Stages of Obesity-related Heart Failure Are Associated with Natriuretic Peptide Deficiency and an Overall Lack of Neurohormonal Activation: The Copenhagen Heart Failure Risk Study

Objective:This study evaluated the associations between the natriuretic peptide activity and the neurohormonal response in non-obese and obese outpatients with and without heart failure (HF).Background:Obesity-related HF may be a distinct subtype of HF. Obesity is associated with lower plasma concentrations of natriuretic peptides. The associations between obesity and neurohormonal activation estimated by mid-regional pro-adrenomedullin (MR-proADM) and copeptin in patients with HF is not elucidated.Methods:This prospective cohort-study included 392 outpatients ≥60years, plus ≥1 risk-factor(-s) for HF (hypertension, ischemic heart disease, atrial fibrillation, diabetes, chronic kidney disease), and without known HF. Patients were categorized ‘non-obese’ BMI = 18.5–29.9 kg/m2 (n = 273) and ‘obese’ BMI ≥ 30 kg/m2 (n = 119). The diagnosis of HF required signs, symptoms, and abnormal echocardiography. NT-proBNP, MR-proANP, MR-proADM, and copeptin were analyzed.Results:Obese patients were younger, had a higher prevalence of diabetes and chronic kidney disease, but a lower prevalence of atrial fibrillation. A total of 39 (14.3%) non-obese and 26 (21.8%) obese patients were diagnosed with HF. In obese patients, HF was not associated with higher plasma concentrations of NT-proBNP (Estimate: 0.063; 95%CI: –0.037–1.300; P = 0.064), MR-proANP (Estimate: 0.207; 95%CI: –0.101–0.515; P = 0.187), MR-proADM (Estimate: 0.112; 95%CI: –0.047–0.271; P = 0.168), or copeptin (Estimate: 0.093; 95%CI: –0.333–0.518; P = 0.669). Additionally, obese patients with HF had lower plasma concentrations of NT-proBNP (Estimate: –0.998; 95%CI: –1.778–0.218; P = 0.012), and MR-proANP (Estimate: –0.488; 95%CI: –0.845–0.132; P = 0.007) compared to non-obese patients with HF, whereas plasma concentrations of MR-proADM (Estimate: 0.066; 95%CI: –0.119–0.250; P = 0.484) and copeptin (Estimate: 0.140; 95%CI: –0.354–0.633; P = 0.578) were comparable.Conclusions:Patients with obesity-related HF have natriuretic peptide deficiency and lack of increased plasma concentrations of MR-proADM and copeptin suggesting that patients with obesity-related HF have a blunted overall neurohormonal activity.

Sensitive and selective quantification of mid-regional proadrenomedullin in human plasma using ultra-performance liquid chromatography coupled with tandem mass spectrometry

Mid-regional pro-adrenomedullin (MR-proADM) is suggested to be a prognostic indicator for various diseases. Plasma MR-proADM concentration is commonly measured using immunoassays based on its immunochemical characteristics. However, some immunological interactions affect the measured concentration. We developed and validated a sensitive and selective method for measuring plasma MR-proADM concentration using ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) and evaluated its clinical applicability. Plasma samples were prepared by protein precipitation and solid-phase extraction. Samples obtained from healthy volunteers (n = 38), patients with chronic kidney disease (CKD) stages 3 and 4–5 (non-dialysis; n = 20 and 17, respectively), and CKD stage 5D (dialysis; n = 34) were analyzed. Within-batch and batch-to-batch accuracy of the UPLC-MS/MS assay for quality control samples ranged from −0.69 % to 8.05 % and from 1.72 % to 5.76 %, respectively. The lower limit of quantification was 0.4 ng mL−1. The MR-proADM concentration determined using the UPLC-MS/MS assay correlated strongly with that determined using the immunoassay (Pearson’s product-moment correlation coefficient [r] = 0.7875, p < 0.001). Median (range) plasma MR-proADM concentrations of healthy volunteers, patients with CKD stages 3 and 4–5, and patients with CKD stage 5D were 0.67 (0.43–1.27), 1.89 (0.65–6.68), 3.86 (1.60–8.75) and 3.97 (0.66–9.20) ng mL−1, respectively, and a significant difference among four groups was confirmed. We established a sensitive and selective method for determining plasma MR-proADM concentration using UPLC-MS/MS. Our novel UPLC-MS/MS assay for determining plasma MR-proADM concentration can be used in the clinical setting and may have better selectivity than the immunoassay method.

Biomarkers and clinical scores to identify patient populations at risk of delayed antibiotic administration or intensive care admission

BackgroundThe performance of blood biomarkers (mid-regional proadrenomedullin (MR-proADM), procalcitonin (PCT), C-reactive protein (CRP), and lactate) and clinical scores (Sequential Organ Failure Assessment (SOFA), National Early Warning Score (NEWS), and quick SOFA) was compared to identify patient populations at risk of delayed treatment initiation and disease progression after presenting to the emergency department (ED) with a suspected infection.MethodsA prospective observational study across three EDs. Biomarker and clinical score values were calculated upon presentation and 72 h, and logistic and Cox regression used to assess the strength of association. Primary outcomes comprised of 28-day mortality prediction and delayed antibiotic administration or intensive care (ICU) admission, whilst secondary outcomes identified subsequent disease progression.ResultsSix hundred eighty-four patients were enrolled with hospitalisation, ICU admission, and infection-related 28-day mortality rates of 72.8%, 3.4%, and 4.4%, respectively. MR-proADM and NEWS had the strongest association with hospitalisation and the requirement for antibiotic administration, whereas MR-proADM alone had the strongest association with ICU admission (OR [95% CI]: 5.8 [3.1 - 10.8]) and mortality (HR [95% CI]: 3.8 [2.2 - 6.5]). Patient subgroups with high MR-proADM concentrations (≥ 1.77 nmol/L) and low NEWS (< 5 points) values had significantly higher rates of ICU admission (8.1% vs 1.6%; p < 0.001), hospital readmission (18.9% vs. 5.9%; p < 0.001), infection-related mortality (13.5% vs. 0.2%; p < 0.001), and disease progression (29.7% vs. 4.9%; p < 0.001) than corresponding patients with low MR-proADM concentrations. ICU admission was delayed by 1.5 [0.25 – 5.0] days in patients with high MR-proADM and low NEWS values compared to corresponding patients with high NEWS values, despite similar 28-day mortality rates (13.5% vs. 16.5%). Antibiotics were withheld in 17.4% of patients with high MR-proADM and low NEWS values, with higher subsequent rates of ICU admission (27.3% vs. 4.8%) and infection-related hospital readmission (54.5% vs. 14.3%) compared to those administered antibiotics during ED treatment.ConclusionsPatients with low severity signs of infection but high MR-proADM concentrations had an increased likelihood of subsequent disease progression, delayed antibiotic administration or ICU admission. Appropriate triage decisions and the rapid use of antibiotics in patients with high MR-proADM concentrations may constitute initial steps in escalating or intensifying early treatment strategies.

Procalcitonin, mid-regional proadrenomedullin and C-reactive protein in predicting treatment outcome in community-acquired febrile urinary tract infection

BackgroundA reduction in duration of antibiotic therapy is crucial in minimizing the development of antimicrobial resistance, drug-related side effects and health care costs. The minimal effective duration of antimicrobial therapy for febrile urinary tract infections (fUTI) remains a topic of uncertainty, especially in male patients, those of older age or with comorbidities. Biomarkers have the potential to objectively identify the optimal moment for cessation of therapy.MethodsA secondary analysis of a randomized placebo-controlled trial among 35 primary care centers and 7 emergency departments of regional hospitals in the Netherlands. Women and men aged ≥18 years with a diagnosis of fUTI were randomly assigned to receive antibiotic treatment for 7 or 14 days. Patients indicated to receive antimicrobial treatment for more than 14 days were excluded from randomization. The biomarkers procalcitonin (PCT), mid-regional proadrenomedullin (MR-proADM), and C-reactive protein (CRP) were compared in their ability to predict clinical cure or failure through the 10–18 day post-treatment visit.ResultsBiomarker concentrations were measured in 249 patients, with a clinical cure rate of 94% in the 165 randomized and 88% in the 84 non-randomized patients. PCT, MR-proADM and CRP concentrations did not differ between patients with clinical cure and treatment failure, and did not predict treatment outcome, irrespective of 7 or 14 day treatment duration (ROCAUC 0.521; 0.515; 0.512, respectively). PCT concentrations at presentation were positively correlated with bacteraemia (τ = 0.33, p < 0.001) and presence of shaking chills (τ = 0.25, p < 0.001), and MR-proADM levels with length of hospital stay (τ = 0.40, p < 0.001), bacteraemia (τ = 0.33, p < 0.001), initial intravenous treatment (τ = 0.22, p < 0.001) and time to defervescence (τ = 0.21, p < 0.001). CRP did not display any correlation to relevant clinical parameters.ConclusionsAlthough the biomarkers PCT and MR-proADM were correlated to clinical parameters indicating disease severity, they did not predict treatment outcome in patients with community acquired febrile urinary tract infection who were treated for either 7 or 14 days. CRP had no added value in the management of patients with fUTI.Trial registrationThe study was registered at ClinicalTrials.gov [NCT00809913; December 16, 2008] and trialregister.nl [NTR1583; December 19, 2008].

Elevated levels of adrenomedullin in eutopic endometrium and plasma from women with endometriosis

To test adrenomedullin (Adm, ADM) as a downstream target of signal transducer and activator of transcription 3 (STAT3) in endometrial cells and to test midregional proadrenomedullin (MR-proADM) as a biomarker of endometriosis. Cross-sectional analysis of Adm expression in eutopic endometrium and of MR-proADM in plasma from women with and without endometriosis; and prospective study of MR-proADM levels in women with endometriosis undergoing surgical resection of ectopic lesions. Academic medical centers. Fifteen patients with endometriosis and 11 healthy control subjects who donated eutopic endometrial biopsies; and 28 patients with endometriosis and 19 healthy control subjects who donated plasma for MR-proADM analysis. None. Adm mRNA levels according to quantitative real-time polymerase chain reaction after activation of STAT3 by interleukin-6 (IL-6) in Ishikawa cells; immunohistochemistry for ADM in eutopic endometrial biopsies from women with endometriosis compared with healthy donors; and MR-proADM levels measured by commercial immunoassay in plasma from healthy women and women with endometriosis who subsequently underwent surgical resection of ectopic lesions. Activation of STAT3 by IL-6 up-regulated Adm mRNA expression in Ishikawa cells. ADM protein levels were elevated in the eutopic endometrium of women with endometriosis. MR-proADM concentrations were higher in women with endometriosis but were not correlated with disease stage, corrected by surgery, or predictive of fertility outcome. MR-proADM may be able to serve as a biomarker of endometriosis, but it is unknown whether elevated MR-proADM levels are secondary to the estrogenic and inflammatory properties of endometriosis or an inciting pathogenic factor.

Biomarker guided triage can reduce hospitalization rate in community acquired febrile urinary tract infection

Febrile urinary tract infections (fUTI) can often be treated safely with oral antimicrobials in an outpatient setting. However, a minority of patients develop complications that may progress into septic shock. An accurate assessment of disease severity upon emergency department (ED) presentation is therefore crucial in order to guide the most appropriate triage and treatment decisions. Consecutive patients were enrolled with presumptive fUTI across 7 EDs in the Netherlands. The biomarkers mid-regional proadrenomedullin (MR-proADM), procalcitonin (PCT), C-reactive protein (CRP), and a clinical score (PRACTICE), were compared in their ability to predict a clinically severe course of fUTI, initial hospital admission and subsequent readmission using area under the receiver operating characteristic (AUROC) curves. Biomarker concentrations were measured in 313 patients, with 259 (83%) hospitalized upon ED presentation, and 54 (17%) treated as outpatients. Of these outpatients, 12 (22%) were later hospitalized. MR-proADM had the highest diagnostic accuracy for predicting a complicated fUTI (AUROC [95% CI]: 0.86 [0.79-0.92]), followed by PCT (AUROC [95% CI]: 0.69 [0.58-0.80]). MR-proADM concentrations were unique in being significantly elevated in patients directly admitted and in outpatients requiring subsequent hospitalization, compared to those completing treatment at home. A virtual triage algorithm with an MR-proADM cut-off of 0.80nmol/L resulted in a hospitalization rate of 66%, with only 2% secondary admissions. MR-proADM could accurately predict a severe course in patients with fUTI, and identify greater patient numbers who could be safely managed as outpatients. An initial assessment on ED presentation may focus resources to patients with highest disease severities.

The use of mid-regional proadrenomedullin to identify disease severity and treatment response to sepsis - a secondary analysis of a large randomised controlled trial

BackgroundThis study assessed the ability of mid-regional proadrenomedullin (MR-proADM) in comparison to conventional biomarkers (procalcitonin (PCT), lactate, C-reactive protein) and clinical scores to identify disease severity in patients with sepsis.MethodsThis is a secondary analysis of a randomised controlled trial in patients with severe sepsis or septic shock across 33 German intensive care units. The association between biomarkers and clinical scores with mortality was assessed by Cox regression analysis, area under the receiver operating characteristic and Kaplan-Meier curves. Patients were stratified into three severity groups (low, intermediate, high) for all biomarkers and scores based on cutoffs with either a 90% sensitivity or specificity.Results1089 patients with a 28-day mortality rate of 26.9% were analysed. According to the Sepsis-3 definition, 41.2% and 58.8% fulfilled the criteria for sepsis and septic shock, with respective mortality rates of 20.0% and 32.1%. MR-proADM had the strongest association with mortality across all Sepsis-1 and Sepsis-3 subgroups and could facilitate a more accurate classification of low (e.g. MR-proADM vs. SOFA: N = 265 vs. 232; 9.8% vs. 13.8% mortality) and high (e.g. MR-proADM vs. SOFA: N = 161 vs. 155; 55.9% vs. 41.3% mortality) disease severity. Patients with decreasing PCT concentrations of either ≥ 20% (baseline to day 1) or ≥ 50% (baseline to day 4) but continuously high MR-proADM concentrations had a significantly increased mortality risk (HR (95% CI): 19.1 (8.0–45.9) and 43.1 (10.1–184.0)).ConclusionsMR-proADM identifies disease severity and treatment response more accurately than established biomarkers and scores, adding additional information to facilitate rapid clinical decision-making and improve personalised sepsis treatment.