Bioactive adrenomedullin (bio-ADM) is associated with endothelial dysfunction in infants and children with complex congenital heart disease undergoing open-heart surgery on cardiopulmonary bypass.

OBJECTIVES: Children with congenital heart disease (CHD) undergoing cardiac surgery on cardiopulmonary bypass (CPB) are at risk for systemic inflammation leading to endothelial dysfunction associated with increased morbidity. Bioactive adrenomedullin (bio-ADM) is a peptide regulating vascular tone and endothelial permeability. The aim of this study was to evaluate the dynamics of plasma bio-ADM in this patient cohort and its role in capillary leak. METHODS: Plasma samples from 73 pediatric CHD patients were collected for bio-ADM measurement at five different timepoints (TP) in the pre-, intra-, and post-operative period. The primary endpoint was a net increase in bio-ADM levels after surgery on CPB. Secondary endpoints included association of bio-ADM levels with clinical signs for endothelial dysfunction. RESULTS: Bio-ADM levels increased after surgery on CPB from pre-operative median of 12 pg/mL (IQR [interquartile range] 12.0-14.8 pg/mL) to a maximum post-operative median of 48.8 pg/mL (IQR 34.5-69.6 pg/mL, p<0.001). Bio-ADM concentrations correlated positively with post-operative volume balance, (r=0.341; p=0.005), increased demand for vasoactive medication (duration: r=0.415; p<0.001; quantity: TP3: r=0.415, p<0.001; TP4: r=0.414, p<0.001), and hydrocortisone treatment for vasoplegia (bio-ADM median [IQR]:129.1 [55.4-139.2] pg/mL vs. 37.9 [25.2-64.6] pg/mL; p=0.034). Patients who required pleural effusion drainage revealed higher bio-ADM levels compared to those who did not (median [IQR]: 66.4 [55.4-90.9] pg/mL vs. 40.2 [28.2-57.0] pg/mL; p<0.001). CONCLUSIONS: Bio-ADM is elevated in children after cardiac surgery and higher levels correlate with clinical signs of capillary leakage. The peptide should be considered as biomarker for endothelial dysfunction and as potential therapeutic target in this indication.

Plasma proenkephalin A and incident chronic kidney disease and albuminuria in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort.

BACKGROUND: Plasma proenkephalin A (PENK-A) is a precursor of active enkephalins. Higher blood concentrations have been associated with estimated glomerular filtration rate (eGFR) decline in European populations. Due to the significant disparity in incident chronic kidney disease (CKD) between White and Black people, we evaluated the association of PENK-A with incident CKD and other kidney outcomes among a biracial cohort in the U.S. METHODS: In a nested cohort of 4,400 participants among the REasons for Geographic And Racial Differences in Stroke, we determined the association between baseline PENK-A concentration and incident CKD using the creatinine-cystatin C CKD-EPI 2021 equation without race coefficient, significant eGFR decline, and incident albuminuria between baseline and a follow-up visit 9.4 years later. We tested for race and sex interactions. We used inverse probability sampling weights to account for the sampling design. RESULTS: At baseline, mean (SD) age was 64 (8) years, 49% were women, and 52% were Black participants. 8.5% developed CKD, 21% experienced ≥ 30% decline in eGFR and 18% developed albuminuria. There was no association between PENK-A and incident CKD and no difference by race or sex. However, higher PENK-A was associated with increased odds of progressive eGFR decline (OR: 1.12; 95% CI 1.00, 1.25). Higher PENK-A concentration was strongly associated with incident albuminuria among patients without diabetes mellitus (OR: 1.29; 95% CI 1.09, 1.53). CONCLUSION: While PENK-A was not associated with incident CKD, its associations with progression of CKD and incident albuminuria, among patients without diabetes, suggest that it might be a useful tool in the evaluation of kidney disease among White and Black patients.

Proenkephalin A as a marker for glomerular filtration rate in critically ill children: validation against gold standard iohexol GFR measurements.

OBJECTIVES: Accurate determination of glomerular filtration rate (GFR) is important. Several endogenous biomarkers exist for estimating GFR, yet, they have limited accuracy, especially in the paediatric population. Proenkephalin A 119-159 (PENK) is a novel and promising GFR marker, but its relation with age in children remains unknown. Also, the value of PENK has never been validated against measured GFR (mGFR) in children when compared to traditional GFR markers including serum creatinine (SCr), SCr-based estimated GFR (eGFR) and cystatin C (cysC). METHODS: Critically ill children and term-born neonates were included in this single-centre, prospective study. Iohexol-based mGFR, SCr, and cysC were determined in each patient. eGFR was calculated using the bedside Schwartz equation, incorporating SCr and height. Spearman correlation coefficients were calculated to determine the correlation between mGFR and PENK, SCr, cysC and eGFR. RESULTS: For 97 patients (56 children and 41 neonates), mGFR, SCr, cysC and PENK levels were available. PENK levels were higher in young children and decreased to adult PENK reference values around two years of age. PENK levels were highly correlated with mGFR (ρ=-0.88, p<0.001), and similar to mGFR-eGFR correlation (ρ=-0.87, p<0.001). For cysC and SCr the correlation with mGFR was lower (ρ=-0.77 and ρ=-0.46, respectively. Both p<0.001). CONCLUSIONS: The correlation of PENK with mGFR was as good as SCr-based eGFR-mGFR correlation. To determine the added value of PENK in paediatric clinical care and prior to implementation, PENK reference values are needed and the development and validation of a paediatric PENK-based eGFR equation is necessary.

Plasma Pro-Enkephalin A and Ischemic Stroke Risk: The Reasons for Geographic and Racial Differences in Stroke Cohort.

OBJECTIVES: The opioid neuropeptide pro-enkephalin A (PENK-A) may be a circulating marker of cardiovascular risk, with prior findings relevant to heart failure, kidney disease, and vascular dementia. Despite these findings, the association of PENK-A with ischemic stroke is unknown, so we examined this association in a prospective cohort study and analyzed differences by race and sex. MATERIALS AND METHODS: The REasons for Geographic and Racial Differences in Stroke study (REGARDS) is a prospective cohort study of 30,239 Black and White adults. Plasma PENK-A was measured in 473 participants that developed first-time ischemic stroke over 5.9 years and 899 randomly selected participants. Cox models adjusted for demographics and stroke risk factors were used to calculate hazard ratios (HRs) of stroke by baseline PENK-A. RESULTS: PENK-A was higher with increasing age, female sex, White race, lower body mass index, and antihypertensive medication use. Each SD higher increment of PENK-A was associated with an adjusted HR of 1.20 (95% CI 1.01-1.42) for stroke, with minimal confounding by stroke risk factors. Spline plots suggested a U-shaped relationship, particularly in White men, with an adjusted HR 3.88 (95% CI 1.94-7.77) for the 95th versus 50th percentile of PENK-A in White men. CONCLUSIONS: Higher baseline plasma PENK-A was independently associated with future stroke risk in REGARDS. This association was most apparent among White men. There was little confounding by established stroke risk factors, suggesting a possible causal role in stroke etiology. Further research is needed to understand the role of endogenous opioids in stroke pathogenesis.

Precursor fractions of neurotensin and enkephalin might point to molecular mechanisms of cancer risk modulation during a lifestyle-intervention in germline BRCA1/2 gene mutation carriers.

BACKGROUND: Germline BRCA1/2 mutation carriers (gBMC) face increased cancer risks that are modulated via non-genetic lifestyle factors whose underlying molecular mechanisms are unknown. The peptides Neurotensin (NT) and Enkephalin (ENK)-involved in tumorigenesis and obesity-related diseases-are of interest. We wanted to know whether these biomarkers differ between gBMC and women from the general population and what effect a 1-year lifestyle-intervention has in gBMC. METHODS: The stable precursor fragments pro-NT and pro-ENK were measured at study entry (SE), after 3 and 12 months for 68 women from LIBRE-1 (a controlled lifestyle-intervention feasibility trial for gBMC involving structured endurance training and the Mediterranean Diet). The SE values were compared with a cohort of the general population including female subjects with and without previous cancer disease, non-suggestive for hereditary breast and ovarian cancer (OMA-reference). For LIBRE-1, we analysed the association between the intervention-related change in the two biomarkers and certain lifestyle factors. RESULTS: At SE, gBMC had a higher median pro-NT than OMA-reference (in the subgroups with previous cancer 117 vs. 91 pmol/L, p = 0.002). Non-diseased gBMC had lower median pro-ENK levels when compared to the non-diseased reference group. VO2peak and pro-NT 1-year change in LIBRE-1 were inversely correlated (r = - 0.435; CI - 0.653 to - 0.151; p = 0.004). Pro-ENK correlated positively with VO2peak at SE (r = 0.323; CI 0.061-0.544; p = 0.017). Regression analyses showed an inverse association of 1-year changes for pro-NT and Omega-6/Omega-3 (Estimate: - 37.9, p = 0.097/0.080) in multivariate analysis. CONCLUSION: Our results give first indications for lifestyle-related modification particularly of pro-NT in gBMC.

Circulating pro-neurotensin levels predict bodyweight gain and metabolic alterations in children.

BACKGROUND AND AIMS: Neurotensin (NT) is an intestinal peptide released after fat ingestion, which regulates appetite and facilitates lipid absorption. Elevated plasma levels of its stable precursor pro-neurotensin (pro-NT) are associated with type 2 diabetes, obesity and cardiovascular mortality in adult populations; no data on pro-NT and metabolic disease are available in children. Aim of the study was to evaluate plasma pro-NT in relation to the presence of obesity in children, and to test if high pro-NT associates with the development of metabolic impairment later in life. METHODS AND RESULTS: For this longitudinal retrospective study, we studied 151 overweight/obese children undergoing metabolic evaluations at University of Cagliari, Italy. Pro-NT was also assessed in 46 normal-weight, age-, sex-comparable normal-weight children, selected as a reference group. At the baseline, pro-NT was comparable between overweight/obese and normal-weight children and correlated positively with age (p < 0.001), triglycerides (p < 0.001) and inversely with HDL levels (p = 0.008). Plasma pro-NT associated with high triglycerides with OR = 5.9 (95%CI: 1.24-28.1; p = 0.026) after adjustment for multiple confounders. At the 6.5-year follow-up, high basal pro-NT associated with impaired ß-cell function to compensate for insulin-resistance (disposition index: r = -0.19, p = 0.035) and predicted bodyweight increase, as indicated by percentage change of standard deviation score BMI (median(95%CI) = +20.8(+4.9-+27.5)% in the highest tertile), independently from age, sex, triglycerides and insulin-resistance (standardized ß = 0.24; p = 0.036). CONCLUSIONS: Elevated pro-NT levels in children are significantly associated with weight gain later in life and may represent a marker of susceptibility to metabolic impairment in presence of obesity.

Proenkephalin as a new biomarker for pediatric acute kidney injury - reference values and performance in children under one year of age.

Objectives Acute kidney injury (AKI) is common in critically ill children, but current biomarkers are suboptimal. Proenkephalin A 119-159 (PENK) is a promising new biomarker for AKI in adults, but pediatric data is lacking. We determined PENK reference intervals for healthy children, crucial for clinical implementation, and explored concentrations in critically ill infants aged under 1 year. Methods Observational cohort study in healthy infants and critically ill children aged 0-1 years. Reference values were determined using generalized additive models. Plasma PENK concentrations between healthy children and critically ill children with and without AKI, were compared using linear mixed modelling. The performance of PENK as AKI biomarker was compared to cystatin C (CysC) and ß-trace protein (BTP) using receiver-operating-characteristic (ROC) analysis. Results PENK concentrations in 100 healthy infants were stable during the first year of life (median 517.3 pmol/L). Median PENK concentrations in 91 critically ill children, were significantly higher in those with AKI (n=40) (KDIGO Stage 1 507.9 pmol/L, Stage 2 704.0 pmol/L, Stage 3 930.5 pmol/L) than non-AKI patients (n=51, 432.2 pmol/L) (p < 0.001). PENK appeared to relate better to AKI diagnosis than CysC and BTP (AUROC PENK 0.858, CysC 0.770 and BTP 0.711) in the first 24 h after recruitment. Conclusions PENK reference values are much higher in young infants than adults, but clearly discriminate between children with and without AKI, with comparable or better performance than CysC and BTP. Our results illustrate the importance of establishing age-normalized reference values and indicate PENK as a promising pediatric AKI biomarker.

Circulating bioactive adrenomedullin as a marker of sepsis, septic shock and critical illness.

BACKGROUND: Biomarkers can be of help to understand critical illness and to identify and stratify sepsis. Adrenomedullin is a vasoactive hormone, with reported prognostic and potentially therapeutic value in sepsis. The primary aim of this study was to investigate the association of circulating bioactive adrenomedullin (bio-ADM) levels at intensive care unit (ICU) admission with mortality in sepsis patients and in a general ICU population. Secondary aims included the association of bio-ADM with organ failure and the ability of bio-ADM to identify sepsis. METHODS: In this retrospective observational study, adult patients admitted to one of four ICUs during 2016 had admission bio-ADM levels analysed. Age-adjusted odds ratios (OR) with 95% CI for log-2 transformed bio-ADM, and Youden's index derived cut-offs were calculated. The primary outcome was 30-day mortality, and secondary outcomes included the need for organ support and the ability to identify sepsis. RESULTS: Bio-ADM in 1867 consecutive patients were analysed; 632 patients fulfilled the sepsis-3 criteria of whom 267 had septic shock. The median bio-ADM in the entire ICU population was 40 pg/mL, 74 pg/mL in sepsis patients, 107 pg/mL in septic shock and 29 pg/mL in non-septic patients. The association of elevated bio-ADM and mortality in sepsis patients and the ICU population resulted in ORs of 1.23 (95% CI 1.07-1.41) and 1.22 (95% CI 1.12-1.32), respectively. The association with mortality remained after additional adjustment for lactate in sepsis patients. Elevated bio-ADM was associated with an increased need for dialysis with ORs of 2.28 (95% CI 2.01-2.59) and 1.97 (95% CI 1.64-2.36) for the ICU population and sepsis patients, respectively, and with increased need of vasopressors, OR 1.33 (95% CI 1.23-1.42) (95% CI 1.17-1.50) for both populations. Sepsis was identified with an OR of 1.78 (95% CI 1.64-1.94) for bio-ADM, after additional adjustment for severity of disease. A bio-ADM cut-off of 70 pg/mL differentiated between survivors and non-survivors in sepsis, but a Youden's index derived threshold of 108 pg/mL performed better. CONCLUSIONS: Admission bio-ADM is associated with 30-day mortality and organ failure in sepsis patients as well as in a general ICU population. Bio-ADM may be a morbidity-independent sepsis biomarker.

Postoperatively increased bioactive adrenomedullin is related to adverse outcome after complex aortic surgery.

Background: Open and endovascular thoracoabdominal aortic aneurysm repair is related to major complications and increased mortality rates. Up to now, specific biomarkers for adverse outcome are scarce, although routine usage of such biomarkers could enable an earlier and more appropriate treatment of complications during the postoperative course after complex aortic aneurysm repair. Patients and methods: In a prospective single-center study including 33 patients (48.5 % women, mean age 63.0 ± 16.2 years) undergoing elective complex open and endovascular aortic aneurysm repair, bioactive adrenomedullin (bio-ADM) was measured for 72 h perioperatively and an association with clinical endpoints, namely cardiogenic shock, death and the combined endpoint of the two aforementioned parameters was assessed. Furthermore, the association between bio-ADM and baseline characteristics and perioperative details including sepsis biomarkers score were assessed. Results: 51.5 % (n = 17) of patients developed postoperative acute kidney injury, 21.2 % (n = 7) pneumonia and 18.2 % (n = 6) sepsis. Cardiogenic shock was observed in 12.1 % (n = 4) patients. The in-hospital mortality rate was 18.2 % (n = 6), and 24.2 % (n = 8) of patients developed cardiogenic shock and/or died in hospital. A significant correlation of bio-ADM concentrations from all available time points was observed with leukocytes (r = 0.37, P < 0.0001), C-reactive protein (r = 0.56, P < 0.001) and serum creatinine levels (r = 0.52, P < 0.001). Increased bio-ADM at 12 h, 24 h, 48 h and 72 h after admission to ICU was associated with both, in-hospital death and cardiogenic shock, with an area under the curve for the combined endpoint of 0.598, 0.720, 0.880 and 0.967. Bio-ADM concentrations at 48 h and 72 h after admission to ICU were predictive for in-hospital death and cardiogenic shock (both P < 0.01). Conclusions: Bio-ADM may serve as postoperative biomarker for cardiogenic shock and death after complex open and endovascular aortic aneurysm repair, potentially enabling an earlier and by that more adequate treatment of adverse outcome after major surgery.

Organ-Specific Oxidative Events under Restrictive Versus Full Reperfusion Following Hemorrhagic Traumatic Shock in Rats.

Background aim: Reperfusion after hemorrhagic traumatic shock (HTS) is often associated with complications that are partly ascribed to the formation of reactive oxygen species (ROS). The aim of our study was to compare the effects of restrictive reperfusion (RR) to rapid full reperfusion (FR) on ROS formation and/or oxidative events. MATERIALS AND METHODS: Anesthetized male rats were randomly subjected to HTS followed by FR (75 mL/kg/h) or RR (30 mL/kg/h for 40 min, followed by 75 mL/kg/h) with Ringer's solution (n = 8/group). Compartment-specific ROS formation was determined by infusion of ROS scavenger 1-hydroxy-3-carboxy-2,2,5,5-tetramethyl-pyrrolidine hydrochloride (CP-H) during resuscitation, followed by electron paramagnetic resonance spectroscopy. Sham-operated animals (n = 8) served as controls. The experiment was terminated 100 min post-shock. RESULTS: Mean arterial pressure was significantly higher in the FR compared to the RR group during early reperfusion. Only RR animals, not FR animals, showed significantly higher ROS concentrations in erythrocytes (1951 ± 420 vs. 724 ± 75 AU) and in liver (474 ± 57 vs. 261 ± 21 AU) compared to sham controls. This was accompanied by elevated alanine aminotransferase and creatinine levels in RR animals compared to both shams and FR animals, while lipid peroxidation products (thiobarbituric acid reactive substances) were significantly increased only in the kidney in the FR group (p < 0.05). RR animals showed significantly higher plasma peroxiredoxin-4 values when compared to the FR group (20 ± 2 vs. 14 ± 0.5 RLU). CONCLUSION: Restrictive reperfusion after HTS is associated with increased ROS formation in erythrocytes and liver compared to sham controls. Moreover, the restrictive reperfusion is associated with a more pronounced injury to the liver and kidney, which is likely mediated by other than lipid peroxidation process and/or oxidative stress reactions.

Circulating peroxiredoxin 4 and type 2 diabetes risk: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study.

AIMS/HYPOTHESIS: Oxidative stress plays a key role in the development of type 2 diabetes mellitus. We previously showed that the circulating antioxidant peroxiredoxin 4 (Prx4) is associated with cardiometabolic risk factors. We aimed to evaluate the association of Prx4 with type 2 diabetes risk in the general population. METHODS: We analysed data on 7,972 individuals from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study (49% men, aged 28-75 years) with no diabetes at baseline. Logistic regression models adjusted for age, sex, smoking, waist circumference, hypertension and family history of diabetes were used to estimate the ORs for type 2 diabetes. RESULTS: During a median follow up of 7.7 years, 496 individuals (288 men; 58%) developed type 2 diabetes. The median (Q1-Q3) Prx4 level was 0.84 (0.53-1.40) U/l in individuals who developed type 2 diabetes and 0.68 (0.43-1.08) U/l in individuals who did not develop type 2 diabetes. For every doubling of Prx4 levels, the adjusted OR (95% CI) for type 2 diabetes was 1.16 (1.05-1.29) in the whole population; by sex, it was 1.31 (1.14-1.50) for men and 1.03 (0.87-1.21) for women. Further adjustment for other clinical measures did not materially change the results. The addition of Prx4 to a validated diabetes risk score significantly improved the prediction of type 2 diabetes in men (p = 0.002 for reclassification improvement). CONCLUSIONS/INTERPRETATION: Our findings suggest that elevated serum Prx4 levels are associated with a higher risk of incident type 2 diabetes. For men, taking Prx4 into consideration can improve type 2 diabetes prediction over a validated diabetes risk score; in contrast, there is no improvement in risk prediction for women.

Plasma Pro-Enkephalin A and Incident Cognitive Impairment: The Reasons for Geographic and Racial Differences in Stroke Cohort.

Background Cardiovascular disease is a risk factor for cognitive impairment. Evidence links both lower and higher concentration of the circulating opioid pro-enkephalin A (PENK-A) with stroke risk. We studied the association of plasma PENK-A with incident cognitive impairment. Methods and Results REGARDS (Reasons for Geographic and Racial Differences in Stroke) is a prospective cohort study of 30 239 adults enrolled from 2003 to 2007. Baseline PENK-A was measured in a nested case-control study of 462 participants who developed cognitive impairment over 4.7 years, and 556 controls. Logistic regression and spline plots adjusted for confounders estimated odds ratios (ORs) of cognitive impairment by baseline PENK-A. Interaction terms tested for differences in associations by age, sex, and race. Baseline PENK-A was comparable between cases and controls. There were significant differences in the association of PENK-A with cognitive impairment by sex and age (adjusted P=0.003 and 0.06, respectively). In women but not men, spline plots showed that higher and lower PENK-A were associated with decreased odds of cognitive impairment (ORs for 10th and 90th percentiles versus median, 0.65 [95% CI, 0.43-0.96] and 0.64 [95% CI, 0.41-0.99]), with no difference by age. In men ≥65 years of age but not younger men, higher PENK-A was associated with decreased odds for cognitive impairment (OR for fourth versus first quartile 0.47 [95% CI, 0.22-0.99]); this pattern was not confirmed with spline plotting. Conclusions High and low levels of circulating opioid PENK-A were associated with decreased odds of future cognitive impairment in specific subgroups. Additional research is warranted to understand the biology underlying this association and the observed differences by sex.

Peptidylglycine α-amidating monooxygenase and adrenomedullin measurement in patients with hepatic cirrhosis.

Background: Peptidylglycine α-amidating monooxygenase (PAM) is an enzyme involved in the maturation of regulatory peptides. Here we examined PAM activity and adrenomedullin (bio-ADM) concentrations in patients with hepatic cirrhosis and determined net changes across the liver, kidneys and leg. Materials & methods: A total of 48 patients with hepatic cirrhosis and 16 control subjects were included. All patients and controls underwent an invasive procedure with blood collected across organs. Results: PAM activity was increased in cirrhotic patients but without a net change across the liver, leg or kidney. In contrast, bio-ADM concentrations were associated with severity of disease and found to be higher in venous blood from the liver. Conclusion: Increased PAM activity in patients with hepatic cirrhosis may reflect other organs involved in cirrhotic disease.

Severe liver disease is a life-threatening condition that affects people all over the world. To improve doctors' ability to diagnose the disease and to follow the disease as it progresses, there is a need for new tools. Biomarkers are often used as such tools for measuring the presence and severity of a disease. In this study, we examined two potential biomarkers in blood from patients with severe liver disease: peptidylglycine α-amidating monooxygenase (PAM) activity and bioactive adrenomedullin (bio-ADM). We examined whether these biomarkers are present in blood and in amounts associated with disease severity. We also tested if the diseased liver releases the biomarkers. We found that bio-ADM is increased in blood from patients with severe liver disease and that the liver itself releases bio-ADM to the bloodstream. For PAM activity, we also detected increased activity in blood associated with disease severity. In contrast, however, this biomarker was not shown to be released by the liver. Taken together, the two biomarkers may help to improve severe liver disease diagnosis and maybe allow for biochemical follow-up as the disease progresses.

Assessing GFR With Proenkephalin.

Introduction: In clinical practice, kidney (dys)function is monitored through creatinine-based estimations of glomerular filtration rate (eGFR: Modification of Diet in Renal Disease [MDRD], Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]). Creatinine is recognized as a late and insensitive biomarker of glomerular filtration rate (GFR). The novel biomarker proenkephalin (PENK) may overcome these limitations, but no PENK-based equation for eGFR is currently available. Therefore, we developed and validated a PENK-based equation to assess GFR. Methods: In this international multicenter study in 1354 stable and critically ill patients, GFR was measured (mGFR) through iohexol or iothalamate clearance. A generalized linear model with sigmoidal nonlinear transfer function was used for equation development in the block-randomized development set. Covariates were selected in a data-driven fashion. The novel equation was assessed for bias, precision (mean ± SD), and accuracy (eGFR percentage within ±30% of mGFR, P30) in the validation set and compared with MDRD and CKD-EPI. Results: Median mGFR was 61 [44-81] ml/min per 1.73 m2. In order of importance, PENK, creatinine, and age were included, and sex or race did not improve performance. The PENK-based equation mean ± SD bias of the mGFR was 0.5 ± 15 ml/min per 1.73 m2, significantly less compared with MDRD (8 ± 17, P < 0.001) and 2009 CKD-EPI (5 ± 17, P < 0.001), not reaching statistical significance compared with 2021 CKD-EPI (1.3 ± 16, P = 0.06). The P30 accuracy of the PENK-based equation was 83%, significantly higher compared with MDRD (68%, P < 0.001) and 2009 CKD-EPI (76%, P < 0.001), similar to 2021 CKD-EPI (80%, P = 0.13). Conclusion: Overall, the PENK-based equation to assess eGFR performed better than most creatinine-based equations without using sex or race.

Bioactive adrenomedullin in sepsis patients in the emergency department is associated with mortality, organ failure and admission to intensive care.

BACKGROUND: Adrenomedullin is a vasoactive hormone with potentially prognostic and therapeutic value, which mainly has been investigated in intensive care unit (ICU) settings. The triaging in the emergency department (ED) of patients to the right level of care is crucial for patient outcome. OBJECTIVES: The primary aim of this study was to investigate the association of bioactive adrenomedullin (bio-ADM) with mortality among sepsis patients in the ED. Secondary aims were to investigate the association of bio-ADM with multiple organ failure (MOF), ICU admission and ED discharge. METHODS: In this prospective observational cohort study, adult sepsis patients in the ED (2013-2015) had blood samples collected for later batch analysis of bio-ADM. Odds ratios (OR) with 95% confidence interval (CI) for bio-ADM were calculated. RESULTS: Bio-ADM in 594 sepsis patients was analyzed of whom 51 died within 28 days (8.6%), 34 developed severe MOF, 27 were ICU admitted and 67 were discharged from the ED. The median (interquartile range) bio-ADM was 36 (26-56) and 63 (42-132) pg/mL among survivors and non-survivors, respectively, 81 (56-156) pg/mL for patients with severe MOF and 77 (42-133) pg/mL for ICU admitted patients. Each log-2 increment of bio-ADM conferred an OR of 2.30 (95% CI 1.74-3.04) for mortality, the adjusted OR was 2.39 (95% CI 1.69-3.39). The area under the receiver operating characteristic curve of a prognostic mortality model based on demographics and biomarkers increased from 0.80 to 0.86 (p = 0.02) when bio-ADM was added. Increasing bio-ADM was associated with severe MOF, ICU admission and ED discharge with adjusted ORs of 3.30 (95% CI 2.13-5.11), 1.75 (95% CI 1.11-2.77) and 0.46 (95% CI 0.32-0.68), respectively. CONCLUSION: Bio-ADM in sepsis patients in the ED is associated with mortality, severe MOF, ICU admission and ED discharge, and may be of clinical importance for triage of sepsis patients in the ED.

Bioactive adrenomedullin a prognostic biomarker in patients with mild to moderate dyspnea at the emergency department: an observational study.

Acute dyspnea with underlying congestion is a leading cause of emergency department (ED) visits with high rates of hospitalization. Adrenomedullin is a vasoactive neuropeptide hormone secreted by the endothelium that mediates vasodilation and maintains vascular integrity. Plasma levels of biologically active adrenomedullin (bio-ADM) predict septic shock and vasopressor need in critically ill patients and are associated with congestion in patients with acute heart failure (HF) but the prognostic value in unselected dyspneic patients at the ED is unknown. The purpose of this study is to test if bio-ADM predicts adverse outcomes when sampled in patients with acute dyspnea at presentation to the ED. In this single-center prospective observational study, we included 1402 patients from the ADYS (Acute DYSpnea at the Emergency Department) cohort in Malmö, Sweden. We fitted logistic regression models adjusted for sex, age, N-terminal pro-B-type natriuretic peptide (NT-proBNP), creatinine, and C-reactive protein (CRP) to associate bio-ADM plasma levels to mortality, hospitalization, intravenous (IV) diuretic treatment and HF diagnosis. Using receiver operating characteristic (ROC) curve analysis we evaluated bio-ADM discrimination for these outcomes compared to a reference model (sex, age, NT-proBNP, creatinine, and CRP). Model performance was compared by performing a likelihood ratio test on the deviances of the models. Bio-ADM (per interquartile range from median) predicts both 90-day mortality [odds ratio (OR): 1.5, 95% confidence interval (CI) 1.2-2.0, p < 0.002] and hospitalization (OR: 1.5, 95% CI 1.2-1.8, p < 0.001) independently of sex, age, NT-proBNP, creatinine, and CRP. Bio-ADM statistically significantly improves the reference model in predicting mortality (added χ2 9.8, p = 0.002) and hospitalization (added χ2 14.1, p = 0.0002), and is associated with IV diuretic treatment and HF diagnosis at discharge. Plasma levels of bio-ADM sampled at ED presentation in acutely dyspneic patients are independently associated with 90-day mortality, hospitalization and indicate the need for decongestive therapy.

Plasma Proneurotensin and Prediction of Cause-Specific Mortality in a Middle-aged Cohort During Long-term Follow-up.

CONTEXT: Neurotensin is associated with cardiometabolic diseases but its role with mortality risk in humans is unknown. OBJECTIVE: This work aims to examine the prediction of proneurotensin (Pro-NT) with respect to total and cause-specific mortality in a middle-aged cohort. METHODS: In the population-based middle-aged cohort (n = 4632; mean age, 57 years) of the Malmö Diet and Cancer Study, Pro-NT was assessed and total as well as cause-specific mortality was studied. Main cause of death was based on the International Classification of Diseases. RESULTS: During a mean follow-up of 20 ±â€…3 years, 950 men and 956 women died. There was significantly increased mortality risk in individuals belonging to the highest quartile (Q) of Pro-NT (Q4, Pro-NT ≥ 149 pmol/L) compared with Qs 1 to 3 (Pro-NT < 149 pmol/L), hazard ratio (HR), 95% CI of 1.29 (1.17-1.42; P < .001). Data were adjusted for sex and age. No significant interaction was observed between Pro-NT and sex on mortality risk. Individuals within Q4 vs Qs 1 to 3 had an HR of 1.41 (95% CI, 1.18-1.68; P < .001) for death due to cardiovascular disease (n = 595/4632); 2.53 (95% CI, 1.37-4.67; P = .003), due to digestive tract disease (n = 42/4632), 1.62 (95% CI, 1.04-2.52; P = .032) due to mental and behavioral disease (n = 90/4632); and 1.91 (95% CI, 1.15-3.19; P = .013) due to unspecific causes (n = 64/4632). There was no significant relationship between Pro-NT and deaths due to cancer, infections, neurological, or other causes. Adjustment for cardiovascular risk factors only marginally changed these results. CONCLUSION: The relationship between Pro-NT and total mortality risk was mainly driven by cardiovascular mortality, but high Pro-NT also predicts death from digestive, mental, and behavioral disease and deaths attributed to unspecific causes.

Pro-neurotensin/Neuromedin N and Hypertension Risk: A Prospective Study.

BACKGROUND: Neurotensin, a neuropeptide with direct cardiac effects, has been associated with prospective risk of hypertension-related conditions through measurement of its precursor, pro-neurotensin/neuromedin N (pro-NT/NMN). Its association with incident hypertension has not been evaluated. METHODS: From 2003 to 2007, the REasons for Geographic And Racial Differences in Stroke (REGARDS) study enrolled 30,239 Black or White adults age ≥45. Pro-NT/NMN was measured in 1,692 participants without baseline hypertension (self-reported antihypertensive use or blood pressure ≥140/90 mm Hg) who underwent follow-up assessment in 2013-2016. A sensitivity analysis was conducted using a lower threshold (≥130/80 mm Hg) to define hypertension. Three robust Poisson regression models were fitted to risk of incident hypertension, adding demographics, cardiometabolic risk factors, and dietary covariates. RESULTS: Six hundred and fourteen participants developed hypertension over 9.4 years of follow-up. Pro-NT/NMN ranged from 14 to 1,246 pmol/l, with median [interquartile range] 154 [112, 206] pmol/l. Pro-NT/NMN was not associated with hypertension overall (fully adjusted incidence rate ratio per SD increment log pro-NT/NMN 1.03, 95% confidence interval 0.95-1.11). Results of sensitivity analysis did not differ substantially. CONCLUSIONS: Baseline pro-NT/NMN was not associated with incident hypertension. This may be a result of neurotensin's long-term interactions with other molecular regulators of blood pressure, such as the renin-angiotensin-aldosterone system.

Bioactive adrenomedullin for assessment of venous congestion in heart failure.

AIMS: Bioactive adrenomedullin (bio-ADM) is a vascular-derived peptide hormone that has emerged as a promising biomarker for assessment of congestion in decompensated heart failure (HF). We aimed to evaluate diagnostic and prognostic performance of bio-ADM for HF in comparison to amino-terminal pro-B-type natriuretic peptide (NT-proBNP), with decision thresholds derived from invasive haemodynamic and population-based studies. METHODS AND RESULTS: Normal reference ranges for bio-ADM were derived from a community-based cohort (n = 5060). Correlations with haemodynamic data were explored in a cohort of HF patients undergoing right heart catheterization (n = 346). Mortality and decision cutoffs for bio-ADM was explored in a cohort of patients presenting in the ER with acute dyspnoea (n = 1534), including patients with decompensated HF (n = 570). The normal reference range was 8-39 pg/mL. The area under the receiver operating characteristic curve (AUROC) for discrimination of elevated mean right atrial pressure (mRAP) and pulmonary arterial wedge pressure (PAWP) was 0.74 (95% CI = 0.67-0.79) and 0.70 (95% CI = 0.64-0.75), respectively, with optimal bio-ADM decision cutoff of 39 pg/mL, concordant with cubic spline analyses. NT-proBNP discriminated PAWP slightly better than mRAP (AUROC 0.73 [95% CI = 0.68-0.79] and 0.68 [95% CI = 0.61-0.75]). Bio-ADM correlated with (mRAP, r = 0.55) while NT-proBNP correlated with PAWP. Finally, a bio-ADM decision cutoff of 39 pg/mL associated with 30 and 90 day mortality and conferred a two-fold increased odds of HF diagnosis, independently from NT-proBNP. CONCLUSIONS: Bio-ADM tracks with mRAP and associates with measures of systemic congestion and with mortality in decompensated HF independently from NT-proBNP. Our findings support utility of bio-ADM as a biomarker of systemic venous congestion in HF and nominate a decision threshold.