45 research outputs found
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.This work was supported by the Netherlands Heart Foundation, Dutch Diabetes Research Foundation and Dutch Kidney Foundation. This research was performed within the framework of CTMM, the Center for Translational Molecular Medicine (www.ctmm.nl); project PREDICCt (grant 01C-104-07). Dr. A. Abbasi is supported by a Rubicon grant from the Netherlands Organization for Scientific Research (NWO).This is the final published version, which can also be found on the publisher's website here: http://link.springer.com/article/10.1007%2Fs00125-014-3278-
Proenkephalin and the risk of new-onset heart failure:data from prevention of renal and vascular end-stage disease
BACKGROUND: Enkephalins of the opioid system exert several cardiorenal effects. Proenkephalin (PENK), a stable surrogate, is associated with heart failure (HF) development after myocardial infarction and worse cardiorenal function and prognosis in patients with HF. The association between plasma PENK concentrations and newâonset HF in the general population remains to be established. HYPOTHESIS: We hypothesized that plasma PENK concentrations are associated with newâonset HF in the general population. METHODS: We included 6677 participants from the prevention of renal and vascular endâstage disease study and investigated determinants of PENK concentrations and their association with newâonset HF (both reduced [HFrEF] and preserved ejection fraction [HFpEF]). RESULTS: Median PENK concentrations were 52.7 (45.1â61.9) pmol/L. Higher PENK concentrations were associated with poorer renal function and higher NTâproBNP concentrations. The main determinants of higher PENK concentrations were lower estimated glomerular filtration rate (eGFR), lower urinary creatinine excretion, and lower body mass index (all pâ<â.001). After a median 8.3 (7.8â8.8) years followâup, 221 participants developed HF; 127 HFrEF and 94 HFpEF. PENK concentrations were higher in subjects who developed HF compared with those who did not, 56.2 (45.2â67.6) versus 52.7 (45.1â61.6) pmol/L, respectively (p = .003). In competingârisk analyses, higher PENK concentrations were associated with higher risk of newâonset HF (hazard ratio [HR] = 2.09[1.47â2.97], pâ<â.001), including both HFrEF (HR = 2.31[1.48â3.61], pâ<â.001) and HFpEF (HR = 1.74[1.02â2.96], p = .042). These associations were, however, lost after adjustment for eGFR. CONCLUSIONS: In the general population, higher PENK concentrations were associated with lower eGFR and higher NTâproBNP concentrations. Higher PENK concentrations were not independently associated with newâonset HFrEF and HFpEF and mainly confounded by eGFR
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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% experiencedââ„â30% 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 and bioactive adrenomedullin are useful for risk prognostication in cardiac surgery
IntroductionVarious clinical scores have been developed to predict organ dysfunction and mortality in patients undergoing cardiac surgery, but outcome prediction may be inaccurate for some patient groups. Proenkephalin A (penKid) and bioactive adrenomedullin (bio-ADM) have emerged as promising biomarkers correlating with shock and organ dysfunction. This imposes the question of whether they can be used as prognostic biomarkers for risk stratification in the perioperative setting of cardiac surgery.MethodsPatients undergoing cardiac surgery were prospectively enrolled in this observational study. PenKid and bio-ADM plasma levels, as well as markers evaluating inflammation and organ dysfunction, were measured at five perioperative time points from before the induction of anesthesia to up to 48 h postoperatively. Clinical data regarding organ dysfunction and patient outcomes were recorded during the intensive care unit (ICU)-stay with a special focus on acute kidney injury (AKI).ResultsIn 136 patients undergoing cardiac surgery, the bio-ADM levels increased and the penKid levels decreased significantly over time. PenKid was associated with chronic kidney disease (CKD), the incidence of AKI, and renal replacement therapy (RRT). Bio-ADM was associated with lactate and the need for vasopressors. PenKid was useful to predict an ICU-length of stay (LOS)>1 day and added prognostic value to the European System for Cardiac Operative Risk Evaluation Score (EuroSCORE) II when measured after the end of cardiopulmonary bypass and 24 h after cardiac surgery. For bio-ADM, the same was true when measured 24 h after surgery. PenKid also added prognostic value to the EuroSCORE II for the combined outcome âICU length of stay >1 day and in-hospital mortality.âConclusionThe combination of preoperative EuroSCORE II and intraoperative measurement of penKid may be more useful to predict a prolonged ICU LOS and increased mortality than EuroSCORE II alone. Bio-ADM correlates with markers of shock. More research is encouraged for early risk stratification and validation of penKid and bio-ADM as a tool involved in clinical decisions, which may enable the early initiation of organ protective strategies
Serum Peroxiredoxin 4:A Marker of Oxidative Stress Associated with Mortality in Type 2 Diabetes (ZODIAC-28)
BACKGROUND: Oxidative stress plays an underlying pathophysiologic role in the development of diabetes complications. The aim of this study was to investigate peroxiredoxin 4 (Prx4), a proposed novel biomarker of oxidative stress, and its association with and capability as a biomarker in predicting (cardiovascular) mortality in type 2 diabetes mellitus. METHODS: Prx4 was assessed in baseline serum samples of 1161 type 2 diabetes patients. Cox proportional hazard models were used to evaluate the relationship between Prx4 and (cardiovascular) mortality. Risk prediction capabilities of Prx4 for (cardiovascular) mortality were assessed with Harrell's C statistic, the integrated discrimination improvement and net reclassification improvement. RESULTS: Mean age was 67 and the median diabetes duration was 4.0 years. After a median follow-up period of 5.8 years, 327 patients died; 137 cardiovascular deaths. Prx4 was associated with (cardiovascular) mortality. The Cox proportional hazard models added the variables: Prx4 (model 1); age and gender (model 2), and BMI, creatinine, smoking, diabetes duration, systolic blood pressure, cholesterol-HDL ratio, history of macrovascular complications, and albuminuria (model 3). Hazard ratios (HR) (95% CI) for cardiovascular mortality were 1.93 (1.57 - 2.38), 1.75 (1.39 - 2.20), and 1.63 (1.28 - 2.09) for models 1, 2 and 3, respectively. HR for all-cause mortality were 1.73 (1.50 - 1.99), 1.50 (1.29 - 1.75), and 1.44 (1.23 - 1.67) for models 1, 2 and 3, respectively. Addition of Prx4 to the traditional risk factors slightly improved risk prediction of (cardiovascular) mortality. CONCLUSIONS: Prx4 is independently associated with (cardiovascular) mortality in type 2 diabetes patients. After addition of Prx4 to the traditional risk factors, there was a slightly improvement in risk prediction of (cardiovascular) mortality in this patient group
Characterization of peroxiredoxin 4 as a biomarker of oxidative stress
Die FrĂŒherkennung schwerer KrankheitsverlĂ€ufe kann erheblich zur Anpassung der
Therapie und zur Verringerung von MortalitÀtsraten beitragen, ist nicht
zuletzt aufgrund des Mangels geeigneter Biomarker jedoch oftmals nur
unzureichend möglich. Es wird angenommen, dass oxidativer Stress als Zeichen
eines Ungleichgewichtes zwischen reaktiven Sauerstoffspezies und
Antioxidantien vielfÀltig in Krankheitsgeschehen involviert ist. Derzeit
besteht Uneinigkeit ĂŒber die Lokalisation und Funktion des antioxidativen
Enzyms Peroxiredoxin 4 (Prx4), welches als möglicher Biomarker fĂŒr oxidativen
Stress infrage kommt. Zum quantitativen Nachweis von Prx4 wurde daher zunÀchst
ein sensitiver Chemilumineszenz-Immunoassay entwickelt und validiert. Im Serum
Gesunder wiesen Frauen leicht höhere Prx4-Konzentrationen auf als MÀnner. Auf
der Intensivstation waren erhöhte Prx4-Serumwerte in Sepsis-Patienten mit dem
Schweregrad und der MortalitÀt assoziiert und zeigten Korrelationen mit
gÀngigen klinischen Punktesystemen (Acute Physiology and Chronic Health
Evaluation II, APACHE II; Sequential Organ Failure Assessment, SOFA) anderen
antioxidativen Substanzen (Albumin, Bilirubin), Infektions- (Procalcitonin)
sowie EntzĂŒndungs-parametern (C-reaktives Protein, Interleukin-6). Auch bei
Patienten, welche mit unspezifischen Beschwerden in die Notaufnahme kommen und
in der Regel ein hohes Alter, viele Begleiterkrankungen sowie eine
umfangreiche medikamentöse Behandlung aufweisen, zeigte Prx4 einen von Alter,
Geschlecht, klinischen Punktesystemen (Charlson Comorbidity Index, CCI;
Activities of Daily Living, ADL) und Krankenhausentlassung unabhÀngigen
kurzzeitprognostischen Nutzen und ermöglicht dem behandelnden Notaufnahmearzt
damit eine Risikostratifizierung der Patienten und eine verbesserte
Ressourcenallokation. Neben dem Nachweis von Prx4 in der Zirkulation konnte
das Enzym in Epithelzellen intrazellulÀr in Kompartimenten des klassischen
Sekretionsweges sowie extrazellulÀr im Kulturmedium lokalisiert werden und
wird folglich als sezerniertes Protein eingeschÀtzt. Die ansteigende
Prx4-Sekretion durch Behandlung von MDCK1-Zellen mit Wasserstoffperoxid
unterstĂŒtzt die im Weiteren zu validierende Annahme, dass die deutlich
erhöhten Prx4-Serumwerte in erkrankten Individuen auf vermehrten oxidativen
Stress zurĂŒckzufĂŒhren sind.Early recognition of severe disease courses is highly relevant for therapeutic
decision making and mortality rate reduction, though hampered not least by a
lack of suitable biomarkers. It is assumed that oxidative stress as a sign of
imbalance between reactive oxygen species and antioxidants is variously
involved in pathological processes. Currently, there is disagreement regarding
localization and function of the antioxidative enzyme peroxiredoxin 4 (Prx4),
an eligible biomarker of oxidative stress. First of all, a sensitive
chemiluminescence immunoassay for quantification of Prx4 was developed and
validated. Peroxiredoxin 4 was slightly increased in serum of healthy women
compared to men. On the intensive care unit, increased Prx4 serum
concentrations were associated with severity and mortality in sepsis patients
and correlated with common clinical scores (Acute Physiology and Chronic
Health Evaluation II, APACHE II; Sequential Organ Failure Assessment, SOFA),
other antioxidants (albumin, bilirubin), markers of infection (procalcitonin)
and inflammation (C-reactive protein, interleukin-6). Even in patients that
present with nonspecific complaints to the emergency department and that are
usually composed of elderly with multiple comorbidities and polypharmacy,
short-term prognostic use of Prx4 was independent of age, sex, clinical scores
(Charlson Comorbidity Index, CCI; Activities of Daily Living, ADL) and patient
disposition enabling emergency physicians to risk stratify patients and to
better allocate resources. Besides detection of Prx4 in circulation, the
enzyme was localized intracellularly within compartments of the classical
secretory pathway and extracellularly in the culture medium of epithelial
cells leading to the conclusion that Prx4 is a secreted protein. Treatment of
MDCK1 cells with hydrogen peroxide resulted in an augmented Prx4 secretion
which supports the assumption, subject to validation, that increased Prx4
serum concentrations in patients are due to higher oxidative stress
Bioactive adrenomedullin in sepsis patients in the emergency department is associated with mortality, organ failure and admission to intensive care
BackgroundAdrenomedullin 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.ObjectivesThe 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.MethodsIn this prospective observational cohort study, adult sepsis patients in the ED (2013â2015) had blood samples collected for later batch analysis of bio-ADM. Odds ratios (OR) with 95% confidence interval (CI) for bio-ADM were calculated.ResultsBio-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 (26â56) and 63 (42â132) pg/mL among survivors and non-survivors, respectively, 81 (56â156) pg/mL for patients with severe MOF and 77 (42â133) pg/mL for ICU admitted patients. Each log-2 increment of bio-ADM conferred an OR of 2.30 (95% CI 1.74â3.04) for mortality, the adjusted OR was 2.39 (95% CI 1.69â3.39). 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 2.13â5.11), 1.75 (95% CI 1.11â2.77) and 0.46 (95% CI 0.32â0.68), respectively.ConclusionBio-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) 1.2â2.0, p < 0.002] and hospitalization (OR: 1.5, 95% CI 1.2â1.8, p < 0.001) independently of sex, age, NT-proBNP, creatinine, and CRP. Bio-ADM statistically significantly improves the reference model in predicting mortality (added Ï2 9.8, p = 0.002) and hospitalization (added Ï2 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