Copeptin Levels Research Articles

Risk assessment of sepsis through measurement of proAVP (copeptin): a secondary analysis of the TRIAGE study.

ObjectiveSystemic infections and sepsis lead to strong activation of the vasopressin system, which is pivotal for stimulation of the endocrine stress response and, in addition, has vasoconstrictive and immunomodulatory effects. Our aim was to assess the significance of the vasopressor system through measurement of C-terminal proAVP (copeptin) regarding mortality prediction in a large prospective cohort of patients with systemic infection.Design and methodsThis secondary analysis of the observational cohort TRIAGE study included consecutive, adult, medical patients with an initial diagnosis of infection seeking emergency department care. We used multivariable regression analysis to assess associations of copeptin levels in addition to the Sequential Organ Failure Assessment (SOFA) score with 30-day mortality. Discrimination was assessed by calculation of the area under the curve (AUC).ResultsOverall, 45 of 609 (7.4%) patients with infection died within 30 days. Non-survivors had a marked upregulation of the vasopressin system with a more than four-fold increase in admission copeptin levels compared to non-survivors (199.9 ± 204.7 vs 46.6 ± 77.2 pmol/L). In a statistical model, copeptin was significantly associated with mortality (adjusted odds ratio of 1.04, 95% CI 1.01 to 1.07, P = 0.002). Regarding discrimination, copeptin alone showed an AUC of 0.82, while adding copeptin to the SOFA score significantly improved its prognostic ability (AUC 0.83 vs 0.86, P = 0.027).ConclusionActivation of the vasopressin system mirrored by an increase in copeptin levels provided significant information regarding mortality risk and improved the SOFA score for prediction of sepsis mortality.

A meta-analysis and trial sequential analysis of serum copeptin level in adult patients with Obstructive Sleep Apnoea Syndrome

Copeptin can act as a stable biomarker in inflammation and stress response that obstructive sleep apnoea syndrome (OSAS), can induce oxidative stress and consequently promotes systemic inflammation. The purpose of the study is to appraise serum copeptin level in adult patients with OSAS compared to the controls. Electronic search was done in the databases of PubMed/Medline, Web of Science, Scopus, and Cochrane Library until June 2021, without any restrictions. For comparison of the serum copeptin level between groups, the mean difference (MD) and 95% confidence interval (CI) were calculated by the Review Manager 5.3 software. Trial sequential analysis (TSA) was used by applying TSA software. Among the databases, five articles (involving 495 OSAS patients and 135 controls) were included. To report the serum copeptin level in OSAS patients compared to controls, the pooled OR became 12.21pg/mL (95%CI: 2.31 to 22.11; P=0.02) and also the pooled OR for comparison of serum copeptin level in severe versus moderate/mild OSAS patients was 5.96pg/mL (95%CI: 1.46 to 10.47; P=0.009). The results of TSA illustrated that the Z-curve has not crossed the monitoring boundary curves and did not reach the required information size. The main findings recommended that copeptin had a significantly higher serum level in OSAS patients compared to controls, as well as a significantly higher level in severe patients compared to mild/moderate OSAS patients for the serum level of copeptin.

Association between copeptin levels and treatment responses to hypertonic saline infusion in patients with symptomatic hyponatremia: a prospective cohort study.

BackgroundCopeptin is secreted in equimolar amounts as arginine vasopressin, main hormone regulating body fluid homeostasis. A recent study reported a copeptin-based classification of osmoregulatory defects in syndromes of inappropriate antidiuresis that may aid in prediction of therapeutic success. We investigated usefulness of copeptin for differentiating etiologies of hyponatremia and predicting efficacy and safety of hypertonic saline treatment in hyponatremic patients.MethodsWe performed a multicenter, prospective cohort study of 100 inpatients with symptomatic hyponatremia (corrected serum sodium [sNa] ≤ 125 mmol/L) treated with hypertonic saline. Copeptin levels were measured at baseline and 24 hours after treatment initiation, and patients were classified as being below or above median of copeptin at baseline or at 24 hours, respectively. Correlations between target, under correction, and overcorrection rates of sNa within 24 hours/24–48 hours and copeptin levels at baseline/24 hours were analyzed.ResultsMean sNa and median copeptin levels were 117.9 and 16.9 pmol/L, respectively. Ratio of copeptin-to-urine sodium allowed for an improved differentiation among some (insufficient effective circulatory volume), but not all hyponatremia etiologic subgroups. Patients with below-median copeptin levels at baseline achieved a higher target correction rate in 6/24 hours (odds ratio [OR], 2.97; p = 0.02/OR, 6.21; p = 0.006). Patients with below-median copeptin levels 24 hours after treatment showed a higher overcorrection rate in next 24 hours (OR, 18.00, p = 0.02).ConclusionThere is a limited diagnostic utility of copeptin for differential diagnosis of hyponatremia. However, copeptin might be useful for predicting responses to hypertonic saline treatment in hyponatremic patients.

Higher Copeptin Levels are Associated with the Risk of Atrial Fibrillation in Patients with Rheumatic Mitral Stenosis.

Correlations between increased copeptin levels and various cardiovascular diseases have been described. In this study, we aimed to investigate the correlation between increased copeptin levels and paroxysmal atrial fibrillation (PAF) in rheumatic mitral stenosis (MS). Patients with mild/moderate rheumatic MS and sinus rhythm were consecutively recruited from an echocardiography laboratory. Patients with a history of PAF and those with PAF on 24-48-hour ambulatory electrocardiography (ECG) monitoring constituted the study group, and those without PAF on ambulatory ECG monitoring constituted the control group. Clinical characteristics, echocardiographic parameters and levels of copeptin, plasma N-terminal proBNP (NT-proBNP) and high-sensitivity C-reactive protein (hs-CRP) were evaluated. Twenty-nine patients with PAF and 124 control MS patients were studied. Patients in the PAF group were older, but the mitral valve areas and transmitral gradients were not different between the groups. In the PAF group, hs-CRP (1.2 vs. 0.8 mg/L, p < 0.001), NT-proBNP (335 vs. 115 pg/mL, p < 0.001) and copeptin (6.9 vs. 4.0 pmol/L, p < 0.001) levels were significantly higher than in the control group. Multivariable logistic regression analysis revealed that age [odds ratio (OR) 1.19, 95% confidence interval (CI) 1.04-1.38; p = 0.024], left atrial volume index (OR 1.23, 95% CI 1.06-1.41; p = 0.032), copeptin levels (OR 2.81, 95% CI 1.30-5.29; p < 0.001) and hs-CRP levels (OR 15.5, 95% CI 1.41-71.5; p = 0.012) were independent predictors of PAF. In patients with mild/moderate rheumatic MS, higher copeptin and hs-CRP levels predicted a higher risk of developing atrial fibrillation.

Gender features of structural and functional changes of the heart and levels of copeptin and NTproBNP in patients with acute Q-myocardial infarction in the presence of pulmonary hypertension

The aim. To evaluate the gender features of structural and functional changes in the heart and levels of copeptin and NTproBNP in patients with acute myocardial infarction (AMI) with concomitant pulmonary hypertension (PH). Materials and methods. 74 patients with AMI and concomitant PH who were treated in the intensive care unit and emergency cardiology for patients with myocardial infarction of the Municipal Non-Profit Enterprise “City Hospital of Emergency and Ambulance” of Zaporizhzhia City Council were examined. The patients were divided into two groups: the first group consisted of 42 male patients (mean age 71.06 ± 2.21 years) and 32 female patients (mean age 76.41 ± 2.32 years). All the patients were examined in the first three days by two-dimensional echocardiography on a device MyLab50 (“Esaote”, Italy). The serum levels of kopeptin and NTproBNP were determined by enzyme-linked immunosorbent assay using a set of reagents Elabscience (USA). Results. There was a trend towards a predominantly anterior AMI in the group of men and lower AMI – in the group of women. Individuals with functional class III and IV heart failure predominated (76.1 %) among the men with AMI and PH. At the same time, there were significantly more persons with III and IV functional class in the group of men than in the group of women (P &lt; 0.05). There was a significant diastolic left ventricular posterior wall thickening in women compared to men (8.4 %; P &lt; 0.05) and a tendency to diastolic interventricular septal thickening in females. There was an upward trend in end-systolic and end-diastolic sizes in the group of men compared to women; however, the differences did not reach the required level of significance. Evaluation of serum copeptin and NTproBNP in patients with AMI and PH revealed significantly higher levels of these indicators in the group of men compared to women (P &lt; 0.05). Conclusions. Men with AMI and PH had more severe heart failure compared to women due to the predominance of patients with functional classes III and IV. Women with AMI and PH demonstrated predominantly concentric type of remodeling in the form of significantly thickened LV posterior wall and the tendency to increase interventricular septum wall thickness, and eccentric hypertrophy in the form of LV dilatation prevailed in men. Men with AMI and PH had significantly higher serum copeptin and NTproBNP levels compared to women.

Copeptin (CTproAVP) - A Biomarker of a Circulatory Impairment in Liver Transplant Recipients? A Prospective, Observational Study

Copeptin, an easily measured and stable surrogate marker of arginine vasopressin, is a biomarker of a homeostasis disorder and a circulatory impairment in a wide spectrum of morbidities. The aim of this study was to evaluate the potential of copeptin as a biomarker of a circulatory impairment in patients undergoing liver transplantation (LT). This was a prospective, observational study. Blood samples were obtained from 38 patients undergoing LT. Serum copeptin level was measured by means of a sandwich immunoassay pre-, intra-, and postoperatively up to 21 days after the operation. The mean concentration of copeptin remained in the range of values slightly below 1000 pg/mL during the analyzed observation period and remained higher than the values observed in healthy individuals. Intraoperative and immediately postoperative copeptin levels did not correlate with hemodynamic parameters. There was also no correlation between preoperative copeptin levels (C1) and preoperative Model for End-Stage Liver Disease scores, serum creatinine levels, plasma transaminase levels, international normalized ratio, or hematocrit (Spearman ρ, P > .05). Preoperative copeptin levels are elevated in most LT recipients and remain elevated for 21 days after surgery. There was no correlation between the concentration of copeptin and the Model for End-Stage Liver Disease-Sodium score or the cause of a hepatic failure. It cannot be concluded that copeptin is a biomarker of a circulatory impairment in patients with transplanted liver in the perioperative period. The secretion of vasopressin, as measured by copeptin concentration during and after LT, requires further study.

Prognostic value of copeptin in patients with acute myocardial infarction treated with percutaneous coronary intervention: a prospective cohort study.

BackgroundIschemic myocardial injury leads to neurohormonal system activation and increased release of copeptin. Although diagnostic value of copeptin has been widely described, data on its prognostic performance in patients with myocardial infarction is inconclusive. The aim of this study was to asses if elevated copeptin concentration provides prognostic information for long-term adverse cardiac events in a cohort of first acute myocardial infarction patients treated with percutaneous coronary intervention.MethodsCopeptin concentration was assessed in a cohort of 100 consecutive patients (39% women; mean age 63±7 years) presenting with first acute myocardial infarction and subjected to percutaneous coronary intervention. Samples were collected at the time of admission and on the 4th/5th day of hospitalisation. All patients were followed-up prospectively for 12 months for the occurrence of major adverse cardiovascular events defined as reinfarction, unscheduled coronary revascularisation and all-cause death.ResultsElevated copeptin concentration on the 4th/5th day of hospitalisation was identified as a predictor of major adverse cardiovascular events (P=0.0445). The increase between copeptin level on admission and on day 4th/5th was associated with the requirement for unscheduled coronary revascularisation in receiver operating characteristics (ROC) analysis (AUC =0.639; 95% CI: 0.504–0.773; P=0.0430). In a multivariate analysis, copeptin concentration on the 4th/5th day of hospitalisation and left ventricular ejection fraction assessed by transthoracic echocardiography, were the only predictors for major adverse cardiac events during follow-up (P=0.024 and P=0.001, respectively).ConclusionsCopeptin seems to be a prognostic marker in patients with first myocardial infarction treated with percutaneous coronary intervention.

Value of Serum Copeptin Estimation for the Diagnosis of Diabetic Nephropathy in Type 2 Diabetes Mellitus Patients

Background: Serum copeptin, the terminal part of the arginine vasopressin (AVP), is stable in plasma. The AVP is increased in diabetic patients and may play a role in the development of diabetic kidney disease. Objective: To evaluate the role of serum copeptin in the diagnosis of diabetic nephropathy in type-2 diabetes mellitus. Patients and Methods: 40 type-2 diabetes mellitus (T2DM) patients; divided into two groups, (20 with poor glycemic control, and 20 with good glycemic control), in addition to 20 non-diabetic healthy control subjects. The following investigations had been made; HbA1C, FBS, blood urea, serum creatinine and sodium, creatinine clearance (Ccr), glomerular filtration rate (eGFR), urinary protein, and urinary sodium. Serum copeptin levels were measured using an enzyme-linked immunoassay (ELISA). Results: Serum copeptin levels were significantly higher in (T2DM) patients with poor glycemic control than in (T2DM) patients with good glycemic control compared to the healthy control group. There was a significant positive correlation between serum copeptin and FBS, HbA1C, blood urea, serum creatinine, urinary Na, and 24-hour urinary protein, and a significant negative correlation with serum Na, eGFR, and creatinine clearance. The receiver operating characteristic (ROC) curve for the validity of serum copeptin, as a marker for diabetic nephropathy, at cutoff point 3452 pg/ml, showed 90% sensitivity, and 95% specificity. Conclusion: Serum copeptin is independently related to markers of kidney injury in T2DM and may be used as a marker for diabetic nephropathy.

The effects of water immersion and epidural analgesia on cellular immune response, neuroendocrine, and oxidative markers

Background/aim Water immersion and epidural analgesia are the most preferred pain relief methods during the labor process. Adverse effects related to these methods, impact on the labor, and perception of pain is well studied in the literature. We aimed to investigate the cord blood level of copeptin, total serum oxidant (TOS), antioxidant (TAS), interleukin (IL)-1, IL-6, and oxytocin after the labor with water immersion, epidural analgesia, and vaginal birth without pain relief. Materials and methodsThe study was conducted with 102 healthy pregnant women admitted to the obstetric delivery unit for noncomplicated term birth. Copeptin, oxytocin, TAS, TOS, IL-1, and IL-6 levels of cord blood and obstetric and neonatal results after vaginal birth were compared.Results The study included a total of 102 patients (group 1 = 30, group 2 = 30, and group 3 = 42). We found no significant difference between the three groups in terms of BMI, age, gravidity, parity, birth week, birth weight, interventional birth, perineal trauma, breastfeeding, duration of labor, oxytocin, IL-1 and IL-6 levels (p > 0.05). Neonatal intensive care unit (NICU) need, TAS, TOS, and copeptin levels were higher. Apgar scores were lower in the epidural group (p = 0.011, p = 0.036, p = 0.027, p < 0.001, and p < 0.001 respectively).Conclusion Epidural analgesia has deteriorated oxidative stress status and lower neonatal Apgar scores with higher NICU administration compared with water birth and vaginal birth without pain relief.

Copeptin in Patients with Pregnancy-Induced Hypertension.

Pregnancy-induced hypertension (PIH) occurs in 6–8% of pregnancies, and increases the risk of many severe obstetric complications. The etiology of PIH has not been fully explained, and hence, treatment is only palliative in nature, and prevention is not fully effective. It has been proposed that PIH development is influenced by the arginine vasopressin pathway, whose surrogate biomarker is copeptin. The aim of this study is a prospective assessment of the relationship between the level of copeptin in pregnant women and the occurrence of PIH, and to identify its usefulness in predicting complications. The study involved a group of 21 pregnant women who developed PIH and 37 women with uncomplicated pregnancies as a control group. Blood samples were collected at the three trimesters of gestation (<13 HBD, between 13 and 26 and >26 HBD) and then frozen. Copeptin levels [pg/mL] were measured in serum samples obtained in the first, second and third trimesters of gestation from women in the PIH and control groups. The concentration of copeptin in the second and third trimesters of pregnancy was statistically significantly higher in the PIH group (p < 0.05). For copeptin determined in the first trimester, which could be used to screen for PIH, the area under the ROC curve was 0.650. The highest risk of PIH occurred in patients with high concentrations of copeptin in the first trimester of pregnancy and obesity OR = 5.5 (95% CI 1.0–31.3). The risk of PIH was augmented in patients with high levels of copeptin and an abnormal Doppler result of the uterine arteries OR = 28.4 (95% CI 5.3–152). In conclusion, copeptin levels were found to be elevated in pregnant women before the diagnosis of PIH; however, copeptin should not be used as a stand-alone marker. The combination of copeptin concentration with the other risk factors (diabetes, maternal age and preeclampsia in previous pregnancy) did not improve the diagnostic values of the use of copeptin in the PIH risk assessment, but the combination of copeptin concentration with BMI may be useful in clinical practice. Measurement of copeptin together with a Doppler examination of uterine arteries in the first trimester of pregnancy may be a useful marker in predicting the development of PIH.

Increased angiotensin II formation in the brain modulates cardiovascular homeostasis and erythropoiesis.

In spite of the fact that the modulatory effects of angiotensin II (Ang II) on the sympathetic nerve activity to targeted organs involved in blood pressure (BP) regulation is well acknowledged, the local production of this peptide in the brain and the consequences of enhanced central Ang II beyond the cardiovascular system are not yet well comprehended. In the present study, we generated and validated a new transgenic mouse line overexpressing the rat full-length angiotensinogen (Agt) protein specifically in the brain (Agt-Tg). Adult Agt-Tg mice presented overall increased gene expression of total Agt in the brain including brainstem and hypothalamus. In addition, the excess of Agt led to abundantly detectable brain Ang II levels as well as increased circulating copeptin levels. Agt-Tg displayed raised BP in acute recordings, while long-term telemetrically measured basal BP was indistinguishable from wild-types. Agt-Tg has altered peripheral renin-angiotensin system and vasomotor sympathetic tone homeostasis because renal gene expression analysis, plasma Ang II measurements and ganglionic blockade experiments revealed suppressed renin expression and reduced Ang II and higher neurogenic pressure response, respectively. Plasma and urine screens revealed apparently normal fluid and electrolyte handling in Agt-Tg. Interestingly, hematological analyses showed increased hematocrit in Agt-Tg caused by enhanced erythropoiesis, which was reverted by submitting the transgenic mice to a long-term peripheral sympathectomy protocol. Collectively, our findings suggest that Agt-Tg is a valuable tool to study not only brain Ang II formation and its modulatory effects on cardiovascular homeostasis but also its role in erythropoiesis control via autonomic modulation.

Altered endocannabinoid-dynamics in craniopharyngioma patients and their association with HPA-axis disturbances.

Patients with craniopharyngioma (CP) frequently suffer from morbid obesity. Endocannabinoids (ECs) are involved in weight gain and rewarding behavior but have not been investigated in this context. Cross-sectional single-center study. Eighteen patients with CP and 16 age- and sex-matched controls were included. Differences in endocannabinoids (2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)) and endocannabinoid-like molecules (oleoyl ethanolamide (OEA), palmitoylethanolamide (PEA), and arachidonic acid (AA) were measured at baseline and following endurance exercise. We further explored ECs-dynamics in relation to markers of HPA-axis activity (ACTH, cortisol, copeptin) and hypothalamic damage. Under resting conditions, independent of differences in BMI, 2-AG levels were more than twice as high in CP patients compared to controls. In contrast, 2-AG and OEA level increased in response to exercise in controls but not in CP patients, while AEA levels decreased in controls. As expected, exercise increased ACTH and copeptin levels in controls only. In a mixed model analysis across time and group, HPA measures did not provide additional information for explaining differences in 2-AG levels. However, AEA levels were negatively influenced by ACTH and copeptin levels, while OEA levels were negatively predicted by copeptin levels only. There were no significant differences in endocannabinoids depending on hypothalamic involvement. Patients with CP show signs of a dysregulated endocannabinoid system under resting conditions as well as following exercise in comparison to healthy controls. Increased 2-AG levels under resting conditions and the missing response to physical activity could contribute to the metabolic phenotype of CP patients.

Copeptin as a predictive marker of incident heart failure.

AimsHeart failure (HF) is a common disease with increasing prevalence and poor prognosis. The vasopressin (VP) marker copeptin predicts development of diabetes mellitus, diabetic heart disease, coronary artery disease, and premature mortality. Copeptin is elevated in HF patients and predicts a worse outcome. This study aims to investigate whether copeptin can predict HF development.MethodsCopeptin was analysed in 5297 individuals (69.6% men) without prevalent HF from the Malmö Preventive Project, a population‐based prospective cohort. Cox proportional hazards models were used to analyse risk of incident HF by copeptin levels after adjusting for conventional cardiovascular risk factors.ResultsDuring a median follow‐up time of 11.1 years, 350 subjects (6.6%) were diagnosed with HF. Of these events, 99 were classified as myocardial infarction (MI) related HF and 251 as non‐MI‐related HF. Individuals in the top quartile of copeptin had, after multivariate adjustment for conventional risk factors (age, sex, systolic blood pressure, diabetes mellitus, body mass index, antihypertensive therapy, smoking, low‐density lipoprotein cholesterol, and high‐density lipoprotein cholesterol), a significantly increased risk of developing HF by 1.63 [confidence interval (CI) 1.20–2.21] for HF compared with the reference quartile 1. After adjustment for conventional risk factors, the hazard ratio (HR) per standard deviation increase of log‐transformed copeptin for any HF was 1.30 (95% CI 1.17–1.46), whereas it was 1.39 (CI 1.13–1.71) for MI‐related HF and 1.26 (CI 1.11–1.44) for non‐MI‐related HF. The associations remained after additional adjustment for estimated glomerular filtration rate [HR 1.24 (95% CI: 1.10–1.40)] and for pro atrial natriuretic peptide on top of conventional risk factors [HR 1.14 (95% CI: 1.02–1.28)].ConclusionsElevated copeptin predicts development of HF in older adults. Copeptin is a risk marker of VP‐driven HF susceptibility and a candidate to guide prevention efforts of HF targeting the VP system.

Value of Serum Copeptin Estimation in the Diagnosis of Kidney Injury in Preeclampsia

Background: Copeptin is a peptide secreted from the hypothalamus, with the arginine vasopressin (AVP). Also, as copeptin is excreted by the kidneys and is stable in plasma, it can be used as a biomarker for AVP secretion. Aim: This study was conducted to evaluate the role of serum copeptin in the diagnosis of kidney injury in pregnant females with preeclampsia. Methods: This study included a total of 60 women; 20 pregnant with preeclampsia, 20 with normal pregnancy, and 20 healthy non-pregnant control. The following investigations had been made; HbA1C, blood urea, serum creatinine, serum uric acid, creatinine clearance, glomerular filtration rate (GFR), urinary protein, urinary sodium (Na), liver function tests, and serum copeptin levels were measured by an enzyme-linked immunoassay (ELISA). Results: Serum copeptin levels in pg/ml mean±SD were significantly higher in preeclampsia (3778.5±265.45) than in normal pregnancy (1452.9±397.81), and non-pregnant control (253.88±294.6) (p < 0.05) (S). Serum copeptin showed a positive correlation with the blood pressure, HbA1C, serum creatinine, uric acid, bilirubin, ALT and AST, urinary Na, blood urea, and urinary proteins (p < 0.05) (S), and a negative correlation with the GFR and creatinine clearance (p < 0.05) (S). Receiver Operating Characteristic (ROC) curve for serum copeptin as a marker for kidney injury in preeclampsia; at a cutoff point 3100 pg/ml, showed 95.0% sensitivity, 85.0% specificity (p < 0.05) (S). Conclusion: Serum copeptin can be used as a marker for the diagnosis of kidney injury in preeclampsia, with high sensitivity and specificity.

The relationship between cardiac resynchronization therapy and serum levels of copeptin in patients with chronic heart failure

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): The present study was supported by a grant from Slovak Hearth Rhythm Association (Prognostic value of MR-proANP and MR-proADM in patients undergoing cardiac resynchronization therapy). Background Chronic heart failure (CHF) is a complex syndrome characterized by an abnormal neurohormonal activation, including arginine vasopressin (AVP). Copeptin is an indicator of AVP activation, which levels are elevated in CHF and have prognostic importance. Cardiac resynchronization therapy (CRT) is an important device therapy for patients with advanced CHF, left ventricular (LV) systolic dysfunction and evidence of electromechanical dyssynchrony. The aim of the present study was to determine the possible relationship between CRT and serum copeptin levels. Methods We have included CRT patients with ischemic as well as nonischemic etiology of CHF. The levels of copeptin were measured at baseline and 12 months respectively after CRT implantation. Echocardiography was also performed pre and 12 months post CRT implantation. A CRT response was defined as a ≥ 15 % reduction in LV end-systolic volume (LVESV). Results The study population consisted of 41 patients. The mean copeptin level was 20.50 ± 15.77 pmol/l. Copeptin levels positively correlated with New York Heart Association class, left atrial diameter, creatinine levels and NT-proBNP levels. CRT responders have significant reduction in copeptin levels from baseline to 12 months (from 16.96 ± 12.80 pmol/l to 6.20 ± 6.44 pmol/l, p &amp;lt; 0.001). No significant changes in copeptin levels were observed in CRT nonresponders. Reduction &amp;gt; 45 % in copeptin levels was predictor of CRT-response (OR 6.72, 95 % CI 1.01 - 18.11, p = 0.045). Conclusion The copeptin serum levels can be a useful biomarker in the evaluation of the CRT response.

The differential activation of cardiovascular hormones across distinct stages of portal hypertension predicts clinical outcomes

Background and aimsThe cardiovascular hormones renin/angiotensin/aldosterone (RAA), brain-type natriuretic peptide (BNP)and arginine-vasopressin (AVP) are key regulators of systemic circulatory homeostasis in portal hypertension (PH). We assessed (i) the activation of renin, BNP and AVP across distinct stages of PH and (ii) whether activation of these hormones correlates with clinical outcomes.MethodsPlasma levels of renin, proBNP and copeptin (AVP biomarker) were determined in 663 patients with advanced chronic liver disease (ACLD) undergoing hepatic venous pressure gradient (HVPG) measurement at the Vienna General Hospital between 11/2011 and 02/2019. We stratified for Child stage (A–C), HVPG (6–9 mmHg, 10–15 mmHg, ≥ 16 mmHg) and compensated vs. decompensated ACLD.ResultsWith increasing PH, hyperdynamic state was indicated by higher heart rates (6–9 mmHg: median 71.0 [IQR 18.0] bpm, 10–15 mmHg: 76.0 [19.0] bpm, ≥ 16 mmHg: 80.0 [22.0] bpm; p < 0.001), lower mean arterial pressure (6–9 mmHg: 103.0 [13.5] mmHg, 10–15 mmHg: 101.0 [19.5] mmHg, ≥ 16 mmHg: 99.0 [21.0] mmHg; p = 0.032) and lower serum sodium (6–9 mmHg: 139.0 [3.0] mmol/L, 10–15 mmHg: 138.0 [4.0] mmol/L, ≥ 16 mmHg: 138.0 [5.0] mmol/L; p < 0.001). Across HVPG strata (6–9 mmHg vs. 10–15 mmHg vs ≥ 16 mmHg), median plasma levels of renin (21.0 [50.5] vs. 25.1 [70.9] vs. 65.4 [219.6] µIU/mL; p < 0.001), proBNP (86.1 [134.0] vs. 63.6 [118.0], vs. 132.2 [208.9] pg/mL; p = 0.002) and copeptin (7.8 [7.7] vs. 5.6 [8.0] vs. 10.7 [18.6] pmol/L; p = 0.024) increased with severity of PH. Elevated renin levels independently predicted first hepatic decompensation (adjusted hazard ratio [aHR]: 1.69; 95% confidence interval [95% CI] 1.07–2.68; p = 0.025) and mortality in compensated patients (aHR: 3.15; 95% CI 1.70–5.84; p < 0.001) and the overall cohort aHR: 1.42; 95% CI 1.01–2.01; p = 0.046). Elevated copeptin levels predicted mortality in decompensated patients (aHR: 5.77; 95% CI 1.27–26.33; p = 0.024) and in the overall cohort (aHR: 3.29; 95% CI 1.36–7.95; p = 0.008). ProBNP levels did not predict clinical outcomes.ConclusionsThe cardiovascular hormones renin, proBNP and AVP are activated with progression of ACLD and PH. Renin activation is a risk factor for hepatic decompensation and mortality, especially in compensated patients. Increased plasma copeptin is a risk factor for mortality, in particular in decompensated patients.

Oxytocin Levels in Response to Pituitary Provocation Tests in Healthy Volunteers

Background: Oxytocin, secreted into the circulation through the posterior pituitary, regulates lactation, weight, and socio-behavioral functioning. Oxytocin deficiency has been suggested in patients with hypopituitarism, however, diagnostic testing for oxytocin deficiency has not been developed. Known stimuli used in the diagnosis of pituitary deficiencies - the hypertonic saline and arginine infusion tests stimulating copeptin levels, and the oral macimorelin test stimulating growth hormone levels - have also been shown to stimulate oxytocin secretion in animal models. We hypothesized that these provocation tests would stimulate plasma oxytocin levels in humans. Methods: Basal plasma oxytocin levels were measured for all three tests. Stimulated plasma oxytocin was measured once plasma sodium >150 mmol/l for the hypertonic saline and after 45 minutes for the arginine infusion and the oral macimorelin test, expected peak of copeptin and growth hormone levels, respectively. Primary outcome was change between basal and stimulated oxytocin levels using a paired t-test. Results: Median (IQR) age of all participants was 24 years (22, 28), 51% were female. As expected, copeptin increased in response to hypertonic saline from 4.0 pmol/L [3.3, 6.7] to 34.2 pmol/L [23.2, 45.4] (p-value <0.001) and in response to arginine infusion from 4.6 pmol/L [3.2, 6.2] to 8.3 pmol/L [6.4, 10.8] (p-value <0.001). Growth hormone increased in response to oral macimorelin from 1.6 ng/mL [0.3, 17.2] to 106.0 ng/mL [73.3, 127.2] (p-value <0.001). Oxytocin levels increased in response to hypertonic saline infusion from 0.3 pg/mL [0.3, 0.5] to 0.6 pg/mL [0.4, 0.7] (p-value 0.007), while there was no change in response to arginine infusion (basal 0.4 pg/mL [0.4, 0.6], stimulated 0.4 pg/mL [0.3, 0.6], p-value 0.6), nor to oral macimorelin (basal 38.7 pg/mL [31.1, 66.9], stimulated 34.2 pg/mL [31.2, 48.2], p-value 0.3). Conclusion: We found that hypertonic saline infusion results in doubling of oxytocin levels. Further research will be important to determine whether this test could be used diagnostically to identify patients with oxytocin deficiency. In contrast to animal data, arginine and macimorelin did not stimulate oxytocin.

Copeptin Levels Before and After Transsphenoidal Surgery for Cushing Disease: A Potential Marker of Remission

Abstract Objectives: Chronic hypercortisolemia suppresses AVP secretion. Copeptin makes up the C-terminal portion of the AVP precursor pre-pro-AVP, is released in stoichiometric amounts with AVP, and is a stable surrogate marker of AVP.A post-operative increase in plasma copeptin was hypothesized to be a marker of remission of Cushing Disease (CD). Methods: Plasma copeptin was obtained in patients with CD before and daily in the first week after transsphenoidal surgery (TSS), measured using the Brahm Kryptor Compact PLUS sandwich immunofluorescent assay. Urine output, serum sodium, urine specific gravity, and urine/serum osmolality were used to determine development of central diabetes insipidus (DI) and/or syndrome of inappropriate anti-diuretic hormone secretion (SIADH). Change in copeptin reflects pre-TSS to peak post-TSS copeptin levels. Statistical analyses were completed using non-parametric tests. Results are presented as median (inter-quartile range). Results: Forty-four patients (64% female, 7-55 years old) were included. After TSS, 8 (18%) developed DI, 13 (30%) developed SIADH, 4 (9%) developed both DI and SIADH, and 19 (43%) developed neither. Thirty-three patients had a follow-up at 3-6 months. Overall, there was no difference in peak post-TSS copeptin for patients in remission versus those not in remission [6.1 pmol/L (4.3-12.1) vs. 7.3 pmol/L (5.4-8.4), p=0.88]. There was, also, no difference in the copeptin change for those in remission versus not in remission [2.3 pmol/L (-0.5-8.2) vs. 0.1 pmol/L (-0.1-2.2), p=0.46]. When we excluded patients who developed a water balance disorder postoperatively, there was a difference in peak post-TSS copeptin for those in remission [10.2 pmol/L (6.9-21.0)] vs. those not in remission [5.4 pmol/L (4.6-7.3), p=0.032], but not in the change in copeptin for those in remission vs. not in remission [5.1 pmol/L (0.3-19.5) vs. 1.1 pmol/L (-0.1-2.2), p=0.39]. Conclusions: Post-TSS plasma copeptin may be a useful early marker to predict remission of CD after TSS. However, the utility of this test may be limited to those who do not develop water balance disorders post-operatively. Additional studies with larger sample sizes are needed to confirm these findings and to determine a post-operative plasma copeptin cutoff level that may predict remission of CD.

The Arginine Stimulation Test Allows Rapid Diagnosis of Central Diabetes Insipidus in Children

Introduction: Water deprivation testing (H2O-dep) is usually required to distinguish between diabetes insipidus (DI) and primary polydipsia (PP) in children with polydipsia-polyuria syndrome (PP-S). The H2O-dep is challenging for children and their families. The prolonged fasting may provoke hypoglycemia and dehydration, particularly in younger children. Serum concentrations of copeptin (COP) (a surrogate marker of AVP, which is easier to measure by a robust assay), are known to increase in adults and children undergoing IV arginine (ARG) stimulation testing (ASTT). Objective: To test the hypothesis that COP levels during ASTT would differentiate between DI and PP. Methods: Serum COP responses to ARG were measured in 13 healthy short children being tested for GH deficiency (controls); and in 4 patients with PP-S. Arginine-HCl (500 mg/Kg) was infused IV from 0 to 30 min, with blood sampling at 0, 15, 30, 45, 60 min; seven of 13 controls also received clonidine PO (150 mcg/m2) at 0 min. COP was measured with a 2-site immunometric assay (BRAHMS Platform, Quest Diagnostics). Results: A-Controls. As the COP values at each time point were similar in the ARG and ARG-Clonidine controls, the data from both groups were combined. COP peaked at 45-60 min post ARG in the 13 controls. COP (Mean+SD; pMol/l)) increased from 9.7+4.3, (range 3-17) to a peak of 12.4+5.0 (range 6-21) at 60 min; Δ% increase 47+50 % (range 0-133). The peak COP values on ASTT showed no correlation with subjects’ age or peak GH response. Results B: Subjects with PP-S: On the basis of H2O-dep, MRI findings, and long-term response to desmopressin therapy, 3 of 4 children were diagnosed with central DI, and 1 with PP. Abbreviations: S[Osm], U[Osm]= serum, urine osmolality (mOsm/Kg); values obtained at the end of the H2O Dep: Subject 1. 3 y-old male, diagnosed with PP. After H2O-dep S[Osm] / U[Osm] 286 / 615. On ASTT COP (base vs. peak) 15 vs.116 pMol/l. Subject 2. 8 y-old male, diagnosed with central DI with Langerhans cell histiocytosis (LCH). MRI: absent bright spot. After H2O-dep S[Osm] / U[Osm] 318/202; On ASTT COP (base vs. peak) 2 vs. 2 pMol/l. Subject 3. 2 y-old male. diagnosed with central DI, possible LCH; MRI: absent bright spot. No H2O-dep; On ASTT COP (base vs. peak) 3 vs 3 pMol/l. Subject 4. Male, 3 y-old. Diagnosed with partial DI with LCH. MRI: absent bright spot. After H2O-dep S[Osm] / U[Osm] 297/569. On ASTT COP (base vs. peak) 5 vs. 6 pMol/l. Comment: In all DI patients, COP concentrations remained flat in the ASTT, at 2-3 pmol/L in 2 subjects with complete DI, and 5-6 pmol/L in 1 subject with partial DI. The latter response overlapped with that of 1 of 13 control subjects. Conclusions: These preliminary data support the hypothesis that ASTT is an easy, minimally invasive test, valuable for differentiating the etiology of PP-S in children. However, patients with partial DI may have low-normal COP responses at ASTT that overlap with values in normal children.

A Rare Case of Nephrogenic Diabetes Insipidus From Tenofovir

Introduction: Diabetes insipidus (DI) is a clinical condition which manifests as excessive urine output, either because of impaired or inadequate antidiuretic hormone (ADH) secretion, or an inability of the kidneys to respond to ADH. Nephrogenic DI is more often drug induced. Recent clinical reports have shown that medications like tenofovir may result in nephrogenic DI as well. Tenofovir is a well-known nucleoside reverse transcriptase inhibitor analog of adenosine used in the management of both human immunodeficiency virus (HIV) and chronic hepatitis B. With its increased use, reports of adverse outcomes have been documented, mainly its effect on renal function including nephrogenic DI, renal failure and Fanconi syndrome. We present a case of nephrogenic DI whilst on Biktarvy (a combination of bictegravir, emtricitabine and tenofovir alafenamide). Case: A 59-year-old African American female with a history of HIV on Biktarvy, T2DM, HLD, HTN, MI, CAD, COPD presented to our hospital with weakness and falls for 1-2 months associated with polydipsia and polyuria. She had started Biktarvy for HIV about 2 months ago after which her symptoms got worse. Labs showed a serum Na of 151, potassium of 3.2 on admission with serum osmolality of 323 and urine osmolality of 134. During hospitalization, she was challenged with 100ug oral Desmopressin. Urine labs failed to correct after Desmopressin administration which was highly indicative of severe nephrogenic DI. The challenge was repeated with 200ug oral Desmopressin with similar results. Pituitary DI was considered given the patient’s falls; however urine osmolality did not improve following desmopressin challenge. Furthermore, her serum Co-peptin level was elevated at 36.1 that ruled out central DI. The patient’s hypokalemia was believed to be driving her nephrogenic DI which has been reported in various case reports with patients on Tenofovir, but has never been reported in patients taking Biktarvy (which includes Tenofovir Alafenamide). She was subsequently placed on fluid restriction during which time the patient’s serum Na and Cr increased while urine osmolality did not correct. HCTZ was ultimately started as a treatment for nephrogenic DI and patient was transitioned of biktarvy to lamivudine and dolutegravir. Her polyuria and polydipsia improved, however she developed hyponatremia likely because of HCTZ. Patient concentrating ability improved off biktarvy and HCTZ was discontinued on the day prior to discharge without issue. Her subsequent serum sodium and potassium levels were normal. Conclusions: Our case highlights a rare incidence of tenofovir induced hypokalemia leading to nephrogenic DI. This case illustrates the importance of monitoring patients on tenofovir for signs of renal [tubular] dysfunction. In a polyuric patient on tenofovir, there should be a high index of suspicion for nephrogenic diabetes insipidus.