Copeptin as a novel biomarker of cardiometabolic syndrome.

Arginine vasopressin (AVP), which is also called antidiuretic hormone (ADH), is a neurohormone synthetized from a pre-pro-hormone precursor in the supraoptic and paraventricular nuclei of the hypothalamus in response to increased plasma osmolality and decreased blood volume. AVP exerts several effects by binding to three different receptors: V1aR, V1bR, and V2R. In recent years, it has been suggested that increased plasma concentration of AVP may play a causal role in the development of type 2 diabetes, the metabolic syndrome, renal dysfunction and cardiovascular disease by influencing glucose homeostasis and lipid metabolism through several possible mechanisms involving V1aR and V1bR. V1aR located in the liver is involved in hepatic glycogenolysis and gluconeogenesis. V1bR, found in the pituitary gland and pancreas, mediates secretion of adrenocorticotrophic hormone (ACTH), insulin, and glucagon. However, AVP's clinical use as a biomarker is limited due to its short half-life in plasma (16-20 minutes), small size, and poor stability, which make direct measurement difficult. Copeptin, the biologically inactive, stable, C-terminal part of pro-vasopressin, is co-secreted with AVP in equimolar amounts and thus is considered an adequate and clinically useful surrogate marker of AVP. The aim of this review is to assess the current state of knowledge about the potential role of copeptin as a novel biomarker of cardiometabolic syndrome on the basis of recent scientific literature published up to December 2020 and searches of the PubMed, Google Scholar, and Web of Science databases.

Copeptin - a new diagnostic and prognostic biomarker in neurological and cardiovascular diseases.

Copeptin, arginine vasopressin (AVP)-associated 39 aminoacid glycopeptide, is a C-terminal part of pro-AVP. AVP acts through V1a, V1b, and V2 receptors. The effect on V1a receptors is connected with arterial vasoconstriction, on V2 with antidiuretic action, and on V1b with the secretion of ACTH, insulin, glucagon. Copeptin is found in the circulation in equimolar amounts with AVP. It is a very stable peptide and easy to estimate. Copeptin is a good diagnostic marker in many disorders in which vasopressinergic dysfunction plays a role in pathogenesis such as a polyuria-polydipsia syndrome, neurological disease (ischemic stroke, nontraumatic, intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage and neurodegenerative disease (multiple sclerosis). Copeptin is a diagnostic and prognostic marker in cardiovascular diseases like heart failure (HF) and acute myocardial infarct (AMI). Copeptin is a sensitive diagnostic marker in the early stage of AMI especially in patients with non-ST segment elevation and post AMI complications. Copeptin is also an important diagnostic and prognostic marker in metabolic diseases (diabetes mellitus, metabolic syndrome, insulin resistance), connected with some neurological and cardiovascular diseases. In the future, these findings may have also therapeutic applications in conditions where the AVP receptor antagonist therapy is appropriate.

Water intake keeps type 2 diabetes away? Focus on copeptin.

INTRODUCTION: In both diabetic subjects and animal models high levels of vasopressin (AVP) have beendetected. The relationship between AVP and glucose metabolism is mediated through several direct andindirect effects and most of them are still unknown. METHODS: We have reviewed 100 manuscripts retrieved from Cochrane Library, Embase and Pubmeddatabases in order to highlight a possible relationship between copeptin and type 2 diabetes and to provideinsights on the molecular mechanism that could explain this association. RESULTS AND CONCLUSIONS: AVP potentiates CRH action at pituitary level resulting in an increased ACTH secretion and in turn in an increased cortisol secretion that escapes the negative feedback loop. Further, AVP regulates insulin and glucagon secretion through V1b receptor and promotes hepatic glycogenolysis and gluconeogenesis through V1a receptor. In addition to worsen glucose metabolism, AVP has been reported to have a role in the pathogenesis of diabetic complications such as cardiovascular diseases, kidney and ocular complications. Due to the very low concentration of AVP in the blood, the small size and poor stability, the assay of AVP is very difficult to perform. Thus, copeptin, the stable C-terminal portion of the prepro-vasopressin peptide has been identified as an easier assay to be measured and that mirrors AVP activity. Although there are promising evidence that copeptin could be involved in the pathogenesis of type 2 diabetes, further studies need to demonstrate the importance of copeptin as clinical marker to predict glucose metabolism derangements.

The copeptin response after physical activity is not associated with cardiac biomarkers or asymptomatic coronary artery disease: The North Sea Race Endurance Exercise Study (NEEDED) 2013.

BACKGROUND: Copeptin concentrations increase both during acute coronary syndrome and following physical exercise. The relationship between copeptin increase following physical exercise and coronary artery disease (CAD) is uncertain. The aim of this study was to 1) describe the copeptin response following strenuous physical exercise, and 2) investigate the determinants of exercise induced copeptin concentrations, particularly in relation to cardiac biomarkers and CAD. METHODS: Serum samples were collected from 97 recreational cyclists 24h before, and immediately, 3 and 24h after a 91-km bike race. Three subjects were subsequently diagnosed with significant asymptomatic CAD. Delta copeptin concentrations were correlated to patient characteristics and to biomarker concentrations. RESULTS: Participants were 42.8±9.6years, and 76.3% were male. Copeptin concentrations increased to maximal levels immediately after the race and were normalized in >90% after 3h. A total of 53% and 39% exceeded the 95th and 99th percentile of the assay (10 and 19pmol/L) respectively. In multivariate models, race time, serum sodium, creatinine and cortisol were significant predictors of copeptin levels. There was no correlation between changes in copeptin and changes in cardiac biomarkers (hs-cTnI, hs-cTnT and BNP). Copeptin concentrations were normal in the subjects with asymptomatic CAD. CONCLUSIONS: The moderate, short-term, exercise induced copeptin increase observed in the present study was not related to hs-cTn or BNP levels. Copeptin was normal in three asymptomatic recreational athletes with significant CAD.

The vasopressin system: new insights for patients with kidney diseases: Epidemiological evidence and therapeutic perspectives.

People with chronic kidney disease (CKD) are at risk of severe outcomes, such as end-stage renal disease or cardiovascular disease, and CKD is a globally increasing health burden with a high personal and economic cost. Despite major progresses in prevention and therapeutics in last decades, research is still needed to reverse this epidemic trend. The regulation of water balance and the state of activation of the vasopressin system have emerged as factors tightly associated with kidney health, in the general population but also in specific conditions; among them, various stages of CKD, diabetes and autosomal dominant polycystic kidney disease (ADPKD). Basic science findings and also epidemiological evidence have justified important efforts towards interventional studies supporting causality, and opening therapeutic avenues. On the basis of recent clinical data, the blockade of V2 vasopressin receptors using tolvaptan in patients with rapidly progressing ADPKD has been granted in several countries, and a long-term randomized trial evaluating the effect of an increase in water intake in patients with CKD is on-going.

Vasopressin and metabolic disorders: translation from experimental models to clinical use.

Vasopressin has many physiological actions in addition to its well-defined role in the control of fluid homeostasis and urine concentration. An increasing body of evidence suggests that the vasopressin-hydration axis plays a role in glucose homeostasis. This review summarizes the knowledge accumulated over the last decades about the influence of vasopressin in the short-term regulation of glycaemia. It describes the possible role of this hormone through activation of V1a and V1b receptors on liver and pancreas functions and on the hypothalamic-pituitary-adrenal axis. Moreover, we report recent in vivo studies demonstrating the role of vasopressin in the long-term regulation of glycaemia. Indeed, V1a- or double-V1aV1b-receptor knockout mice display significant changes in the glucose and lipid metabolism. In rats, sustained high V1aR activation increases basal glycaemia and aggravates glucose intolerance in obese rats. Finally, the translation from animal findings to human was evidenced by epidemiological and genetic studies that showed that high vasopressin level is a risk factor for hyperglycaemia, metabolic disorders and diabetes.

Vasopressin: physiology, assessment and osmosensation.

Vasopressin (AVP) plays a major role in the regulation of water and sodium homeostasis by its antidiuretic action on the kidney, mediated by V2 receptors. AVP secretion is stimulated by a rise in plasma osmolality, a decline in blood volume or stress. V1a receptors are expressed in vascular smooth muscle cells, but the role of vasopressin in blood pressure regulation is still a matter of debate. AVP may also play a role in some metabolic pathways, including gluconeogenesis, through its action on V1a receptors expressed in the liver. It is now understood that thirst and arginine vasopressin (AVP) release are regulated not only by the classical homeostatic, intero-sensory plasma osmolality negative feedback, but also by novel, extero-sensory, anticipatory signals. AVP measurement is time-consuming, and AVP level in the blood in the physiological range is often below the detection limit of the assays. Recently, an immunoassay has been developed for the measurement of copeptin, a fragment of the pre-provasopressin molecule that is easier to measure. It has been shown to be a good surrogate marker of AVP.

Diagnosis and Treatment of Hyponatremia: Compilation of the Guidelines.

Hyponatremia is a common water balance disorder that often poses a diagnostic or therapeutic challenge. Therefore, guidelines were developed by professional organizations, one from within the United States (2013) and one from within Europe (2014). This review discusses the diagnosis and treatment of hyponatremia, comparing the two guidelines and highlighting recent developments. Diagnostically, the initial step is to differentiate hypotonic from nonhypotonic hyponatremia. Hypotonic hyponatremia is further differentiated on the basis of urine osmolality, urine sodium level, and volume status. Recently identified parameters, including fractional uric acid excretion and plasma copeptin concentration, may further improve the diagnostic approach. The treatment for hyponatremia is chosen on the basis of duration and symptoms. For acute or severely symptomatic hyponatremia, both guidelines adopted the approach of giving a bolus of hypertonic saline. Although fluid restriction remains the first-line treatment for most forms of chronic hyponatremia, therapy to increase renal free water excretion is often necessary. Vasopressin receptor antagonists, urea, and loop diuretics serve this purpose, but received different recommendations in the two guidelines. Such discrepancies may relate to different interpretations of the limited evidence or differences in guideline methodology. Nevertheless, the development of guidelines has been important in advancing this evolving field.

Reduction in central venous pressure enhances erythropoietin synthesis: role of volume-regulating hormones.

AIMS: Erythropoiesis is a tightly controlled biological event, but its regulation under non-hypoxic conditions, however, remains unresolved. We examined whether acute changes in central venous blood pressure (CVP) elicited by whole-body tilting affect erythropoietin (EPO) concentration according to volume-regulating hormones. METHODS: Plasma EPO, angiotensin II (ANGII), aldosterone, pro-atrial natriuretic peptide (proANP) and copeptin concentrations were measured at supine rest and up to 3 h during 30° head-up (HUT) and head-down tilt (HDT) in ten healthy male volunteers. Plasma albumin concentration was used to correct for changes in plasma volume and CVP was estimated through the internal jugular vein (IJV) aspect ratio with ultrasonography. RESULTS: From supine rest, the IJV aspect ratio was decreased and increased throughout HUT and HDT respectively. Plasma EPO concentration increased during HUT (13%; P = 0.001, P for linear component = 0.017), independent of changes in albumin concentration. Moreover, ANGII and copeptin concentrations increased during HUT, while proANP decreased. The increase in EPO concentration during HUT disappeared when adjusted for changes in copeptin. During HDT, EPO, ANGII and copeptin concentrations remained unaffected while proANP increased. In regression analyses, EPO was positively associated with copeptin (ß = 0.55; 95% CI = 0.18, 0.93; P = 0.004) irrespective of changes in other hormones and albumin concentration. CONCLUSION: Reduction in CVP prompts an increase in plasma EPO concentration independent of hemoconcentration and hence suggests CVP per se as an acute regulator of EPO synthesis. This effect may be explained by changes in volume-regulating hormones.

Glycopeptidolipid of Mycobacterium smegmatis J15cs Affects Morphology and Survival in Host Cells.

Mycobacterium smegmatis has been widely used as a mycobacterial infection model. Unlike the M. smegmatis mc(2)155 strain, M. smegmatis J15cs strain has the advantage of surviving for one week in murine macrophages. In our previous report, we clarified that the J15cs strain has deleted apolar glycopeptidolipids (GPLs) in the cell wall, which may affect its morphology and survival in host cells. In this study, the gene causing the GPL deletion in the J15cs strain was identified. The mps1-2 gene (MSMEG_0400-0402) correlated with GPL biosynthesis. The J15cs strain had 18 bps deleted in the mps1 gene compared to that of the mc(2)155 strain. The mps1-complemented J15cs mutant restored the expression of GPLs. Although the J15cs strain produces a rough and dry colony, the colony morphology of this mps1-complement was smooth like the mc(2)155 strain. The length in the mps1-complemented J15cs mutant was shortened by the expression of GPLs. In addition, the GPL-restored J15cs mutant did not survive as long as the parent J15cs strain in the murine macrophage cell line J774.1 cells. The results are direct evidence that the deletion of GPLs in the J15cs strain affects bacterial size, morphology, and survival in host cells.

In planta processing and glycosylation of a nematode CLAVATA3/ENDOSPERM SURROUNDING REGION-like effector and its interaction with a host CLAVATA2-like receptor to promote parasitism.

Like other biotrophic plant pathogens, plant-parasitic nematodes secrete effector proteins into host cells to facilitate infection. Effector proteins that mimic plant CLAVATA3/ENDOSPERM SURROUNDING REGION-related (CLE) proteins have been identified in several cyst nematodes, including the potato cyst nematode (PCN); however, the mechanistic details of this cross-kingdom mimicry are poorly understood. Plant CLEs are posttranslationally modified and proteolytically processed to function as bioactive ligands critical to various aspects of plant development. Using ectopic expression coupled with nanoliquid chromatography-tandem mass spectrometry analysis, we show that the in planta mature form of proGrCLE1, a multidomain CLE effector secreted by PCN during infection, is a 12-amino acid arabinosylated glycopeptide (named GrCLE1-1Hyp4,7g) with striking structural similarity to mature plant CLE peptides. This glycopeptide is more resistant to hydrolytic degradation and binds with higher affinity to a CLAVATA2-like receptor (StCLV2) from potato (Solanum tuberosum) than its nonglycosylated forms. We further show that StCLV2 is highly up-regulated at nematode infection sites and that transgenic potatoes with reduced StCLV2 expression are less susceptible to PCN infection, indicating that interference of the CLV2-mediated signaling pathway confers nematode resistance in crop plants. These results strongly suggest that phytonematodes have evolved to utilize host cellular posttranslational modification and processing machinery for the activation of CLE effectors following secretion into plant cells and highlight the significance of arabinosylation in regulating nematode CLE effector activity. Our finding also provides evidence that multidomain CLEs are modified and processed similarly to single-domain CLEs, adding new insight into CLE maturation in plants.

A systematic review and collaborative meta-analysis to determine the incremental value of copeptin for rapid rule-out of acute myocardial infarction.

Multiple studies have evaluated copeptin, a surrogate for arginine vasopressin, in the diagnosis of acute myocardial infarction (AMI) with mixed results. A systematic review and collaborative meta-analysis were performed for diagnosis of AMI and assessment of prognosis in patients presenting to the emergency department with chest pain. MEDLINE/PubMed, Cochrane CENTRAL, and EMBASE were searched for studies assessing copeptin in such patients. Study investigators were contacted, and many provided previously unpublished data. Random-effects methods were used to compare the data for copeptin, troponin, and their combination. There were a total of 9,244 patients from the 14 included studies. Mean age was 62 years; 64% were men; and 18.4% were ultimately diagnosed with AMI. Patients with AMI had a higher presentation copeptin level than those without AMI (22.8 vs 8.3 pmol/L, respectively, p <0.001). Although troponin had better diagnostic accuracy than copeptin for AMI, the combination of copeptin and troponin significantly improved the sensitivity (0.905 [0.888 to 0.921] vs 0.686 [0.661 to 0.710], respectively, p <0.001) and negative predictive value (0.97 [0.964 to 0.975] vs 0.93 [0.924 to 0.936], respectively, p <0.001) compared with troponin alone. Elevation in copeptin carried a similar risk of all-cause mortality to an elevation in troponin (odds ratio 5.84 vs 6.74, respectively, p = 0.67). In conclusion, copeptin not only identifies patients at risk of all-cause mortality, but its addition to troponin improved the sensitivity and negative likelihood ratio for diagnosis of AMI compared with troponin alone. Thus, copeptin may help identify patients who may be safely discharged early from the emergency department.

vanO, a new glycopeptide resistance operon in environmental Rhodococcus equi isolates.

We describe here the sequence and gene organization of a new glycopeptide resistance operon (vanO) in Rhodococcus equi from soil. The vanO operon has low homology to enterococcal van operons and harbors a vanHOX cluster transcribed in the direction opposite that of the vanS-vanR regulatory system and composed of three open reading frames with unknown function. This finding has clinical interest, since glycopeptides are used to treat R. equi infections and resistance has been reported in clinical isolates.

Mycothiol: a promising antitubercular target.

Tuberculosis (TB) is the world's second commonest cause of death next to HIV/AIDS. The increasing emergence of multi drug resistance and the recalcitrant nature of persistent infections pose an additional challenge for the treatment of TB. Due to the development of resistance to conventional antibiotics there is a need for new therapeutic strategies to combat M. tuberculosis. One such target is Mycothiol (MSH), a major low molecular-mass thiol in mycobacteria, an important cellular anti-oxidant. MSH is present only in actinomycetes and hence is a good target. This review explores mycothiol as a potential target against tuberculosis and various research ongoing worldwide.

Copeptin during rest and exercise in major depression.

BACKGROUND: High vasopressin levels and a correlation between vasopressin and cortisol has been observed in patients with depression. The aim was to assess copeptin, the c-terminal of provasopressin, and the association between cortisol, adrenocorticotropic hormone (ACTH) and copeptin in patients with depression. Secondly, to examine the copeptin response to acute exercise and aerobic training. METHODS: Copeptin, ACTH, and cortisol were measured in 111 patients with depression and 57 controls at rest. Copeptin was also measured during exercise. The depressed patients were subsequently randomized to an aerobic training intervention or an exercise control intervention. RESULTS: The plasma level of copeptin in depressed subjects was 5.14 pg/ml (IQR 3.4-8.4) and 4.82 pg/ml (IQR 2.8-7.5) in healthy controls (p=.66). The association between copeptin and cortisol was.02 (95% CI -.44 to.48; p=.93) and the association between copeptin and ACTH was -.06 (95% CI -.17 to.05; p=.27). All associations were independent of depression status (p=.15). Aerobic exercise training did not influence copeptin levels at rest (p=.09) or the response to acute exercise (p=.574). Copeptin decreased at rest in response to aerobic training in participants with high compliance to the exercise intervention (p=.04). LIMITATIONS: We did not measure plasma osmolality, which is a possible confounder in this study. CONCLUSIONS: Copeptin levels are not elevated or associated to ACTH or cortisol in depressed patients. Aerobic exercise training decreased copeptin levels in high attenders only. This study does not support a role of copeptin or vasopressin in depression.

[Kidney damage by antibiotics and chemotherapy]. / Il danno renale da antibiotici e chemioterapici.

Kidney damage caused by antibiotics is a common occurrence. In hospital wards it accounts for approximately 10% of episodes of acute renal failure and 60% of drug-related kidney damage. At greatest risk are elderly patients, especially those with preexisting chronic renal failure or comorbidities, suffering from dehydration, or hospitalized in intensive care units. The kidney's marked susceptibility to this type of damage is due to various factors including the high concentration of the toxic agent and the elevated blood flow in the kidney, and the relatively hypoxic environment. Kidney damage from antibiotics is characterized by different pathogenetic mechanisms and all kidney structures may be affected, resulting in different clinical syndromes. It is therefore of paramount importance to identify those antibiotics which have potential nephrotoxic effects so that their dosage can be based on the patient's renal function and all factors that may potentiate the toxicity can be corrected.

Changes in copeptin and bioactive vasopressin in runners with and without hyponatremia.

OBJECTIVE: To evaluate changes in both the N-terminal (arginine vasopressin; AVP) and C-terminal (copeptin) fragments of the vasopressin prohormone before, during, and after an ultramarathon race and to assess vasopressin and copeptin concentrations in runners with and without hyponatremia. DESIGN: Observational study. SETTING: Three trials (2 sodium balance and 1 hyponatremia treatment) in 2 separate approximately 160-km footraces [Western States Endurance Run (WSER) and Javelina Jundred (JJ100)]. PARTICIPANTS: Six hyponatremic and 20 normonatremic runners; 19 finishers with 7 completing 100 km. MAIN OUTCOME MEASURES: Plasma AVP ([AVP]p), copeptin ([copeptin]p), sodium ([Na]p), and protein (%plasma volume change; %PV) concentrations. RESULTS: In the WSER Sodium Trial, a 3-fold prerace to postrace increase in both [AVP]p (0.7 ± 0.4 to 2.7 ± 1.9 pg/mL; P < 0.05) and [copeptin]p (10.3 ± 12.5 to 28.2 ± 16.3 pmol/L; nonsignificant) occurred, despite a 2 mEq/L decrease in [Na]p (138.7 ± 2.3 to 136.7 ± 1.6 mEq/L; NS). A significant correlation was noted between [AVP]p and [copeptin]p postrace (r = 0.82; P < 0.05). In the WSER Treatment Trial, despite the presence of hyponatremia pretreatment versus posttreatment ([Na]p = 130.3 vs 133.5 mEq/L, respectively), both [AVP]p (3.2 vs 2.1 pg/mL) and [copeptin]p (22.5 vs 24.9 pmol/L) were well above the detectable levels. A significant correlation was noted between [AVP]p and [copeptin]p 60 minutes after treatment (r = 0.94; P < 0.05). In the JJ100 Sodium Trial, significant correlations were found between [copeptin]p change and %PV change (r = -0.34; P < 0.05) and between [AVP]p change and [Na]p change (r = 0.39; P < 0.05) but not vice-versa. CONCLUSIONS: [Copeptin]p seems to be a reliable surrogate of stimulated [AVP]p during exercise. Nonosmotic vasopressin stimulation occurs during ultradistance running. [Copeptin]p may better reflect chronic (%PV) vasopressin secretion under conditions of endurance exercise.

Vasopressin beyond water: implications for renal diseases.

PURPOSE OF REVIEW: This review aims to analyze the relationships between arginine vasopressin (AVP) and chronic kidney disease (CKD) and to define the potential of vasopressin receptor antagonists beyond the treatment of water metabolism disorders. RECENT FINDINGS: Experimental studies in rat and observational studies in humans suggest that AVP may play a role in the genesis and exacerbation of renal damage and chronic renal insufficiency. SUMMARY: A sustained stimulation of vasopressin receptors induces intrarenal renin-angiotensin system activation, podocyte alterations, glomerular hyperfiltration and hypertrophy eventuating in proteinuria and kidney damage. Furthermore, AVP directly stimulates contraction and proliferation of mesangial cells and accumulation of extracellular matrix and glomerulosclerosis. Whether a chronic increase in water intake (determining a reduction in endogenous AVP levels) and/or the administration of vasopressin receptor antagonists are useful for the prevention and treatment of CKD remains to be tested in clinical trials.

Copeptin: a biomarker of cardiovascular and renal function.

Arginine vasopressin (AVP or antidiuretic hormone) is one of the key hormones in the human body responsible for a variety of cardiovascular and renal functions. It has so far escaped introduction into the routine clinical laboratory due to technical difficulties and preanalytical errors. Copeptin, the C-terminal part of the AVP precursor peptide, was found to be a stable and sensitive surrogate marker for AVP release. Copeptin behaves in a similar manner to mature AVP in the circulation, with respect to osmotic stimuli and hypotension. During the past years, copeptin measurement has been shown to be of interest in a variety of clinical indications, including cardiovascular diseases such as heart failure, myocardial infarction, and stroke. This review summarizes the recent progress on the diagnostic use of copeptin in cardiovascular and renal diseases and discusses the potential use of copeptin measurement in the context of therapeutic interventions with vasopressin receptor antagonists.