Pathophysiology of copeptin in kidney disease and hypertension

Copeptin is derived from the cleavage of the precursor of arginine vasopressin (AVP), produced in an equimolar ratio in hypothalamus and processed during axonal transport AVP is an unstable peptide and has a short half-life of 5–20 min. Unlike AVP, copeptin is a stable molecule and can easily be measured. Recent evidence suggest that increased copeptin levels have been associated with worse outcomes in various clinical conditions including chronic kidney disease (CKD) and hypertension. In this review, the data regarding copeptin with kidney function (evaluated as glomerular filtration rate, increased albumin/protein excretion or both) and hypertension with regard to performed studies, prognosis and pathogenesis was summarised.


Background
Copeptin firstly described in 1972 by Holwerda is 39amino acids glycopeptide with leucine-rich core segment [1]. It is derived from the cleavage of the precursor of arginine vasopressin (AVP), produced in an equimolar ratio in hypothalamus and processed during axonal transport [2]. AVP is an unstable peptide, both in vivo and ex vivo, and has a short half-life of 5-20 min [3]. Unlike AVP, copeptin is a stable molecule and can easily be measured [4]. This fact stimulated the research regarding copeptin -as a measure of AVP -in various clinical conditions. Elevated levels of copeptin serve as a prognostic marker for unfavorable outcome in sepsis, shock, pneumonia, stroke, acute coronary syndrome and diabetes [5][6][7]. Additionally copeptin levels have been associated with kidney function in various studies.
In this review, the data regarding copeptin with kidney function (evaluated as glomerular filtration rate, increased albumin/protein excretion or both) with regard to performed studies, prognosis and pathogenesis was summarised.
Pub Med/Medline was searched for previous relevant reports. The search terms included copeptin and albuminuria, copeptin and proteinuria, copeptin and chronic kidney disease and copeptin and hypertension. When these terms are separately analyzed, they were mostly found to be duplicate. In final analysis, 22 studies were included for this review (Tables 1 and 2). These studies are heterogeneous with respect to inclusion criteria, design of the study and outcome measurement. Some studies included only chronic kidney disease (CKD) patients and some studies included healthy population and some studies included both (Table 1). Some studies examined only baseline relationships but others also investigate longitudinal data. In Tables 1 and 2 these studies are summarized with exclusion of dialysis patients.

Discussion
In the current manuscript the relationship between copeptin, albuminuria and GFR was reviewed. After the review of manuscripts regarding these issues some findings were emerged such as: i) Copeptin and GFR is usually negatively correlated ii) Copeptin and albuminuria/proteinuria is positively correlated iii) Copeptin and elevated BP were usually associated with each other Many studies have shown that increased copeptin concentrations are linked to renal insufficiency and copeptin is negatively associated with estimated glomerular filtration in ACR after adjusment (β: 0.07, P:0.08) but associated with a decrease in eGFR ( β -0.09, P:0.03) -There was no significant association between copeptin and change in ACR or eGFR in patients using RAASi at baseline.
-Copeptin level was borderline significantly associated with change in mGFR after adjusting for these variables (p = 0.09).
Li et al. [50] GFR and copeptin were inversely assocaited with (R:0.571, No data 86 non-dialysis patients with CKD and 20 control patients -Among CKD patients, who had atherosclerotic plagues as measured by CIMT and left ventricular hypertrophy, had higher co-peptin levels compated to CKD patients without these pathologies.
-Elevated co-peptin was independently associated with GFR, left ventricular hypertrophy, CIMT and previous history of CVD in multivariate analysis.
Sontrop et al. [51] Both at baseline (R:-0.53; P:0.003) and at 6 weeks follow-up, copeptin was inversely correlated Roussel et al. [52] No  [5,8]. Why increased copeptin was associated with GFR and with CKD? The exact mechanisms regarding the relationship between copeptin, albuminuria and GFR are not known but two mechanisms were suggested. First, as copeptin is cleared by kidney excretion, copeptin levels would tend to increase as kidney function decreases. Second, in patients with lower kidney function, more copeptin is released, because the AVP system is activated due impaired urine concentrating capacity to maintain water homeostasis [9]. However, these ideas were challenged as it was shown that copeptin was not associated with GFR in healthy living kidney donors and copeptin levels did not change after donation despite a significant drop in kidney function after nephrectomy. These data suggest that GFR alone is not a principal determinant of copeptin [10]. Indeed, longitudinal studies in humans have shown that plasma copeptin levels increase before eGFR decreases [11]. In most studies copeptin was positively associated with urinary albumin/protein excretion [5] Population-based studies have shown copeptin to be strongly associated with microalbuminuria [12]. It was suggested that increased AVP might have albuminuric effect [11]. Indeed, V2 antagonists decrease proteinuria in animal models, one can hypothesize that albuminuria is somehow related to tubular V2Rs [13,14]. Besides well-known antidiuretic effects at the collecting duct level, a V2-receptor -The responder rate was 47.5% on 24 h ABPM. (defined as a drop in systolic ABPM 5 mmHg) -The mean systolic 24 h blood pressure dropped from 152 ± 10 mmHg to 147 ± 17 mmHg (p: .044) in the six month follow up.
-Copeptin levels did not change over time after renal denervation.
BP Blood Pressure, RAS Renin-angiotensin system, ABPM Ambulatory Blood Pressure Monitoring, RDN Renal sympathetic denervation agonist was shown to induce glomerular hyperfiltration and to increase UAE in normal rats [14,15]. What are the mechanisms behind the adverse effects of copeptin on renal function? This question is not answered completely although some mechanisms were suggested (Fig. 1). In the following section these mechanisms are discussed.
Apart from classical stimulants for AVP secretion such as drop in blood pressure and hyperosmolarity, copeptin is also a marker of the body's endocrine stress response, which is mediated through the hypothalamus-pituitaryadrenal system, and is activated in acute illness [16]. For example, copeptin levels spike in concert with cortisol and corticotropin-releasing hormone within hours of acute myocardial infarction onset [17]. It is unclear, however, whether copeptin is simply a marker of stress or illness, or if it plays a direct causative role in the pathophysiology of cardiovascular and chronic kidney disease [18].
Based on the studies and findings mentioned, one can speculate that elevation of AVP plays a role in the development of CKD, presumably through an effect on the V2R. Thus, increased water intake or pharmacological vasopressin blockade are interesting candidates for preventing the decline of eGFR and development of CKD. Water ingestion, which readily decreases circulating AVP/copeptin levels, may modify CKD progression [19], Studies in the 5/6 nephrectomized rat model suggested that increased water intake decreases circulating AVP levels and slows down the progression of kidney disease [20]. As suggested above increased GFR [15] and resulting proteinuria [14] causing and accelerated renal function decline [21] and tubulo-interstitial fibrosis [22].
These findings can be considered as adverse actions of increased copeptin on kidney function.
AVP also suggest influencing composition of the tubular fluid at the macula densa that influence tubuloglomerular feedback control of GFR, as well as an increase in intraglomerular pressure subsequent to afferent arteriole vasodilatation. Results obtained in rodent models of diabetes suggest that the underlying mechanism may be that AVP leads to hyperfiltration and then to albuminuria and glomerulosclerosis [23]. Indeed, it has been suggested that high AVP levels stimulate RAAS, resulting in vasoconstriction and consequently higher systemic and glomerular BP [24].
AVP has also other deterious actions. For example AVP play a role in glucose homeostasis, insulin resistance, and lipid and fat metabolism [25][26][27]. AVP has prothrombotic properties [28] and induces von Willebrand factor release from endothelial cells [29]. It also induces secretion of endothelin 1 and prostaglandin D2 from endothelial cells [30] which aggravates the diabetes-associated endothelial dysfunction and altered coagulation. Chronic inflammation may be other explanation. Several studies have shown that proinflammatory cytokines can activate VP secretion [31]. Therefore, inflammation could induce both VP secretion and accelerated decline in renal function.
The relationship between copeptin and hypertension is also worth to mention. Most of the studies have shown a positive association with copeptina and hypertension ( Table 2) Recent evidence suggests that elevated blood pressure is associated with increased copeptin levels. For example, in hypertensive adolescents, copeptin levels were higher in normotensive adolesants. Not only office blood pressure but ambulatory blood pressures (both systolic and diastolic) were associated with copeptin levels [32][33][34]. In another recent study, the relationship between copeptin and resistant hypertension were investigated. Baseline plasma copeptin concentration was positively associated with male sex, plasma osmolality, BP, and negatively with glomerular filtration rate. It was higher in the resistant hypertension than in the controlled blood pressure group [geometric mean 5.7 (confidence interval 95% 5.1-6.4) vs. 2.9 (2.3-3.9) fmol/ml, adjusted P < 0.0001) [35]. In fact older studies have already suggested that AVP may have a role in development of hypertension [36,37]. However, Kawano et al. demonstrated that AVP did not play an important role in mild essential hypertension [38][39][40]. The lack of consensus on the role of vasopressin in essential hypertension may be the result of the fact that AVP is an unstable molecule both in vivo and ex vivo. In contrast to copeptin is stable molecule and it is considered to be a reliable and clinically useful surrogate marker for AVP. As suggested, copeptin has been associated with elevated blood pressure in various studies. Several lines of evidence suggest a role of copeptin in hypertension. One of the suggested mechanisms is the local tissue Renin Angiotensin Aldosterone System (RAAS) activation in supraoptic and paraventricular nuclei which stimulates the production and release of arginine vasopressin. Second mechanisms involve the vasoconstriction. This vasoconstriction is due to both direct effects on smooth muscle cells and by indirectly increasing renin secretion [32]. Third mechanism is the effect of copeptin on increased tubular sodium retention [41]. Thus copeptin may be common marker for essential hypertension and kidney disease.
The role of copeptin in renal denervation was also investigated [42]. Schwerg et al, investigated the change in copeptin levels in 40 resistant hypertensive patients after renal sympathetic denervation (RDN).-The responder rate was 47.5% on 24 h ABPM. which was defined as a drop in systolic ABPM 5 mmHg. The mean systolic 24 h blood pressure dropped from 152 ± 10 mmHg to 147 ± 17 mmHg (p :044) and diastolic blood pressure values decreased from 83 ± 11 to 81 ± 15 mmHg. (p:0.26 ) in the six month follow up. The mean baseline level of Copeptin was 7.4 pmol/l (interquartile range 3.7-11.6) for responders and 8.4 pmol/l (interquartile range 5.7-11-8) for non-responders (p:0.53). The authors concluded that copeptin levels did not change over time after renal denervation [42].
By the light of aforementioned data it is hypothetical that copeptin/avp play a role for the development and progression of CKD. Therefore, the blockage of copeptin/avp may be beneficial in halting development of CKD. However before doing that, full mechanisms need to be clarified. Phase studies should be planned regarding the efficiency of copeptin/avp blockage. Lastly, it needs to be tested whether high water intake will decrease the incidence of CKD by reducing copeptin/avp.

Conclusion
In conclusion, copeptin is related with kidney function and hypertension and serve as a prognostic tool in these clinical conditions. Various mechanisms are thought to be responsible. More research is needed to highlight underlying mechanisms.