CT-pro-AVP as a tool for assessment of intravascular volume depletion in severe hyponatremia

Highlights

• Hyponatremia is associated with substantial morbidity and mortality.

• The assessment of intravascular volume is crucial to decide appropriate treatment.

• The intravascular volume is often difficult to evaluate at the bedside.

• Plasma CT-pro-AVP may reflect intravascular volume status.

• Combined CT-pro-AVP and Ur/Cr measures could be relevant in hyponatremia management.

Abstract

Background

Assessment of volume status is essential to best manage hyponatremic patients but is not always accurate in clinical practice. The aim of this study was to evaluate the reliability of C-terminal portion of pro-arginine-vasopressin (CT-pro-AVP), a surrogate biomarker of vasopressin release, in assessing intravascular volume (IVV) depletion in hypoosmolar hyponatremic patients.

Methods

Plasma CT-pro-AVP and urea-to-creatinine ratio (Ur/Cr) were performed in 131 hospitalized patients presenting chronic severe hypoosmolar hyponatremia. At hospital discharge, their IVV was evaluated regardless of CT-pro-AVP concentrations. All patients were then classified as decreased or as normal/expanded IVV group.

Results

Plasma CT-pro-AVP levels were higher in patients with decreased IVV (34.6 vs. 11.3 pmol/L, p < 0.001) and exhibited a reliable performance for assessment of decreased IVV (ROC AUC at 0.717 [95% CI 0.629–0.805]). The combination of CT-pro-AVP and Ur/Cr resulted in an improved ROC AUC up to 0.787 (95% CI 0.709–0.866).

Conclusions

Our findings support the hypothesis that CT-pro-AVP plasma level may reflect IVV and would be a tool for its assessment. This performance has been magnified by its combination with Ur/Cr. A dual-marker strategy may help clinicians to optimize the management of severe hyponatremia especially in case of confusing clinical presentations.

Introduction

Hyponatremia, defined as a plasma sodium concentration of less than 135 mmol/L, occurs frequently in hospitalized patients and has prognostic implications. A recent study of 13,276 Intensive Care Unit patients reported the prevalence of hyponatremia at 12.9% and of severe hyponatremia (sodium level ≤ 125 mmol/L) at 5.9%. Hospital mortality reached more than 40% among these severe patients [1]. This mortality was not only due to the associated cause of hyponatremia but also to its therapeutic management. Indeed, the evaluation of hyponatremia is not always accurate because of the lack of constant and specific signs. In the study of Hula et al., significant management errors were reported in 33% of hyponatremia and conferred a higher mortality [2].

Hypotonic hyponatremia is an imbalance of water and sodium homeostasis induced by a proportional excess of total body water relative to the total body sodium [3], [4], [5]. The assessment of effective intravascular volume (IVV) is a main condition to decide appropriate treatment as rehydration [5]. The routine approach consists of patient's history and physical examination but the assessment of volume status is not always reliable and the distinction between total extracellular volume (ECV) and effective IVV status is difficult in clinical practice [4], [5], [6]. In fact, as seen in Fig. 1, an expanded ECV could be associated with a decreased IVV, such as congestive heart failure, hepatic cirrhosis, and nephrotic syndrome, or with an expanded IVV such as renal failure.

Arginine vasopressin (AVP) is one of the key hormones of water homeostasis. Urine sodium concentration and osmolality are usually measured to assess its activity. The suppression of AVP activity by increased IVV generally results in urine osmolality < 100 mOsm/kg [5], while its stimulation by hypovolemia increases urine osmolality above serum osmolality. Consequently, urine osmolalities between 100 mOsm/kg and the level of plasma osmolality represent a gray area in which it is difficult to precisely assess fluid status [5], [7]. However, urine analysis is influenced by diuretics and urine samples are often difficult to be taken, especially in emergency units. Direct measurement of endogenous AVP in plasma could be therefore useful to assess IVV [8], [9], but it is not suitable for use in clinical practice due to the binding of AVP to platelets and its unstability in isolated plasma [10], [11]. In contrast, the C-terminal portion of provasopressin (CT-pro-AVP), which is co-secreted with AVP, is much easier to quantify. CT-pro-AVP is a 39-amino acid glycopeptide that may have a role during the intracellular processing of provasopressin. It is produced together with AVP in an equimolar ratio and has similar kinetics as described for AVP. CT-pro-AVP is now frequently used as a surrogate marker for AVP secretion in clinical studies [8], [9], [10], [11], [12].

The aim of this study was therefore to evaluate the reliability of the plasma CT-pro-AVP concentration in assessing IVV status in hypoosmolar hyponatremic patients. Our hypothesis was that CT-pro-AVP may reflect IVV and should help for the management of severe hyponatremia. If IVV is decreased, AVP levels, and so CT-pro-AVP levels, should dramatically increase much more than in the case of syndrome of inappropriate secretion of antidiuretic hormone or in the case of expanded IVV (in which CT-pro-AVP concentrations should decrease). We sought also to compare it to routine biological parameters used to diagnosis hyponatremia in clinical settings including the ratio of plasma urea to plasma creatinine [13], [14], [15].