FGF-21 levels in polyuria-polydipsia syndrome

The pathomechanism of primary polydipsia is poorly understood. Recent animal data reported a connection between fibroblast growth factor 21 (FGF-21) and elevated fluid intake independently of hormonal control by the hormone arginine-vasopressin (AVP) and osmotic stimulation. We therefore compared circulating FGF-21 levels in patients with primary polydipsia to patients with AVP deficiency (central diabetes insipidus) and healthy volunteers. In this prospective cohort study, we analyzed FGF-21 levels of 20 patients with primary polydipsia, 20 patients with central diabetes insipidus and 20 healthy volunteers before and after stimulation with hypertonic saline infusion targeting a plasma sodium level ≥150 mmol/L. The primary outcome was the difference in FGF-21 levels between the three groups. Baseline characteristics were similar between the groups except for patients with central diabetes insipidus being heavier. There was no difference in baseline FGF-21 levels between patients with primary polydipsia and healthy volunteers (122 pg/mL (52,277) vs 193 pg/mL (48,301), but higher levels in patients with central diabetes insipidus were observed (306 pg/mL (114,484); P = 0.037). However, this was not confirmed in a multivariate linear regression analysis after adjusting for age, sex, BMI and smoking status. Osmotic stimulation did not affect FGF-21 levels in either group (difference to baseline: primary polydipsia −23 pg/mL (−43, 22); central diabetes insipidus 17 pg/mL (−76, 88); healthy volunteers −6 pg/mL (−68, 22); P = 0.45). To conclude, FGF-21 levels are not increased in patients with primary polydipsia as compared to central diabetes insipidus or healthy volunteers. FGF-21 therefore does not seem to be causal of elevated fluid intake in these patients

FGF-21 levels in polyuria-polydipsia syndrome

The pathomechanism of primary polydipsia is poorly understood. Recent animal data reported a connection between fibroblast growth factor 21 (FGF-21) and elevated fluid intake independently of hormonal control by the hormone arginine-vasopressin (AVP) and osmotic stimulation. We therefore compared circulating FGF-21 levels in patients with primary polydipsia to patients with AVP deficiency (central diabetes insipidus) and healthy volunteers. In this prospective cohort study, we analyzed FGF-21 levels of 20 patients with primary polydipsia, 20 patients with central diabetes insipidus and 20 healthy volunteers before and after stimulation with hypertonic saline infusion targeting a plasma sodium level >= 150 mmol/L. The primary outcome was the difference in FGF-21 levels between the three groups. Baseline characteristics were similar between the groups except for patients with central diabetes insipidus being heavier. There was no difference in baseline FGF-21 levels between patients with primary polydipsia and healthy volunteers (122 pg/mL (52,277) vs 193 pg/mL (48,301), but higher levels in patients with central diabetes insipidus were observed (306 pg/mL (114,484);P=0.037). However, this was not confirmed in a multivariate linear regression analysis after adjusting for age, sex, BMI and smoking status. Osmotic stimulation did not affect FGF-21 levels in either group (difference to baseline: primary polydipsia -23 pg/mL (-43, 22);central diabetes insipidus 17 pg/mL (-76, 88);healthy volunteers -6 pg/mL (-68, 22);P=0.45). To conclude, FGF-21 levels are not increased in patients with primary polydipsia as compared to central diabetes insipidus or healthy volunteers. FGF-21 therefore does not seem to be causal of elevated fluid intake in these patients

Fluid Overload Is Associated With Late Poor Outcomes in Neonates Following Cardiac Surgery*

Hyperosmolality, osmotic stimulus or stress results in vasopressin release. Animal and human in vitro studies have shown that inflammatory parameters such as interleukin-8 (IL-8) and tumour necrosis factor-α (TNF-α) increase in parallel in the central nervous system and bronchial, corneal or intestinal epithelial cell lines in response to osmotic stimulus. Whether osmotic stimulus directly causes a systemic inflammatory response in humans is unknown. We therefore investigated the influence of osmotic stimulus on circulatory markers of systemic inflammation in healthy volunteers. In this prospective cohort study, 44 healthy volunteers underwent a standardized test protocol with an osmotic stimulus leading into the hyperosmotic/hypernatremic range (serum sodium ≥150mmol/l) by hypertonic-saline infusion. Copeptin (a marker indicating vasopressin activity), serum sodium and osmolality, plasma IL-8 and TNF-α were measured at baseline and directly after osmotic stimulus. Median (range) serum sodium increased from 141 mmol/l (136, 147) to 151 mmol/l (145, 154) (p-value <0.01), serum osmolality increased from 295 mmol/l (281, 306) to 315 mmol/l (304, 325) (p-value <0.01). Median (range) copeptin increased from 4.3 pg/l (1.1, 21.4) to 28.8 pg/l (19.9, 43.4) (p-value <0.01). Median (range) IL-8 levels showed a trend to decrease from 0.79 pg/ml (0.37, 1.6) to 0.7 pg/ml (0.4, 1.9) (p-value 0.09) and TNF-α levels decreased from 0.53 pg/ml (0.11, 1.1) to 0.45 pg/ml (0.12, 0.97) (p-value 0.036). Contrary to data obtained in vitro, circulating proinflammatory cytokines tend to or decrease in human plasma after osmotic stimulus. Osmotic stress does not to stimulate circulating markers of systemic inflammation

The challenges of sodium measurements - indirect versus direct ion selective method

Diagnosis and treatment of dysnatremia is challenging and further complicated by the pitfalls of different sodium measurement methods. Routinely used sodium measurements are the indirect (plasma/serum) and direct (whole blood) ion selective electrode (ISE) method, showing discrepant results especially in the setting of acute illness. Few clinicians are aware of differences between the methods in clinically stable patients or healthy volunteers.; Data of 140 patients and 91 healthy volunteers undergoing osmotic stimulation with hypertonic saline infusion were analyzed. Sodium levels were measured simultaneously by indirect and direct ISE method before and at different time points during osmotic stimulation up to a sodium threshold of ≥150 mmol/l. The primary outcome was the difference in sodium levels between the indirect and the direct ISE method.; 878 sodium measurements were analyzed. Mean (SD) sodium levels ranged from 141mmol/l (2.9) to 151mmol/ (2.1) by the indirect ISE compared to 140mmol/l (3) to 149mmol/l (2.8) by the direct ISE method. The interclass correlation coefficient between the two methods was 0.844 (95%-CI 0.823, 0.863). On average, measurements by the indirect ISE were 1.9mmol/l (95%-CI limits -3.2; 6.9) higher than by the direct ISE method (p<0.001). The tendency of the indirect ISE method resulting in higher levels increased with increasing sodium levels.; Intra-individual sodium levels differ significantly between the indirect and direct ISE method also in the absence of acute illness. It is therefore crucial to adhere to the same method in critical situations to avoid false decisions due to measurement differences

Release and Decay Kinetics of Copeptin vs AVP in Response to Osmotic Alterations in Healthy Volunteers

Abstract Context Copeptin is the C-terminal fragment of the arginine vasopressin (AVP) prohormone whose measurement is more robust than that of AVP. Similar release and clearance characteristics have been suggested promoting copeptin as a surrogate marker. Objective To characterize the physiology of osmotically regulated copeptin release and its half-life in direct comparison with plasma AVP. Design Ninety-one healthy volunteers underwent a standardized three-phase test protocol including (1) osmotic stimulation into the hypertonic range by hypertonic-saline infusion followed by osmotic suppression via (2) oral water load and (3) subsequent glucose infusion. Plasma copeptin, AVP, serum sodium, and osmolality levels were measured in regular intervals. Results In phase 1, an increase in median osmotic pressure [289 (286; 291) to 311 (309; 314) mOsm/kg H2O] caused similar release kinetics of plasma copeptin [4 (3.1; 6) to 29.3 (18.6; 48.2) pmol/L] and AVP [1 (0.7; 1.6) to 10.3 (6.8; 18.8) pg/mL]. Subsequent osmotic suppression to 298 (295; 301) mOsm/kg at the end of phase 3 revealed markedly different decay kinetics between both peptides—an estimated initial half-life of copeptin being approximately 2 times longer than that of AVP (26 vs 12 minutes). Conclusion Copeptin is released in equimolar amounts with AVP in response to osmotic stimulation, suggesting its high potential as an AVP surrogate for differentiation of osmotic disorders. Furthermore, we here describe the decay kinetics of copeptin in response to osmotic depression enabling to identify a half-life for copeptin in direct comparison with AVP