Copeptin improves prediction of treatment response in children with monosymptomatic nocturnal enuresis.

OBJECTIVE: One of the main medical treatment options for monosymptomatic nocturnal enuresis (MNE) is the vasopressin analog desmopressin. But not all children respond to desmopressin treatment, and no reliable treatment predictor has yet been established. We hypothesize that plasma copeptin, a surrogate marker for vasopressin, can be used to predict treatment response to desmopressin in children with MNE. DESIGN/METHODS: In this prospective observational study, we included 28 children with MNE. At baseline, we assessed the number of wet nights, morning, and evening plasma copeptin, and plasma sodium and started treatment with desmopressin (120 µg daily). Desmopressin was increased to 240 µg daily if clinically necessary. The primary endpoint was reduction in the number of wet nights following 12 weeks of treatment with desmopressin using plasma copeptin ratio (evening/morning copeptin) at baseline. RESULTS: Eighteen children responded to desmopressin treatment at 12 weeks, while 9 did not. A copeptin ratio cutoff of 1.34 (sensitivity 55.56%, specificity 94.12%, area under the curve 70.6%, P = .07) was best at predicting treatment response, with a lower ratio indicating a better treatment response. In contrast, neither the number of wet nights at baseline (P = .15) nor serum sodium (P = .11) alone or in combination with plasma copeptin improved outcome prediction. CONCLUSIONS: Our results indicate that, of our investigated parameters, plasma copeptin ratio is the best predictor for treatment response in children with MNE. Plasma copeptin ratio could thus be useful to identify children with the highest benefit of desmopressin treatment and improve individualized treatment of MNE.

Validity of different copeptin assays in the differential diagnosis of the polyuria-polydipsia syndrome.

The aim of this study was to correlate three commercially available copeptin assays and their diagnostic accuracy in the differential diagnosis of the polyuria-polydipsia syndrome. Analyzed data include repeated copeptin measures of 8 healthy volunteers and 40 patients with polyuria-polydipsia syndrome undergoing osmotic stimulation and of 40 patients hospitalized with pneumonia. Copeptin was measured using the automated Brahms KRYPTOR, the manual Brahms LIA and the manual Cloud Clone ELISA assay. Primary outcome was the interrater correlation coefficient (ICC) and diagnostic accuracy in the polyuria-polydipsia syndrome of the three assays. In healthy volunteers, there was a moderate correlation for the KRYPTOR and LIA (ICC 0.74; 95% CI 0.07 to 0.91), and a poor correlation for the KRYPTOR and ELISA (ICC 0.07; 95% CI - 0.06 to 0.29), as for the LIA and ELISA (ICC 0.04; 95% CI - 0.04 to 0.17). The KRYPTOR had the highest diagnostic accuracy (98% (95% CI 83 to100)), comparable to the LIA (88% (95% CI 74 to 100)), while the ELISA had a poor diagnostic accuracy (55% (95% CI 34 to 68)) in the differential diagnosis of the polyuria-polydipsia syndrome. The KRYPTOR and LIA yield comparable copeptin concentrations and high diagnostic accuracy, while the ELISA correlates poorly with the other two assays and shows a poor diagnostic accuracy for polyuria-polydipsia patients. The current copeptin cut-off is valid for the KRYPTOR and LIA assay. Our results indicate that interpretation with other assays should be performed with caution and separate validation studies are required before their use in differentiating patients with polyuria-polydipsia syndrome.Trial registration: NCT02647736 January 6, 2016/NCT01940614 September 12, 2013/NCT00973154 September 9, 2009.

Examinations and assessments in patients with a newly acquired spinal cord injury - retrospective chart analysis as part of a quality improvement project.

AIMS OF THE STUDY: Examinations and assessments can be used to ensure good quality rehabilitation. Within the framework of a quality improvement project, the aims of the current analysis were: first, to analyse the time points of selected examinations and assessments in the rehabilitation process of patients with a newly acquired spinal cord injury. Second, to identify differences between the subgroups with different aetiologies, levels and completeness of spinal cord injuries. And third, to compare the examinations and assessments performed with the guideline recommendations and to use discrepancies as a starting point for a quality improvement project. METHODS: In this retrospective chart analysis, adult patients with a newly acquired spinal cord injury who were admitted to a single specialised acute care and rehabilitation clinic for their first rehabilitation between December 2013 and December 2014 were included and assessed until discharge. The main objective was to assess the time to examinations or assessments after injury or hospital admission in comparison to the respective recommendations. Analyses were done using time-to-event analysis and represented graphically using Kaplan-Meier plots. RESULTS: Of the 105 patients included in this study (median age 58 years, 29% female), 61% had a traumatic and 39% a non-traumatic spinal cord injury; 39% were paraplegic and 61% were quadriplegic; and 59% had a motor complete and 41% a sensor-motor incomplete spinal cord injury. The percentage of patients for whom the respective assessment or examination was performed and the percentage of these patients for whom it performed within the recommended time were: 90% and 71% for magnetic resonance imaging; 85% and 90% for computed tomography; 87% and 79% for the manual muscle test; 95% and 59% for the International Standards for Neurological Classification of Spinal Cord (ISNCSCI); 84% and 50% for electrophysiological assessment; 73% and 90% for urodynamic testing; and 49% and 53% for lung function testing. CONCLUSIONS: Our data suggest a relevant gap between recommendations and clinical routine for time to some assessments after spinal cord injury. Within the framework of a quality improvement project, the next steps should be to build a national and international consensus on specific time frames for examinations and assessments in patients with a newly acquired spinal cord injury and thereafter, to develop an institutional implementation strategy.    .

Effects of alcohol consumption on copeptin levels and sodium-water homeostasis.

Alcohol consumption influences sodium-water homeostasis. However, the effect of alcohol on vasopressin levels is controversial. The aim of the present study was to evaluate physiological changes of alcohol consumption on the stable vasopressin surrogate marker copeptin. In addition, we aimed at investigating the effect of additional sodium and/or water consumption on plasma sodium, osmolality, and copeptin levels. Ten healthy men underwent four interventions in random order: 1) beer consumption only, 2) beer consumption with additional water, 3) beer consumption with additional stock, or 4) water consumption only. Fluid consumption was equal between interventions and calculated to reach a blood alcohol concentration of 0.8‰ in the beer interventions. Blood and urinary samples were taken at six time points over the observation period of 720 min. The primary end point was the mean difference in copeptin levels 90 min after the start of fluid consumption, which showed no in-between group differences (P = 0.4). However, a higher total urinary volume excretion in all alcohol compared with water interventions was observed (P = 0.01). Furthermore, plasma copeptin, sodium, and urinary osmolality levels increased significantly at the end of the observation period in all alcohol compared with water-only interventions (P = 0.02). In conclusion, initial copeptin suppression does not differ between alcohol or water interventions but seems to be prolonged in the alcohol interventions. This leads to increased volume loss followed by a counterregulation with increased copeptin levels and water retention after 720 min in alcohol compared with interventions. Additional sodium and/or water consumption with alcohol did not change the observed alcohol-induced effects.

Mild to moderate hyponatremia at discharge is associated with increased risk of recurrence in patients with community-acquired pneumonia.

BACKGROUND: Hyponatremia is the most common electrolyte disorder in hospitalized patients with pneumonia. Different studies have shown an association of hyponatremia on admission and worse patient's outcome. Yet, the impact of hyponatremia at discharge or of hyponatremia correction on patient's prognosis is unknown. METHODS: This is a preplanned secondary data analysis from a double-blind, randomized, placebo-controlled trial of hospitalized patients with community-acquired pneumonia and prednisone treatment. The primary outcome was the impact of hyponatremia on admission and at discharge on patient relevant outcomes (i.e. mortality, rehospitalization and recurrence rate) within 180 days. RESULTS: Of the 708 included patients, 185 (26.1%) were hyponatremic on admission. Of these, 28 (15.1%) were still hyponatremic at discharge. 34 (4.8%) patients developed hyponatremia during hospitalization despite being normonatremic on admission. Patients with hyponatremia at discharge had a higher rate of pneumonia recurrence as compared to normonatremic patients (OR 2.68; 95%-CI 1.09-6.95; p = 0.037). Among patients with hyponatremia at discharge, patients who were already hyponatremic on admission showed the strongest association with increased recurrence rate (OR 4.01; 95%-CI 1.08-12.64; p = 0.022). In contrast, recurrence rate was not affected in patients who were hyponatremic on admission but had normalized serum sodium levels at discharge (p = 0.73). CONCLUSION: Mild to moderate hyponatremia at discharge is associated with an increased risk of recurrence in hospitalized patients with pneumonia. This association is particularly strong for patients who are hyponatremic both on admission and at discharge, emphasizing the importance of hyponatremia correction during hospitalization.

Markers of systemic inflammation in response to osmotic stimulus in healthy volunteers.

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 tumor 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 ≥150 mmol/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 < 0.01), serum osmolality increased from 295 mmol/L (281, 306) to 315 mmol/L (304, 325) (P < 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 < 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 < 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 < 0.036). Contrary to data obtained in vitro, circulating proinflammatory cytokines tend to or decrease in human plasma after osmotic stimulus. In this study, osmotic stimulus does not increase circulating markers of systemic inflammation.

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

BACKGROUND: 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 the differences between the methods in clinically stable patients or healthy volunteers. METHODS: 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 direct ISE method. RESULTS: 878 sodium measurements were analyzed. Mean (s.d.) sodium levels ranged from 141 mmol/L (2.9) to 151 mmol/L (2.1) by the indirect ISE compared to 140 mmol/L (3) to 149 mmol/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 1.9 mmol/L (95% CI limits: -3.2 to 6.9) higher than those by the direct ISE method (P < 0.001). The tendency of the indirect ISE method resulting in higher levels increased with increasing sodium levels. CONCLUSION: 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.

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.