The Relationship between the Ratio of Urine Osmolality to Serum Osmolality and Neurological Outcomes in Out-of-hospital Cardiac Arrest Patients.

Background: Progressive ischemic brain injury after cardiac arrest can cause damage to the hypothalamic-pituitary axis, particularly the pituitary gland. This may impact serum osmolality (SOsm) and urine osmolality (UOsm) in patients who have experienced out-of-hospital cardiac arrest (OHCA). We assumed that a low ratio of UOsm to SOsm (USR) is related to poor outcomes among OHCA patients. Therefore, the present study was designed to evaluate the association between the USR within 72 h after the restoration of spontaneous circulation (ROSC) and 6-month neurological outcomes in OHCA patients. Methods: This prospective, observational study included OHCA patients with targeted temperature management at Chonnam National University Hospital in Gwangju, Korea, between January 2016 and December 2022. We collected SOsm and UOsm data at admission (T0) and 24 (T1), 48 (T2), and 72 h (T3) after ROSC. The primary outcome was a poor neurological outcome at 6 months defined by cerebral performance categories 3, 4, or 5. Results: This study included 319 patients. The mean UOsm and USRs at T0, T1, T2, and T3 of patients with poor outcomes were lower than those of patients with good outcomes. Multivariable analysis indicated that the USRs at T1 (odds ratio [OR], 0.363; 95% confidence interval [CI], 0.221-0.594), T2 (OR, 0.451; 95% CI, 0.268-0.761), and T3 (OR, 0.559; 95% CI, 0.357-0.875) were associated with a poor outcome. The areas under the receiver operating characteristic curves of USRs at T0, T1, T2, and T3 for predicting poor outcomes were 0.615 (95% CI, 0.559-0.669), 0.711 (95% CI, 0.658-0.760), 0.724 (95% CI, 0.671-0.772), and 0.751 (95% CI, 0.699-0.797), respectively. Conclusions: The USRs within 72 h of ROSC were associated with poor neurological outcomes at 6 months in OHCA patients.

The association between renal medullary and cortical fibrosis, stiffness, and concentrating capacity: an observational, single-center cross-sectional study.

BACKGROUND: Fibrosis is a common final pathway leading to end-stage renal failure. As the renal medulla and cortex contain different nephron segments, we analyzed the factors associated with the progression of renal medullary and cortical fibrosis. METHODS: A total of 120 patients who underwent renal biopsy at Kawashima Hospital between May 2019 and October 2022 were enrolled in this retrospective study. Renal medullary and cortical fibrosis and stiffness were evaluated using Masson's trichrome staining and shear wave elastography, respectively. Maximum urine osmolality in the Fishberg concentration test was also examined. RESULTS: Medullary fibrosis was positively correlated with cortical fibrosis (p < 0.0001) and log-converted urinary ß2-microglobulin (MG) (log urinary ß2-MG) (p = 0.022) and negatively correlated with estimated glomerular filtration rate (eGFR) (p = 0.0002). Cortical fibrosis also correlated with log urinary ß2-MG, eGFR, and maximum urine osmolality. Multivariate analysis revealed that cortical fibrosis levels (odds ratio [OR]: 1.063) and medullary stiffness (OR: 1.089) were significantly associated with medullar fibrosis (≧45%). The severe fibrosis group with both medullary fibrosis (≧45%) and cortical fibrosis (≧25%) had lower eGFR and maximum urine osmolality values and higher urinary ß2-MG levels than the other groups. CONCLUSIONS: Patients with disorders involving both renal medullary and cortical fibrosis had decreased maximum urine osmolality but had no abnormalities in the urinary concentrating capacities with either condition. Renal medullary and cortical fibrosis were positively correlated with urinary ß2-MG, but not with urinary N-acetyl-beta-D-glucosaminidase.

Searching for the urine osmolality surrogate: an automated machine learning approach.

OBJECTIVES: Automated machine learning (AutoML) tools can help clinical laboratory professionals to develop machine learning models. The objective of this study was to develop a novel formula for the estimation of urine osmolality using an AutoML tool and to determine the efficiency of AutoML tools in a clinical laboratory setting. METHODS: Three hundred routine urinalysis samples were used for reference osmolality and urine clinical chemistry analysis. The H2O AutoML engine completed the machine learning development steps with minimum human intervention. Four feature groups were created, which include different urinalysis measurements according to the Boruta feature selection algorithm. Method comparison statistics including Spearman's correlation, Passing-Bablok regression analysis were performed, and Bland Altman plots were created to compare model predictions with the reference method. The minimum allowable bias (24.17%) from biological variation data was used as the limit of agreement. RESULTS: The AutoML engine developed a total of 183 ML models. Conductivity and specific gravity had the highest variable importance. Models that include conductivity, specific gravity, and other urinalysis parameters had the highest R2 (0.70-0.83), and 70-84% of results were within the limit of agreement. CONCLUSIONS: Combining urinary conductivity with other urinalysis parameters using validated machine learning models can yield a promising surrogate. Additionally, AutoML tools facilitate the machine learning development cycle and should be considered for developing ML models in clinical laboratories.

Variation in urine osmolality throughout pregnancy: a longitudinal, randomized-control trial among women with overweight and obesity.

PURPOSE: Water needs increase during pregnancy, and proper hydration is critical for maternal and fetal health. This study characterized weekly hydration status changes throughout pregnancy and examined change in response to a randomized, behavioral intervention. An exploratory analysis tested how underhydration during pregnancy was associated with birth outcomes. METHODS: The Healthy Mom Zone Study is a longitudinal, randomized-control trial intervention aiming to regulate gestational weight gain (GWG) in pregnant women with overweight/obesity (n = 27). Fourteen women received standard of care; 13 women additionally received weekly guidance on nutrition, physical activity, water intake, and health-promoting behaviors. Hydration status was measured weekly via overnight urine osmolality (Uosm) from ~ 8-36 weeks gestation; underhydration was dichotomized (Uosm ≥ 500 mOsm/kg). Gestational age- and sex-standardized birth weight and length z scores and percentiles were calculated. We used mixed-effect and linear regression models to test covariate-adjusted relationships. RESULTS: No differences existed in Uosm or other characteristics between control and intervention women at baseline. Significant interactions (p = 0.01) between intervention and week of pregnancy on Uosm indicated intervention women maintained lower Uosm, whereas control women had a significant quadratic (inverse-U) relationship and greater Uosm in the second and early third trimesters. Results were consistent across robustness and sensitivity checks. Exploratory analyses suggest underhydration was associated with birth weight, but not length, in opposite ways in the second vs. third trimester. CONCLUSION: A multi-component behavioral intervention helped women with overweight/obesity maintain better hydration throughout pregnancy. Future studies should confirm birth outcome results as they have important implications for early life nutrition. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03945266; registered May 10, 2019 retrospectively.

Efficacy of tolvaptan on advanced chronic kidney disease with heart failure: a randomized controlled trial.

BACKGROUND: Tolvaptan (TLV) is reported to improve diuretic effects in patients with chronic kidney disease (CKD) when furosemide (FUR) is not sufficiently effective. However, it is not clear whether TLV addition is effective for advanced CKD patients with heart failure. METHODS: An open-label, parallel-group randomized trial was performed. The subjects were 33 patients with CKD stage G3-G5 who had fluid overload despite taking 20-100 mg/day FUR. They were divided into two groups: a group administered 15 mg/day TLV plus their original FUR dose for 7 days (TLV group), and a group administered 120-200 mg/day FUR (i.e., 100 mg/day over their previous dose) for 7 days (FUR group). RESULTS: The mean change in urine volume was significantly higher in the TLV group compared to the FUR group (637 ml vs 119 ml; p < 0.05). The difference was greater when the urine osmolality before treatment was high. Serum creatinine was increased only in the FUR group. The incidence of worsening renal function (WRF) was significantly lower in the TLV group (18.8% vs 58.8%; p < 0.05). Serum sodium decreased significantly in the FUR group, but did not change in the TLV group. CONCLUSIONS: In patients with advanced CKD with fluid overload, the addition of TLV achieved a significantly higher urine volume with less adverse effects on renal function compared with increasing the dose of FUR. The efficacy and safety of TLV were higher in patients who had higher urine osmolality and lower serum sodium before treatment. CLINICAL TRIAL REGISTRATION: UMIN000014763.

Associations between urinary hydration markers and metabolic dysfunction: a cross-sectional analysis of NHANES data, 2008-2010.

PURPOSE: Growing evidence suggests hydration plays a role in metabolic dysfunction, however data in humans are scarce. This study examined the cross-sectional association between hydration and metabolic dysfunction in a representative sample of the US population. METHODS: Data from 3961 adult NHANES (National Health and Nutrition Examination Survey) participants (49.8% female; age 46.3 ± 0.5 years) were grouped by quartile of urine specific gravity (USG, 2007-2008 cohort) or urine osmolality (UOsm, 2009-2010 cohort) as measures of hydration. Metabolic dysfunction was assessed by glycemic and insulinemic endpoints and by components of the metabolic syndrome. Multivariate-adjusted linear and logistic regression models were used. RESULTS: Increasing quartiles of USG but not UOsm was associated with higher fasting plasma glucose (FPG), glycated hemoglobin (all P < 0.01), HOMA-IR and elevated insulin (all P < 0.05). Compared with the lowest quartile, those with the highest USG but not UOsm had greater risk of metabolic syndrome (Q4 vs. Q1, OR (99% CI): 1.6 (1.0, 2.7), P = 0.01) and diabetes (Q4 vs. Q1, OR: 1.8 (1.0, 3.4), P < 0.05). Additionally, those with USG > 1.013 or UOsm > 500 mOsm/kg, common cut-off values for optimal hydration based on retrospective analyses of existing data, had less favorable metabolic markers. In a subset of participants free from diabetes mellitus, impaired kidney function, hypertension and diuretic medication, USG remained positively associated with FPG (P < 0.01) and elevated FPG (P < 0.05). CONCLUSION: These analyses provide population-based evidence that USG as a proxy for hydration is associated with glucose homeostasis in NHANES 2007-2008. The same association was not significant when UOsm was used as a proxy for hydration in the 2009-2010 wave. CLINICAL TRIAL REGISTRY: Not applicable, as this was a reanalysis of existing NHANES data.

The association of urine osmolality with decreased kidney function and/or albuminuria in the United States.

BACKGROUND: Decreased kidney function is commonly caused by hypovolemia. When hypovolemic, the kidney reabsorbs water resulting in concentrated urine. Osmolality is a measure of urine concentration which is more objective than self-reported fluid intake. It has a positive association with hypovolemia. However, it remains controversial whether osmolality is associated with decreased kidney function and/or albuminuria. METHODS: We conducted a cross-sectional analysis of the 2009-2012 National Health and Nutrition Examination Survey, a standardized survey in the U.S. POPULATION: Participants aged 18-70 years old with random urine osmolality were included. Osmolality was categorized as quartiles. Decreased kidney function was defined by estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 and albuminuria was defined by albumin-to-creatinine ratio ≥ 30 mg/gm. We performed multivariable regression via four sequential models. RESULTS: Our study sample included 7,373 participants. The mean age was 42.9 ± 0.4 years. Overall, 51.4% were male and 67.3% were white. The mean osmolality was 603.8 mOsm/kg and 629.1 mOsm/kg in those with and without decreased eGFR and/or albuminuria, respectively. The number of cases was 610 (6.7%). The prevalence from the lowest to highest quartiles of osmolality was 116 (6.2%), 213 (8.6%), 179 (7.5%), and 102 (4.3%), respectively (p-value for trend = 0.02). The relationship between osmolality and eGFR appeared nonlinear. After adjustment for demographic, social, cardiovascular, and dietary risk factors, there was no significant association of osmolality quartiles with decreased eGFR and/or albuminuria (odds ratio [OR] 0.77, 95% confidence interval [CI] 0.56, 1.07). In sensitivity analyses, osmolality ≥ 500 mOsm/kg was associated with lower eGFR (adjusted ß -1.13, 95% CI -1.98, -0.28). In pre-specified subgroup analyses, osmolality had a statistically significant negative correlation with eGFR among individuals with eGFR ≥ 60 mL/min/1.73m2, but a positive correlation among those with eGFR < 60 mL/min/1.73m2 (adjusted ß -0.19, 95% CI -0.36, -0.01 versus adjusted ß 0.50, 95% CI 0.05, 0.96; p-value for interaction = 0.016). CONCLUSIONS: Higher osmolality was significantly associated with lower eGFR among adults with eGFR ≥ 60 mL/min/1.73m2 Future research should examine the relationship between osmolality and change in kidney function over time among adults with normal eGFR.

Evaluation of conductivity-based osmolality measurement in urine using the Sysmex UF5000.

BACKGROUND: Automated flow cytometry-based urine analyzer is increasingly being used to identify and enumerate cells and particles in urine specimens. It measures electrical conductivity which could be transformed to osmolality. Using this machine, all urine specimens could be screened for osmolality without requiring a separate dedicated device. We evaluated the performance of the new instrument, the UF-5000 (Sysmex Corporation), in the measurement of urine osmolality. METHODS: The precision of urine osmolality measurement by the UF-5000 was evaluated for 20 days and 4 times a day for 2 concentrations. The linearity and detection capability were evaluated according to the Clinical and Laboratory Standards Institute guidelines. For comparison, 270 random urine specimens from patients were tested simultaneously using the UF5000 and the OsmoPro micro-osmometer (Advanced instruments). RESULTS: The laboratory-based coefficient variations were less than 5%. Urine osmolality using the UF-5000 has a verified linear range (y = 1.097x + 16.91, R2  = .997). Within the comparison analysis, the mean difference was not large (-7.72%) but each differences were largely dispersed with 95% limits of agreement (LoA) from -70.5 to 55.06%, and the mean absolute difference -28.3 mOsm/kg with 95% LoA from -295.13 to 238.45 mOsm/kg. Cohen's kappa value was 0.54 (95% CI, 0.45-0.63). CONCLUSIONS: The UF-5000 measured conductivity and generated an acceptable quantitative analysis of urine osmolality. When compared with the results of the freezing point depression method used by the OsmoPro, a percentage of the measured urine osmolality by the UF-5000 was outside the allowable limit.

Impaired urinary concentration ability is a sensitive predictor of renal disease progression in Joubert syndrome.

BACKGROUND: Joubert syndrome (JS) is an inherited ciliopathy characterized by a complex midbrain-hindbrain malformation and multiorgan involvement. Renal disease, mainly juvenile nephronophthisis (NPH), was reported in 25-30% patients although only ∼18% had a confirmed diagnosis of chronic kidney disease (CKD). NPH often remains asymptomatic for many years, resulting in delayed diagnosis. The aim of the study was to identify a biomarker able to quantify the risk of progressive CKD in young children with JS. METHODS: Renal features were investigated in 93 Italian patients, including biochemical tests, ultrasound and 1-deamino-8D-arginine vasopressin test in children with reduced basal urine osmolality. A subset of patients was followed-up over time. RESULTS: At last examination, 27 of 93 subjects (29%) presented with CKD, ranging from isolated urinary concentration defect (UCD) to end-stage renal disease. Both normal and pathological urine osmolality levels remained stable over time, even when obtained at very early ages. Follow-up data showed that the probability of developing CKD can be modelled as a function of the urine osmolality value, exceeding 75% for levels <600 mOsm/kg H2O, and significantly increased in patients with an early diagnosis of isolated UCD. CONCLUSIONS: We conclude that the frequency of CKD in JS increases with age and is higher than previously reported. Urine osmolality represents an early sensitive quantitative biomarker of the risk of CKD progression.

Urinary markers of hydration during 3-day water restriction and graded rehydration.

PURPOSE: This investigation had three purposes: (a) to evaluate changes in hydration biomarkers in response to a graded rehydration intervention (GRHI) following 3 days of water restriction (WR), (b) assess within-day variation in urine concentrations, and (c) quantify the volume of fluid needed to return to euhydration as demonstrated by change in Ucol. METHODS: 115 adult males and females were observed during 1 week of habitual fluid intake, 3 days of fluid restriction (1000 mL day-1), and a fourth day in which the sample was randomized into five different GRHI groups: no additional water, CON; additional 500 mL, G+0.50; additional 1000 mL, G+1.00; additional 1500 mL, G+1.50; additional 2250 mL, G+2.25. All urine was collected on 1 day of the baseline week, during the final 2 days of the WR, and during the day of GRHI, and evaluated for urine osmolality, color, and specific gravity. RESULTS: Following the GRHI, only G+1.50 and G+2.25 resulted in all urinary values being significantly different from CON. The mean volume of water increase was significantly greater for those whose Ucol changed from > 4 to < 4 (+ 1435 ± 812 mL) than those whose Ucol remained ≥ 4 (+ 667 ± 722 mL, p < 0.001). CONCLUSIONS: An additional 500 mL of water is not sufficient, while approximately 1500 mL of additional water (for a total intake between 2990 and 3515 mL day-1) is required to return to a urine color associated with adequate water intake, following 3 days of WR.

High water intake and low urine osmolality are associated with favorable metabolic profile at a population level: low vasopressin secretion as a possible explanation.

PURPOSE: Elevated plasma concentration of the vasopressin marker copeptin and low water intake are associated with elevated blood glucose and diabetes risk at a population level. Moreover, in individuals with low urine volume and high urine osmolality (u-Osm), water supplementation reduced fasting plasma (fp) copeptin and fp-glucose. In this observational study, we investigated if low total water intake or high u-Osm correlated with high fp-copeptin and components of the metabolic syndrome at the population level. METHODS: In the population-based Malmö Offspring Study (MOS, n = 2599), fp-copeptin and u-Osm from morning urine samples were measured, and diet and total water intake (from beverages and food moisture) was assessed by a 4-day web-based record. RESULTS: Increasing water intake by tertile was after adjustment for age and sex associated with low fp-triglycerides (p = 0.002) and high fp-HDL (p = 0.004), whereas there was no association with the other investigated metabolic traits (HbA1c, fp-glucose, BMI or waist circumference). Increasing u-Osm by tertile was, after adjustment for age and sex, associated with high fp-glucose (p = 0.007), and borderline significantly associated with high HbA1c (p = 0.053), but no association was observed with fp-HDL, fp-triglycerides, BMI or waist circumference. Fp-copeptin concentration correlated significantly with water intake (r = - 0.13, p < 0.001) and u-Osm (r = 0.27, p < 0.001). High copeptin was associated with all investigated metabolic traits (p < 0.001 for all). CONCLUSION: Low concentrations of the vasopressin marker copeptin is linked to high water intake, low u-Osm, and a favorable metabolic profile, suggesting that vasopressin lowering lifestyle interventions, such as increased water intake, may promote metabolic health.

Desmopressin response in nocturnal enuresis showing concentrated urine.

BACKGROUND: In Japan, the use of desmopressin (1-desamino-8-D-arginine vasopressin) is only recommended for nocturnal enuresis with unconcentrated first morning urine, which suggests a relative deficiency of antidiuretic hormone secretion during sleep. However, no such limitations have been described in a standardization document of the International Children's Continence Society. We aimed to determine whether desmopressin treatment induces any response in nocturnal enuresis with concentrated first morning urine. METHODS: Outpatients aged 6-15 years who exhibited monosymptomatic nocturnal enuresis were examined. Data were obtained from 41 treatment-naive patients (median age 9.7 years) with nocturnal enuresis, who received desmopressin as their first line of treatment. The patients were divided into two groups demonstrating unconcentrated (osmolality < 800 mOsm/L, Low-Osm group) and concentrated (osmolality ≥ 800 mOsm/L, High-Osm group) first morning urine, respectively; we compared the response to desmopressin treatment between the groups at 1 month after the administration or updosing of desmopressin; responses were defined as partial or complete according to the International Children's Continence Society standards. Mann-Whitney U-tests or Fisher's exact tests were used for analysis. RESULTS: The Low-Osm (median age 9.6 years) and High-Osm groups (median age 9.7 years) had 14 and 27 patients, respectively; the response rates to desmopressin treatment were 64.3% and 59.2%, respectively, indicating no significant differences (P = 0.99). CONCLUSION: Desmopressin treatment may be a feasible option for treating nocturnal enuresis with concentrated first morning urine.

Signs of Dehydration after Hip Fracture Surgery: An Observational Descriptive Study.

Background and Objectives: Dehydration might be an issue after hip fracture surgery, but the optimal tools to identify the dehydrated condition have not been determined. The aim of the present study was to compare the characteristics of elderly postoperative patients who were classified as dehydrated according to the methods used in the clinic. Materials and Methods: Thirty-eight patients aged between 65 and 97 (mean, 82) years were studied after being admitted to a geriatric department for rehabilitation after hip fracture surgery. Each patient underwent blood analyses, urine sampling, and clinical examinations. Results: Patients ingested a mean of 1,008 mL (standard deviation, 309 mL) of fluid during their first day at the clinic. Serum osmolality increased significantly with the plasma concentrations of sodium, creatinine, and urea. Seven patients had high serum osmolality (≥300 mosmol/kg) that correlated with the presence of tongue furrows (p < 0.04), poor skin turgor (p < 0.03), and pronounced albuminuria (p < 0.03). Eight patients had concentrated urine (urine-specific gravity ≥ 1.025) that correlated with a low intake of liquid and with a decrease in body weight during the past month of -3.0 kg (25-75 th percentiles, -5.1 to -0.9) versus +0.2 (-1.9 to +2.7) kg (p < 0.04). Conclusions: Renal fluid conservation of water, either in the form of hyperosmolality or concentrated urine, was found in 40% of the patients after hip fracture surgery. Hyperosmolality might not indicate a more severe fluid deficit than is indicated by concentrated urine but suggests an impaired ability to concentrate the urine.

Fasting Urinary Osmolality, CKD Progression, and Mortality: A Prospective Observational Study.

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) characterized by decreased glomerular filtration rate (GFR) is often accompanied by various degrees of impaired tubular function in the cortex and medulla. Assessment of tubular function may therefore be useful in establishing the severity of kidney disease and identifying those at greater risk for CKD progression. We explored reductions in urinary concentrating ability, a well-known feature of CKD, as a risk factor for GFR decline and end-stage renal disease (ESRD). STUDY DESIGN: Prospective longitudinal cohort study. SETTING & PARTICIPANTS: 2,084 adult patients with CKD stages 1 to 4 from the French NephroTest Cohort Study. PREDICTOR: Fasting urinary osmolality measured using delta cryoscopy. OUTCOMES: ESRD, mortality before ESRD, and measured GFR (mGFR) assessed using 51Cr-EDTA renal clearance. ANALYTICAL APPROACH: Cause-specific hazards models were fit to estimate crude and adjusted associations of urinary osmolality with ESRD and death before ESRD. Linear mixed models with random intercepts were fit to evaluate the association of urinary osmolality with slope of decline in mGFR. RESULTS: At baseline, mean age was 58.7±15.2 (SD) years with a median mGFR of 40.2 (IQR, 29.1-54.5) mL/min/1.73m2 and a median fasting urinary osmolality of 502.7±151.7mOsm/kg H2O. Baseline fasting urinary osmolality was strongly associated with mGFR (R=0.54; P < 0.001). 380 ESRD events and 225 deaths before ESRD occurred during a median follow-up of 5.9 (IQR, 3.8-8.2) years. Patients with lower baseline fasting urinary osmolality had higher adjusted risk for ESRD but not for mortality (HRs of 1.97 [95% CI, 1.26-3.08] and 0.99 [95% CI, 0.68-1.44], respectively, for the lowest vs highest tertile). Based on a mixed linear model adjusted for baseline mGFR and clinical characteristics, patients in the lowest tertile of baseline urinary osmolality had a steeper decline in kidney function (-4.9% ± 0.9% per year; P < 0.001) compared with patients in the highest tertile. LIMITATIONS: Fasting was self-reported. CONCLUSIONS: Fasting urinary osmolality may be a useful tool, in addition to GFR and albuminuria, for assessing nonglomerular damage in patients with CKD who are at higher risk for CKD progression.

Pharmacokinetic and Pharmacodynamic Properties of a Micro-Dose Nasal Spray Formulation of Desmopressin (AV002) in Healthy Water-Loaded Subjects.

PURPOSE: Antidiuretic therapy with desmopressin for nocturia has been hampered by formulations with high doses, low bioavailability and variable pharmacokinetics. AV002 (SER120), a novel, emulsified, microdose desmopressin nasal spray, with a permeation enhancer (cylcopentadecanolide), was developed to have pharmacokinetic characteristics suitable for nocturia treatment. METHODS: Twelve healthy subjects participated in an open-label, dose-escalating study. Water-loaded subjects were sequentially dosed every 48 h with AV002 0.5, 1.0, 2.0 µg and 0.12 µg desmopressin subcutaneous (SC) bolus injection. RESULTS: AV002 intranasal administration produced a time-to-maximum concentration (Tmax) between 15 and 30 min and a maximum concentration (Cmax) <10 pg/mL. Cmax and area under the curve showed dose proportionality. Coefficient of variation for AV002 was similar to that observed for the SC dose. Bioavailability of AV002 was approximately 8% compared to SC injection. AV002 demonstrated pharmacodynamic effects within 20 min of dosing and showed increasing magnitude and duration with escalating doses. AV002 2.0 µg had maximum median urine osmolality of 629 mOsm/kg and median urine output ≤2 mL/min for 5-6 h. CONCLUSIONS: AV002 demonstrated rapid absorption, high bioavailability, limited duration of action, and low coefficient of variation, suggesting it may be a suitable formulation for nocturia treatment. Trial registration not required (single-center, phase 1).

Estimated urinary osmolality based on combined urinalysis parameters: a critical evaluation.

Background Urinary conductivity allows a coarse prediction of urinary osmolality in most cases but is insensitive to the osmolal contribution of uncharged particles and the presence of roentgen contrast media. Urinary osmolality can be estimated on the recently introduced Sysmex UF-5000 urine analyzer using conductivity. In this study, we evaluated the analytical performance of this research parameter. Secondly, we aimed to improve the manufacturer's algorithm for estimating urinary osmolality, based on standard urinalysis parameters (creatinine, glucose, relative density). Methods The analytical performance was determined and a prediction model to estimate urinary osmolality based on urinalysis parameters was developed. We further developed and validated a prediction model using another set of routine urine samples. In addition, the influence of roentgen contrast media on urinary osmolality was studied. Results The within-run and between imprecision for osmolality and conductivity measured on the Sysmex UF-5000 ranged from 1.1% to 4.9% and 0.7% to 4.8%, respectively. Multiple regression analysis revealed urinary creatinine, conductivity and relative density to be the strongest predictors to estimate urinary osmolality. A mean difference of 1.3 mOsm/kg between measured and predicted osmolality demonstrated that the predictive performance of our model was favorable. An excellent correlation between the relative density and % contrast media was demonstrated. Conclusions Urinary osmolality is an important parameter for assessing specimen dilution in urinalysis. Urinary conductivity, along with relative density and urinary creatinine allows a coarse prediction of urinary osmolality and is insensitive to the osmolal contribution of uncharged particles and the presence of roentgen contrast media.

Urine Osmolality and Renal Outcome in Patients with Chronic Kidney Disease: Results from the KNOW-CKD.

BACKGROUND: Urine osmolality indicates the ability of the kidney to concentrate the urine and reflects the antidiuretic action of vasopressin. However, results about the association between urine osmolality and adverse renal outcomes in chronic kidney disease (CKD) are conflicting. We investigated the association between urine osmolality and adverse renal outcomes in a nationwide prospective CKD cohort. METHODS: A total of 1,999 CKD patients were categorized into 3 groups according to their urine osmolality tertiles. Primary outcome was a composite of 50% decline in the estimated glomerular filtration rate (eGFR), initiation of dialysis, or kidney transplantation. RESULTS: During a mean follow-up of 35.2 ± 19.0 months, primary outcome occurred in 432 (21.6%) patients; 240 (36.4%), 162 (24.3%), and 30 (4.5%) in the lowest, middle, and highest tertiles, respectively. Low urine osmolality was independently associated with a greater risk of CKD progression (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.12-2.59). This association was particularly evident in patients with CKD stages 3-4 (per 10 mosm/kg decrease; HR, 1.02; 95% CI, 1.00-1.03). Adding urine osmolality to a base model with conventional factors significantly increased the ability to predict CKD progression (C-statistics, 0.86; integrated discrimination improvement [IDI], 0.021; both p < 0.001). However, adding both urine osmolality and eGFR did not further improve the predictive ability compared with the addition of eGFR only (C-statistics, p = 0.29; IDI, p = 0.09). CONCLUSIONS: Low urine osmolality was an independent risk factor for adverse renal outcomes in CKD patients, but its predictive ability did not surpass eGFR. Thus, kidney function should be considered while interpreting the clinical significance of urine osmolality.

Effect of increased water intake on plasma copeptin in healthy adults.

PURPOSE: Inter-individual variation in median plasma copeptin is associated with incident type 2 diabetes mellitus, progression of chronic kidney disease, and cardiovascular events. In this study, we examined whether 24-h urine osmolality was associated with plasma copeptin and whether increasing daily water intake could impact circulating plasma copeptin. METHODS: This trial was a prospective study conducted at a single investigating center. Eighty-two healthy adults (age 23.6 ± 2.9 years, BMI 22.2 ± 1.5 kg/m2, 50% female) were stratified based upon habitual daily fluid intake volumes: arm A (50-80% of EFSA dietary reference values), arm B (81-120%), and arm C (121-200%). Following a baseline visit, arms A and B increased their water intake to match arm C for a period of 6 consecutive weeks. RESULTS: At baseline, plasma copeptin was positively and significantly associated with 24-h urine osmolality (p = 0.002) and 24-h urine specific gravity (p = 0.003) but not with plasma osmolality (p = 0.18), 24-h urine creatinine (p = 0.09), and total fluid intake (p = 0.52). Over the 6-week follow-up, copeptin decreased significantly from 5.18 (3.3;7.4) to 3.90 (2.7;5.7) pmol/L (p = 0.012), while urine osmolality and urine specific gravity decreased from 591 ± 206 to 364 ± 117 mOsm/kg (p < 0.001) and from 1.016 ± 0.005 to 1.010 ± 0.004 (p < 0.001), respectively. CONCLUSIONS: At baseline, circulating levels of copeptin were positively associated with 24-h urine concentration in healthy young subjects with various fluid intakes. Moreover, this study shows, for the first time, that increased water intake over 6 weeks results in an attenuation of circulating copeptin. CLINICAL TRIAL REGISTRATION NUMBER: NCT02044679.

Bendamustine-Induced Nephrogenic Diabetes Insipidus in a Patient With AL Amyloidosis.

Nephrogenic diabetes insipidus is a condition characterized by polyuria with dilute urine due to the inability of the principal cells of the renal collecting ducts to respond to antidiuretic hormone and concentrate urine. Nephrogenic diabetes insipidus can be drug induced, and several chemotherapeutic agents have been reported to cause it. Bendamustine is a traditional chemotherapeutic agent being studied for treatment for relapsed systemic AL amyloidosis. We report a case of a 59-year-old man with AL amyloidosis who developed partial nephrogenic diabetes insipidus after receiving bendamustine for treatment of AL amyloidosis. The nephrogenic diabetes insipidus responded well to sodium restriction, hydrochlorothiazide, and desmopressin treatment, allowing the patient to receive subsequent bendamustine cycles without polyuria. Nephrogenic diabetes insipidus resolved shortly after completion of bendamustine therapy.

Effects of tolvaptan in patients with chronic kidney disease and chronic heart failure.

BACKGROUND: Tolvaptan, a vasopressin V2 receptor blocker, has a diuretic effect for patients with heart failure. However, there were a few data concerning the effects of tolvaptan in patients with chronic kidney disease (CKD). METHODS: We retrospectively analyzed 21 patients with chronic heart failure and CKD. Tolvaptan was co-administered with other diuretics in-use, every day. We compared clinical parameters before and after the treatments with tolvaptan. Furthermore, we examined the correlations between baseline data and the change of body weight. RESULTS: Tolvaptan decreased the body weight and increased the urine volume (p = 0.001). The urine osmolality significantly decreased throughout the study period. Urinary Na/Cr ratio and FENa changed significantly after 4 h, and more remarkable after 8 h (p = 0.003, both). Serum creatinine increased slightly after 1 week of treatment (p = 0.012). The alteration of body weight within the study period correlated negatively with the baseline urine osmolality (r = -0.479, p = 0.038), the baseline urine volume (r = -0.48, p = 0.028), and the baseline inferior vena cava diameter (IVCD) (r = -0.622, p = 0.017). Hyponatremia was improved to the normal value, and the augmentations of the sodium concentration were negatively associated with the basal sodium levels (p = 0.01, r = -0.546). CONCLUSIONS: Tolvaptan is effective in increasing diuresis and improved hyponatremia, even in patients with CKD. The baseline urine osmolality, urine volume, and IVCD may be useful predictors for diuretic effects of tolvaptan.