Association between nocturia and serum albumin in the U.S. adults from NHANES 2005-2012.

BACKGROUND: Nocturia, a prevalent chronic condition, impacts individuals' quality of life but remains underexplored. This study aimed to assess the association between serum albumin levels and nocturia. METHODS: Based on the analysis of the National Health and Nutrition Examination Survey (NHANES) database (2005-2012), our study included a total of 6345 adults (≥20 years old). Nocturia was defined as ≥2 nocturnal voiding episodes. Logistic regression and smooth curve fitting analyzed the linear and nonlinear correlations between serum albumin and nocturia, with subgroup analysis. RESULTS: Among 6345 participants, 1821 (28.7%) experienced nocturia. Logistic regression analysis revealed a linear negative correlation between serum albumin and nocturia risk (OR = 0.9549, 95% CI = 0.9280 ~ 0.9827, P = 0.002). Even after quartile division of serum albumin concentration, this correlation persisted within each group, and a smooth curve fitting validated the nonlinear negative correlation between the two. Subgroup analysis further demonstrated significant impacts of body mass index (BMI), alcohol consumption, and age on this association. CONCLUSION: This cross-sectional study indicated that higher serum albumin levels were associated with a reduced risk of nocturia in U.S. adults aged 20 and older, highlighting the importance of serum albumin in the prevention and treatment of nocturia and providing clinical guidance.

Effects of fatty acid metabolites on nocturia.

Dysregulation of circadian rhythm can cause nocturia. Levels of fatty acid metabolites, such as palmitoylethanolamide (PEA), 9-hydroxy-10E,12Z-octadecadienoic acid (9-HODE), and 4-hydroxy-5E,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid (4-HDoHE), are higher in the serum of patients with nocturia; however, the reason remains unknown. Here, we investigated the circadian rhythm of fatty acid metabolites and their effect on voiding in mice. WT and Clock mutant (ClockΔ19/Δ19) mice, a model for nocturia with circadian rhythm disorder, were used. Levels of serum PEA, 9-HODE, and 4-HDoHEl were measured every 8 h using LC/MS. Voiding pattern was recorded using metabolic cages after administration of PEA, 9-HODE, and 4-HDoHE to WT mice. Levels of serum PEA and 9-HODE fluctuated with circadian rhythm in WT mice, which were lower during the light phase. In contrast, circadian PEA and 9-HODE level deteriorated or retreated in ClockΔ19/Δ19 mice. Levels of serum PEA, 9-HODE, and 4-HDoHE were higher in ClockΔ19/Δ19 than in WT mice. Voiding frequency increased in PEA- and 4-HDoHE-administered mice. Bladder capacity decreased in PEA-administered mice. The changes of these bladder functions in mice were similar to those in elderly humans with nocturia. These findings highlighted the novel effect of lipids on the pathology of nocturia. These may be used for development of biomarkers and better therapies for nocturia.

Association between NT-proBNP and nocturia among community-dwelling elderly males and females: A cross-sectional analysis of the HEIJO-KYO study.

AIMS: To investigate the association between B-type natriuretic peptide (BNP) and nocturia among community-dwelling males and females. METHODS: A total of 1096 participants (mean age 71.9 ± 7.1 years, 518 [47.2%] males) were included in the study. The number of nocturnal voids was recorded in a self-reported urination diary, and nocturia was defined as two or more voids per night. Daytime serum concentration of the N-terminal fragment of BNP precursor (NT-proBNP) was measured. Multivariable logistic regression analysis was performed to determine the association between NT-proBNP and nocturia. RESULTS: Nocturia was observed in 23.5% of females and 37.1% of males. Higher NT-proBNP (log pg/ml) was associated with nocturia in both gender groups (females: odds ratio [OR]: 1.67, 95% confidence interval [95% CI], 1.21-2.34, p = .002; males: OR: 1.26, 95% CI, 1.01-1.59, p = .046), independent of confounding variables including night-time blood pressure, mean voided volume, and chronic kidney disease. Although the increase in prevalence of nocturia with higher NT-proBNP was equivalent in both genders, some effect of gender on the relationship between NT-proBNP and nocturia was observed (p = .037). Nocturnal urine volume was also significantly and independently associated with NT-proBNP level (females: ß = 32.9 ml, 95% CI, 5.63-60.2, p = .018; males: ß = 34.6 ml, 95% CI, 9.40-59.9, p = .007). CONCLUSIONS: This study revealed higher serum NT-proBNP is significantly and independently associated with the prevalence of nocturia in both males and females. This is an exploratory cross-sectional study and the analyses are post hoc, so further research works are needed to clarify the causality and clinical value.

Future Considerations in Nocturia and Nocturnal Polyuria.

Nocturnal polyuria (NP), the most common etiology of nocturia, can be caused by various medical conditions, including cardiovascular disease, obstructive sleep apnea, renal tubular dysfunction, as well as medications (eg, diuretics) and/or behavioral patterns. NP in the absence of underlying medical conditions has been described as NP syndrome and is thought be the result of impaired circadian release of endogenous arginine vasopressin. Desmopressin, a synthetic arginine vasopressin analog, has been shown to be an effective replacement therapy in adults with nocturia due to NP. Further studies on the subset of patients with NP syndrome are warranted to maximize benefit from antidiuretic treatment. In addition, a connection between the pathophysiological mechanisms underlying NP and essential hypertension has been suggested, and hypertension has been shown to be a significant risk factor for nocturia, while an association between NP and brain natriuretic peptide levels has also been reported in patients with nocturia. Hypertension is now viewed as a disorder of blood vessels and treatment is directed at the vasculature rather than the blood pressure, with the latter currently serving as a biomarker for arterial injury. Nocturia is thought to be associated with the beginning of this cardiovascular continuum as studies have reported a link between coronary heart disease and nocturia. Therefore, there is an increasing need to elucidate the complex mechanisms implicated in the association between nocturia and hypertension to promote the development of more individualized therapies for the treatment of nocturia.

Liquid chromatography-mass spectrometry identification of serum biomarkers for nocturia in aged men.

PURPOSE: We aimed to investigate the association between nocturia and serum metabolites identified using metabolomics analysis. METHODS: This study enrolled 66 men aged 65-80 years, recruited from the outpatient department of a university hospital. The participants were stratified as follows: Nocturia group [45 men with any total international prostate symptom score (IPSS) and an average of 3 nights ≥ 1.5 micturitions/night] and Control group (21 men with total IPSS < 8 and an average of 3 nights < 1.5 micturitions/night). The 24-h frequency-volume chart, IPSS, and Quality-of-Life questionnaire were used to evaluate micturition behavior. Serum metabolite profiles were obtained using liquid chromatography-mass spectrometry (LC-MS)-based metabolomics analysis and compared between the two groups using the unpaired t test. The relationship between serum metabolites and nocturia was determined using multivariable logistic regression analysis. RESULTS: There were no differences in background factors between the Nocturia and Control groups. In the IPSS, mean total scores in the Nocturia and Control groups were 12.4 and 4.0, respectively. On frequency-volume chart analysis, nocturnal urine volume and micturition frequency during daytime and nighttime were significantly higher in the Nocturia group. LC-MS highlighted 13 serum metabolites as potential biomarkers of nocturia. On multivariate analysis, increased levels of palmitoylethanolamide, 4-hydroxydocosahexaenoic acid, 9-hydroxyoctadecadienoic acid, 20-hydroxydocosahexaenoic acid, 13-hydroxyoctadecadienoic acid, arachidonoylethanolamide, eicosapentaenoic acid, 12-hydroxy-eicosatetraenoic acid, and arachidonic acid were associated with nocturia. CONCLUSIONS: In aged men, the pathogenesis of nocturia involves abnormal metabolism in several signaling pathways involving omega-3 and omega-6 polyunsaturated fatty acids, as well as endocannabinoids.

Relationship between serum testosterone and nocturia in men without benign prostate enlargement.

Recent studies have focused on the relationship between nocturia and serum testosterone because testosterone is thought to be an important factor of prostate growth. However, it remains unclear whether altered serum concentrations of testosterone is associated with an increased risk of nocturia because patients who were taking diuretics or who had a large prostate, which may precipitate nocturia, were not excluded from most previous studies. We analyzed the clinical records of 596 non-benign prostatic enlargement (BPE) male patients to explore the relationship between serum total testosterone and nocturia. All patients were evaluated using a serum prostate-specific antigen (PSA) assay, measurement of serum total testosterone, transrectal ultrasonography, uroflowmetry, and a compilation of the International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF) questionnaires. Nocturia was defined as ≥2 nocturnal voiding episodes. The number of nocturia episodes was assessed using IPSS question 7. To evaluate the effect of serum testosterone on nocturia, multivariate regression analysis was performed including the covariates of age, IPSS, IIEF score, body mass index, PSA, prostate volume, and maximal urine flow rate. Based on multivariate linear analysis, serum testosterone level was not significantly associated with the severity of nocturia. However, with regard to the relationship between prevalence of nocturia and serum testosterone, prevalence of nocturia was significantly positively associated with age (OR = 1.048, p = 0.005), total IPSS (OR = 1.217, p < 0.001), and testosterone level (OR = 1.150, p = 0.041). Therefore, in men without an enlarged prostate, testosterone may play an opposing role in the etiology of nocturia.

Low-dose desmopressin combined with serum sodium monitoring can prevent clinically significant hyponatraemia in patients treated for nocturia.

OBJECTIVE: To explore risk factors for desmopressin-induced hyponatraemia and evaluate the impact of a serum sodium monitoring plan. SUBJECTS AND METHODS: This was a meta-analysis of data from three clinical trials of desmopressin in nocturia. Patients received placebo or desmopressin orally disintegrating tablet (ODT; 10-100 µg). The incidence of serum sodium <130 mmol/L was recorded by age, sex and dose. Potential predictors of clinically significant hyponatraemia were identified using multivariate analysis in a Cox proportional hazards model. RESULTS: Dose, age, baseline serum sodium level and kidney function, according to estimated GFR clearance, were significant risk factors for hyponatraemia in both sexes; similar to the known risk factors associated with hyponatraemia in the general population. In men, arthritis and use of drugs for bone disease were also predictive of hyponatraemia, while in women, raised monocytes and absence of lipid-modifying drugs increased the risk of hyponatraemia. Use of the proposed monitoring scheme and the minimum effective dose would have omitted all patients with clinically significant hyponatraemia from further treatment. CONCLUSIONS: The incidence of hyponatraemia can be reduced by using minimum effective gender-specific dosing with the ODT formulation of desmopressin (25 µg in women, 50 µg in men). A sodium monitoring plan is proposed whereby baseline sodium must be ≥135 mmol/L (especially important in the elderly), with additional monitoring at week 1 and month 1 for those at elevated risk because they are aged ≥65 years or receiving concomitant medication associated with hyponatraemia. This monitoring plan would help to prevent some at-risk patients developing hyponatraemia; retrospective application of the monitoring plan showed that, once at-risk patients were appropriately screened out, only mild, non-clinically significant hyponatraemia was observed, within ranges of other drugs associated with hyponatraemia and similar to the background prevalence in the treatment population.

Delaying time to first nocturnal void may have beneficial effects on reducing blood glucose levels.

Experimental studies disrupting sleep and epidemiologic studies of short sleep durations indicate the importance of deeper and longer sleep for cardiometabolic health. We examined the potential beneficial effects of lengthening the first uninterrupted sleep period (FUSP) on blood glucose. Long-term data (≥3 months of treatment) were derived from three clinical trials, testing low-dose (10-100 µg) melt formulations of desmopressin in 841 male and female nocturia patients (90 % of which had nocturnal polyuria). We performed post hoc multiple regression with non-fasting blood glucose as dependent variable and the following potential covariates/factors: time-averaged change of FUSP since baseline, age, gender, race, ethnicity, baseline glucose, baseline weight, change in weight, patient metabolic status (normal, metabolic syndrome, type II diabetes), dose, follow-up interval, and time of random glucose sampling. Increases in FUSP resulted in statistically significant reductions in blood glucose (p = 0.0131), even after controlling for all remaining covariates. Per hour increase in time to first void was associated with glucose decreases of 1.6 mg/dL. This association was more pronounced in patients with increased baseline glucose levels (test of baseline glucose by FUSP change interaction: p < 0.0001). Next to FUSP change, other statistically significant confounding factors/covariates also associated with glucose changes were gender, ethnicity, metabolic subgroup, and baseline glucose. These analyses indicate that delaying time to first void may have beneficial effects on reducing blood glucose in nocturia patients. These data are among the first to suggest that improving sleep may have salutary effects on a cardiometabolic measure.

Nocturia in Patients With Sleep-Disordered Breathing and Cardiovascular Disease.

BACKGROUND: Sleep apnea is a common condition and a cardiovascular risk factor. Continuous positive airway pressure (CPAP) reduces cardiovascular events and sleep apnea-related symptoms, especially in patients with obstructive sleep apnea (OSA), who occasionally experience nocturia, a common problem in individuals of advanced age. METHODS AND RESULTS: The present study was a prospective, observational study including 1,429 consecutive patients with cardiovascular disease (CVD). A questionnaire on nocturia was administered and nocturnal pulse oximetry was performed. Patients with moderate-to-severe sleep-disordered breathing (SDB) underwent polysomnography, and patients with OSA received CPAP therapy. Nocturia was observed in 561 of 666 patients included in the analysis. A multiple logistic regression analysis revealed that nocturia was associated with oxygen desaturation defined as a 3% decrease (P=0.0335) independent of age (P<0.0001), male sex (P=0.0078), hypertension (P=0.0139), and B-type natriuretic peptide (BNP) level (P=0.0185). Nocturia was reduced in patients who continued CPAP treatment and they also showed a decrease in the apnea-hypopnea index (45.3±13.6 vs. 2.5±3.7 events/h, P<0.0001), systolic blood pressure (121.6±11.9 vs. 113.4±8.8 mmHg, P=0.0002), and BNP level (57.7 [15.0-144.4] vs. 27.4 [8.5-111.7] pg/ml, P=0.0006). CONCLUSIONS: CPAP has the potential to reduce nocturia and risk factors for SDB such as increased blood pressure and BNP level, which may be beneficial in older men with CVD and OSA.

The risk of hyponatremia with desmopressin use for nocturnal polyuria.

BACKGROUND: Desmopressin is used for treating nocturnal polyuria, but hyponatremia is an associated concern in the elderly due to impaired urinary dilution. This study was undertaken to characterize hyponatremia occurring in adults using desmopressin for nocturnal polyuria. METHODS: Data from 172 patients who were prescribed desmopressin for nocturnal polyuria at a urology clinic from September 2010 through February 2013 were retrospectively analyzed. Demographic and laboratory parameters were investigated to examine the risk factors for desmopressin-associated hyponatremia. RESULTS: The average follow-up serum sodium measured 21 ± 22 days after using desmopressin was 138 ± 5 mmol/l. Hyponatremia (<135 mmol/l) was found in 24 patients (14%), and it was severe in 7 (<126 mmol/l). In the hyponatremic patients, serum sodium decreased by 11 ± 6 mmol/l. Patients with hyponatremia were older than those with normonatremia (78 ± 7 vs. 68 ± 9 years, p < 0.0001). The presence of either hyponatremia-predisposing comorbidities or concurrent medications was associated with hyponatremia. Patients with hyponatremia had lower basal hemoglobin (11 ± 2 vs. 13 ± 2 g/dl, p < 0.001) and serum sodium (139 ± 2 vs. 140 ± 2 mmol/l, p < 0.05) than those with normonatremia. Multivariate logistic regression after adjustment for basal serum sodium showed that advanced age (OR 1.15; 95% CI 1.03-1.27) and lower hemoglobin level (OR 0.64; 95% CI 0.43-0.94) were independently associated with hyponatremia. CONCLUSION: Hyponatremia is not infrequently associated with desmopressin use. Those with advanced age (≥65 years) and lower hemoglobin are at risk of desmopressin-associated hyponatremia and need to be carefully monitored.

Relationship between asymmetric dimethylarginine and nocturia in the general elderly population: The HEIJO-KYO cohort.

AIMS: To evaluate the relationship between asymmetric dimethylarginine (ADMA) and nocturia. METHODS: A total of 862 community-based elderly individuals were examined in this cross-sectional study (mean age, 72.1 years). We measured nocturnal void frequency and serum ADMA levels. Nocturia was ascertained for a frequency of two or more nocturnal voids. RESULTS: Nocturia was observed in 262 (30.4%) participants. Univariate logistic regression models revealed a significant association between prevalent nocturia and ADMA levels (crude odds ratio [OR], 1.556 [2nd vs. 1st tertile]; 95% confidence interval [CI], 1.066-2.270; P = 0.022; crude OR, 2.114 [3rd vs. 1st tertile]; 95% CI, 1.453-3.072; P < 0.001). Univariate logistic regression models also revealed marginal to significant associations between prevalent nocturia and age, gender, calcium channel blocker use, nitric oxide-related drug use, diabetes, estimated glomerular filtration rate, insomnia, benign prostatic hyperplasia, overnight urine volume, and endogenous melatonin levels. In the multivariate model simultaneously adjusted for the former variables, higher ADMA levels were significantly associated with higher OR for nocturia (adjusted OR, 1.556 [3rd vs. 1st tertiles]; 95% CI, 1.010-2.397; P = 0.045). CONCLUSION: Serum ADMA levels, an endogenous inhibitor of nitric oxide synthase, are significantly associated with prevalent nocturia in the general elderly population.

Nocturnal polyuria and decreased serum testosterone: is there an association in men with lower urinary tract symptoms?

OBJECTIVES: To investigate the putative association between nocturia and decreased serum testosterone in men with lower urinary tract symptoms. METHODS: Frequency volume charts and serum testosterone levels of patients visiting the outpatient clinic for lower urinary tract symptoms were collected and analyzed. Age, prostate volume, body mass index and the presence of comorbidities were accounted for. Frequency volume charts were analyzed for pathophysiological components of nocturnal polyuria, global polyuria, decreased nocturnal bladder capacity and increased frequency to identify associated risks. Frequency volume charts were also used to chart 8-h changes of volume, frequency and capacity to identify time diurnal interactions with risk factors based on serum testosterone levels. RESULTS: A total of 2180 patients were enrolled in the study. Multivariate analysis showed testosterone decreased 0.142 ng/mL for every increase in nocturia, independent of other factors. Logistic regression analysis showed a significant difference between pathophysiological components. Decreased testosterone was shown to carry a significant independent risk for overall nocturia (odds ratio 1.60, 95% confidence interval 1.013-2.527, P = 0.044), and particularly nocturnal polyuria (odds ratio 1.934, 95% confidence interval 1.001-3.737, P = 0.027). Repeated measurement models showed patients with serum testosterone below 2.50 ng/mL to have a paradoxical increase in nocturnal urine volume at night. CONCLUSIONS: Nocturia, especially nocturnal polyuria, is associated with decreased serum testosterone. Patients with low serum testosterone show increased nocturnal urine output.

B-type natriuretic peptide as an independent correlate of nocturnal voiding in Japanese women.

AIMS: To investigate whether objective cardiovascular parameters have an independent association with nocturnal voiding in women. METHODS: Thirty-two parameters derived from questionnaires, and anthropometric, physiological and biochemical measures of 5,980 women were applied for analysis. Nocturnal voiding was assessed by the International Prostate Symptom Score and the Overactive Bladder Symptom Score. We measured variables including previously reported correlates of nocturnal voiding, such as age, a history of hypertension, and a history of diabetes, as well as those focusing on cardiovascular function, such as the cardio-ankle vascular index, the augmentation index, the ankle-brachial index, plasma B-type natriuretic peptide (BNP), and C-reactive protein (CRP). RESULTS: Age [odds ratio (OR): 1.058, P < 0.001], length of sleep (OR: 1.194, P < 0.001), sleeplessness (OR: 2.841, P < 0.001), urgency (OR: 1.528, P < 0.001), log(BNP) (OR: 2.031, P < 0.001), waist circumference (OR: 1.037, P = 0.002), body mass index (OR: 0.935, P = 0.007), menopause (OR: 1.503, P = 0.043), and history of hypertension (OR: 1.225, P = 0.029) were independently associated with nocturnal voiding ≥2 times. Age (ß = 0.256, P < 0.001), urgency (ß = 0.195, P < 0.001), sleeplessness (ß = 0.181, P < 0.001), length of sleep (ß = 0.088, P < 0.001), log(BNP) (ß = 0.072, P < 0.001), waist circumference (ß = 0.086, P < 0.001), and low-density lipoprotein-cholesterol (ß = -0.038, P = 0.003) were significantly correlated with the severity of nocturnal voiding. CONCLUSIONS: Plasma BNP, which represents cardiac load, is strongly associated with the prevalence and severity of nocturnal voiding in Japanese women, as well as previously known correlates including age, urgency, quality and quantity of sleep, and obesity.

Relationship of sex hormones and nocturia in lower urinary tract symptoms induced by benign prostatic hyperplasia.

OBJECTIVE: The study sought to clarify the relationship between sex hormone levels and lower urinary tract symptoms (LUTS) in patients with benign prostate hyperplasia. METHODS: Between 2007 and 2010, serum total testosterone (TT), free testosterone, and estradiol were prospectively measured in patients who were transferred to our university hospital. The 924 subjects were divided into two groups. Group I (n = 646) were treated with an alpha blocker only and group II (n = 278) were treated with an alpha blocker + a 5-alpha reductase inhibitor over 3 months before their visit. Clinical conditions were assessed by digital rectal examination, prostate-specific antigen, International Prostate Symptom Score (IPSS), transrectal ultrasonography and maximum urinary flow rate and postvoid residual urine. RESULTS: The mean age was 69.65 ± 6.56 years. The total IPSS and subscore (storage symptom) was significantly associated with age (p < 0.001/p < 0.05) and the TT level (p < 0.05/p < 0.05). TT level was significantly decreased in patients with ≥ 4 episodes of nocturia. The TT level was significantly related to the presence of severe LUTS (p < 0.05). CONCLUSIONS: Endogenous testosterone may have a beneficial effect on lower urinary tract function and that a high frequency of nocturia may induce testosterone deficiency.

Serum testosterone levels significantly correlate with nocturia in men aged 40-79 years.

OBJECTIVE: To investigate the association between serum sex hormone levels and lower urinary tract symptoms in men aged 40-79 years. METHODS: A cross-sectional study was conducted in 509 men (mean age 58 years). The serum total testosterone (TT), dihydrotestosterone, and estradiol levels were measured. The total prostate volume measured by transrectal ultrasonography and International Prostate Symptom Score (IPSS) questionnaire were obtained. Correlations were determined using univariate and multivariate regression analysis. RESULTS: The subjects with moderate to severe lower urinary tract symptoms (total IPSS≥8) were older, with a greater incidence of hypertension and diabetes, a larger prostate, and had lower serum TT levels. On the univariate analysis, the serum TT levels were negatively associated with the total IPSS, IPSS storage subscore, weak stream, and nocturia. After adjusting for age, hypertension, diabetes, and total prostate volume, only the serum TT level was significantly associated with nocturia (>2 times/night; P=.042), and men with serum TT levels in the greatest quartile had a 44% reduced risk of nocturia than in the lowest quartile (P=.037). CONCLUSION: In our relative healthy male cohort, most IPSS items showed no significant association with serum sex hormone levels, except for nocturia, which showed a negative correlation with the serum testosterone level.

Gender difference in antidiuretic response to desmopressin.

Increased age and female gender are well-known risk factors for the development of desmopressin-induced hyponatremia. However, little focus has been on exploring gender differences in the antidiuretic response to desmopressin. Based on an exploratory analysis from three clinical trials, we report a significant gender difference in the effects of desmopressin on nocturnal urine volume that could not be explained by pharmacokinetic differences. Mean desmopressin concentration profiles were tested for covariates, and age and gender were not statistically significant and only weight was significant for log(C(max)) (P = 0.0183) and borderline significant for log(AUC) (P = 0.0571). The decrease in nocturnal urine volume in nocturia patients treated with desmopressin over 28 days was significantly larger for women at the lower desmopressin melt doses of 10 and 25 µg than for men. The ED(50) for men was modeled to be 43.2 µg and 16.1 µg for women, with the ED(50) men/women estimated to be 2.7 (1.3-8.1 95% CI), corresponding to significantly higher sensitivity to desmopressin in women. An increasing incidence of hyponatremia with increasing dose was found, and at the highest dose level of 100 µg decreases in serum sodium were approximately twofold greater in women over 50 yr of age than in men. A new dose recommendation stratified by gender is suggested in the treatment of nocturia: for men, 50- to 100-µg melt is an efficacious and safe dose, while for women a dose of 25 µg melt is recommended as efficacious with no observed incidences of hyponatremia. Areas for further research are proposed to uncover pathophysiological mechanism(s) behind these gender differences.