Neurourology and Urodynamics 34:561–565 (2015)
Exploring Nocturia: Gender, Age, and Causes An-Sofie Goessaert,1* Louise Krott,2 Johan Vande Walle,3 and Karel Everaert1 1
Department of Urology, Ghent University Hospital, Ghent, Belgium 2 Faculty of Medicine, Ghent University, Ghent, Belgium 3 Department of Pediatric Nephrology, Ghent University Hospital, Ghent, Belgium Purpose: This study aims to clarify differences in parameters based on frequency volume chart (FVC) and on daytime and nighttime urine according to the nocturia frequency, age, and gender. Materials and Methods: This observational study was executed between 2011 and 2013. Participants (>18 years, 65 years) with or without nocturia (controls) were included and completed a 72 hr FVC; osmolality and sodium excretion were analyzed on daytime and nighttime urine. Results: (1) Nocturia severity: Compared to controls (N ¼ 38), those with 2 nocturia episodes (N ¼ 29) have higher nocturnal voided volume (NVV) (P < 0.001) based on increased sodium excretion (P ¼ 0.003) and lower functional bladder capacity (P < 0.001). Those with one nocturia episode (N ¼ 21) present with lower bladder capacity (P ¼ 0.005). (2) Gender: women with 1 and 2 episodes have lower bladder capacity than controls (P ¼ 0.047 and P < 0.001, respectively). Men with 2 episodes present with increased NVV (P ¼ 0.001) and decreased bladder capacity (P ¼ 0.049). (3) Age: Younger participants (65 years old), in the age range between 35 and 65 we used an increase of 2% per 5 years. Polyuria was present when total urine output exceeds 40 ml/kg per 24 hr. During 24 hr, eight urine samples were collected, five during daytime and three during nighttime, mean concentrations of daytime and nighttime osmolality, sodium, and creatinine
were analyzed. The collection started after the first morning void of Day 1 and ended after the first morning void of Day 2. This study was approved by the Ghent University Hospital Review Board (EC 2011/565). The Declaration of Helsinki was followed, written informed consent for study participation was obtained from all participants.
Statistical Analysis
Statistical analysis was performed with SPSS v.21 (IBM Corp, Armonk, NY). Medians, ranges, and frequencies were recorded as descriptive statistical parameters. Differences between groups were assessed using Kruskal– Wallis test for more than two nonparametric variables and Mann–Whitney U-test for two nonparametric variables. Chi-squared test was used to compare dichotomous variables. A P-value < 0.05 was considered statistically significant.
RESULTS
In total, 88 patients met the inclusion criteria and were analyzed. Mean age was 47 years old (SD 14.5) and 55% of the participants were female. Of the 50 participants with nocturia, 42% were found to get up once at night, 32% twice, 10% had three to four nocturia episodes, 4% had five episodes, and 2% had seven. Table I shows the general characteristics and sleeping and drinking patterns of participants with no nocturia, with one nocturia episode and with two or more. There are no significant differences in age, gender, or BMI between both groups. Participants with two or more nocturia episodes have a significantly longer bed rest compared to the other subgroups. Participants with one nocturia episode get up between 2.5 hr (32%) to 7 hr (80%) of the total bed rest, whereas in case of two or more nocturia episodes, participants get up after 0.6 hr (7%) to 4 hr (40%) of the total bed rest. This correlates with worse sleep quality (P ¼ 0.019) and higher intake of sleep medication (P ¼ 0.028) in the latter group.
TABLE I. General, Sleeping and Drinking Characteristics
General characteristics (median, range) Age (yrs) Gender (M/F, % female) BMI Sleep characteristics (median, range) Total hours in bed (hr) Hours until first void (hr) Hours until first void/total hours of sleep (%) Sleep quality (%) Very good Fairly good Fairly bad Very bad Snoring (%) Sleep medication (%) Drinking characteristics (median, range) Total drinking volume (ml) Nocturnal drinking volumee (ml) Nocturnal drinking volume/total drinking volume (%) a e
0 (N ¼ 38)
1 (N ¼ 21)
2 or more (N ¼ 29)
P-value
49 [18–65] 18/20 [53%] 24 [18–35]
51 [21–64] 8/13 [62%] 24 [18–33]
55 [21–65] 14/15 [52%] 24 [17–37]
0.204 0.740 0.981
8.4 [4.9–10.2] 8.3 [4.9–10.2] 100 [83–100]
8.1 [6.7–9.0] 4.2 [2.5–7.0] 50 [32–80]
8.7 [6.8–11.8] , 2.0 [0.6–4.0] , 25 [7–40] ,
0.022 0.001 0.001
29 60 11 0 24 13
20 55 25 0 25a 15a
7 38 38 17 28a 39a
0.019 0.064 0.116 / 0.935 0.028
1,794 [810–3,253]b 367 [0–1,133]b 24 [0–42]b
1,882 [840–3,653]c 350 [33–1,280]c 22 [4–32]c
2,162 [767–4,567]d 350 [33–1,200]d 20 [2–35]d
0.214 0.760 0.675
1 missing value, b4 missing values, c3 missing values, d2 missing values.
Nocturnal drinking volume considers fluid intake 4 hr before going to bed until getting up the next morning.
P < 0.05 between 1 and 0;
P < 0.05 between 2 and 0;
sleep medication). P < 0.05—Kruskal–Wallis test.
Neurourology and Urodynamics DOI 10.1002/nau
P < 0.05 between 2 and 1—Mann–Whitney U-test (Fisher’s exact for sleep quality, snoring, and
Exploring Nocturia: Gender, Age, and Causes
563
TABLE II. Frequency Volume Chart and Renal Function Profile According to the Number of Nocturia Episodes
Frequency volume chart (median, range) 24 hr voided volume (ml) Nocturnal voided volume (ml) Nocturnal polyuria index (%) Mean functional bladder capacity (ml) Maximum voided volume (ml) Nocturia index Voiding frequency day (N) Renal function profile (median, range) Day-to-night ratio osmolality Mean nocturnal osmolality (mosm/kg) Day-to-night ratio sodium excretion Mean nocturnal sodium excretion (mmol/L)/(mg/dl) creatinine
0 (N ¼ 38)
1 (N ¼ 21)
2 or more (N ¼ 29)
P-value
1,745 [760–3,500] 385 [180–817] 27 [12–40] 280 [133–663] 459 [237–867] 0.8 [0.0–1.2] 6 [3–10]
1,658 [583–3,640] 392 [150–917] 26 [10–60] 186 [61–438] 353 [93–637] 1.3 [0.0–1.9] 8 [4–14]
2,048 [590–5,143] 757 [237–1,567] , 35 [13–56] 170 [74–483] 317 [100–620] 2.0 [0.0–3.7] 8 [5–15]
0.148 0.001 0.001 0.001 0.001 0.001 0.001
1.0 [0.4–2.5] 627 [165–1,122] 1.1 [0.5–2.8] 1.0 [0.3–3.2]
1.0 [0.5–2.6] 532 [183–888] 1.2 [0.8–4.3] 1.0 [0.2–2.0]
1.0 [0.5–2.1] 498 [270–896] 0.9 [0.2–2.0] 1.5 [0.5–2.9] ,
0.759 0.020 0.016 0.007
yrs, years; M, male; F, female; BMI, body mass index.
P < 0.01 between 1 and 0; P < 0.01 between 2 and 0; P < 0.01 between 2 and 1—Mann–Whitney U-test. P < 0.05—Kruskal–Wallis test.
Comparing drinking habits between the three subgroups shows no significant differences for total drinking volume in 24 hr nor for nocturnal drinking volume (4 hr before going to bed until the next morning); also, no gender or age-related differences are found. Table II shows urological factors according to the nocturia frequency, based on the FVC and urine samples. In case of two or more nocturia episodes, participants present with a higher NVV, a lower functional bladder capacity and MVV and a higher voiding frequency during daytime compared to no nocturia (P < 0.001 for all parameters). Participants with one nocturia episode also have a lower bladder capacity (P ¼ 0.005) and a higher daytime voiding frequency (P ¼ 0.001) compared to controls, but no significant increase in NVV is found (P ¼ 0.490). The nocturia index (NI—calculated by dividing NVV by MVV) rises with increasing nocturia frequency (P ¼ 0.001); a NI > 1, indicating a mismatch between NVV and MVV, is seen in 9%, 54%, and 91% in those without nocturia, with one nocturia episode and with two or more, respectively. No significant difference is found in day-to-night ratio of osmolality, although the mean nocturnal osmolality is significantly lower in participants with two nocturia episodes compared to those without nocturia (P ¼ 0.009). Day-to-night ratio of sodium excretion differs between those with one or two or more nocturia episodes, with a lower ratio in the latter group (P ¼ 0.031). Mean nocturnal sodium excretion is higher in participants with two or more nocturia episodes compared to both one episode (P ¼ 0.015) and no episodes (P ¼ 0.003). Figure 1 shows boxplots for NVV, functional bladder capacity, nocturnal osmolality, and sodium excretion, the determining parameters in nocturia, for gender and age subdivided in two groups, from 18 to 44 years old and from 45 to 65 years old. Women (mean age: 48 years old) present with a significant decrease in functional bladder capacity in case of one nocturia episode or two or more (P ¼ 0.047, P < 0.001, respectively). Men (mean age: 56 years old) present with both an increase in NVV (P ¼ 0.001) and a decrease of functional bladder capacity (P ¼ 0.049) in case of two or more nocturia episodes. Nocturnal osmolality is significantly higher in men without nocturia compared to those getting up twice at night (P ¼ 0.009); nocturnal sodium excretion is significantly higher in the latter group, both compared to no nocturia (P ¼ 0.004) and one episode (P ¼ 0.029). Both osmolality and sodium excretion do not differ significantly between no nocturia and one episode. Neurourology and Urodynamics DOI 10.1002/nau
Younger participants between 18 and 44 years old (74% female) show no significant increase in NVV with increasing nocturia episodes, however, they do present with a decrease in functional bladder capacity (P < 0.001) and in case of two or more nocturia episodes a significantly higher nocturnal sodium excretion is found compared to one nocturia episode (P ¼ 0.040). In older participants between 45 and 65 years old (43% female), a combination of increasing NVV and decreasing bladder capacity is seen in concordance to the nocturia frequency (P < 0.001). Osmolality is significantly higher in participants without nocturia compared to both participants with one nocturia episode (P ¼ 0.035) and with two or more episodes (P ¼ 0.015). Sodium excretion is significantly higher in those getting up twice at night compared to those without nocturia (P ¼ 0.029). With the urological parameters derived from the FVC, diagnoses regarding the underlying problem of nocturia can be made. Figure 2 shows the distribution of the main causes, based on gender, age group, and nocturia frequency. A significant difference in distribution of diagnoses based on FVC is found comparing no nocturia, one nocturia episode, and two or more episodes (P ¼ 0.002). No statistically significant difference in percentage of isolated reduced bladder capacity is found (P ¼ 0.113). The percentage of isolated NP decreases (P ¼ 0.005), whereas the combination of both causes increases with an increase in nocturia frequency (P ¼ 0.020). Polyuriarelated causes do not differ significantly (P ¼ 0.247). The number of participants not fitting to any of the diagnostic criteria decreases, with no participants with two or more nocturia episodes per night without a diagnosis (P ¼ 0.020). DISCUSSION
Nocturia is a condition affecting men and women of all ages; however, clinicians often underestimate the bother and potential underlying risks of this LUT symptom such as fall injuries, cardiovascular events, and poor sleep quality. Also, patients do not always mention the fact that they are bothered by nocturia, as they attribute this to the aging process and/or are uncertain about the treatment options available.16,17 Increased awareness of nocturia and its associated factors is required, starting with the clinicians. Therefore, a comprehensive approach of both diagnostics and treatment is needed. This study aims to contribute to this, by analyzing urological and renal parameters and linking these to gender and age.
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Goessaert et al.
Fig. 1. Comparing cases and controls according to gender and age group (18–44 years vs. 45–65 years). P < 0.05—Mann–Whitney U-test.
It is logical that the higher the nocturia frequency, the earlier you have to get up the first time. The restoring phase of sleep is the slow wave sleep phase in the first 3–4 hr of the night.18 Our results show that the subgroups with two or more nocturia episodes per night get up after about 2 hr or 25% of the total bed rest, resulting in worse sleep quality. Our results also show that nocturia indeed is the result of a mismatch between NVV and bladder capacity, as described by Rembratt et al.5 comparing the voiding diaries of 108 nonnocturics and 116 nocturics and by Weiss et al.19 analyzing voiding diaries of 845 patients with OAB and nocturia. Our study demonstrates some clear gender and age differences. Bladder capacity is significantly affected in women with nocturia, whereas in men, a higher NVV seems the most important cause. This NP correlates not only with impaired urinary osmolality but also with impaired sodium excretion, a phenomenon that becomes more prominent with age.20 In participants between 45 and 65 years old, an increase of NVV is
Fig. 2. Potential causes of nocturia based on frequency volume charts. P < 0.05—chi-squared test; ‘‘8’’ refers to polyuria or a combination of polyuria with reduced bladder capacity or NP or both. NUP, nocturnal urine production; TUP, total urine production (24 hr).
Neurourology and Urodynamics DOI 10.1002/nau
mainly combined with reduced bladder capacity. A limitation we recognize is that sex ratio is different between the younger and older age group, although we doubt that this would have influenced our conclusions. Paick et al.21 observed a higher NVV too in older men in a study on 71 age-matched female– male pairs. In this study, women had a significantly lower bladder capacity, which is also confirmed by our results.21 Weiss et al.19 found a predominance of reduced nocturnal bladder capacity in younger patients and a predominance of NP in older patients. Clinical trials on nocturia therapy so far focus on patients with two or more nocturia episodes per night, since only this is believed to be clinically relevant, despite the ICS definition including one nocturia episode. Our results show that only in the subpopulation of patients with one nocturia episode, the majority has only a single parameter in the NVV/BC ratio that is abnormal, making monotherapy a rational choice. The majority of patients with two or more nocturia episodes have combined disturbance of bladder function and diuresis, probably explaining the low success rates of monotherapy in literature.22 Our data are suggestive that patients with one or two or more nocturia episodes and NP are likely to be desmopressin responsive, since there is a lower nocturnal osmolality (only significantly in those with two or more nocturia episodes). Response rates of desmopressin therapy are expected to be lower in patients with NP and associated bladder dysfunction and/or disturbed sodium handling, as seen in desmopressin treatment of children with NP and nocturnal enuresis, a condition very similar to nocturia in adulthood.23 An increased sodium excretion overnight secondary to water and sodium retention during daytime, could increase the risk of side effects. Since these characteristics are predominantly present in patients with two or more nocturia episodes, we believe that by restricting desmopressin to patients without bladder
Exploring Nocturia: Gender, Age, and Causes dysfunction and with normal sodium handling might increase response rate and maybe decrease side-effect risk. However, evidence is lacking so far. Our data give enough evidence that future therapies might have higher success rates if a comprehensive diagnostic approach is followed leading to better subtyping of the patients. Despite the significant age and gender differences, the large standard deviations clearly demonstrate the heterogeneity of the patients, making an individualized therapy approach based on a noninvasive screening the optimal therapeutic approach. Regarding the diagnostic approach of nocturia, a thorough anamnesis, clinical examination and simply observing the patient can already give an indication on the underlying cause of nocturia. The diagnosis should be confirmed by an FVC, the gold standard for examining LUT symptoms.15 In case of NP, analysis of daytime and nighttime urine of solute handling might give additional information on the possible pathophysiologic mechanisms involved in excessive urine production leading to a rationalized choice for treatment.11 It is also important to mention that in the diagnostic work up, the need for treatment should be determined; if the patient is not bothered by nocturia and there is no medical need, one should be reluctant to expose patients to the potential risk of side effects of any medical treatment. Anyhow, adapting possible lifestyle factors should be considered as a first step. Although our results indicate no significant influence of drinking habits, it should be explored in the individual patient. Study Limitations
This analysis focused on three main factors that can easily be taken into account in daily practice: age, gender, and cause of nocturia. Since a patient population as seen in daily practice was included, there are differences among participants regarding comorbidities and medication. We do emphasize that these and other factors can influence development of nocturia, such as sleep apnea, which was not specifically questioned or examined in this population. Furthermore, we see that the diagnoses of small bladder capacity, nocturnal polyuria, or polyuria that lead to nocturia are also highly prevalent in the participants without nocturia. This indicates that isolated reduced bladder capacity or NP or anything else does not necessarily lead to getting up at night, because the other factors are within the normal ranges. However, it might indicate a problem with the current definitions. There is no exact cutoff for small bladder capacity and there are up to 15 different definitions of NP; major issues in research on nocturia. These results were obtained in a small study sample and in participants up to 65 years old, reflecting an active population with limited comorbidities and medication that might influence the occurrence of nocturia (as often seen in elderly). Therefore, to be able to extrapolate these results to the general population, large case–control studies need to be conducted. CONCLUSION
With an increase in nocturia episodes, a decrease in functional bladder capacity and an increase in nocturnal urine output is seen. This mismatch demands a comprehensive diagnostic approach to subtype the patient properly, which involves anamnesis, FVC, and analysis of daytime and nighttime urine. One nocturia episode per night is often based on an isolated cause, which is expected to be more easily to treat than a Neurourology and Urodynamics DOI 10.1002/nau
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combination of causes, although it is questionable if one nocturia episode requires treatment. Getting up twice or more is mostly caused by a combination of a small bladder and NP, the latter can be based on low nocturnal osmolality and/or high nocturnal sodium excretion. This is definitely age dependent, with a possible male predominance, although this needs to be elucidated with larger studies. Clinicians should be aware that investigating the problem of nocturia thoroughly and searching for an optimal treatment can be very rewarding for the general health and quality of sleep of those affected. FUNDING
This research was funded by Ferring, Pfizer, and Bard. This was an unrestricted funding, with no interference in protocol, execution of the trial, analysis, and interpretation of the results. REFERENCES 1. Bosch JLHR, Weiss JP. The prevalence and causes of nocturia. J Urol 2010;184:440–6. 2. Tikkinen KAO, Johnson TM, Tammela TLJ, et al. Nocturia frequency, bother, and quality of life: How often is too often? A population-based study in Finland. Eur Urol 2010;57:488–96. 3. van Kerrebroeck P, Abrams P, Chaikin D, et al. The standardization of terminology in nocturia: Report from the standardization subcommittee of the International Continence Society. BJU Int 2002;90:11–5. 4. Cornu JN, Abrams P, Chapple CR, et al. A contemporary assessment of nocturia: Definition, epidemiology, pathophysiology, and management—A systematic review and meta-analysis. Eur Urol 2012;62:877–90. 5. Rembratt A, Norgaard JP, Andersson KE. Differences between nocturics and non-nocturics in voiding patterns: An analysis of frequency-volume charts from community-dwelling elderly. BJU Int 2003;91:45–50. 6. Weiss JP, Wein AJ, van Kerrebroeck P, et al. Nocturia: New directions. Neurourol Urodynam 2011;30:700–3. 7. Irwin DE, Abrams P, Milsom I, et al. Understanding the elements of overactive bladder: Questions raised by the EPIC study. BJU Int 2008;101:1381–7. 8. Asplund R. Diuresis pattern, plasma vasopressin and blood pressure in healthy elderly persons with nocturia and nocturnal polyuria. Neth J Med 2002;60:276–80. 9. Natsume O. A clinical investigation of nocturnal polyuria in patients with nocturia: A diurnal variation in arginine vasopressin secretion and its relevance to mean blood pressure. J Urol 2006;176:660–4. 10. Friedman FM, Weiss JP. Desmopressin in the treatment of nocturia: Clinical evidence and experience. Ther Adv Urol 2013;5:310–7. 11. Herek J, Fitzgerald M, Mohindra M, et al. Solute and water excretion patterns in patients with nocturnal polyuria. Int J Nephrourol 2010;2:526–31. 12. Kirkland JL, Lye M, Levy DW, et al. Patterns of urine flow and electrolyte excretion in healthy elderly people. Br Med J 1983;287:1665–7. 13. Juul KV, Klein BM, Sandstrom R, et al. Gender difference in antidiuretic response to desmopressin. Am J Physiol Renal Physiol 2011;300:F1116–22. 14. Neveus T, Lackgren G, Tuvemo T, et al. Enuresis—Background and treatment. Scand J Urol Nephrol 2000;34:1–44. 15. Abrams P, Klevmark B. Frequency volume charts: An indispensable part of lower urinary tract assessment. Scand J Urol Nephrol 1996;30:47–53. 16. Booth JM, Lawrence M, O’Neill K, et al. Exploring older peoples’ experiences of nocturia: A poorly recognised urinary condition that limits participation. Disabil Rehabil 2010;32:765–74. 17. Chen FY, Dai YT, Liu CK, et al. Perception of nocturia and medical consulting behavior among community-dwelling women. Int Urogynecol J 2007;18: 431–6. 18. Jennum P. Sleep and nocturia. BJU Int 2002;90:21–4. 19. Weiss JP, Blaivas JG, Jones M, et al. Age related pathogenesis of nocturia in patients with overactive bladder. J Urol 2007;178:548–51. 20. Matthiesen TB, Rittig S, Norgaard JP, et al. Nocturnal polyuria and natriuresis in male patients with nocturia and lower urinary tract symptoms. J Urol 1996;156:1292–9. 21. Paick JS, Kim SW, Oh SJ, et al. Voiding patterns in men and women with lower urinary tract symptoms combined with nocturia. Int J Urol 2007;14: 699–703. 22. Jeong JY, Kim SJ, Cho HJ, et al. Influence of type of nocturia and lower urinary tract symptoms on therapeutic outcome in women treated with desmopressin. Korean J Urol 2013;54:95–9. 23. Dehoorne JL, Raes AM, Van Laecke E, et al. Desmopressin resistant nocturnal polyuria secondary to increased nocturnal osmotic excretion. J Urol 2006;176:749–53.
Exploring Nocturia: Gender, Age, and Causes An-Sofie Goessaert,1* Louise Krott,2 Johan Vande Walle,3 and Karel Everaert1 1
Department of Urology, Ghent University Hospital, Ghent, Belgium 2 Faculty of Medicine, Ghent University, Ghent, Belgium 3 Department of Pediatric Nephrology, Ghent University Hospital, Ghent, Belgium Purpose: This study aims to clarify differences in parameters based on frequency volume chart (FVC) and on daytime and nighttime urine according to the nocturia frequency, age, and gender. Materials and Methods: This observational study was executed between 2011 and 2013. Participants (>18 years, 65 years) with or without nocturia (controls) were included and completed a 72 hr FVC; osmolality and sodium excretion were analyzed on daytime and nighttime urine. Results: (1) Nocturia severity: Compared to controls (N ¼ 38), those with 2 nocturia episodes (N ¼ 29) have higher nocturnal voided volume (NVV) (P < 0.001) based on increased sodium excretion (P ¼ 0.003) and lower functional bladder capacity (P < 0.001). Those with one nocturia episode (N ¼ 21) present with lower bladder capacity (P ¼ 0.005). (2) Gender: women with 1 and 2 episodes have lower bladder capacity than controls (P ¼ 0.047 and P < 0.001, respectively). Men with 2 episodes present with increased NVV (P ¼ 0.001) and decreased bladder capacity (P ¼ 0.049). (3) Age: Younger participants (65 years old), in the age range between 35 and 65 we used an increase of 2% per 5 years. Polyuria was present when total urine output exceeds 40 ml/kg per 24 hr. During 24 hr, eight urine samples were collected, five during daytime and three during nighttime, mean concentrations of daytime and nighttime osmolality, sodium, and creatinine
were analyzed. The collection started after the first morning void of Day 1 and ended after the first morning void of Day 2. This study was approved by the Ghent University Hospital Review Board (EC 2011/565). The Declaration of Helsinki was followed, written informed consent for study participation was obtained from all participants.
Statistical Analysis
Statistical analysis was performed with SPSS v.21 (IBM Corp, Armonk, NY). Medians, ranges, and frequencies were recorded as descriptive statistical parameters. Differences between groups were assessed using Kruskal– Wallis test for more than two nonparametric variables and Mann–Whitney U-test for two nonparametric variables. Chi-squared test was used to compare dichotomous variables. A P-value < 0.05 was considered statistically significant.
RESULTS
In total, 88 patients met the inclusion criteria and were analyzed. Mean age was 47 years old (SD 14.5) and 55% of the participants were female. Of the 50 participants with nocturia, 42% were found to get up once at night, 32% twice, 10% had three to four nocturia episodes, 4% had five episodes, and 2% had seven. Table I shows the general characteristics and sleeping and drinking patterns of participants with no nocturia, with one nocturia episode and with two or more. There are no significant differences in age, gender, or BMI between both groups. Participants with two or more nocturia episodes have a significantly longer bed rest compared to the other subgroups. Participants with one nocturia episode get up between 2.5 hr (32%) to 7 hr (80%) of the total bed rest, whereas in case of two or more nocturia episodes, participants get up after 0.6 hr (7%) to 4 hr (40%) of the total bed rest. This correlates with worse sleep quality (P ¼ 0.019) and higher intake of sleep medication (P ¼ 0.028) in the latter group.
TABLE I. General, Sleeping and Drinking Characteristics
General characteristics (median, range) Age (yrs) Gender (M/F, % female) BMI Sleep characteristics (median, range) Total hours in bed (hr) Hours until first void (hr) Hours until first void/total hours of sleep (%) Sleep quality (%) Very good Fairly good Fairly bad Very bad Snoring (%) Sleep medication (%) Drinking characteristics (median, range) Total drinking volume (ml) Nocturnal drinking volumee (ml) Nocturnal drinking volume/total drinking volume (%) a e
0 (N ¼ 38)
1 (N ¼ 21)
2 or more (N ¼ 29)
P-value
49 [18–65] 18/20 [53%] 24 [18–35]
51 [21–64] 8/13 [62%] 24 [18–33]
55 [21–65] 14/15 [52%] 24 [17–37]
0.204 0.740 0.981
8.4 [4.9–10.2] 8.3 [4.9–10.2] 100 [83–100]
8.1 [6.7–9.0] 4.2 [2.5–7.0] 50 [32–80]
8.7 [6.8–11.8] , 2.0 [0.6–4.0] , 25 [7–40] ,
0.022 0.001 0.001
29 60 11 0 24 13
20 55 25 0 25a 15a
7 38 38 17 28a 39a
0.019 0.064 0.116 / 0.935 0.028
1,794 [810–3,253]b 367 [0–1,133]b 24 [0–42]b
1,882 [840–3,653]c 350 [33–1,280]c 22 [4–32]c
2,162 [767–4,567]d 350 [33–1,200]d 20 [2–35]d
0.214 0.760 0.675
1 missing value, b4 missing values, c3 missing values, d2 missing values.
Nocturnal drinking volume considers fluid intake 4 hr before going to bed until getting up the next morning.
P < 0.05 between 1 and 0;
P < 0.05 between 2 and 0;
sleep medication). P < 0.05—Kruskal–Wallis test.
Neurourology and Urodynamics DOI 10.1002/nau
P < 0.05 between 2 and 1—Mann–Whitney U-test (Fisher’s exact for sleep quality, snoring, and
Exploring Nocturia: Gender, Age, and Causes
563
TABLE II. Frequency Volume Chart and Renal Function Profile According to the Number of Nocturia Episodes
Frequency volume chart (median, range) 24 hr voided volume (ml) Nocturnal voided volume (ml) Nocturnal polyuria index (%) Mean functional bladder capacity (ml) Maximum voided volume (ml) Nocturia index Voiding frequency day (N) Renal function profile (median, range) Day-to-night ratio osmolality Mean nocturnal osmolality (mosm/kg) Day-to-night ratio sodium excretion Mean nocturnal sodium excretion (mmol/L)/(mg/dl) creatinine
0 (N ¼ 38)
1 (N ¼ 21)
2 or more (N ¼ 29)
P-value
1,745 [760–3,500] 385 [180–817] 27 [12–40] 280 [133–663] 459 [237–867] 0.8 [0.0–1.2] 6 [3–10]
1,658 [583–3,640] 392 [150–917] 26 [10–60] 186 [61–438] 353 [93–637] 1.3 [0.0–1.9] 8 [4–14]
2,048 [590–5,143] 757 [237–1,567] , 35 [13–56] 170 [74–483] 317 [100–620] 2.0 [0.0–3.7] 8 [5–15]
0.148 0.001 0.001 0.001 0.001 0.001 0.001
1.0 [0.4–2.5] 627 [165–1,122] 1.1 [0.5–2.8] 1.0 [0.3–3.2]
1.0 [0.5–2.6] 532 [183–888] 1.2 [0.8–4.3] 1.0 [0.2–2.0]
1.0 [0.5–2.1] 498 [270–896] 0.9 [0.2–2.0] 1.5 [0.5–2.9] ,
0.759 0.020 0.016 0.007
yrs, years; M, male; F, female; BMI, body mass index.
P < 0.01 between 1 and 0; P < 0.01 between 2 and 0; P < 0.01 between 2 and 1—Mann–Whitney U-test. P < 0.05—Kruskal–Wallis test.
Comparing drinking habits between the three subgroups shows no significant differences for total drinking volume in 24 hr nor for nocturnal drinking volume (4 hr before going to bed until the next morning); also, no gender or age-related differences are found. Table II shows urological factors according to the nocturia frequency, based on the FVC and urine samples. In case of two or more nocturia episodes, participants present with a higher NVV, a lower functional bladder capacity and MVV and a higher voiding frequency during daytime compared to no nocturia (P < 0.001 for all parameters). Participants with one nocturia episode also have a lower bladder capacity (P ¼ 0.005) and a higher daytime voiding frequency (P ¼ 0.001) compared to controls, but no significant increase in NVV is found (P ¼ 0.490). The nocturia index (NI—calculated by dividing NVV by MVV) rises with increasing nocturia frequency (P ¼ 0.001); a NI > 1, indicating a mismatch between NVV and MVV, is seen in 9%, 54%, and 91% in those without nocturia, with one nocturia episode and with two or more, respectively. No significant difference is found in day-to-night ratio of osmolality, although the mean nocturnal osmolality is significantly lower in participants with two nocturia episodes compared to those without nocturia (P ¼ 0.009). Day-to-night ratio of sodium excretion differs between those with one or two or more nocturia episodes, with a lower ratio in the latter group (P ¼ 0.031). Mean nocturnal sodium excretion is higher in participants with two or more nocturia episodes compared to both one episode (P ¼ 0.015) and no episodes (P ¼ 0.003). Figure 1 shows boxplots for NVV, functional bladder capacity, nocturnal osmolality, and sodium excretion, the determining parameters in nocturia, for gender and age subdivided in two groups, from 18 to 44 years old and from 45 to 65 years old. Women (mean age: 48 years old) present with a significant decrease in functional bladder capacity in case of one nocturia episode or two or more (P ¼ 0.047, P < 0.001, respectively). Men (mean age: 56 years old) present with both an increase in NVV (P ¼ 0.001) and a decrease of functional bladder capacity (P ¼ 0.049) in case of two or more nocturia episodes. Nocturnal osmolality is significantly higher in men without nocturia compared to those getting up twice at night (P ¼ 0.009); nocturnal sodium excretion is significantly higher in the latter group, both compared to no nocturia (P ¼ 0.004) and one episode (P ¼ 0.029). Both osmolality and sodium excretion do not differ significantly between no nocturia and one episode. Neurourology and Urodynamics DOI 10.1002/nau
Younger participants between 18 and 44 years old (74% female) show no significant increase in NVV with increasing nocturia episodes, however, they do present with a decrease in functional bladder capacity (P < 0.001) and in case of two or more nocturia episodes a significantly higher nocturnal sodium excretion is found compared to one nocturia episode (P ¼ 0.040). In older participants between 45 and 65 years old (43% female), a combination of increasing NVV and decreasing bladder capacity is seen in concordance to the nocturia frequency (P < 0.001). Osmolality is significantly higher in participants without nocturia compared to both participants with one nocturia episode (P ¼ 0.035) and with two or more episodes (P ¼ 0.015). Sodium excretion is significantly higher in those getting up twice at night compared to those without nocturia (P ¼ 0.029). With the urological parameters derived from the FVC, diagnoses regarding the underlying problem of nocturia can be made. Figure 2 shows the distribution of the main causes, based on gender, age group, and nocturia frequency. A significant difference in distribution of diagnoses based on FVC is found comparing no nocturia, one nocturia episode, and two or more episodes (P ¼ 0.002). No statistically significant difference in percentage of isolated reduced bladder capacity is found (P ¼ 0.113). The percentage of isolated NP decreases (P ¼ 0.005), whereas the combination of both causes increases with an increase in nocturia frequency (P ¼ 0.020). Polyuriarelated causes do not differ significantly (P ¼ 0.247). The number of participants not fitting to any of the diagnostic criteria decreases, with no participants with two or more nocturia episodes per night without a diagnosis (P ¼ 0.020). DISCUSSION
Nocturia is a condition affecting men and women of all ages; however, clinicians often underestimate the bother and potential underlying risks of this LUT symptom such as fall injuries, cardiovascular events, and poor sleep quality. Also, patients do not always mention the fact that they are bothered by nocturia, as they attribute this to the aging process and/or are uncertain about the treatment options available.16,17 Increased awareness of nocturia and its associated factors is required, starting with the clinicians. Therefore, a comprehensive approach of both diagnostics and treatment is needed. This study aims to contribute to this, by analyzing urological and renal parameters and linking these to gender and age.
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Fig. 1. Comparing cases and controls according to gender and age group (18–44 years vs. 45–65 years). P < 0.05—Mann–Whitney U-test.
It is logical that the higher the nocturia frequency, the earlier you have to get up the first time. The restoring phase of sleep is the slow wave sleep phase in the first 3–4 hr of the night.18 Our results show that the subgroups with two or more nocturia episodes per night get up after about 2 hr or 25% of the total bed rest, resulting in worse sleep quality. Our results also show that nocturia indeed is the result of a mismatch between NVV and bladder capacity, as described by Rembratt et al.5 comparing the voiding diaries of 108 nonnocturics and 116 nocturics and by Weiss et al.19 analyzing voiding diaries of 845 patients with OAB and nocturia. Our study demonstrates some clear gender and age differences. Bladder capacity is significantly affected in women with nocturia, whereas in men, a higher NVV seems the most important cause. This NP correlates not only with impaired urinary osmolality but also with impaired sodium excretion, a phenomenon that becomes more prominent with age.20 In participants between 45 and 65 years old, an increase of NVV is
Fig. 2. Potential causes of nocturia based on frequency volume charts. P < 0.05—chi-squared test; ‘‘8’’ refers to polyuria or a combination of polyuria with reduced bladder capacity or NP or both. NUP, nocturnal urine production; TUP, total urine production (24 hr).
Neurourology and Urodynamics DOI 10.1002/nau
mainly combined with reduced bladder capacity. A limitation we recognize is that sex ratio is different between the younger and older age group, although we doubt that this would have influenced our conclusions. Paick et al.21 observed a higher NVV too in older men in a study on 71 age-matched female– male pairs. In this study, women had a significantly lower bladder capacity, which is also confirmed by our results.21 Weiss et al.19 found a predominance of reduced nocturnal bladder capacity in younger patients and a predominance of NP in older patients. Clinical trials on nocturia therapy so far focus on patients with two or more nocturia episodes per night, since only this is believed to be clinically relevant, despite the ICS definition including one nocturia episode. Our results show that only in the subpopulation of patients with one nocturia episode, the majority has only a single parameter in the NVV/BC ratio that is abnormal, making monotherapy a rational choice. The majority of patients with two or more nocturia episodes have combined disturbance of bladder function and diuresis, probably explaining the low success rates of monotherapy in literature.22 Our data are suggestive that patients with one or two or more nocturia episodes and NP are likely to be desmopressin responsive, since there is a lower nocturnal osmolality (only significantly in those with two or more nocturia episodes). Response rates of desmopressin therapy are expected to be lower in patients with NP and associated bladder dysfunction and/or disturbed sodium handling, as seen in desmopressin treatment of children with NP and nocturnal enuresis, a condition very similar to nocturia in adulthood.23 An increased sodium excretion overnight secondary to water and sodium retention during daytime, could increase the risk of side effects. Since these characteristics are predominantly present in patients with two or more nocturia episodes, we believe that by restricting desmopressin to patients without bladder
Exploring Nocturia: Gender, Age, and Causes dysfunction and with normal sodium handling might increase response rate and maybe decrease side-effect risk. However, evidence is lacking so far. Our data give enough evidence that future therapies might have higher success rates if a comprehensive diagnostic approach is followed leading to better subtyping of the patients. Despite the significant age and gender differences, the large standard deviations clearly demonstrate the heterogeneity of the patients, making an individualized therapy approach based on a noninvasive screening the optimal therapeutic approach. Regarding the diagnostic approach of nocturia, a thorough anamnesis, clinical examination and simply observing the patient can already give an indication on the underlying cause of nocturia. The diagnosis should be confirmed by an FVC, the gold standard for examining LUT symptoms.15 In case of NP, analysis of daytime and nighttime urine of solute handling might give additional information on the possible pathophysiologic mechanisms involved in excessive urine production leading to a rationalized choice for treatment.11 It is also important to mention that in the diagnostic work up, the need for treatment should be determined; if the patient is not bothered by nocturia and there is no medical need, one should be reluctant to expose patients to the potential risk of side effects of any medical treatment. Anyhow, adapting possible lifestyle factors should be considered as a first step. Although our results indicate no significant influence of drinking habits, it should be explored in the individual patient. Study Limitations
This analysis focused on three main factors that can easily be taken into account in daily practice: age, gender, and cause of nocturia. Since a patient population as seen in daily practice was included, there are differences among participants regarding comorbidities and medication. We do emphasize that these and other factors can influence development of nocturia, such as sleep apnea, which was not specifically questioned or examined in this population. Furthermore, we see that the diagnoses of small bladder capacity, nocturnal polyuria, or polyuria that lead to nocturia are also highly prevalent in the participants without nocturia. This indicates that isolated reduced bladder capacity or NP or anything else does not necessarily lead to getting up at night, because the other factors are within the normal ranges. However, it might indicate a problem with the current definitions. There is no exact cutoff for small bladder capacity and there are up to 15 different definitions of NP; major issues in research on nocturia. These results were obtained in a small study sample and in participants up to 65 years old, reflecting an active population with limited comorbidities and medication that might influence the occurrence of nocturia (as often seen in elderly). Therefore, to be able to extrapolate these results to the general population, large case–control studies need to be conducted. CONCLUSION
With an increase in nocturia episodes, a decrease in functional bladder capacity and an increase in nocturnal urine output is seen. This mismatch demands a comprehensive diagnostic approach to subtype the patient properly, which involves anamnesis, FVC, and analysis of daytime and nighttime urine. One nocturia episode per night is often based on an isolated cause, which is expected to be more easily to treat than a Neurourology and Urodynamics DOI 10.1002/nau
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combination of causes, although it is questionable if one nocturia episode requires treatment. Getting up twice or more is mostly caused by a combination of a small bladder and NP, the latter can be based on low nocturnal osmolality and/or high nocturnal sodium excretion. This is definitely age dependent, with a possible male predominance, although this needs to be elucidated with larger studies. Clinicians should be aware that investigating the problem of nocturia thoroughly and searching for an optimal treatment can be very rewarding for the general health and quality of sleep of those affected. FUNDING
This research was funded by Ferring, Pfizer, and Bard. This was an unrestricted funding, with no interference in protocol, execution of the trial, analysis, and interpretation of the results. REFERENCES 1. Bosch JLHR, Weiss JP. The prevalence and causes of nocturia. J Urol 2010;184:440–6. 2. Tikkinen KAO, Johnson TM, Tammela TLJ, et al. Nocturia frequency, bother, and quality of life: How often is too often? A population-based study in Finland. Eur Urol 2010;57:488–96. 3. van Kerrebroeck P, Abrams P, Chaikin D, et al. The standardization of terminology in nocturia: Report from the standardization subcommittee of the International Continence Society. BJU Int 2002;90:11–5. 4. Cornu JN, Abrams P, Chapple CR, et al. A contemporary assessment of nocturia: Definition, epidemiology, pathophysiology, and management—A systematic review and meta-analysis. Eur Urol 2012;62:877–90. 5. Rembratt A, Norgaard JP, Andersson KE. Differences between nocturics and non-nocturics in voiding patterns: An analysis of frequency-volume charts from community-dwelling elderly. BJU Int 2003;91:45–50. 6. Weiss JP, Wein AJ, van Kerrebroeck P, et al. Nocturia: New directions. Neurourol Urodynam 2011;30:700–3. 7. Irwin DE, Abrams P, Milsom I, et al. Understanding the elements of overactive bladder: Questions raised by the EPIC study. BJU Int 2008;101:1381–7. 8. Asplund R. Diuresis pattern, plasma vasopressin and blood pressure in healthy elderly persons with nocturia and nocturnal polyuria. Neth J Med 2002;60:276–80. 9. Natsume O. A clinical investigation of nocturnal polyuria in patients with nocturia: A diurnal variation in arginine vasopressin secretion and its relevance to mean blood pressure. J Urol 2006;176:660–4. 10. Friedman FM, Weiss JP. Desmopressin in the treatment of nocturia: Clinical evidence and experience. Ther Adv Urol 2013;5:310–7. 11. Herek J, Fitzgerald M, Mohindra M, et al. Solute and water excretion patterns in patients with nocturnal polyuria. Int J Nephrourol 2010;2:526–31. 12. Kirkland JL, Lye M, Levy DW, et al. Patterns of urine flow and electrolyte excretion in healthy elderly people. Br Med J 1983;287:1665–7. 13. Juul KV, Klein BM, Sandstrom R, et al. Gender difference in antidiuretic response to desmopressin. Am J Physiol Renal Physiol 2011;300:F1116–22. 14. Neveus T, Lackgren G, Tuvemo T, et al. Enuresis—Background and treatment. Scand J Urol Nephrol 2000;34:1–44. 15. Abrams P, Klevmark B. Frequency volume charts: An indispensable part of lower urinary tract assessment. Scand J Urol Nephrol 1996;30:47–53. 16. Booth JM, Lawrence M, O’Neill K, et al. Exploring older peoples’ experiences of nocturia: A poorly recognised urinary condition that limits participation. Disabil Rehabil 2010;32:765–74. 17. Chen FY, Dai YT, Liu CK, et al. Perception of nocturia and medical consulting behavior among community-dwelling women. Int Urogynecol J 2007;18: 431–6. 18. Jennum P. Sleep and nocturia. BJU Int 2002;90:21–4. 19. Weiss JP, Blaivas JG, Jones M, et al. Age related pathogenesis of nocturia in patients with overactive bladder. J Urol 2007;178:548–51. 20. Matthiesen TB, Rittig S, Norgaard JP, et al. Nocturnal polyuria and natriuresis in male patients with nocturia and lower urinary tract symptoms. J Urol 1996;156:1292–9. 21. Paick JS, Kim SW, Oh SJ, et al. Voiding patterns in men and women with lower urinary tract symptoms combined with nocturia. Int J Urol 2007;14: 699–703. 22. Jeong JY, Kim SJ, Cho HJ, et al. Influence of type of nocturia and lower urinary tract symptoms on therapeutic outcome in women treated with desmopressin. Korean J Urol 2013;54:95–9. 23. Dehoorne JL, Raes AM, Van Laecke E, et al. Desmopressin resistant nocturnal polyuria secondary to increased nocturnal osmotic excretion. J Urol 2006;176:749–53.
