Neurourology and Urodynamics 33:S2–S5 (2014)
Terminology, Epidemiology, Etiology, and Pathophysiology of Nocturia Philip Van Kerrebroeck,1* and Karl-Erik Andersson2
1
2
Department of Urology, Maastricht University Medical Center, Maastricht, The Netherlands Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina
Nocturia, awaking from sleep to void, has a negative impact on health and well-being. Nocturia affects men and women and is more prevalent among the elderly. More than two nocturnal voids is considered to be a clinically meaningful threshold associated with significant negative outcomes for health and well-being, and the timing of awakening has a significant bearing on the negative consequences of nocturia. Several serious underlying pathophysiologic conditions may be associated with nocturia. A thorough history and assessment of number and times of voids, void volume, and fluid intake is essential for determining the etiology of a patient’s nocturia. With data obtained from the frequency-volume chart (FVC), which is used to collect quantitative voiding data, a patient’s nocturia may be classified as global polyuria, nocturnal polyuria, reduced bladder capacity, or a combination of these categories. Global polyuria is defined as 24-hr urinary output that exceeds 40 ml/kg body weight and results in increased 24-hr urinary frequency. Nocturnal polyuria is defined as more than 20% of daily urine output at night in young patients and more than 33% in elderly patients. Reduced bladder capacity may be a result of idiopathic or neurogenic detrusor overactivity, bladder outlet obstruction, or reduced nocturnal bladder capacity. The pathophysiology underlying the findings of the FVC falls into five main categories: global polyuria, nocturnal polyuria, reduced bladder capacity, sleep disorders, and circadian clock disorders. This review discusses the epidemiology, etiology, and pathophysiology of nocturia. Neurourol. Urodynam. 33:S2–S5, 2014. # 2014 Wiley Periodicals, Inc. Key words: epidemiology; etiology; nocturia; pathophysiology
WHAT IS NOCTURIA?
Urologists and general practitioners are becoming increasingly aware of and interested in nocturia, as indicated by the recent increase in large epidemiologic studies and analyses1–5 and by initiatives such as the Nocturia Think Tank6 and The Consensus Statement from the Interdisciplinary Conference on Nocturia.7 The International Continence Society (ICS) defined nocturia in 2002 as the complaint that the individual has to wake at night 1 or more times to void; each void is preceded and followed by sleep.8 However, our understanding of nocturia and its characteristics associated with negative consequences for patients has evolved since the inception and dissemination of the ICS definition. This increased insight into frequent voiding during sleep time and its consequences for health and well-being has prompted a recommendation to revise the definition of nocturia to encompass the most current understanding and implications of the condition. The ICS definition refers to nocturia as a complaint, which may suggest that the condition is bothersome rather than clinically important. Although a key factor in the decision to consult a doctor to seek treatment is patient bother, use of the word disorder rather than complaint would support the medical seriousness of nocturia to the health of the patient. Nocturia is not just a complaint that should be borne; it is often a disorder that can be caused by many possibly serious underlying pathophysiologies. Inclusion of the word night in the definition of nocturia excludes a substantial proportion of the population. A more holistic definition would use sleep time, acknowledging that some patients with nocturia may not have their main stretch of sleep at night. However, of greater scientific interest is whether the time of sleep affects the risk of nocturia. Research examining the proportion of shift workers with nocturia in #
2014 Wiley Periodicals, Inc.
comparison with the general population may provide further understanding of the role of disrupted circadian rhythm in the etiology of nocturia. Sleep deprivation is associated with diuresis and natriuresis,9 but whether disrupted sleep patterns have an impact on diuresis remains uncertain. It should be considered whether the patient awakens from the sensation of a full bladder and the need to void. Diagnosing patients with nocturia who have sleep disruptions due to a cause not related to the bladder, even if they void because of wakefulness, may be counterproductive. An important element of the definition of nocturia is the number of voids during the sleep period. More than two nocturnal voids is considered a clinically meaningful threshold associated with significant negative outcomes for health and well-being.10,11 Furthermore, the timing of awakening has a significant bearing on the negative consequences of nocturia. Deep sleep predominates in the first 3 to 4 hr of sleep. Awakening during deep sleep has a greater negative impact on sleep quality, and therefore on well-being and health, than awakening during periods of rapid eye movement or light sleep.12 Although many studies have shown an association between nocturia and morbidity,3,4,13 further research is required to determine whether nocturia is an indicator of another
Christopher Chapple led the peer-review process as the Associate Editor responsible for the paper. Correspondence to: Phillip Van Kerrebroeck, Department of Urology, Maastricht University Medical Center, Maastricht, The Netherlands. E-mail: [email protected] Received 25 November 2013; Accepted 20 February 2014 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/nau.22595
Epidemiology and Pathophysiology of Nocturia underlying disorder (e.g., sleep apnea, diabetes), or whether nocturia can bring about subsequent illness. Despite these associations with serious morbidities and growing recognition of the deleterious effects of nocturia on health and quality of life, nocturia remains an underreported, understudied, and very infrequently recognized problem in adults.14 PREVALENCE OF NOCTURIA
Nocturia traditionally has been regarded as a predominantly male condition,15 but it is just as prevalent in women as in men.1,16 In a population-based survey of 19,165 adults in five European countries, the overall prevalence of nocturia (i.e., 1 void/night) in respondents 18 years of age and older was 48.6% in men and 54.5% in women.16 When nocturia was defined as 2 voids/night, the prevalence decreased to 20.9% in men and 24.0% in women.16 Although the prevalence of nocturia is higher among men and women older than age 70,1 nocturia is not just a disease of elderly people. Two or more nocturnal voids have been reported by 2%–18% of adults 20–39 years of age,1 highlighting the significant frequency among the general working population, for whom nocturia has been shown to have the greatest burden on daytime activity.17 CAUSES AND DIAGNOSIS OF NOCTURIA
Nocturia typically has been considered one of the hallmarks of lower urinary tract symptoms (LUTS), which include the overactive bladder syndrome (OABs) and symptoms associated with benign prostatic hyperplasia (BPH). However, although patients with LUTS frequently report nocturia, the modest clinical response with LUTS medications18 supports the hypothesis that nocturia not only is a symptom of OABs and BPH, but it is a condition in its own right, with various potential etiologies unrelated to bladder or prostate disorders. Although bladder function or prostate bladder outlet obstruction (BOO) may contribute to nocturia in some patients, nonurologic factors may play a major causal role in many cases. Nonurologic causes of nocturia include divergent factors such as hormonal imbalance, uncompensated heart disease, sleep problems, and lifestyle choices (e.g., intake of fluid close to bedtime).8 Urologic causes of nocturia, in addition to those connected to bladder storage symptoms such as decreased bladder capacity and BOO, may be kidney related and may manifest as overproduction of urine, either generally or only during sleep (global or nocturnal polyuria, respectively) (Fig. 1). A thorough assessment is essential to determine the etiology of a patient’s nocturia. In addition to a thorough history, key
S3
quantitative data including number and times of voids, void volume, and fluid intake can be obtained from the frequencyvolume chart (FVC). The FVC is an effective tool to guide diagnosis and appropriate treatment of nocturia.19 The FVC can be structured to record time of going to bed and time of rising. Based on data obtained from an FVC, a patient’s nocturia may be classified into one or more of five categories: global polyuria, nocturnal polyuria, reduced bladder capacity, sleep disorders, or circadian clock disorders.19,20 Global polyuria is defined as 24-hr urinary output that exceeds 40 ml/kg body weight8 and results in increased 24-hr urinary frequency.8 Nocturnal polyuria is increased urine production at nighttime. Various definitions have been used to describe nocturnal polyuria, including nocturnal urine volume >6.4 ml/kg, nocturnal diuresis 0.9 ml/min, and a nocturnal polyuria index (NPI, nocturnal urine production as a percentage of total 24-hr urine production) above a certain threshold, depending on age.6,8 The ICS defines nocturnal polyuria as an NPI >20% in young patients or >33% in elderly patients.8,21 Reduced bladder capacity may indicate detrusor overactivity (idiopathic or neurogenic), BOO, or reduced nocturnal bladder capacity (occurring during sleep). Other urologic causes of reduced bladder capacity include bladder cancer, bladder calculi, and cystitis, which may be bacterial, interstitial, or due to tuberculosis or radiation.7 Nonurologic causes of reduced bladder capacity may include learned voiding dysfunction, anxiety disorder, and side effects of medications such as beta-blockers. In addition to polyuria and reduced bladder capacity, nocturia can be caused by sleep disorders and circadian clock disorders. Algorithms for the treatment and classification of nocturia based on an FVC assessment are given in Figure 2. Nocturnal polyuria is a major contributory factor to the etiology of nocturia in men and women of all ages.22 In elderly patients, nocturnal polyuria is a factor in 85% of cases.23 Among patients with nocturia, 76–88% of patients 18 years of age and older screened for inclusion in a clinical trial had nocturnal polyuria.22 Although the association between nocturnal polyuria and nocturia is clear and robust, a recent metaanalysis investigating the relationship between nocturnal polyuria and nocturia found that many people with nocturnal polyuria do not appear to have nocturia, and the clinical importance of this association appears to be less obvious than previously suggested.24 However, some patients who suffer from nocturnal polyuria but have a bladder large enough to contain large volumes of urine may not report nocturia, whereas patients who have a small bladder and no nocturnal polyuria may report nocturia. PATHOPHYSIOLOGY
Nocturia
The pathophysiology underlying the findings of the FVC falls into five main categories: global polyuria, nocturnal polyuria, reduced bladder capacity, sleep disorders, and circadian clock disorders.20 Global Polyuria
Urologic causes • • • •
Reduced bladder capacity Nocturnal polyuria Detrusor overactivity Mixed etiology
Nonurologic causes • Untreated diabetes mellitus or insipidus • Sleep disorders • Uncompensated heart disease • Primary polydipsia
Fig. 1. Urologic and nonurologic causes of nocturia.8,15
Neurourology and Urodynamics DOI 10.1002/nau
Global polyuria may result from several different pathophysiologies. Polyuria due to polydipsia may simply be behavioral. However, high fluid intake may be secondary to dehydration due to poorly controlled diabetes mellitus.25 Nephrogenic diabetes insipidus results from tubular dysfunction, which reduces the capacity to concentrate urine. Central or neurogenic diabetes insipidus causes global polyuria because of a deficiency of secretion of the antidiuretic hormone, arginine vasopressin (AVP). This deficiency may be due to pituitary
S4
Van Kerrebroeck and Andersson
A
Nocturia
Patient desires treatment
Patient does not desire treatment
Screening
Lifestyle advice Further investigation
Polyuria
Nocturnal polyuria
Mixed etiology
Apparent bladder storage problems
BPO
OABs
B Nocturia
Nocturnal urine volumea 24-Hour volume >33%
Nocturnal polyuria
Reduced voided volumes
OABs BPO Varia
24-Hour urine volume >40 mL/kg
24-Hour polyuria
Fig. 2. Simple treatment algorithm (A)8 and algorithm based on values from frequency-volume chart (B). aThreshold value of 33% is for elderly patients. Younger patients have definitions of nocturnal polyuria with lower threshold values. BPO, benign prostatic obstruction; OABs, overactive bladder syndrome.
tumors or to panhypopituitarism.25 Side effects of prescribed medications such as diuretics, selective serotonin reuptake inhibitors, calcium channel blockers, tetracycline, and lithium may also induce polyuria.25 Nocturnal Polyuria
Numerous underlying factors may contribute to overproduction of urine at night, and several of these factors may be present in a single patient. The etiology of nocturnal polyuria may be associated with water diuresis or solute diuresis with accompanying water. Causes of water diuresis may include lifestyle and behavioral choices, such as excessive evening intake of fluid, especially diuretic beverages (e.g., alcohol, caffeine); a circadian defect in the secretion of vasopressin; and a defect in vasopressin action. Alternatively, the condition may be idiopathic. Causes of solute diuresis include congestive heart failure, sleep apnea, and renal insufficiency.8 Conditions such as cardiac impairment, autonomic neuropathy, renal impairment, nephrotic syndrome, hepatic failure, hypoalbuminemia, malnutrition, and venous stasis due to chronic venous insufficiency may result in third-space sequestration of fluids.25 When a patient lies down to sleep, the thirdspace fluid accumulated is no longer under the same hydrostatic pressure, and it returns to the intravascular compartment. This surplus water is then removed by the Neurourology and Urodynamics DOI 10.1002/nau
kidneys, resulting in nocturnal polyuria. Atrial natriuretic peptide (ANP) and brain natriuretic peptide are significantly increased in patients with congestive heart failure and exaggerate the fluid shifts seen. Circadian defects causing reduced nocturnal AVP secretion or activity result in production of more dilute urine.26 These defects may arise because of central nervous system (CNS) lesions of the hypothalamic-pituitary axis, Parkinson disease, or multiple sclerosis.20 Pathologically reduced plasma AVP levels at night have been shown in elderly patients with nocturia26; however, depressed AVP levels may be a physiologic response to increased circulating fluids upon reclining for sleep in patients with lower extremity third-space fluid. Obstructive sleep apnea (OSA) is a causal factor in nocturnal polyuria that is often overlooked. OSA produces negative intrathoracic pressure as the result of inspiratory effort posed against a closed airway. This causes cardiac distention and consequent release of ANP and decrease in AVP secretion as the heart perceives a false signal of volume overload. The increase in ANP causes natriuresis, and the reduced vasopressin increases diuresis, resulting in nocturnal polyuria.27 Risk factors for OSA include excessive weight, which is also a correlate of nocturia.13 Drugs such as diuretics, nonsteroidal anti-inflammatory drugs (via suppression of AVP-inhibiting prostaglandin E2), antidiabetic thiazolidinediones, and steroids are other potential causes of nocturnal polyuria.6 Reduced Bladder Capacity
Reduced bladder capacity is often caused by bladder storage problems due to BPH, OABs, interstitial cystitis, or bladder pain syndrome.8,20 Nocturia is a common complaint of patients with BPH or OABs, although other factors may contribute, and not all patients with BPH or OABs have nocturia.7 Reduced bladder capacity is a feature of neurogenic bladder, which may be due to Parkinson disease, multiple sclerosis, spinal cord injury, or stroke. Voiding disorders resulting in high postvoid residual volume affect the functional storage capacity of the bladder, giving rise to urinary frequency. Other causes of reduced bladder capacity include lower urinary tract cancer, lower urinary tract calculi, drug side effects, and aging.20 Nocturia may be caused by a combination of reduced bladder capacity and nocturnal polyuria. Therefore, nocturnal polyuria should still be considered in patients with BPH or OAB when treatment decisions are made to achieve clinically significant improvement in nocturia for these patients.1 Sleep Disorders
In addition to sleep apnea, primary sleep disorders such as insomnia, restless leg syndrome, narcolepsy, and arousal disorders (e.g., sleepwalking, nightmares) can cause nocturia.20 Sleep disorders should be investigated as causing nocturia when FVC-assessed measurements are within the normal range. Conditions such as cardiac failure, chronic obstructive pulmonary disease, endocrine disorders, and neurologic conditions (e.g., Parkinson disease, dementia, epilepsy) may cause secondary sleep disorders associated with nocturia.20 Other factors that may result in sleep disturbances and associated nocturia are psychiatric conditions such as depression and anxiety, chronic pain disorders, alcohol or drug use (consumption or withdrawal), and various medications (e.g., corticosteroids, beta-blockers, thyroid hormones, psychotropics, antiepileptics).20 Although sleep disorders have been associated with nocturia,3,28 it is not clear whether nocturnal urinary frequency is just a result of wakefulness. However, acute sleep
Epidemiology and Pathophysiology of Nocturia 9
deprivation induces diuresis and sodium output. The association and relationship between nocturia and sleep warrant further research. Circadian Clock Disorders
Behavior, physiology, and metabolism in mammals are subject to a well-controlled daily rhythm, generated by an internal self-sustained molecular oscillator, referred to as the circadian clock.29,30 The circadian clock, also called the peripheral clock, is a molecular genetic transcription– translation feedback mechanism that exists in most organs and cells. This clock is orchestrated by the central clock in the suprachiasmatic nucleus of the brain.29 Although circadian rhythms in fluid intake, urine production, and urine storage have been substantiated in humans (diurnal) and rodents (nocturnal), the underlying mechanisms are largely unknown. For example, a circadian variability in urinary flow values has been demonstrated in men with bladder obstruction,31 showing higher peak urinary flow with a smaller voided volume and thus shorter flow time in the early afternoon when compared with the late evening, early morning, and midnight-to-morning periods. It is well known that there is a mismatch between urine production and storage in nocturia, particularly in elderly people and in children with nocturnal enuresis. Such temporal variation may be related to biological rhythms. The day-tonight change in micturition frequency is linked to the genetic rhythm maintained by the clock system involving brain, kidney, and bladder.32 Such linkage presents a novel paradigm for investigating the pathophysiology of nocturia, which is considered to be loss of rhythm, and of nocturnal enuresis, which is considered to be immaturity in development of the rhythm. CONCLUSIONS
Although nocturia has been defined by the ICS, updating the definition to encompass current understanding and treatment of the condition would help foster new beneficial research with shared foundations. Recent epidemiologic studies have highlighted the substantial prevalence of nocturia among men and women, underscoring the need for further research in nocturia. Nocturia is a complex multifactorial condition that requires careful evaluation for appropriate diagnosis. The FVC is an essential evaluation tool that can facilitate accurate identification of the potential multiple causes of nocturia in an individual patient, providing evidence by which the etiology of nocturia can be categorized into one or a combination of categories of sleep disorders, nocturnal polyuria, global polyuria, and reduced bladder capacity. The role of the circadian clock in the pathophysiology of nocturia deserves further attention. REFERENCES 1. Bosch JL, Weiss JP. The prevalence and causes of nocturia. J Urol 2010; 184:440–6. 2. Coyne KS, Sexton CC, Thompson CL, et al. The prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK and Sweden: Results from the Epidemiology of LUTS (EpiLUTS) study. BJU Int 2009;104:352–60. 3. Kupelian V, Wei JT, O’Leary MP, et al. Nocturia and quality of life: Results from the Boston area community health survey. Eur Urol 2012;61:78–84.
Neurourology and Urodynamics DOI 10.1002/nau
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4. Lightner DJ, Krambeck AE, Jacobson DJ, et al. Nocturia is associated with an increased risk of coronary heart disease and death. BJU Int 2012;110:848–53. 5. van Doorn B, Kok ET, Blanker MH, et al. Mortality in older men with nocturia: A 15-year followup of the Krimpen study. J Urol 2012;187:1727–31. 6. Weiss JP, Bosch JL, Drake M, et al. Nocturia think tank: Focus on nocturnal polyuria: ICI-RS 2011. Neurourol Urodyn 2012;31:330–9. 7. Weiss JP, Blaivas JG, Bliwise DL, et al. The evaluation and treatment of nocturia: A consensus statement. BJU Int 2011;108:6–21. 8. Van Kerrebroeck P, Abrams P, Chaikin D, et al. The standardisation of terminology in nocturia: Report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21:179–83. 9. Kamperis K, Hagstroem S, Radvanska E, et al. Excess diuresis and natriuresis during acute sleep deprivation in healthy adults. Am J Physiol Renal Physiol 2010;299:F404–11. 10. Tikkinen KA, Johnson TM II, Tammela TL, 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. 11. Yu HJ, Chen FY, Huang PC, et al. Impact of nocturia on symptom-specific quality of life among community-dwelling adults aged 40 years and older. Urology 2006;67:713–8. 12. Stanley N. The underestimated impact of nocturia on quality of life. Eur Urol Suppl 2005;4:17–9. 13. Parthasarathy S, Fitzgerald M, Goodwin JL, et al. Nocturia, sleep-disordered breathing, and cardiovascular morbidity in a community-based cohort. PLoS ONE 2012;7:e30969. 14. Chen FY, Dai YT, Liu CK, et al. Perception of nocturia and medical consulting behavior among community-dwelling women. Int Urogynecol J Pelvic Floor Dysfunct 2007;18:431–6. 15. Wein A, Lose GR, Fonda D. Nocturia in men, women and the elderly: A practical approach. BJU Int 2002;90:28–31. 16. Irwin DE, Milsom I, Hunskaar S, et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: Results of the EPIC study. Eur Urol 2006;50:1306–15. 17. Kobelt G, Borgstr€ om F, Mattiasson A. Productivity, vitality and utility in a group of healthy professionally active individuals with nocturia. BJU Int 2003;91:190–5. 18. Smith AL, Wein AJ. Outcomes of pharmacological management of nocturia with non-antidiuretic agents: Does statistically significant equal clinically significant? BJU Int 2011;107:1550–4. 19. Van Kerrebroeck P, Hashim H, Holm-Larsen T, et al. Thinking beyond the bladder: Antidiuretic treatment of nocturia. Int J Clin Pract 2010;64:807–16. 20. 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. 21. Madersbacher S, Cornu JN. Nocturnal polyuria: It’s all about definition, and be patient! Eur Urol 2013;63:548–50. 22. Weiss JP, Van Kerrebroeck PE, Klein BM, et al. Excessive nocturnal urine production is a major contributing factor to the etiology of nocturia. J Urol 2011;186:1358–63. 23. Rembratt A, Nørgaard 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. 24. Hofmeester I, Kollen BJ, Steffens MG, et al. The association between nocturia and nocturnal polyuria in clinical and epidemiological studies: A systematic review and meta-analyses. J Urol 2013;pii:S0022–5347 05839-4. DOI: 10.1016/j.juro.2013.10.100 [Epub ahead of print]. 25. Gulur DM, Mevcha AM, Drake MJ. Nocturia as a manifestation of systemic disease. BJUInt 2011;107:702–13. 26. Asplund R, Aberg H. Diurnal variation in the levels of antidiuretic hormone in the elderly. J Intern Med 1991;229:131–4. 27. Umlauf MG, Chasens ER. Sleep disordered breathing and nocturnal polyuria: Nocturia and enuresis. Sleep Med Rev 2003;7:403–11. 28. Ancoli-Israel S, Bliwise DL, Nørgaard JP. The effect of nocturia on sleep. Sleep Med Rev 2011;15:91–7. 29. Reppert SM, Weaver DR. Coordination of circadian timing in mammals. Nature 2002;418:935–41. 30. Dibner C, Schibler U, Albrecht U. The mammalian circadian timing system: Organization and coordination of central and peripheral clocks. Annu Rev Physiol 2010;72:517–49. 31. Witjes WP, Wijkstra H, Debruyne FM, et al. Quantitative assessment of uroflow: Is there a circadian rhythm? Urology 1997;50:221–8. 32. Negoro H, Kanematsu A, Doi M, et al. Involvement of urinary bladder Connexin43 and the circadian clock in coordination of diurnal micturition rhythm. Nat Commun 2012;3:809.
Terminology, Epidemiology, Etiology, and Pathophysiology of Nocturia Philip Van Kerrebroeck,1* and Karl-Erik Andersson2
1
2
Department of Urology, Maastricht University Medical Center, Maastricht, The Netherlands Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina
Nocturia, awaking from sleep to void, has a negative impact on health and well-being. Nocturia affects men and women and is more prevalent among the elderly. More than two nocturnal voids is considered to be a clinically meaningful threshold associated with significant negative outcomes for health and well-being, and the timing of awakening has a significant bearing on the negative consequences of nocturia. Several serious underlying pathophysiologic conditions may be associated with nocturia. A thorough history and assessment of number and times of voids, void volume, and fluid intake is essential for determining the etiology of a patient’s nocturia. With data obtained from the frequency-volume chart (FVC), which is used to collect quantitative voiding data, a patient’s nocturia may be classified as global polyuria, nocturnal polyuria, reduced bladder capacity, or a combination of these categories. Global polyuria is defined as 24-hr urinary output that exceeds 40 ml/kg body weight and results in increased 24-hr urinary frequency. Nocturnal polyuria is defined as more than 20% of daily urine output at night in young patients and more than 33% in elderly patients. Reduced bladder capacity may be a result of idiopathic or neurogenic detrusor overactivity, bladder outlet obstruction, or reduced nocturnal bladder capacity. The pathophysiology underlying the findings of the FVC falls into five main categories: global polyuria, nocturnal polyuria, reduced bladder capacity, sleep disorders, and circadian clock disorders. This review discusses the epidemiology, etiology, and pathophysiology of nocturia. Neurourol. Urodynam. 33:S2–S5, 2014. # 2014 Wiley Periodicals, Inc. Key words: epidemiology; etiology; nocturia; pathophysiology
WHAT IS NOCTURIA?
Urologists and general practitioners are becoming increasingly aware of and interested in nocturia, as indicated by the recent increase in large epidemiologic studies and analyses1–5 and by initiatives such as the Nocturia Think Tank6 and The Consensus Statement from the Interdisciplinary Conference on Nocturia.7 The International Continence Society (ICS) defined nocturia in 2002 as the complaint that the individual has to wake at night 1 or more times to void; each void is preceded and followed by sleep.8 However, our understanding of nocturia and its characteristics associated with negative consequences for patients has evolved since the inception and dissemination of the ICS definition. This increased insight into frequent voiding during sleep time and its consequences for health and well-being has prompted a recommendation to revise the definition of nocturia to encompass the most current understanding and implications of the condition. The ICS definition refers to nocturia as a complaint, which may suggest that the condition is bothersome rather than clinically important. Although a key factor in the decision to consult a doctor to seek treatment is patient bother, use of the word disorder rather than complaint would support the medical seriousness of nocturia to the health of the patient. Nocturia is not just a complaint that should be borne; it is often a disorder that can be caused by many possibly serious underlying pathophysiologies. Inclusion of the word night in the definition of nocturia excludes a substantial proportion of the population. A more holistic definition would use sleep time, acknowledging that some patients with nocturia may not have their main stretch of sleep at night. However, of greater scientific interest is whether the time of sleep affects the risk of nocturia. Research examining the proportion of shift workers with nocturia in #
2014 Wiley Periodicals, Inc.
comparison with the general population may provide further understanding of the role of disrupted circadian rhythm in the etiology of nocturia. Sleep deprivation is associated with diuresis and natriuresis,9 but whether disrupted sleep patterns have an impact on diuresis remains uncertain. It should be considered whether the patient awakens from the sensation of a full bladder and the need to void. Diagnosing patients with nocturia who have sleep disruptions due to a cause not related to the bladder, even if they void because of wakefulness, may be counterproductive. An important element of the definition of nocturia is the number of voids during the sleep period. More than two nocturnal voids is considered a clinically meaningful threshold associated with significant negative outcomes for health and well-being.10,11 Furthermore, the timing of awakening has a significant bearing on the negative consequences of nocturia. Deep sleep predominates in the first 3 to 4 hr of sleep. Awakening during deep sleep has a greater negative impact on sleep quality, and therefore on well-being and health, than awakening during periods of rapid eye movement or light sleep.12 Although many studies have shown an association between nocturia and morbidity,3,4,13 further research is required to determine whether nocturia is an indicator of another
Christopher Chapple led the peer-review process as the Associate Editor responsible for the paper. Correspondence to: Phillip Van Kerrebroeck, Department of Urology, Maastricht University Medical Center, Maastricht, The Netherlands. E-mail: [email protected] Received 25 November 2013; Accepted 20 February 2014 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/nau.22595
Epidemiology and Pathophysiology of Nocturia underlying disorder (e.g., sleep apnea, diabetes), or whether nocturia can bring about subsequent illness. Despite these associations with serious morbidities and growing recognition of the deleterious effects of nocturia on health and quality of life, nocturia remains an underreported, understudied, and very infrequently recognized problem in adults.14 PREVALENCE OF NOCTURIA
Nocturia traditionally has been regarded as a predominantly male condition,15 but it is just as prevalent in women as in men.1,16 In a population-based survey of 19,165 adults in five European countries, the overall prevalence of nocturia (i.e., 1 void/night) in respondents 18 years of age and older was 48.6% in men and 54.5% in women.16 When nocturia was defined as 2 voids/night, the prevalence decreased to 20.9% in men and 24.0% in women.16 Although the prevalence of nocturia is higher among men and women older than age 70,1 nocturia is not just a disease of elderly people. Two or more nocturnal voids have been reported by 2%–18% of adults 20–39 years of age,1 highlighting the significant frequency among the general working population, for whom nocturia has been shown to have the greatest burden on daytime activity.17 CAUSES AND DIAGNOSIS OF NOCTURIA
Nocturia typically has been considered one of the hallmarks of lower urinary tract symptoms (LUTS), which include the overactive bladder syndrome (OABs) and symptoms associated with benign prostatic hyperplasia (BPH). However, although patients with LUTS frequently report nocturia, the modest clinical response with LUTS medications18 supports the hypothesis that nocturia not only is a symptom of OABs and BPH, but it is a condition in its own right, with various potential etiologies unrelated to bladder or prostate disorders. Although bladder function or prostate bladder outlet obstruction (BOO) may contribute to nocturia in some patients, nonurologic factors may play a major causal role in many cases. Nonurologic causes of nocturia include divergent factors such as hormonal imbalance, uncompensated heart disease, sleep problems, and lifestyle choices (e.g., intake of fluid close to bedtime).8 Urologic causes of nocturia, in addition to those connected to bladder storage symptoms such as decreased bladder capacity and BOO, may be kidney related and may manifest as overproduction of urine, either generally or only during sleep (global or nocturnal polyuria, respectively) (Fig. 1). A thorough assessment is essential to determine the etiology of a patient’s nocturia. In addition to a thorough history, key
S3
quantitative data including number and times of voids, void volume, and fluid intake can be obtained from the frequencyvolume chart (FVC). The FVC is an effective tool to guide diagnosis and appropriate treatment of nocturia.19 The FVC can be structured to record time of going to bed and time of rising. Based on data obtained from an FVC, a patient’s nocturia may be classified into one or more of five categories: global polyuria, nocturnal polyuria, reduced bladder capacity, sleep disorders, or circadian clock disorders.19,20 Global polyuria is defined as 24-hr urinary output that exceeds 40 ml/kg body weight8 and results in increased 24-hr urinary frequency.8 Nocturnal polyuria is increased urine production at nighttime. Various definitions have been used to describe nocturnal polyuria, including nocturnal urine volume >6.4 ml/kg, nocturnal diuresis 0.9 ml/min, and a nocturnal polyuria index (NPI, nocturnal urine production as a percentage of total 24-hr urine production) above a certain threshold, depending on age.6,8 The ICS defines nocturnal polyuria as an NPI >20% in young patients or >33% in elderly patients.8,21 Reduced bladder capacity may indicate detrusor overactivity (idiopathic or neurogenic), BOO, or reduced nocturnal bladder capacity (occurring during sleep). Other urologic causes of reduced bladder capacity include bladder cancer, bladder calculi, and cystitis, which may be bacterial, interstitial, or due to tuberculosis or radiation.7 Nonurologic causes of reduced bladder capacity may include learned voiding dysfunction, anxiety disorder, and side effects of medications such as beta-blockers. In addition to polyuria and reduced bladder capacity, nocturia can be caused by sleep disorders and circadian clock disorders. Algorithms for the treatment and classification of nocturia based on an FVC assessment are given in Figure 2. Nocturnal polyuria is a major contributory factor to the etiology of nocturia in men and women of all ages.22 In elderly patients, nocturnal polyuria is a factor in 85% of cases.23 Among patients with nocturia, 76–88% of patients 18 years of age and older screened for inclusion in a clinical trial had nocturnal polyuria.22 Although the association between nocturnal polyuria and nocturia is clear and robust, a recent metaanalysis investigating the relationship between nocturnal polyuria and nocturia found that many people with nocturnal polyuria do not appear to have nocturia, and the clinical importance of this association appears to be less obvious than previously suggested.24 However, some patients who suffer from nocturnal polyuria but have a bladder large enough to contain large volumes of urine may not report nocturia, whereas patients who have a small bladder and no nocturnal polyuria may report nocturia. PATHOPHYSIOLOGY
Nocturia
The pathophysiology underlying the findings of the FVC falls into five main categories: global polyuria, nocturnal polyuria, reduced bladder capacity, sleep disorders, and circadian clock disorders.20 Global Polyuria
Urologic causes • • • •
Reduced bladder capacity Nocturnal polyuria Detrusor overactivity Mixed etiology
Nonurologic causes • Untreated diabetes mellitus or insipidus • Sleep disorders • Uncompensated heart disease • Primary polydipsia
Fig. 1. Urologic and nonurologic causes of nocturia.8,15
Neurourology and Urodynamics DOI 10.1002/nau
Global polyuria may result from several different pathophysiologies. Polyuria due to polydipsia may simply be behavioral. However, high fluid intake may be secondary to dehydration due to poorly controlled diabetes mellitus.25 Nephrogenic diabetes insipidus results from tubular dysfunction, which reduces the capacity to concentrate urine. Central or neurogenic diabetes insipidus causes global polyuria because of a deficiency of secretion of the antidiuretic hormone, arginine vasopressin (AVP). This deficiency may be due to pituitary
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Van Kerrebroeck and Andersson
A
Nocturia
Patient desires treatment
Patient does not desire treatment
Screening
Lifestyle advice Further investigation
Polyuria
Nocturnal polyuria
Mixed etiology
Apparent bladder storage problems
BPO
OABs
B Nocturia
Nocturnal urine volumea 24-Hour volume >33%
Nocturnal polyuria
Reduced voided volumes
OABs BPO Varia
24-Hour urine volume >40 mL/kg
24-Hour polyuria
Fig. 2. Simple treatment algorithm (A)8 and algorithm based on values from frequency-volume chart (B). aThreshold value of 33% is for elderly patients. Younger patients have definitions of nocturnal polyuria with lower threshold values. BPO, benign prostatic obstruction; OABs, overactive bladder syndrome.
tumors or to panhypopituitarism.25 Side effects of prescribed medications such as diuretics, selective serotonin reuptake inhibitors, calcium channel blockers, tetracycline, and lithium may also induce polyuria.25 Nocturnal Polyuria
Numerous underlying factors may contribute to overproduction of urine at night, and several of these factors may be present in a single patient. The etiology of nocturnal polyuria may be associated with water diuresis or solute diuresis with accompanying water. Causes of water diuresis may include lifestyle and behavioral choices, such as excessive evening intake of fluid, especially diuretic beverages (e.g., alcohol, caffeine); a circadian defect in the secretion of vasopressin; and a defect in vasopressin action. Alternatively, the condition may be idiopathic. Causes of solute diuresis include congestive heart failure, sleep apnea, and renal insufficiency.8 Conditions such as cardiac impairment, autonomic neuropathy, renal impairment, nephrotic syndrome, hepatic failure, hypoalbuminemia, malnutrition, and venous stasis due to chronic venous insufficiency may result in third-space sequestration of fluids.25 When a patient lies down to sleep, the thirdspace fluid accumulated is no longer under the same hydrostatic pressure, and it returns to the intravascular compartment. This surplus water is then removed by the Neurourology and Urodynamics DOI 10.1002/nau
kidneys, resulting in nocturnal polyuria. Atrial natriuretic peptide (ANP) and brain natriuretic peptide are significantly increased in patients with congestive heart failure and exaggerate the fluid shifts seen. Circadian defects causing reduced nocturnal AVP secretion or activity result in production of more dilute urine.26 These defects may arise because of central nervous system (CNS) lesions of the hypothalamic-pituitary axis, Parkinson disease, or multiple sclerosis.20 Pathologically reduced plasma AVP levels at night have been shown in elderly patients with nocturia26; however, depressed AVP levels may be a physiologic response to increased circulating fluids upon reclining for sleep in patients with lower extremity third-space fluid. Obstructive sleep apnea (OSA) is a causal factor in nocturnal polyuria that is often overlooked. OSA produces negative intrathoracic pressure as the result of inspiratory effort posed against a closed airway. This causes cardiac distention and consequent release of ANP and decrease in AVP secretion as the heart perceives a false signal of volume overload. The increase in ANP causes natriuresis, and the reduced vasopressin increases diuresis, resulting in nocturnal polyuria.27 Risk factors for OSA include excessive weight, which is also a correlate of nocturia.13 Drugs such as diuretics, nonsteroidal anti-inflammatory drugs (via suppression of AVP-inhibiting prostaglandin E2), antidiabetic thiazolidinediones, and steroids are other potential causes of nocturnal polyuria.6 Reduced Bladder Capacity
Reduced bladder capacity is often caused by bladder storage problems due to BPH, OABs, interstitial cystitis, or bladder pain syndrome.8,20 Nocturia is a common complaint of patients with BPH or OABs, although other factors may contribute, and not all patients with BPH or OABs have nocturia.7 Reduced bladder capacity is a feature of neurogenic bladder, which may be due to Parkinson disease, multiple sclerosis, spinal cord injury, or stroke. Voiding disorders resulting in high postvoid residual volume affect the functional storage capacity of the bladder, giving rise to urinary frequency. Other causes of reduced bladder capacity include lower urinary tract cancer, lower urinary tract calculi, drug side effects, and aging.20 Nocturia may be caused by a combination of reduced bladder capacity and nocturnal polyuria. Therefore, nocturnal polyuria should still be considered in patients with BPH or OAB when treatment decisions are made to achieve clinically significant improvement in nocturia for these patients.1 Sleep Disorders
In addition to sleep apnea, primary sleep disorders such as insomnia, restless leg syndrome, narcolepsy, and arousal disorders (e.g., sleepwalking, nightmares) can cause nocturia.20 Sleep disorders should be investigated as causing nocturia when FVC-assessed measurements are within the normal range. Conditions such as cardiac failure, chronic obstructive pulmonary disease, endocrine disorders, and neurologic conditions (e.g., Parkinson disease, dementia, epilepsy) may cause secondary sleep disorders associated with nocturia.20 Other factors that may result in sleep disturbances and associated nocturia are psychiatric conditions such as depression and anxiety, chronic pain disorders, alcohol or drug use (consumption or withdrawal), and various medications (e.g., corticosteroids, beta-blockers, thyroid hormones, psychotropics, antiepileptics).20 Although sleep disorders have been associated with nocturia,3,28 it is not clear whether nocturnal urinary frequency is just a result of wakefulness. However, acute sleep
Epidemiology and Pathophysiology of Nocturia 9
deprivation induces diuresis and sodium output. The association and relationship between nocturia and sleep warrant further research. Circadian Clock Disorders
Behavior, physiology, and metabolism in mammals are subject to a well-controlled daily rhythm, generated by an internal self-sustained molecular oscillator, referred to as the circadian clock.29,30 The circadian clock, also called the peripheral clock, is a molecular genetic transcription– translation feedback mechanism that exists in most organs and cells. This clock is orchestrated by the central clock in the suprachiasmatic nucleus of the brain.29 Although circadian rhythms in fluid intake, urine production, and urine storage have been substantiated in humans (diurnal) and rodents (nocturnal), the underlying mechanisms are largely unknown. For example, a circadian variability in urinary flow values has been demonstrated in men with bladder obstruction,31 showing higher peak urinary flow with a smaller voided volume and thus shorter flow time in the early afternoon when compared with the late evening, early morning, and midnight-to-morning periods. It is well known that there is a mismatch between urine production and storage in nocturia, particularly in elderly people and in children with nocturnal enuresis. Such temporal variation may be related to biological rhythms. The day-tonight change in micturition frequency is linked to the genetic rhythm maintained by the clock system involving brain, kidney, and bladder.32 Such linkage presents a novel paradigm for investigating the pathophysiology of nocturia, which is considered to be loss of rhythm, and of nocturnal enuresis, which is considered to be immaturity in development of the rhythm. CONCLUSIONS
Although nocturia has been defined by the ICS, updating the definition to encompass current understanding and treatment of the condition would help foster new beneficial research with shared foundations. Recent epidemiologic studies have highlighted the substantial prevalence of nocturia among men and women, underscoring the need for further research in nocturia. Nocturia is a complex multifactorial condition that requires careful evaluation for appropriate diagnosis. The FVC is an essential evaluation tool that can facilitate accurate identification of the potential multiple causes of nocturia in an individual patient, providing evidence by which the etiology of nocturia can be categorized into one or a combination of categories of sleep disorders, nocturnal polyuria, global polyuria, and reduced bladder capacity. The role of the circadian clock in the pathophysiology of nocturia deserves further attention. REFERENCES 1. Bosch JL, Weiss JP. The prevalence and causes of nocturia. J Urol 2010; 184:440–6. 2. Coyne KS, Sexton CC, Thompson CL, et al. The prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK and Sweden: Results from the Epidemiology of LUTS (EpiLUTS) study. BJU Int 2009;104:352–60. 3. Kupelian V, Wei JT, O’Leary MP, et al. Nocturia and quality of life: Results from the Boston area community health survey. Eur Urol 2012;61:78–84.
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