Prevalence

Overall prevalence of nocturia for 5500 people in the Boston Area Community Health (BACH) study was 28.4%, affecting 25.2% of men and 31.3% of women (Fitzgerald et al, 2007). Prevalence of nocturia was 48.6% of men and 54.5% in the EPIC study in Europe and Canada, evaluating 19,000 adults with or without overactive bladder (OAB) (Irwin et al, 2006). In a subgroup analysis for men in the EPIC study, nocturia was the most prevalent LUTS (Irwin et al, 2009). In a European survey of nearly 3000 men aged 55 to 75 years in several primary care practices, nocturnal voiding frequency was zero in 20%, one in 45.8%, two in 20.8%, three in 7.1%, four 2.4%, and five or more in 2.6% (Gourova et al, 2006). In the hospital setting, prevalence of nocturia was 87% in a population of 700 women of mean age 59, with greater bother associated with higher number of nocturia episodes and with mixed incontinence (Lowenstein et al, 2007). Differences according to ethnicity are apparent, with an overall prevalence of 38.5% in blacks, 30.7% in Hispanics, and 23.2% in whites (Fitzgerald et al, 2007).

There is a clear impact of aging on prevalence of nocturia. Between the ages of 30 and 39 years old, nocturia prevalence is 19.9% and in those aged between 60 and 79 it is 41.2% (Fitzgerald et al, 2007). In people younger than the age of 40, nocturia is slightly more prevalent in women than men; above the age of 60, prevalence in the two genders is similar (Irwin et al, 2006). In general, younger people are more likely to manifest decreased nocturnal bladder capacity, whereas nocturnal urine overproduction increasingly accounts for nocturia as people age (Weiss et al, 2007). Presence of NP cannot be reliably predicted from daytime LUTS (Swithinbank et al, 2004).

Approaches to diagnosing NP (absolute, relative or functional) were compared in an epidemiologic study (Rembratt et al, 2002). In older patients showing at least two voids per night, 70% fulfilled all three diagnostic approaches. For those people with up to one void per night, 67% fulfilled at least one definition, but only 5% fulfilled all three definitions. Overall, the prevalence of NP in older nocturia patients was 45% to 100% when there were greater than or equal to two voids per night, 8% to 37% of people with up to one void per night, and 4% to 25% of people who did not void overnight.

Quality of Life and Wider Health Impact of Nocturia

The overall duration of sleep can be divided into specific stages according to various parameters including electro-encephalogram, muscle tone, respiration, heart rate, and eye movement. A slow-wave sleep pattern, regarded as the restorative component of sleep, predominately occurs in the first part of the night. Thus early sleep disturbance may result in a more substantial impact on health and ability to carry out activities of daily living. A series of potential causes of sleep disturbance was surveyed by the National Sleep Foundation “Sleep in America Poll” (Foley et al, 2004). These comprised nocturia, physical pain, caregiving, health concerns, cough, night-time heartburn, headache, money problems, family problems, and uncomfortable bed. Nocturia was found to be the leading cause of sleep disturbance in older adults (aged 55 to 84) (Bliwise et al, 2009).

A high proportion of people with nocturia describe themselves as having impaired quality of life as a consequence. Nocturia is one of the main predictors of symptoms (Coyne et al, 2009a, 2009b) and drug treatment (Asplund et al, 2005) of anxiety and depression in people with LUTS. Increased nocturia severity was shown to increase absence from work for health reasons (Asplund et al, 2005). Nocturia impairs work productivity and activity in a nonlinear fashion (Kobelt et al, 2003). Where nocturia of at least two voids per night is reported, impact on quality of life is more problematic at a population level (Fiske et al, 2004; Yu et al, 2006), becoming a major impact at three voids per night or more (Tikkinen et al, 2010), though this is subject to considerable individual variation. Self-reported health status was impaired in people documented as having at least two voids per night in a Dutch population (van Dijk et al, 2002). Consequently, a greater proportion will seek medical input at this level of severity (Chen et al, 2007). In elderly residential care, falls are common at night and are frequently reported to occur in relation to toilet visits. The odds ratio of a fall is 1.84 where there are at least two voids per night, rising to 2.15 for more than three voids per night. Observation of increasing prevalence of hip fracture as a consequence of nocturia has been documented (Asplund, 2006).

Regulation of Body Water Balance; Diuresis and Natriuresis

Tight regulation of total body water and electrolyte loads; relative distribution across the intracellular, extracellular, and intravascular compartments; and specific concentrations within each compartment are crucial homeostatic functions, regulated by hormonal and physical properties (Verbalis, 2006). Balance is achieved by interplay of diverse physiologic influences, in which renal regulation of glomerular filtration and tubular reabsorption play a foremost role, reflected in the composition and rate of production of urine. As a consequence, the lower urinary tract, and hence LUTS, are subordinate to the greater physiologic needs of the organism as a whole. Focusing on nocturia, without consideration of the pathophysiologic context, may prove counterproductive.

Aquaporins (Agre et al, 1998) are a family of regulated channels with a key role in fluid and electrolyte balance. For a recent review of renal aquaporins, read the work of Kwon and colleagues (2009). Various aquaporins are present in the kidney, with a major role attributed to aquaporin-2. Key to rapid adjustment of fluid balance is the process of “trafficking,” the short-term variation of aquaporin-2 channel density and function. Changes in aquaporin-2 and aquaporin-3 can arise over periods of days, influenced by numerous factors. Some aquaporins have been identified in the urothelium of the bladder (Rubenwolf et al, 2008), where their roles have yet to be ascertained (reviewed in Khandelwal et al, 2009).

Arginine vasopressin is a key endocrine determinant of water retention, hence its alternative name of antidiuretic hormone (ADH). It modifies the structure of aquaporin-2 and causes increased insertion of aquaporin water channels at key locations in the nephron, consequently enhancing permeability for reabsorption of water. Human volunteers given ADH show an increase of body weight and a corresponding dilutional decrease in their serum sodium concentration, if not fluid restricted (Leaf et al, 1958). By extrapolation, retained water in the syndrome of inappropriate ADH secretion (SIADH) leads to increased body weight, hyponatremia, and blood pressure problems (Verbalis, 2006). Where there is chronic exposure to elevated levels of ADH, the phenomenon of “escape from antidiuresis” can occur as a result of desensitization of the renal tubules (Leaf et al, 1958), with downregulation of the aquaporin-2 channel (Verbalis, 2006). Accordingly, the chronic nature of impaired fluid and electrolyte balance can lead to a refractory clinical situation unless the overall balance is corrected, and time allowed for recovery. Recognition that other hormones can also influence aquaporin-2 is more recent, including secretin (Chu et al, 2009) or oxytocin (reviewed in (Cheng et al, 2009). These may yield alternative pharmaceutic strategies in the future (Bouley et al, 2008).

Natriuresis is the process of excretion of sodium in the urine and is a consideration in the clinical context (Matthiesen et al, 1996) that is often underestimated. The renin-angiotensin-aldosterone system makes major adjustments to the rates of renal sodium secretion, though at a comparatively slow rate. Brain and atrial natriuretic peptides (BNP and ANP, respectively) cause net sodium excretion, whereas sodium is conserved by aldosterone. Natriuresis lowers the blood sodium concentration and lowers blood volume, as osmotic forces make water follow sodium into the urine. Sympathetic innervation can make rapid adjustments to salt balance. This may explain why global polyuria is common following renal transplantation, with a high prevalence of nocturnal polyuria (Mitsui et al, 2009). There are also intrarenal mechanisms including ATP influence on epithelial sodium channels (Wildman et al, 2009). Excess natriuresis can be caused by medullary cystic disease, Bartter syndrome, Gitelman syndrome, the diuretic phase of acute tubular necrosis, primary renal diseases affecting the renal tubules, and congenital adrenal hyperplasia.

Cardiac Impairment

Impaired cardiac function can result in accumulation of fluid in dependent parts of the body (“third-spacing”), which can then return to the circulating volume when the patient is recumbent. Older patients can demonstrate an increased body weight during the daytime, which is greater in patients with nocturia (mean daytime weight change 0.93 kg compared with 0.60 kg in asymptomatic patients) (Kaye, 2008). This led to a significant difference in overall urine volume passed overnight, along with significant differences in the sodium, potassium, and chloride output.

Ordinarily, blood pressure should reduce overnight (“dipping”). In hypertensive patients, dipping of the blood pressure overnight becomes less apparent, signifying an increased prevalence of cardiac disease and being associated with an increased risk of nocturia (Fitzgerald et al, 2007). Men with benign prostate enlargement (BPE) are significantly more likely to lose the overnight dip in blood pressure, particularly men with nocturia (Turgut et al, 2008). Underlying pathophysiology of nocturia can be related to increased mean arterial blood pressure and blunted circadian variation in ADH (Graugaard-Jensen et al, 2006).

Global Polyuria and Increased Fluid Intake

Urine output in excess of 40 mL per kilogram per 24 hours (equating to 2.8 L per 24 hours in a 70-kg adult) defines polyuria and is likely to lead to increased voiding frequency both day and night. The patient’s fluid intake, either in the form of fluid drunk or free fluid in ingested food, will influence urine output. In many cases, patients deliberately increase their fluid intake volitionally. Evaluation of sustained polyuria has to include consideration of whether there is excessive fluid intake (polydipsia); it is also important to consider whether the polydipsia is a cause of the polyuria or whether it is secondary to thirst induced by other pathologic causes of polyuria. The best known medical examples of secondary polydipsia are poorly controlled diabetes mellitus and diabetes insipidus (DI), where thirst results from excessive fluid loss. Fluid loss in diabetes mellitus results from increased solute load (glucose) in the glomerular filtrate; if polyuria is present in a seemingly well-controlled diabetic, breakthrough hyperglycemia and other causes of polyuria (e.g., impaired renal tubular function) should be considered. DI can be a consequence of impaired ADH secretion (neurogenic/central DI) or impaired renal responsiveness to ADH (nephrogenic DI). DI can occur in conjunction with other problems such as panhypopituitarism, and it is part of DIDMOAD syndrome (DI, diabetes mellitus, optic atrophy, and deafness) (Barrett et al, 1995).

Nocturnal Polyuria

Ordinarily there is a circadian reduction in urine production overnight, which is largely regulated by endocrine or neural mechanisms but which is yet to be fully explained. This circadian pattern relates to increased secretion of ADH during the hours of sleep (Graugaard-Jensen et al, 2006), thus lower volumes of more concentrated urine (Asplund and Aberg, 1991). Loss of circadian reduction in overnight urine production is important clinically (Matthiesen et al, 1996). Plasma ADH levels may be pathologically undetectable during the night in elderly subjects with nocturia (Asplund and Aberg, 1991). Central nervous system lesions due to CVA can affect the hypothalamic-pituitary axis, causing a loss of ADH circadian rhythmicity (Ozawa et al, 1998). However, there remains a strong possibility of further underlying mechanisms yet to be elucidated.

Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) results from intermittent occlusion of the airway during sleep, leading to profound hypoxia, which is relieved by a gasping respiratory pattern. The fluctuating hypoxia pattern impairs sleep patterns directly. In addition, the gasping intakes of breath substantially raise intrathoracic pressures. The increased right atrial transmural pressure resulting from hypoxia-induced pulmonary vasoconstriction leads to an elevation in ANP, which precipitates increased urine output (Yalkut et al, 1996). Risk factors for OSA include morbid obesity, acromegaly, asthma, hypertension, adult onset diabetes mellitus, and craniofacial abnormalities. New-onset snoring in an older patient should prompt evaluating clinicians to consider overnight oximetry monitoring or polysomnographic sleep studies.

Increasing severity of OSA has been corresponded with nocturia (Fitzgerald et al, 2006), with reduction in nocturia episodes achieved by OSA treatment using continuous positive airway pressure. Elderly patients with severe sleep disordered breathing have a greater number of nocturia episodes (Endeshaw et al, 2004). The link between nocturia and OSA is sufficiently close that it has even been suggested that nocturia is as sensitive as snoring as a predictive symptom of OSA (Romero et al, 2010). OSA should be considered in any nocturia patient, even where OAB is clearly apparent in the daytime (Lowenstein et al, 2008).