Nocturia has been defined as the need for

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1 Nocturia and Aging: Diagnosis and Treatment Sarinya Boongird, Nirav Shah, Thomas D. Nolin, and Mark L. Unruh Nocturia is a frequently encountered problem in clinical practice and a reason for nephrology consultation. Many studies have clearly shown the negative effect of nocturia on several aspects of health-related quality of life and morbidity. Age-associated physiological, structural, hormonal, and histological changes play an important role in the increasing incidence of nocturia in elderly individuals. Besides urologic conditions, nocturia may also be the initial presenting symptom in chronic kidney disease, as well as other systemic diseases. Therefore, it is essential to understand the complex pathophysiology among these factors to establish a precise diagnosis and appropriate management strategies. This review will provide an overview of the effect of aging on the kidneys and urinary system, the pathophysiology, clinical assessment, and treatment strategies of nocturia, and its effect on health-related quality of life. Q 2010 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Nocturia, Aging, Nocturnal polyuria, Chronic kidney disease, Health-related quality of life Nocturia has been defined as the need for an individual to wake up 1 or more times during the night to void. 1 The prevalence of nocturia varies markedly, depending on the definition and age group surveyed. Nevertheless, one common finding is that the prevalence of nocturia increases with age, ranging from 4% in children aged 7 to 15 years to approximately 70% in adults aged.60 years. 2,3 Tikkinen and colleagues 4 assessed the occurrence of nocturia in 6000 subjects aged 18 to 79 years and found that the prevalence increased with age, but the estimates depended on whether nocturia was defined as 1 or 2 voids per night. In this report, in men and women aged,29 years, the prevalence of at least 2 voids was less than 10%, in those aged 40 to 49 years nearly 10%, and those aged.70 years the prevalence of at least 2 voids per evening was 40%. 4 The actual prevalence, however, may be even higher than previously reported, as some patients consider it as From Division of General Internal Medicine, Department of Medicine, University of Pittsburgh Medical Center Shadyside, Pittsburgh, PA; Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA; and Department of Pharmacy and Therapeutics, University of Pittsburgh Medical Center, Pittsburgh, PA. Address correspondence to Nirav Shah, MD, Renal- Electrolyte Division, Department of Medicine, University of Pittsburgh Medical Center, C 1112 UPMC Presbyterian, 200 Lothrop Street, Pittsburgh, PA nas65@pitt.edu Ó 2010 by the National Kidney Foundation, Inc. All rights reserved /$36.00 doi: /j.ackd normal or part of normal aging, and do not seek help from healthcare professionals. The clinical significance and the degree of bother have been explored by Tikkenen and colleagues who noted that the degree of bother and health-related quality of life (HRQoL) correlates with the number of voids. However, not all bother is correlated to episodes of nocturia. This suggests that bother may also be related to comorbidities that can affect HRQoL. 45 The clinical significance of nocturia is more important than the number of episodes of nocturia. Although the prevalence of nocturia does increase with age, it would be difficult to conclude that nocturia is a normal part of aging because it is not universally present in all older adults. Many of the physiological, structural, and hormonal risk factors for nocturia are known to increase with age. The clinical significance of nocturia has been difficult to quantify but has been increasingly recognized because of associations with reduced HRQoL, and increased morbidity and mortality. 6-9 Recently, Agarwal and colleagues have noted associations of nocturia with non-dipping and effects on hypertension (HTN). 10 The causes of nocturia are varied, involving both urologic and nonurologic conditions influenced by the aging process. There is an increasing role for nephrologists in managing nocturia in collaboration with urologists and primary care physicians because it affects HRQoL and may also be the initial presenting symptom in chronic kidney disease (CKD), as well as other systemic diseases, such as Advances in Chronic Kidney Disease, Vol 17, No 4 (July), 2010: pp e27-e40 e27

2 e28 Boongird et al congestive heart failure (CHF), diabetes mellitus (DM), or sleep disorders. This review helps examine the roles of aging and kidneys in promoting nocturia as well as nonpharmacologic and pharmacologic therapies for the treatment of nocturia. Nocturnal Urine Production and Aging Age-associated physiological, structural, hormonal, and histologic changes play an important role in the increasing incidence of nocturia in the elderly population. Mismatch between amounts of urine produced at night and the bladder s capacity to hold adequate urine volumes during sleep accounts for a common mechanism of nocturia. With aging, several factors which determine kidney sodium handling, water conserving mechanism, and circadian rhythm of glomerular filtration rate (GFR) have been altered in the direction of promoting nocturnal diuresis. The concentrating ability of the kidney has been shown to decline with increasing age owing to impaired responsiveness to arginine vasopressin (AVP). 5,11 In young healthy adult, AVP normally has a circadian pattern of release in which its blood concentration peaks during the night, resulting in nocturnal urine production falling to approximately 25% or less of total daily urine output. 12 However, in elderly individuals, the AVP response to volume and osmotic stimuli remains intact, but circadian nocturnal AVP secretion is disrupted. 5,12,14 This results in a shift of the diurnal rhythm of urine production toward increasing nighttime urine excretion. Additionally, Asplund and Aberg demonstrated that dysregulation of AVP secretion is only partly responsible for nocturnal polyuria among elderly patients. 15 It has been observed by some investigators that attenuation of the decrement of GFR during sleep may also contribute to increased nocturnal urine production and urinary sodium excretion rates in the elderly population. 11,12 Besides age-related changes in kidney, there are multiple alterations in the hormonal systems governing water and sodium regulation that can occur with aging. Atrial natriuretic peptide (ANP) is an important factor in controlling sodium excretion through its direct natriuretic effect, and suppression of renal renin and aldosterone secretion. With advanced age, the basal ANP level has been shown to be 3- to 5-fold higher than those of young adults. 5,15 Moreover, plasma renin and aldosterone activities are also decreased with aging. As a consequence, the aforementioned hormonal changes promote natriuresis and result in diuresis. Effect of Aging on Structural Urinary System Age-related decrements in both functional and structural capacity impair the bladder s ability to store urine overnight. It has been shown that nocturnal bladder capacity and detrusor contractility diminish with age because of an increased collagen to smooth muscle ratio. 12,16,17 Ouslander has outlined the current understanding of sensory innervation of the bladder and highlighted potential targets for therapeutic advances. 18 Although nocturia in elderly men with other lower urinary tract symptoms is frequently attributed to bladder outlet obstruction caused by benign prostatic hyperplasia (BPH), other urologic conditions that cause reduction in bladder capacity, such as bladder irritation from stone or infection, and urogenital neoplasm should also be considered and investigated as well. In women, age-associated structural and hormonal changes may be significant contributing factors. Estrogen deficiency in postmenopausal women results in structural and physiologic changes, including urogenital atrophy, pelvic organ prolapse, pelvic floor relaxation, and neurogenic detrusor hyperactivity. Consequently, these alterations cause irritative symptoms and nocturia. 19 Nocturia in CKD Nocturia is an early and common manifestation and has been reported as one of the most prevalent and severe symptoms among patients with CKD. 21 There are several factors accounting for nocturia in CKD. The widely described hypothesis is the inability to concentrate urine because of the diminished ability of the medullary interstitium to generate and maintain a countercurrent system, and decreased responsiveness of cortical collecting duct to AVP, resulting in a relative water

3 Nocturia and Aging e29 diuresis. 22 However, recent work has shown that osmotic diuresis and not water diuresis is responsible for the main mechanism of nocturia in CKD. 23,24 The major osmotic component and the mechanism of increased nocturnal solute excretion, however, are still inconclusive. Fukuda and colleagues 24 measured urinary sodium, potassium, urea excretion, and osmolar excretion rates, as well as free-water clearance, and correlated the values obtained with urinary volume during daytime and nighttime in CKD patients. It was reported that nocturnal urine volume in CKD patients was determined principally by natriuresis and not by water diuresis or urea excretion. Interestingly, the enhanced natriuresis has been found to be associated with a lack of nocturnal blood pressure fall, a common phenomenon in CKD patients known as nondipping. 10,24 Recently, Agarwal and colleagues demonstrated that increased nighttime physical activity contributed to nondipping blood pressure patterns in CKD patients, presumably mediated by frequent nocturia. 10 Nevertheless, the relationship between nondipping and nocturia remains unclear, thus stressing the need for further studies to be carried out. Some authors propose that nocturia may be another marker indicating progression of kidney injury that should prompt primary care physicians to consider screening for CKD when evaluating patients with nocturia, and vice versa. 20,25 Alternatively, Agarwal studied 98 patients with CKD (egfr,60) and failed to demonstrate a trend toward increased severity of nocturia with worsening renal function. The multiple etiologies of CKD may explain the variable presentation of nocturia. 21 Pathophysiology of Nocturia The pathogenesis of nocturia is complex and sometimes multifactorial, involving several organ systems. Furthermore, some conditions or diseases are complicated by environmental, behavioral, and pathologic factors. The mechanism responsible for nocturia includes any conditions resulting in abnormally increased urine production, decreased bladder storage capacity, or disturbed sleep pattern leading to waking at night. Looking into the mechanism of nocturia involved in different disease states gives further insight into the complex multifaceted pathophysiology. For example, although the mechanism between nocturia and HTN is not fully explained, McKeigue s work showed that HTN and nocturia may share similar pathophysiology with alterations in nitric oxide metabolism and resetting of the pressure natriuresis balance in the kidney leading to sodium retention and compensatory nocturnal natriuresis. 26 Overproduction of Urine or Polyuria Diurnal polyuria is defined as having a urine production of more than 40 ml/kg of body weight over a 24-hour period. It may result from either free water diuresis (eg, diabetes insipidus [DI] or excessive fluid intake) or osmotic diuresis (eg, poorly controlled diabetes mellitus). Central DI is characterized by decreased production of AVP, whereas nephrogenic DI results from a decrease in the ability of the kidneys to concentrate urine because of an impaired renal tubular response to AVP. In addition, diurnal polyuria may be because of either primary polydipsia or excessive fluid intake, which is distinguished from DI by water deprivation test. In patients with edema-forming states, such as CHF and CKD, fluid and solute accumulated in the lower extremities while standing during the day may become mobilized into the circulatory systems at night, inducing ANP release. Enhanced ANP secretion because of medical conditions can also cause nocturnal polyuria. ANP is released by atrial myocytes in response to atrial distension and sympathetic stimulation. It affects the kidneys by increasing GFR and filtration fraction, which in turn produces natriuresis and diuresis. Similarly, respiratory diseases associated with increased airway resistance, such as obstructive sleep apnea (OSA), stimulate ANP secretion through hypoxic-induced vasoconstriction causing increased right atrial pressure. 27 Studies have shown the increase in frequency of nocturia in OSA patients as well as positive correlation between severity

4 e30 Boongird et al of OSA and frequency of nocturnal urination. 28 Finally, some behavioral habits can lead to nocturnal polyuria, for example, consuming diuretic in late-evening, or ingestion of fluid or beverages with diuretic-like properties (ie, caffeine, alcohol) shortly before bedtime. Diminished Bladder Capacity Diminished bladder capacity refers to a condition in which voiding occurs at bladder volumes less than functional bladder capacity, leading to awakening to void at night. Reduction in bladder capacity can occur at all times (reduced global bladder capacity), or exclusively at night (reduced nocturnal bladder capacity). Diminished global capacity is often related to urologic conditions, including bladder outlet obstruction resulting in increased postvoid residual urine volume (PVR), bladder irritation from stones, infection or neoplasm, extrinsic bladder compression from ovarian cancer or uterine fibroids, and decreased bladder capacity because of urogenital aging. BPH and overactive bladder (OAB) are 2 main urologic conditions associated with diminished bladder capacity. Traditionally, nocturia in men has been attributed to bladder outlet obstruction relating to BPH. Diminished bladder capacity in BPH is explained by increased PVR and detrusor hyperactivity induced by chronic bladder outlet obstruction. OAB is defined by the International Continence Society as a syndrome of urinary urgency, with or without urge incontinence, usually accompanied by increased frequency and nocturia. 29 OAB symptoms are often attributed to detrusor overactivity, which is corroborated by urodynamic testing. Common causes of overactive bladder are listed in Table 1. In patients with signs of bladder storage problems, urodynamic studies are often required to confirm and determine the classification of these disorders. Consequences or Adverse Effects of Nocturia Some studies have suggested that 2 or more voids per night are clinically significant and correlate with degree of bother. 45 In addition, the consequence or adverse effects of nocturia are important to be noted. For example, Table 1. Etiologies of Nocturia and Associated Conditions Diurnal polyuria Water diuresis: Primary polydipsia: psychogenic or dipsogenic polydipsia Diabetes insipidus: defect in secretion or action of AVP Central diabetes insipidus (eg, hypothalamic or pituitary lesion) Nephrogenic diabetes insipidus (eg, medications, hypercalcemia, hypokalemia, hereditary disorders) Gestational diabetes insipidus Osmotic diuresis Poorly controlled diabetes mellitus Medications (eg, mannitol, sorbitol) Nocturnal polyuria Nocturnal polyuria syndrome Edema-forming states (eg, CHF, CKD, nephrotic syndrome, hypoalbuminemia, chronic liver disease, venous insufficiency) Behavioral factors (eg, excessive fluid intake shortly before retiring, late-evening diuretic intake) Comorbidities (eg, obstructive sleep apnea, Alzheimer s disease, multisystem atrophy, stroke, Parkinsonism) Diminished bladder capacity Overactive bladder syndrome (eg, detrusor overactivity, detrusor underactivity, neurologic conditions causing alteration of efferent and afferent neural voiding pathways) Reduced bladder capacity (eg, bladder cancer, BPH, bladder fibrosis, neurogenic bladder) Others (eg, infection, stones, tumor, pelvic floor laxity, medication) Sleep disturbances Sleep apnea syndrome Periodic limb movement disorder Abbreviations: AVP, arginine vasopressin; CHF, congestive heart failure; CKD, chronic kidney disease; BPH, benign prostatic hyperplasia.

5 Nocturia and Aging e31 nocturia has been associated with reduced daytime performance, low productivity at work, absenteeism, and depression. 4 Short and fragmented sleep has been linked with an increased risk of cardiovascular disease, traumatic injury, and possibly mortality. 4,7 Nocturia not only imposes a burden on HRQoL in the individual, but also on others, as interruption of sleep to void can result in frequent awakenings and difficulty falling asleep in their partners or caregivers and may even influence the decision to institutionalize the elderly people. 31,41 The consequences of nocturia are profound and explain the heightened interest into understanding the epidemiology, pathophysiology, and explore any possible treatment options. There are several nocturia-specific HRQoL questionnaires or instruments available to physicians such as the International Consultation on Incontinence Modular Questionnaire-Nocturia Quality of life, and the Nocturia, Nocturnal Enuresis, and Sleepinterruption Questionnaire In addition, sleep questionnaires such as the Pittsburgh Sleep Quality Index assess nocturnal voiding as a single item. 35 To our knowledge, there are no universally accepted definitions to determine the frequency of nocturia per night that would be clinically meaningful. Some authors suggested that $2 voids per night are bothersome and clinically significant. 6,36,45 In the clinical setting, it would be important to assess both how frequently the patient wakes to void and to what extent the nocturia bothers the patient. The degree of bother and clinical significance of nocturia is important to help guide the health care provider in providing therapy that may also involve its own risks. Nocturia and Sleep Disturbances Nocturia has been shown to be associated with poor sleep quality and several types of sleep disorders, including obstructive and central apnea syndrome, periodic limb movement disorder, and sleep disorders related to medical or neurologic diseases. Nocturia is an independent predictor for self-reported insomnia and sleep fragmentation. 37 Short and fragmented sleep has been associated with poor sleep quality, fatigue, daytime sleepiness, impaired daytime performance, and increased risk of cardiovascular disease events and premature death. 38,39 Sleep deprivation also increases the chance of traumatic injury through falling or daytime somnolence. Nocturia not only imposes a burden on HRQoL in individuals, but also on the others as interruption of sleep to void can result in frequent awakenings and difficulty falling asleep in their partners or caregivers. 40,41 Disturbed sleep in the elderly population and caregivers appeared to have a significant influence on the decision to institutionalize the elderly people. 41 Nocturia and interruption of sleep have been frequently reported in several neurologic conditions, particularly neurodegenerative diseases and stroke ,46 Disrupted neurobiologic changes in neuronal networks governing the sleep wake cycle along with alteration in circadian system have been proposed to explain sleep disturbances and increased nocturnal urine production. Loss of circadian rhythm in the AVP secretion has been observed in patients with Alzheimer s disease and poststroke patients. 43,44 It is not the amount of AVP contained in hypothalamic neurons but rather the neuron s ability to release AVP into the circulation that has been affected in Alzheimer s disease ,46 In poststroke patients, the underlying pathophysiology of this phenomenon is attributable to the direct neuronal damage to central neuronal pathways involved in micturition. Overall, it is difficult to determine whether nocturia per se causes frequent nocturnal awakening to void (true nocturia, based on the International Continence Society definition), or is a consequence of sleep problems. Careful noting of patient history is essential to differentiate between these 2 entities. Clinical Assessment of Nocturia Nocturia involves various organ systems and several factors including environmental, behavioral, and psychological factors. The patient may present to the physician specifically with nocturia, or with indirect symptoms relating to it, such as insomnia,

6 e32 Boongird et al daytime sleepiness, or injury. In contrast, many patients may consider nocturia as an inevitable consequence of aging, and do not report it to physicians. The complex pathophysiology of nocturia includes multiple risk factors, some of which may increase with aging. However, it is incorrect to assume that nocturia is a normal part of aging as it is not universally present. The prevalence increases with age and the decision to investigate further and to treat depends on the degree of bother and the consequence of nocturia. As some studies suggest a prevalence as high as 70% of nocturia in the elderly population, a more practical method of including patients on the basis of degree of bother as outlined by Tikkinen, 45 with affected HRQoL, and those at risk to suffer the consequences of nocturia would help identify patients who would benefit from a workup and treatment. Physicians should routinely ask at-risk patients about nocturia and use it as a screen test for other serious medical conditions. The identified predictive factors for nocturia include old age, urinary urgency, snoring, obesity, kidney or bladder diseases, BPH, HTN, DM, and cerebrovascular disease. 47,48 Multidisciplinary approaches and appropriate investigations are key to evaluating nocturia. Figure 1 summarizes an algorithm for the diagnostic assessment of nocturia. In general, the etiologies of nocturia can be classified into 4 categories: (1) diurnal polyuria; (2) nocturnal polyuria; (3) bladder dysfunction; and (4) sleep disturbance. The initial assessment begins with a complete history and a thorough physical examination. A detailed history of concurrent illnesses contributing to nocturia should be elicited in all patients including lower urinary tract symptoms (eg, urgency may suggest OAB or infection; dribbling, straining, and a feeling of incomplete emptying may suggest BPH), associated underlying medical conditions resulting in polyuria, impaired kidney concentrating ability (eg, DM, DI, CKD), or edema-forming diseases (eg, CHF, hypoalbuminemia, nephrotic syndrome, venous insufficiency), underlying neurologic disorders (eg, Alzheimer s disease, Parkinsonism, spinal cord injuries, and symptoms suggestive of neurogenic bladder), and sleep disorders. Relevant histories should be obtained as well, including normal or baseline pattern of voiding, nocturia severity, pattern and type of fluid intake, sleep pattern and sleep quality, history of previous genitourinary or gynecological tract surgery, medication history and timing of intake, and comorbidities. Several medications have been associated with nocturia, including diuretics, lithium, and selective serotonin reuptake inhibitors (SSRI) Diuretic use alone is associated with a 2-fold increase in nocturia. 49 Nocturia associated with late-evening diuretic administration is simple to correct if recognized. Movig and colleagues reported an approximately 2-fold increased risk for developing urinary incontinence and nocturia among patients using SSRIs. The plausible mechanism accounting for urinary frequency and nocturia associated with SSRI use is thought to be mediated through an activation of neuronal 5-HT4 receptors located on the bladder detrusor muscle, potentiating cholinergic neuromuscular transmission and detrusor muscle activation. 52,53 A comprehensive physical examination is indicated to detect relevant medical conditions. Body weight should be measured because obesity contributes to OSA. Orthostatic vital signs may give a clue to autonomic dysfunction. General appearance and confrontation visual field testing may suggest endocrine or pituitary abnormalities. Cardiac examination could focus on evidence of CHF. Abdominal examination might reveal a distended bladder suggesting bladder outlet obstruction, or ascites being found in chronic liver diseases. The lower extremities may reveal pitting edema or signs of venous stasis. The neurologic examination should be carefully examined for the absence of perineal sensation, or decreased muscle strength in lower extremities. Rectal examination should be performed to detect prostatic enlargement, mass, or fecal impaction, as well as assessing pelvic floor laxity and sphincter tone. Initial laboratory testing should include a simple urinalysis, urine culture, electrolytes, blood glucose, blood urea nitrogen, creatinine, and calcium. A more focused workup would include liver function tests, albumin, prostate-specific antigen, urine osmolality, and water deprivation test. Ultrasonography and measurement of PVR can identify patients

7 Nocturia and Aging e33 Nocturia History - Normal or baseline pattern of voiding - Nocturia severity - Co-morbidities - History of previous genitourinary or gynecological tract surgery - Medication history and timing of intake - Pattern and type of fluid intake Comprehensive physical examination - General appearance - Orthostatic vital signs - Cardiopulmonary examination: evidence of CHF, OSA - Abdominal and rectal examination: full bladder, enlarged prostate - Neurologic examination: weakness, abnormal perineal sensation - Genitourinary and vaginal examination Initial investigations - Urinalysis, Urine culture, Electrolytes, Blood glucose, BUN, Creatinine and Calcium. - Ultrasonography - Measurement of PVR Clear etiologies Further investigations (optional) -LFTs, Urine Osmolality - A frequency-volume chart - Urodynamic studies Unclear etiologies Lifestyle and behavioral factors Required surgical treatment? Yes Referral to a urological specialist Lifestyle advice No Diurnal polyuria Nocturnal polyuria Bladder dysfunction Sleep disturbance Not improve - Correcting the underlying pathological mechanisms of nocturia - Optimizing co morbid conditions Figure 1. Approach to the clinical assessment of nocturia. with CKD, or urinary retention related to bladder outlet obstruction or neurogenic bladder. If sleep disorders are suspected, a polysomnography should be considered. A frequency-volume chart (F/V chart), a voiding diary recording 24-hour urine volumes voided as well as the time of each micturition, may enable the physician to determine the patient s functional bladder capacity and confirm the diagnosis of nocturnal polyuria. Urodynamic studies such as flow rate and cystometric capacity are often helpful, but require special interpreting skills by experienced urologists. Referral to a urologic specialist for further evaluation and testing (eg, cystoscopy and urodynamic studies) may also be appropriate if initial clinical assessment cannot reveal the etiology of nocturia, or if the patient has been found to have a significant urinary tract pathology necessitating invasive tests.

8 e34 Boongird et al Treatment of Nocturia The goals of therapy are not specifically aimed at reducing the frequency of nocturia, but rather to improve the HRQoL, degree of bother, and optimize comorbidities contributing to nocturia. Therapeutic options for nocturia include non-pharmacological, pharmacological, and surgical therapy. The focused therapy aims at correcting the underlying pathological mechanisms of nocturia. In many cases the therapy may have risks, and in such cases, there should be a careful weighing of the benefits and risks for informed decision-making. Behavioral and Medical Therapy The choice of therapy should be tailored to the underlying pathophysiology of nocturia. In the setting of an uncontrolled medical illness, such as diabetes or congestive heart failure, the first step in treatment of nocturia should be to improve the underlying illness causing the nocturia. In nocturnal polyuria, the initial therapeutic approach is lifestyle and behavioral changes. General behavioral modifications, such as adjustment of timing of fluid intake and type of fluid with diuretic properties, can be a successful strategy in certain patients. 54 Commonly used medications such as diuretics may improve or worsen nocturia depending on the type and timing of medication. In some patients, simply adjusting the timing of diuretics may be helpful in reducing the frequency of nighttime voids. The use of compressive stockings and afternoon leg elevation in the setting of edematous states may help prevent fluid accumulation, and consequently diminish nighttime voiding. Bladder training and pelvic floor muscle exercises administered to elderly women are effective in improving nocturia and HRQoL. 55 The treatment of nocturia by treating underlying sleep disorders has been understudied with only limited study of treating nocturia by using continuous positive airway pressure (CPAP) and melatonin. Margel and colleagues showed that in 97 patients, there was an improvement in the severity of nocturia with successful treatment of the OSA with CPAP. Some patients had responded within 24 hours of treatment. 56 Melatonin may be used to treat insomnia and it has also been used to treat symptomatic nocturia. 57 As with many complications of aging, it may be that a tailored multicomponent therapy provides the most substantial effect on the symptoms of patients. A well done Veterans Administration (VA) pilot study by Vaughan and colleagues used a multicomponent behavioral and medication therapy to target multiple risk factors for nocturia and it was successful in reducing both the episodes of nocturia (2.6 to 1.9 episodes per night) and the degree of bother (American Urology Association scale of 3.1 to 1.1) over a period of 4 weeks. 58 Pharmacologic Therapy Current pharmacologic treatment options for nocturia consists largely of desmopressin, antimuscarinic agents, and compounds aimed at alleviating symptoms associated with BPH in men. 49,57-78 Selected drugs commonly used in the treatment of nocturia are listed in Table 2, along with important pharmacokinetic, dosing, and adverse effects information that should be taken into consideration when prescribing these drugs. Desmopressin Desmopressin (DDAVP) is a synthetic analogue of the antidiuretic hormone, which has been shown to be effective in the treatment of DI and nocturnal polyuria. It increases water reabsorption in the kidneys by binding to V2 receptors in renal collecting ducts, resulting in decreased urine output and nocturia. Desmopressin is widely used in Europe but has not been approved by the Food and Drug Administration for use in nocturia. The efficacy of desmopressin has been supported by a large, multicenter, placebo-controlled trial investigating its role in both short- and long-term use in men and women. The study reported a reduction in the number of nightly voids and an increase in the length of uninterrupted sleep. Major side effects included headache, nausea, and most importantly, hyponatremia. Hyponatremia ranged from mild (asymptomatic) to severe (seizures and deaths). 71 The risk apparently increased with age and abnormal baseline serum sodium concentration. 72 The most recent systemic review reported the incidence of hyponatremia from oral or nasal desmopressin at 7.6% in the

9 Table 2. Selected Drugs Used in the Treatment of Nocturia 48,60-70 Drug CYP F e (%) t 1/2 (hr) Usual Dose Adverse Effects Comments Desmopressin (oral) none mg PO at bedtime Headache, nausea, dizziness, hyponatremia Trospium none IR: 20 IR: 20 mg PO 1-2 times daily Dry mouth, ER: 35 ER: 60 mg PO once daily headache, constipation, blurred vision Oxybutynin 2D6, 3A4,5 IR: 2 ER: 13 TS: 8 IR: 5 mg PO 2-3 times daily ER: 5-30 mg PO once daily TS: 3.9 mg patch Dry mouth, constipation, dizziness, blurred vision, confusion applied topically twice weekly Tolterodine 2D6, 3A4,1 IR: 2 IR: 1-2 mg twice daily Dry mouth, ER: 8 ER: 2-4 mg once daily constipation, dizziness, blurred vision, confusion Fesoterodine 2D6, 3A4, mg PO once daily Dry mouth, constipation, dizziness, blurred vision, confusion Solifenacin 3A mg PO once daily Dry mouth, constipation, blurred vision, headache Darifenacin 2D6, 3A mg PO once daily Dry mouth, constipation, blurred vision, dyspepsia Avoid in patients with CKD, CHF, cirrhosis, primary polydipsia Poor oral absorption, should be administered on empty stomach; avoid in patients with advanced CKD Titrate dose slowly to desired effect; avoid in patients with hepatic disease or receiving concomitant inhibitors of CYP2D6 or 3A4; ER/TS better tolerated than IR Avoid in patients with hepatic disease or receiving concomitant inhibitors of CYP2D6 or 3A4; ER better tolerated than IR Use cautiously in patients with hepatic disease or receiving concomitant inhibitors of CYP2D6 or 3A4 Max dose 5 mg daily in patients with hepatic disease, advanced CKD, or receiving concomitant inhibitors of CYP3A4 Use cautiously in patients with hepatic disease or receiving concomitant inhibitors of CYP2D6 or 3A4 (Continued ) Nocturia and Aging e35

10 e36 Boongird et al Table 2. (Continued) Drug CYP Fe (%) t1/2 (hr) Usual Dose Adverse Effects Comments For use in BPH associated nocturia; use cautiously in patients with hepatic disease or receiving concomitant inhibitors of CYP2D6 or 3A4 Tamsulosin 2D6, 3A4, mg PO once daily Rash, pruritis, diarrhea, priapism For use in BPH associated nocturia; use cautiously in patients with hepatic disease or receiving concomitant inhibitors of CYP3A4 Finasteride 3A4,1 6 5 mg PO once daily Rash, pruritis, erectile dysfunction, decreased libido Abbreviations: CYP, cytochrome P450 metabolic pathway involved in elimination; F e, fraction of administered dose excreted unchanged in urine; t 1/2, elimination halflife; IR, immediate release; ER, extended release; TS, transdermal system; PO, by mouth; BPH, benign prostatic hyperplasia. elderly group. 73 Therefore, desmopressin should be used cautiously in at-risk groups, including patients with CKD, CHF, cirrhosis, and primary polydipsia. 49 The serum sodium concentration should be monitored closely, before and 3 days after the initiation of treatment, and during dose titration. Antimuscarinic Agents Antimuscarinic agents are typically considered first-line therapy for nocturia related to diminished bladder capacity. These drugs act primarily on muscarinic receptors (mainly M2 and M3) present on detrusor muscle cells, resulting in inhibition of bladder contraction and increase in the bladder capacity. Because muscarinic receptors are also located centrally and peripherally in other organ systems throughout the body, adverse effects commonly occur from their use. For example, common peripheral adverse effects of these drugs are dry mouth, blurred vision, constipation, urinary retention, and pruritus. Many of these drugs readily cross the blood-brain barrier, thereby causing adverse effects in the CNS, including headache, dizziness, somnolence, and confusion. 49,59 Moreover, the majority of these drugs are extensively metabolized and are substrates of cytochrome P450 (CYP) metabolic enzymes, namely CYP2D6 and CYP3A4. This renders the drugs particularly susceptible to drug interactions when administered concomitantly with compounds that are inhibitors or inducers of CYP2D6 of 3A4. 49,59 In addition, the pharmacokinetics CYP2D6 substrates such as tolterodine may be dramatically altered in patients expressing CYP2D6 genetic polymorphism Thus, physicians should judiciously prescribe antimuscarinic agents by considering comorbidities as well as drug drug interactions, particularly in vulnerable patients. For example, the elderly individual who has underlying dementia may experience acute confusion after initiation of treatment. Also, there is a concern in the elderly male with BPH because urinary retention might be worsening, so PVR should be evaluated before anticholinergic agents are initiated. Commonly used medications in this group consist of oxybutynin, tolterodine, solifenacin, darifenacin, and trospium (Table 2).

11 Nocturia and Aging e37 The most recent addition to this group is fesoterodine, which was approved by the Food and Drug Administration in Fesoterodine is a pro-drug whose active metabolite is formed by non-cyp pathways, so its pharmacokinetics may be less variable and susceptible to drug interactions and genetic polymorphisms than tolterodine and other CYP substrates in this class of drugs. 60,61 Alpha-1-selective Adrenergic Receptor Blocking Agents Alpha-1-selective adrenergic receptor blocking agents (alpha-1 blockers) such as terazosin and doxazosin have been widely used to alleviate several symptoms associated with BPH, including nocturia. These agents work by relaxing smooth muscles located in the prostate and around the bladder neck, and consequently reduce resistance to urine flow. A large study of 3047 males showed statistical improvement, however moderate, with the use of doxazosin versus placebo that was most notable in elderly males of 0.5 episode reduction per night. Moreover, combination therapy with finasteride offered added benefit as compared with doxazosin therapy alone. 74 The efficacy of alpha-1 blockers in reducing other BPH symptoms has been well demonstrated, but the effect on nocturia improvement was quite moderate. 75 Adverse effects include headaches, dizziness, and orthostatic hypotension. More selective alpha-1 blockers such as tamsulosin and alfuzosin have been reported to have less orthostatic side-effects, and do not require dosage titration. The role of alpha-1 blockers in managing nocturia in women remains unclear. The current data do not support its use on an empirical basis. 76 Testosterone-5-alpha-reductase Inhibitors Finasteride and dutasteride have been used as a second-line treatment in men with BPH, with the aim of reducing the size of the prostate gland by inhibiting the conversion of testosterone to dihydrostestosterone. The beneficial effects of these drugs on nocturia are still unknown as the results from a few studies have been inconsistent. 74,75 Use of finasteride in combination with the alpha-1 blocker doxazosin may lead to improved efficacy as compared with either drug alone. 77 Moreover, there is a concern about the increased rate of high-grade prostate cancers observed in men receiving finasteride from one large study. 78 Therefore, physicians should carefully discuss the risks and benefits associated with this treatment to patients. Botulinum toxin and electrical sacral neuromodulation have been shown to be helpful for controlling detrusor overactivity and nocturia in certain cases, specially in patients who fail pharmacotherapy, and in those who are not good candidates for surgery. 79,80 However, these studies have been limited by small sample sizes. Surgical Therapy Surgical intervention may be appropriate for certain conditions, particularly urologic diseases associated with low bladder capacity. The effect of surgical treatment on nocturia has been most studied in patients with BPH. Transurethral resection of the prostate is considered the mainstay of surgical treatment in symptomatic BPH patients. As a newer surgical technique, laser prostatectomy is a minimally invasive procedure currently being used as an alternative to transurethral resection of the prostate. Interestingly, certain studies have shown that the rate of improvement were lowest for nocturia among the 7 symptoms of the International prostate symptom score (ie, nocturia, frequency, weak urinary stream, hesitancy, intermittence, incomplete emptying, and urgency) after invasive treatment for BPH. 81 Conclusion Nocturia is a common condition which increases with age and in the setting of CKD. Nocturia has been associated with decrements on HRQoL, as well as morbidity and mortality. The causes of nocturia are often multifactorial, and can be broadly categorized into the following: (1) diurnal polyuria; (2) nocturnal polyuria; (3) bladder dysfunction; and (4) sleep disturbance. A detailed history and physical examination are warranted in each patient. The principle of management aims at correcting the underlying pathologic

12 e38 Boongird et al mechanisms of nocturia. The treatment strategies should focus on minimizing the symptoms of nocturnal voiding episodes to improve the quality of life. References 1. 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 21: , Mattsson S: Urinary incontinence and nocturia in healthy schoolchildren. Acta Paediatr 83: , Irwin DE, Milsom I, Hunskaar S, et al: Populationbased survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: Results of the EPIC study. Eur Urol 50: , discussion , Tikkinen KA, Tammela TL, Huhtala H, et al: Is nocturia equally common among men and women? A population based study in Finland. J Urol 175: , Ouslander JG, Nasr SZ, Miller M, et al: Arginine vasopressin levels in nursing home residents with nighttime urinary incontinence. J Am Geriatr Soc 46: , Coyne KS, Zhou Z, Bhattacharyya SK, et al: The prevalence of nocturia and its effect on health-related quality of life and sleep in a community sample in the USA. BJU Int 92: , Asplund R: Mortality in the elderly in relation to nocturnal micturition. BJU Int 84: , Kobelt G: Health-economic issues in nocturia. BJU Int 84(Suppl 1):29-32, Guilleminault C, Lin CM, Goncalves MA, et al: A prospective study of nocturia and the quality of life of elderly patients with obstructive sleep apnea or sleep onset insomnia. J Psychosom Res 56: , Agarwal R, Light RP, Bills JE, et al: Nocturia, nocturnal activity, and nondipping. Hypertension 54: , Tian Y, Serino R, Verbalis JG: Downregulation of renal vasopressin V2 receptor and aquaporin-2 expression parallels age-associated defects in urine concentration. Am J Physiol Renal Physiol 287:F797-F805, Kikuchi Y: Participation of atrial natriuretic peptide (hanp) levels and arginine vasopressin (AVP) in aged persons with nocturia [in Japanese]. Nippon Hinyokika Gakkai Zasshi 86: , Ohashi M, Fujio N, Nawata H: High plasma concentrations of human atrial natriuretic polypeptide in aged men. J Clin Endocrinol Metab 64:81-85, Koopman MG, Koomen GC, Krediet RT, et al: Circadian rhythm of glomerular filtration rate in normal individuals. Clin Sci (Lond) 77: , Asplund R, Aberg H: Diurnal variation in the levels of antidiuretic hormone in the elderly. J Intern Med 229: , Kawauchi A, Tanaka Y, Soh J, et al: Causes of nocturnal urinary frequency and reasons for its increase with age in healthy older men. J Urol 163:81-84, Susset JG, Servot-Viguier D, Lamy F, et al: Collagen in 155 human bladders. Invest Urol 16: , Ouslander JG: Management of overactive bladder. N Engl J Med 350: , Pandit L, Ouslander JG: Postmenopausal vaginal atrophy and atrophic vaginitis. Am J Med Sci 314: , Krol E, Rutkowski B, Czarniak P, et al: Early detection of chronic kidney disease: Results of the PolNef study. Am J Nephrol 29: , Agarwal R: Developing a self-administered CKD symptom assessment instrument. Nephrol Dial Transplant 25: , Conte G, Dal Canton A, Fuiano G, et al: Mechanism of impaired urinary concentration in chronic primary glomerulonephritis. Kidney Int 27: , Feinfeld DA, Danovitch GM: Factors affecting urine volume in chronic renal failure. Am J Kidney Dis 10: , Fukuda M, Motokawa M, Miyagi S, et al: Polynocturia in chronic kidney disease is related to natriuresis rather than to water diuresis. Nephrol Dial Transplant 21: , Hsu CY, Iribarren C, McCulloch CE, et al: Risk factors for end-stage renal disease: 25-year follow-up. Arch Intern Med 169: , McKeigue PM, Reynard JM: Relation of nocturnal polyuria of the elderly to essential hypertension. Lancet 355: , Yalkut D, Lee LY, Grider J, et al: Mechanism of atrial natriuretic peptide release with increased inspiratory resistance. J Lab Clin Med 128: , Kaynak H, Kaynak D, Oztura I: Does frequency of nocturnal urination reflect the severity of sleepdisordered breathing? J Sleep Res 13: , Abrams P, Cardozo L, Fall M, et al: The standardisation of terminology of lower urinary tract function: Report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 21: , Kaye M: Aging, circadian weight change, and nocturia. Nephron Physiol 109:11-18, Cugini P, Lucia P, Di Palma L, et al: Effect of aging on circadian rhythm of atrial natriuretic peptide, plasma renin activity, and plasma aldosterone. J Gerontol 47: B214-B219, Mock LL, Parmelee PA, Kutner N, et al: Content validation of symptom-specific nocturia quality-of-life instrument developed in men: Issues expressed by women, as well as men. Urology 72: , Abraham L, Hareendran A, Mills IW, et al: Development and validation of a quality-of-life measure for men with nocturia. Urology 63: , Bing MH, Moller LA, Jennum P, et al: Validity and reliability of a questionnaire for evaluating nocturia, nocturnal enuresis and sleep-interruptions in an elderly population. Eur Urol 49: , Buysse DJ, Reynolds CF 3rd, Monk TH, et al: The Pittsburgh Sleep Quality Index: A new instrument

13 Nocturia and Aging e39 for psychiatric practice and research. Psychiatry Res 28: , Schatzl G, Temml C, Schmidbauer J, et al: Cross-sectional study of nocturia in both sexes: Analysis of a voluntary health screening project. Urology 56: 71-75, Bliwise DL, Foley DJ, Vitiello MV, et al: Nocturia and disturbed sleep in the elderly. Sleep Med 10: , Kobelt G, Borgstrom F, Mattiasson A: Productivity, vitality and utility in a group of healthy professionally active individuals with nocturia. BJU Int 91: , Patel SR, Ayas NT, Malhotra MR, et al: A prospective study of sleep duration and mortality risk in women. Sleep 27: , Boyle P, Robertson C, Mazzetta C, et al: The relationship between lower urinary tract symptoms and health status: The UREPIK study. BJU Int 92: , Pollak CP, Perlick D: Sleep problems and institutionalization of the elderly. J Geriatr Psychiatry Neurol 4: , Ransmayr GN, Holliger S, Schletterer K, et al: Lower urinary tract symptoms in dementia with Lewy bodies, Parkinson disease, and Alzheimer disease. Neurology 70: , Goudsmit E, Neijmeijer-Leloux A, Swaab DF: The human hypothalamo-neurohypophyseal system in relation to development, aging and Alzheimer s disease. Prog Brain Res 93: , discussion , Sakakibara R, Uchiyama T, Liu Z, et al: Nocturnal polyuria with abnormal circadian rhythm of plasma arginine vasopressin in post-stroke patients. Intern Med 44: , Tikkinen KA, Johnson TM 2nd, Tammela TL, et al: Nocturia frequency, bother, and quality of life: How often is too often? A population-based study in Finland. Eur Urol 57: , Van der Woude PF, Goudsmit E, Wierda M, et al: No vasopressin cell loss in the human hypothalamus in aging and Alzheimer s disease. Neurobiol Aging 16: 11-18, Yoshimura K, Terada N, Matsui Y, et al: Prevalence of and risk factors for nocturia: Analysis of a health screening program. Int J Urol 11: , Tikkinen KA, Auvinen A, Johnson TM 2nd, et al: A systematic evaluation of factors associated with nocturia The population-based FINNO study. Am J Epidemiol 170: , Asplund R: Pharmacotherapy for nocturia in the elderly patient. Drugs Aging 24: , Darowski A, Chambers SA, Chambers DJ: Antidepressants and falls in the elderly. Drugs Aging 26: , Asplund R, Johansson S, Henriksson S, et al: Nocturia, depression and antidepressant medication. BJU Int 95: , Cardozo L, Robinson D: Special considerations in premenopausal and postmenopausal women with symptoms of overactive bladder. Urology 60:64-71, discussion 71, Movig KL, Leufkens HG, Belitser SV, et al: Selective serotonin reuptake inhibitor-induced urinary incontinence. Pharmacoepidemiol Drug Saf 11: , Shiri R, Hakama M, Hakkinen J, et al: The effects of lifestyle factors on the incidence of nocturia. J Urol 180: , Aslan E, Komurcu N, Beji NK, et al: Bladder training and Kegel exercises for women with urinary complaints living in a rest home. Gerontology 54: , Margel D, Shochat T, Getzler O, et al: Continuous positive airway pressure reduces nocturia in patients with obstructive sleep apnea. Urology 67: , Drake MJ, Mills IW, Noble JG: Melatonin pharmacotherapy for nocturia in men with benign prostatic enlargement. J Urol 171: , Vaughan CP, Endeshaw Y, Nagamia Z, et al: A multicomponent behavioural and drug intervention for nocturia in elderly men: Rationale and pilot results. BJU Int 104:69-74, Appell RA, Sand PK: Nocturia: Etiology, diagnosis, and treatment. Neurourol Urodyn 27:34-39, Simon HU, Malhotra B: The pharmacokinetic profile of fesoterodine: Similarities and differences to tolterodine. Swiss Med Wkly 139: , Michel MC: Fesoterodine: A novel muscarinic receptor antagonist for the treatment of overactive bladder syndrome. Expert Opin Pharmacother 9: , Salvatore S, Serati M, Bolis P: Tolterodine for the treatment of overactive bladder. Expert Opin Pharmacother 9: , Wolzt M, Fabrizii V, Dorner GT, et al: Pharmacokinetics of tamsulosin in subjects with normal and varying degrees of impaired renal function: An open-label single-dose and multiple-dose study. Eur J Clin Pharmacol 54: , Wilde MI, McTavish D: Tamsulosin. A review of its pharmacological properties and therapeutic potential in the management of symptomatic benign prostatic hyperplasia. Drugs 52: , Huskey SW, Dean DC, Miller RR, et al: Identification of human cytochrome P450 isozymes responsible for the in vitro oxidative metabolism of finasteride. Drug Metab Dispos 23: , Steiner JF: Clinical pharmacokinetics and pharmacodynamics of finasteride. Clin Pharmacokinet 30: 16-27, Doroshyenko O, Fuhr U: Clinical pharmacokinetics and pharmacodynamics of solifenacin. Clin Pharmacokinet 48: , Biastre K, Burnakis T: Trospium chloride treatment of overactive bladder. Ann Pharmacother 43: , Rembratt A, Graugaard-Jensen C, Senderovitz T, et al: Pharmacokinetics and pharmacodynamics of desmopressin administered orally versus intravenously at daytime versus night-time in healthy men aged years. Eur J Clin Pharmacol 60: , Agerso H, Seiding Larsen L, Riis A, et al: Pharmacokinetics and renal excretion of desmopressin after