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Home , Enuresis, Fluid balance, Nocturnal enuresis, Polyuria, Primary polydipsia, Urinary incontinence

Chapter 17: Fluid Balance Disorders in the Elderly

Myron Miller

Department of Medicine, Johns Hopkins University School of Medicine, and Division of Geriatric Medicine, Department of Medicine, Sinai Hospital of Baltimore, Baltimore, Maryland

Disorders of fluid balance are common in the el- duction to the nighttime period becomes evident. derly and often are caused by age-related alterations With further increase in age, there is often reduc- in urinary tract function, which can present clini- tion in the ratio of day to night flow to the cally as urinary frequency, , and inconti- point that nighttime flow rates become equal to or nence. Among the factors predisposing to the de- exceed daytime rates. Despite the change in circa- velopment of these clinical disturbances are aging dian pattern of urine excretion, total urine produc- changes in the renal and hormonal systems that tion per 24 h is not affected.3 control and excretion along with changes in the reservoir function of the bladder1 (Table 1). This chapter will examine the effect of ARGININE SECRETION aging on the systems involved in urine formation and consider how these changes interact with those Arginine vasopressin [AVP; antidiuretic of bladder function and lead to urinary frequency, (ADH)] is the major hormone responsible for the nocturia, and incontinence. regulation of urine formation. The magnocellular In young, healthy persons there is a circadian supraoptic and paraventricular nuclei of the hypo- pattern to urine production in which nighttime thalamus where AVP is synthesized do not seem to is less than daytime flow rate. In undergo age-related degenerative changes with ei- association with the normal aging process, there is ther morphologic features of cell destruction or de- an increase in nocturnal production of urine, so cline in cell hormone synthetic ability or hormone that nighttime urine flow rate equals or exceeds content. daytime production rate.2 When of sufficient mag- There is some controversy regarding the influ- nitude to result in nocturia, this change has been ence of normal aging on daytime AVP levels. termed nocturnal syndrome. A number of studies have indicated that, under The establishment of a circadian rhythm of urine basal conditions, daytime plasma AVP concentra- flow takes place during childhood, generally be- tion is not affected by increasing age. In contrast, tween the ages of 2 to 5 yr. In normal children with several other studies have reported increased basal a mean age of 7 yr, daytime rate of urine production plasma AVP levels in healthy elderly persons. Fur- is two to three times that of the nighttime period. ther adding to controversy are reports that healthy Delay or failure of the circadian rhythm to develop elderly subjects have daytime plasma AVP concen- during childhood is associated with the presence of trations that are significantly lower than in young nocturnal . In adulthood, the ratio of day- subjects. time to nighttime urine production is usually In healthy adults, there is a diurnal release of greater than 2:1, so that about 25% or less of daily AVP into the circulation with peak blood concen- urine output occurs during . Typical urine tration occurring during the hours of sleep. This production rates are approximately 70 to 80 ml/h rhythm seems to be linked to the wake-sleep cycle during the waking period and 30 to 40 ml/h during sleep. This circadian pattern seems to be linked to the day-night sleep pattern. The circadian pattern Correspondence: Myron Miller, MD, Director, Division of Geriat- of urine flow is paralleled by similar rhythms of re- ric Medicine, Department of Medicine, Sinai Hospital of Balti- more, 2401 West Belvedere Avenue, Baltimore, MD 21215. nal plasma flow and GFR. The circadian pattern is Phone: 410-601-6852; Fax: 410-601-9146; E-mail: myrmiller@pol. maintained in healthy persons until around age 60 net; [email protected] yr when a shift to a greater proportion of urine pro- Copyright ᮊ 2009 by the American Society of

American Society of Nephrology Geriatric Nephrology Curriculum 1 Table 1. Physiologic changes of aging associated with the thick ascending loop of Henle is impaired and can contrib- increased urine production ute to both sodium loss and to impaired tonicity in the renal Age-associated impaired renal concentrating capacity medulla. After the administration of an acute water load with Resistance to AVP action, i.e., “acquired partial nephrogenic consequent expansion of intravascular volume, there is an ex- insipidusЉ aggerated natriuresis in elderly individuals compared with Impaired sodium conservation younger subjects. An excess of sodium excretion with increas- Decreased nocturnal AVP secretion ing age has been described in patients with mild hypertension. Decreased -- secretion The ability of the aged to conserve sodium in response Increased atrial natriuretic hormone secretion to restriction is sluggish. Restriction of dietary sodium in- take to 10 mEq/d resulted in a half-life for reduction of urinary rather than to time of day. The circadian rhythm becomes es- sodium excretion of 17.6 h in young individuals in contrast to tablished during childhood and delay in its maturation is often 30.9 h in old subjects. The tendency to sodium wasting in el- associated with enuresis. With advanced age, there seems to be derly persons can lead to natriuresis with an accompanying blunting of the nocturnal phase of AVP secretion so that day- obligatory osmotic , especially when individuals are in time and nighttime blood levels of the hormone are similar.4,5 the recumbent position. In contrast, elderly persons may have greater response of AVP secretion to several stimuli than younger persons. The plasma AVP response to intravenous hypertonic infu- RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM sion in healthy elder subjects (age 54 to 92 yr) is almost double that of the younger subjects, suggesting that aging results in The ability of the kidney to conserve sodium is partly depen- increased sensitivity. Studies using water depri- dent on the actions of the renin-angiotensin-aldosterone sys- vation, intravenous metoclopramide, or cigarette as tem, a system affected by the normal aging process.6,7 Healthy stimuli for AVP secretion have also shown a similar age-related older individuals (age 62 to 70 yr) who consume a normal enhancement of response. In contrast, the stimulation of AVP amount of dietary sodium have lower levels of both plasma release by BP reduction or upright posture seen in young per- renin activity and aldosterone in the supine position than sons did not occur in elderly subjects, indicating an age-related young healthy persons age 20 to 30 yr. After the combined impairment of volume/pressure mediated AVP release most stimuli of low dietary sodium intake and upright posture, likely related to impaired baroreceptor function. and aldosterone concentration increase in both age groups, but the mean values achieved are signifi- cantly lower in the elderly persons group. Decreased conver- RENAL WATER LOSS sion of inactive to active renin may be at least partially respon- sible for the reduction in active renin concentration in elderly In association with normal aging, there is a decline in renal persons. The age-related decrease in plasma renin results in concentrating capacity. After 24 h of , there is a decreased aldosterone production by the adrenal gland. Age progressive decline in maximal urine osmolality with increas- itself does not affect the ability of the adrenal gland to synthe- ing age. This effect of aging persists even after correction for the size and secrete aldosterone because stimulation of the adrenal age-related decline in GFR. The decline in renal concentrating by corticotropin infusion results in similar increases of both ability of the aging kidney is not caused by an inadequate re- plasma cortisol and aldosterone in young and elderly subjects. sponse of AVP to the stimulus of water deprivation but rather It is likely that the age-related reduction in aldosterone con- to impaired renal tubular response to AVP. Thus, aging can be centration is one of the factors associated with impaired renal considered to lead to the development of an acquired form of sodium conserving ability in elderly persons. There does not partial nephrogenic . Age-associated in- seem to be an effect of age on renal tubular responsiveness to creased excretion of urea can also contribute to increased urine aldosterone. excretion through its osmotic effect. Under conditions of ade- quate intake of fluid, these changes may result in no apparent clinical consequence other than mild increase in urine flow ATRIAL NATRIURETIC HORMONE rate, but the elderly person who has restricted fluid intake may be unable to adequately reduce urine formation and therefore ANH may be a significant factor in mediating the altered renal be at increased risk of dehydration. sodium handling of the elderly. Through its action on the kid- ney, it produces natriuresis and obligatory diuresis. A number of studies have shown that ANH concentration in the blood is RENAL SODIUM LOSS increased with aging. Mean basal plasma ANH levels were five- fold higher in elderly male nursing home residents than in Normal aging is associated with impaired ability of the kidney young normal men. to retain sodium. In very old persons, sodium reabsorption in In addition, the intravenous infusion of normal saline re-

2 Geriatric Nephrology Curriculum American Society of Nephrology sulted in an exaggerated rise in plasma ANH concentration in gency increases to 40 to 49% in men from the fifth to seventh the elderly persons group. Several other studies involving decades and to 40 to 50% in women in their fifth decade and healthy elderly persons have also established that basal plasma beyond. In institutionalized elderly persons with incontinence, ANH concentration is increased and that stimuli that can in- 72% were found to have detrusor instability. The clinical con- crease intracardiac pressure result in a greater rise of plasma sequence of detrusor instability is decline in functional bladder ANH in elderly persons than in the young. There is evidence volume so that small urine volumes result the sensation of full that the renal response to ANH may also be greater in elderly bladder and the initiation of bladder contractions leading to an persons. The natriuretic response to a bolus injection of ANH increase in the frequency of voiding during the day and at night has been observed to be larger in older persons with a mean age (Table 3). of 52 yr than in younger persons with a mean age of 26 yr. ANH has been shown to interact with the renin-angioten- sin-aldosterone system. High levels of ANH suppress renal re- NOCTURNAL POLYURIA SYNDROME nin secretion, plasma renin activity, plasma angiotensin II, and, as a consequence, plasma aldosterone. Even minimal in- The constellation of increased nocturnal urine production and creases of ANH within the physiologic range produced by consequent nocturia with its associated effects on disruption of slow-rate intravenous infusion of ANH are capable of inhibit- sleep has been termed the nocturnal polyuria syndrome.3,9,10 ing angiotensin II-induced aldosterone secretion, providing Several definitions have been used in characterizing individu- support for the functional impact of the increased ANH levels als as having nocturnal polyuria: (1) urine output during sleep in elderly persons. ANH can also suppress plasma aldosterone Ն33% of total 24-h volume; (2) nighttime urine flow rate Ն0.9 by a direct effect on aldosterone secretion. Thus, ANH may be ml/min; and (3) 7:00 p.m. to 7:00 a.m. urine volume Ն50% of an important contributor to age-related impaired renal so- total 24-h volume. A number of clinical states have been asso- dium conserving ability, and concomitant water loss, both ciated with the development of nocturnal polyuria (Table 4). through its direct natriuretic effect and through ANH-induced In persons with nocturnal polyuria, there is an absence of suppression of aldosterone secretion.8 diurnal change in plasma AVP concentration. Both urinary The above studies clearly establish that normal aging is ac- frequency and hourly urine volume are greater at night in older companied by increased urine excretion during the nighttime persons with nocturnal polyuria syndrome and, in these indi- period of sleep. There are multiple physiologic changes in renal viduals, functional bladder capacity is lower at night with an water and sodium conserving mechanisms and in the hor- approximate volume of 200 ml. Patients with nocturia have monal systems governing water and sodium regulation. The significantly lower urine osmolality at night. Both plasma AVP effect of these changes is to alter the diurnal rhythm of urine and angiotensin II are lower at night in patients with nocturnal excretion in the direction of nighttime diuresis (Table 2). polyuria, and plasma ANP levels have been found to be high- er.4,5 Both the nocturnal decrease in AVP and the nocturnal rise in ANP seem to be responsible for the high nighttime urine AGING EFFECTS ON BLADDER RESERVOIR flow and resultant nocturia. In association with reduction in func- FUNCTION tional bladder volume, the clinical consequence is nocturia.

In healthy adults, 24-h urine production is usually in the range Nocturnal Polyuria in Multiple System of 1000 to 1500 ml and bladder capacity generally ranges from (MSA) is a central nervous system approximately 400 to 750 ml. This is associated with a daytime degenerative that most commonly occurs in older voiding frequency of four to five times in men and five to six persons. It affects many areas of the central nervous system times in women and with rare voiding during normal periods and has central autonomic insufficiency or Shy-Drager syn- of sleep. There is a suggestion that voiding frequency increases drome as one its components. Patients with central auto- with age, especially in men. With advancing age, there is a nomic insufficiency have been observed to excrete large progressive increase in the prevalence of urgency, most com- amounts of urine when recumbent at night, and this noc- monly caused by detrusor instability. The prevalence of ur- Table 3. Association between nocturnal urine flow rate, Table 2. Typical parameters related to circadian water bladder volume, and nocturnal urinary frequency in healthy excretion in healthy young and elderly adults* young and elderly adults* Young Elderly Young Elderly Day Night Day Night Nighttime urine flow rate (ml/h) 35 70 Urine volume (ml/h) 75 35 50 70 Time in bed (h) 8 8 Urine osmolality (mosm/kg) 700 830 510 450 Nighttime urine production (ml) 280 560 Plasma AVP (pg/ml) 1.1 2.0 1.9 1.3 Bladder capacity (ml) 400 200 Plasma ANH (pg/ml) 19 17 40 55 Number of voids during sleep period 0 2 *Data show typical values based on literature and/or author’s experience. *Data show typical values based on literature and/or author’s experience.

American Society of Nephrology Geriatric Nephrology Curriculum 3 Table 4. Clinical states associated with nocturnal polyuria Table 5. Factors predisposing patients with Alzheimer’s syndrome disease to nocturia and Nocturnal polyuria syndrome Decreased urine concentrating ability Primary enuresis in children Decreased plasma AVP and loss of circadian rhythm Normal aging Increased nocturnal urine flow rate Multiple system atrophy Decreased functional bladder volume (detrusor instability) Alzheimer’s disease Diminished perception of bladder fullness Diminished appropriate behavior Other causes of increased nocturnal urine production Diminished mobility Edematous states CHF Renal disease Other clinical conditions that may be associated with Hepatic disease increased nocturnal urine production include edematous Venous insufficiency states such as congestive , renal and hepatic Osmotic diuresis disease, and peripheral venous insufficiency, where Diabetes mellitus fluid may be mobilized when individuals are in the recum- Impaired renal concentrating ability bent position. Osmotic diuresis, as occurs in patients with Renal disease poorly controlled diabetes mellitus and after administration of drugs, can also lead to increased nocturnal urine Hypercalcemia flow. Although uncommon in elderly persons, high fluid Increased fluid intake intake states, as may be seen in patients with primary poly- Iatrogenic dipsia or in individuals who ingest large fluid volumes in the Primary belief that doing so is beneficial, can cause nocturnal poly- uria. turnal dieresis is associated with marked decrease in noctur- nal AVP production with a resultant diabetes insipidus-like nocturnal diuresis. Treatment of MSA patients who have THERAPY OF NOCTURNAL POLYURIA SYNDROME nocturnal polyuria with the AVP analogs DDAVP (desmo- pressin) or lysine vasopressin has resulted in reduction of noc- Hormonal turnal polyuria and improvement in the orthostatic The demonstration of reduced daytime and/or nocturnal AVP that is part of the syndrome and worsened by the polyuria-caused secretion in patients with nocturnal polyuria suggests that hor- intravascular volume depletion. mone replacement therapy with AVP or its potent antidiuretic analogs may be beneficial in reversing the syndrome.11–13 Nocturnal Polyuria in Alzheimer’s Disease Short-term treatment with 20 ␮g of intranasal DDAVP for 2 The synthesis of AVP by hypothalamic neurons is not affected wk results in a 25 to 40% reduction of nocturnally voided urine in patients with Alzheimer’s, but AVP release into the circula- with a corresponding reduction in nocturnal frequency. Pro- tion is impaired so that AVP concentration in the blood has longed treatment for 2 mo with 40 ␮g of DDAVP daily has been reported to be lower in patients with Alzheimer’s disease shown a sustained response and a decrease in nocturnal ur- than in comparably aged persons with normal cognitive func- gency and incontinence. tion. In patients with Alzheimer’s disease, there is loss of noc- Intranasal doses of DDAVP ranging from 10 to 40 ␮g turnal AVP secretion and an accompanying reversal of day- daily were capable of producing a 10 to 50% reduction in night urine production and nocturnal polyuria. Both the nocturnal urine volume in Alzheimer’s disease patients with decrease in daytime AVP release and the loss of nocturnal se- nocturnal incontinence. Long-term treatment of these pa- cretion put patients with Alzheimer’s disease at increased risk tients with 10 ␮g DDAVP daily has been observed to result for fluid loss and dehydration. Clinically, this can be expressed in restoration of nighttime continence in some individuals by the high prevalence of nocturia and both daytime and night- (Table 6). time urinary incontinence in patients with Alzheimer’s disease. The use of DDAVP in the treatment of the elderly patient Detrusor instability is commonly present in patients with Alz- with nocturia and nocturnal polyuria may be associated with heimer’s disease. The combination of high nighttime urine adverse effects because of water retention, especially when production, decreased functional bladder volume, and cogni- DDAVP is administered in the intranasal form, with as many tive impairment can readily explain why Ͼ80% of institution- as 20% of treated patients developing . Thus, use alized patients with Alzheimer’s disease have urinary inconti- of DDAVP for treatment of nocturnal polyuria should be lim- nence. When there is impaired mobility as well, the underlying ited to the oral preparation. In addition, DDAVP effect may be factors are likely to result in near 100% presence of inconti- limited by age or disease-associated impairment of renal con- nence (Table 5). centrating response.

4 Geriatric Nephrology Curriculum American Society of Nephrology Table 6. Treatment of nocturnal polyuria syndrome • DDAVP may be an effective intervention in management of nocturia and incontinence in some elderly persons Hormone replacement: DDAVP () Intranasal: 20–40 ␮g Oral: 0.1–0.4 mg DISCLOSURES agents (detrusor antispasmodics) None. : 2.5–5 mg, bid to qid Oxybutynin xl: 5–30 mg once daily Tolteradine: 2–4 mg once daily REFERENCES : 5–10 mg once daily : 7.5–15 mg once daily Trospium: 20 mg, bid *Key References 1. Miller M: Water balance in older persons. In: Contemporary Endocri- : 1 mg/kg body weight orally at 8:00 p.m. nology: of Aging, edited by Morley JE, van den Berg L, Totowa, NJ, Humana Press, 1999, pp 31–41* CONCLUSIONS 2. Nakamura S, Kobayashi Y, Tozuka K, Tokue A, Kimura A, Hamada C: Circadian changes in urine volume and frequency in elderly men. J Urol 156: 1275–1279, 1996 Aging is associated with changes in the renal and hormonal 3. Miller M: Nocturnal polyuria in the elderly: pathophysiology and clin- systems involved in the conservation of water and sodium. As a ical implications. J Am Geriatr Soc 48: 1321–1329, 2000* consequence, there is increase in nocturnal urine production. 4. Asplund R, Aberg H: Diurnal variation in the levels of antidiuretic Concurrent age-related changes occur in the reservoir func- hormone in the elderly. J Intern Med 299: 131–134, 1991 tion of the bladder. The combination of increased urine pro- 5. Ouslander JG, Nasr SZ, Miller M, Withington W, Lee CS, Wiltshire- Clement M, Cruise P, Schnelle JF: Arginine vasopressin levels in duction at night and decrease in functional bladder volume nursing home residents with nighttime urinary incontinence. JAm results in the development of nocturnal urinary frequency and Geriatr Soc 46: 1274–1279, 1998* predisposes to the development of urinary incontinence. Di- 6. Bauer JH: Age-related changes in the renin-aldosterone system: phys- minished AVP secretion in patients with Alzheimer’s disease iological effects and clinical implications. Drugs Ageing 3: 238–245, puts this population at even greater risk for nocturia and in- 1993 7. Cugini P, Lucia P, Di Palma L, Re M, Canova R, Gasbarrone L, Cianetti continence and the risk is further magnified by diminished A: Effect of aging on circadian rhythm of atrial natriuretic peptide, perception of bladder fullness and/or impaired mobility. The plasma renin activity and plasma aldosterone. J Gerontol 47: B140– availability of easily administered hormone replacement in the B19, 1992* form of intranasal or oral DDAVP opens the possibility that for 8. Kikuchi Y: Participation of atrial natriuretic peptide (hANP) levels and some patients there may be an effective intervention available arginine vasopressin (AVP) in aged persons with nocturia. Jap J Urol 86: 1651–1659, 1995 to reduce nocturia and urinary incontinence and the clinical 9. Weiss JP, Blaivas JG, Stember DS, Brooks MM: Nocturia in adults: consequences associated with these disorders. etiology and classification. Neurourol Urodynam 17: 467–472, 1998 10. Matthiesen TB, Rittig S, Nørgaard JP, Pedersen EB, Djurhuus JC: Nocturnal polyuria and natriuresis in male patients with nocturia and TAKE HOME POINTS lower urinary tract symptoms. J Urol 156:1292–1299, 1996 11. Cannon A, Carter PG, McConnell AA, Abrams P: Desmopressin in the • Renal and hormonal changes of normal aging can result in increased treatment of nocturnal polyuria in the male. Br J Urol 84: 20–24, 1999 nocturnal urine production in healthy elderly persons 12. Asplund R, Aberg H: Desmopressin in elderly subjects with increased • Functional bladder volume is often decreased in elderly persons nocturnal diuresis. a two-month treatment study. Scand J Urol Neph- • Increased nocturnal urine production and decreased functional bladder rol 27: 77–82, 1993 volume predispose to nocturia and urinary incontinence 13. Asplund R, Sunberg B, Bengtsson P: Oral desmopressin for nocturnal • Decreased nocturnal AVP production puts patients with Alzheimer’s polyuria in elderly subjects: a double blind, -controlled ran- disease at high risk for nocturia and incontinence domized exploratory study. Br J Urol 83: 591–595, 1999*

American Society of Nephrology Geriatric Nephrology Curriculum 5 REVIEW QUESTIONS: FLUID BALANCE DISORDERS d. Initial laboratory studies to include serum and IN THE ELDERLY , first voided morning urine specimen for osmola- lity 1. All of the following are normal changes of aging that can lead e. Referral to a urologist for possible to increased urine production except which one: a. Acquired resistance to the action of antidiuretic hormone 3. An 83-yr-old woman with attributed to Alzheimer’s b. Increased atrial natriuretic hormone secretion disease is seen for a history of worsening urinary incontinence. c. Increased nocturnal antidiuretic hormone secretion All of the following findings are likely to be present except d. Impaired renal sodium conservation which one: e. Decreased renin-angiotensin-aldosterone secretion a. Urine volume from 7:00 p.m. to 7:00 a.m. is greater than urine volume from 7:00 a.m. to 7:00 p.m. 2. A 73-yr-old male gives a history of nocturia twice nightly for b. Maximum bladder capacity is likely to be Ͼ500 ml the past 3 yr. Your initial evaluation should include all of the c. Plasma level of atrial natriuretic hormone (ANH) will be following except which one: higher than the level in normal persons in the 25 to 50 yr a. Digital rectal examination age range b. Asking the patient to complete and bring in a 3-d voiding d. Urine osmolality in a first voided morning urine specimen diary is likely to be Ͻ700 mOsm/kg c. Taking a careful history of all prescription and nonpre- e. A risk of a therapeutic trial with DDAVP is the develop- scription medications taken ment of hyponatremia

6 Geriatric Nephrology Curriculum American Society of Nephrology