Focus on Nocturia in the Elderly
Aging has been established as the major risk factor in longitudinal studies, as well as in multivariate analysis of cross-sectional studies. There is less certainty over the nature of the association with the many other risk factors studied; particularly whether these are the cause or an effect of nocturia as the evidence is highly heterogeneous and sometimes conflicting. For some of these factors a plausible pathophysiological link to nocturia exists, making the association more credible. This article will focus on those correlates of importance to the elderly population and describe the probable mechanisms at play. A summary of possible etiological factors is provided in Box 1.
A reduction in the capacity of the bladder to store urine resulting in the need for more frequent micturition is essentially the reason why LUT dysfunction leads to nocturia. This reduction may be either functional, consequent upon common conditions such as the detrusor overactivity (DO) seen in association with BPH and overactive bladder syndrome (OAB), or structural due to a reduced bladder capacity consequent upon bladder fibrosis.
LUTS as a consequence of BPH (LUTS/BPH) is a highly prevalent age-related phenomenon in men. It is estimated that 80% of males over the age of 80 years have histological evidence of BPH, 46% of these men having moderate or severe LUTS. The presence of BPH is significantly correlated to nocturia (odds ratio [OR]: 1.35–6.591), and nocturia is often reported as the most bothersome symptom of LUTS/BPH. Data from the 1990s indicated a link between nocturia and risk of prostatectomy, supporting a widely held belief that nocturia occurred purely as a result of BPH, yet subsequently it was shown that nocturia is poorly responsive to surgery, suggesting that other factors may be at play. BPH may lead to reduced bladder capacity in two ways. First, through nonvoluntary contractions of the detrusor muscle during bladder filling, DO, which can be shown urodynamically or secondary to obstruction of the bladder outlet by an encroaching prostate, leading to fibrous infiltration of the bladder wall. Second, obstruction may lead to incomplete bladder emptying causing urine to be retained in the bladder after voiding. This situation effectively leads to filling on top of an already partially filled bladder. During the night time this can lead to overdistention of the bladder and reduced efficiency of detrusor contraction – a probable explanation as to why elderly men commonly report poor urinary flow after waking to void. In 2013, while it is recognized that there is an association between LUTS/BPH and DO and nocturia, this may not necessarily be a causal relationship, but rather an age-related association.
OAB is a common chronic symptom syndrome that is defined by the ICS as "urinary urgency with or without urgency incontinence, usually with frequency and nocturia in the absence of metabolic or pathologic conditions". Most population-based studies have estimated the prevalence to be in the range of 10–20%, generally with an even distribution between the sexes. The prevalence increases with age and was estimated to be 19.1 and 18.3% in men and women over the age of 60 years, respectively. OAB is present in approximately a third of individuals reporting nocturia and up to half of OAB sufferers have nocturia. Urinary urgency is correlated with nocturia (OR: 1.70), as is incontinence. The symptoms of OAB are suggestive of DO during the storage phase, although this is not present in approximately 30% of cases, and can be due to other forms of LUT dysfunction. Theories of causation include increased sensory afferent activity and reduced motor inhibition due to changes in CNS control mechanisms. Urgency is the defining feature of OAB and is described as "the sudden and compelling desire to void, which is difficult to defer" by the ICS. CNS disorders associated with aging, such as stroke and Parkinson's disease, are potential causes of OAB and indeed DO, and stroke has been shown to be independently associated with nocturia (OR: 2.0). An additional factor in aging women is the menopause, where urogenital atrophy due to effects of reduced estrogenization may lead to similar symptoms to OAB.
An overproduction of urine during the hours of sleep will logically result in an increased need to empty the bladder. This phenomenon is termed polyuria and may be global, that is, an actual increase in urine production occurring throughout the 24 h of the day, or nocturnal, a relative increase in urine production occurring during the hours of sleep. In either case, as the bladder fills more quickly, the individual is inevitably troubled by more frequent visits to the toilet, which are appreciably more bothersome during the night.
Several changes that occur with aging may contribute to urine overproduction. The urine concentrating ability of the kidneys declines with age, as demonstrated in the Baltimore longitudinal study of aging where a 20% reduction in maximum urine osmolality, a 50% decrease in the ability to conserve solute and 100% reduction in minimal urine flow rate was observed in older patients (aged 60–79 years) compared with the young (20–39 years). Additionally, aging kidneys have a reduced ability to conserve sodium, which may lead to an obligatory osmotic diuresis. Elderly individuals have also been found to have a higher basal rate of ANP and show a greater renal response to ANP than the young. The elderly may also be less sensitive to stimulants of AVP release, such as blood pressure reduction.
Global polyuria is defined as >2.8 l of urine/24 h or >40 ml/kg. A common cause is diabetes mellitus, which is consistently correlated with nocturia (OR: 1.67–2.73). The probable mechanism is high circulating blood sugar levels leading to an osmotic diuresis. Alternatively, in diabetes insipidus the kidneys fail to concentrate urine, either due to inadequate production of AVP (central diabetes insipidus) or loss of renal receptivity of the kidney to AVP, resulting in polyuria. Global polyuria may also result from excessive fluid intake, termed polydipsia, which may be behavioral or related to a psychiatric problem, such as schizophrenia.
Nocturnal polyuria (NPu) increases with age and is commonly implicated in the etiology of nocturia, yet is often unrecognized. The definition adopted by the ICS is a night time volume of >20% of the daily total in younger patients (<65 years) and >33% in the elderly (>65 years). A study of patients screened for entry into trials of nocturia therapies assessed the frequency volume charts (FVCs) of a total 1763 individuals. Using ICS definitions, NPu was present in 66–83% of patients <65 years and in 90–93% ≥65 years. The recently published results from the Krimpen study group challenge the validity of the current ICS definitions. This group performed a longitudinal study that included 1688 men aged 50–78 years assessed using FVCs with a follow-up of 6 years. Using the ICS criteria of >33%, NPu was present in 77.8% of men at baseline and 80.5% after 6.5 years. At baseline, NPu was found in 91.9% of men with nocturia (defined as ≥two voids) and in 70.1% of men without nocturia. The authors argued that because of the high prevalence of NPu in men without nocturia, the current ICS definition should be reconsidered as it has limited clinical discriminatory value. Using the authors' definition of nocturnal urine production of >90 ml/h, the total prevalence of NPu was 15%, 8% in those without nocturia and 28% in those with nocturia. There were several methodological issues with this study, such as FVCs lasting only 24 h, a high drop-out rate and selection bias. Further studies are needed to confirm these results and the validity of nocturnal urine production of >90ml/h versus the ICS definition, which is based on a relative increase in urine production in terms of clinical relevance.
The pathogenesis of NPu is incompletely understood but it is thought that age-related changes in renal function that compromise water- and sodium-conserving mechanisms are contributory. A specific dysfunction in the diurnal pattern of AVP release, resulting in insufficient circulating levels during the night time may be implicated in some elderly people.
Fluid retention in the feet and legs is independently correlated with nocturia (OR: 1.67) and is associated with conditions that lead to 'third spacing' of fluids, such as venous insufficiency and cardiac failure, which are more common in the elderly. When recumbent, this fluid redistributes centrally leading to expansion of the intravascular volume and increased nocturnal urine production. Obstructive sleep apnea (OSA) increases in prevalence with aging and is strongly associated with nocturia, an association that is confirmed by the dramatic resolution of nocturia when OSA is treated. The probable underlying mechanism is NPu resulting from increased ANP levels induced by the negative intrathoracic pressures generated in OSA.
The occurrence of nocturia is intimately related to the quality of sleep. Consequently, conditions that lead to sleep disturbance are frequently associated with an incidence of nocturia, in particular insomnia, depression and anxiety, pruritus, snoring, burning mouth syndrome and chronic pain. In practice, however, it is often difficult to ascertain whether the nocturia is due to convenience voids taken after waking due to a primary sleep problem or whether nocturia is itself the cause of disturbed sleep. Additionally, patients with OAB often void pre-emptively for fear of incontinence episodes.
Etiological Factors
Aging has been established as the major risk factor in longitudinal studies, as well as in multivariate analysis of cross-sectional studies. There is less certainty over the nature of the association with the many other risk factors studied; particularly whether these are the cause or an effect of nocturia as the evidence is highly heterogeneous and sometimes conflicting. For some of these factors a plausible pathophysiological link to nocturia exists, making the association more credible. This article will focus on those correlates of importance to the elderly population and describe the probable mechanisms at play. A summary of possible etiological factors is provided in Box 1.
Urine Storage
A reduction in the capacity of the bladder to store urine resulting in the need for more frequent micturition is essentially the reason why LUT dysfunction leads to nocturia. This reduction may be either functional, consequent upon common conditions such as the detrusor overactivity (DO) seen in association with BPH and overactive bladder syndrome (OAB), or structural due to a reduced bladder capacity consequent upon bladder fibrosis.
LUTS as a consequence of BPH (LUTS/BPH) is a highly prevalent age-related phenomenon in men. It is estimated that 80% of males over the age of 80 years have histological evidence of BPH, 46% of these men having moderate or severe LUTS. The presence of BPH is significantly correlated to nocturia (odds ratio [OR]: 1.35–6.591), and nocturia is often reported as the most bothersome symptom of LUTS/BPH. Data from the 1990s indicated a link between nocturia and risk of prostatectomy, supporting a widely held belief that nocturia occurred purely as a result of BPH, yet subsequently it was shown that nocturia is poorly responsive to surgery, suggesting that other factors may be at play. BPH may lead to reduced bladder capacity in two ways. First, through nonvoluntary contractions of the detrusor muscle during bladder filling, DO, which can be shown urodynamically or secondary to obstruction of the bladder outlet by an encroaching prostate, leading to fibrous infiltration of the bladder wall. Second, obstruction may lead to incomplete bladder emptying causing urine to be retained in the bladder after voiding. This situation effectively leads to filling on top of an already partially filled bladder. During the night time this can lead to overdistention of the bladder and reduced efficiency of detrusor contraction – a probable explanation as to why elderly men commonly report poor urinary flow after waking to void. In 2013, while it is recognized that there is an association between LUTS/BPH and DO and nocturia, this may not necessarily be a causal relationship, but rather an age-related association.
OAB is a common chronic symptom syndrome that is defined by the ICS as "urinary urgency with or without urgency incontinence, usually with frequency and nocturia in the absence of metabolic or pathologic conditions". Most population-based studies have estimated the prevalence to be in the range of 10–20%, generally with an even distribution between the sexes. The prevalence increases with age and was estimated to be 19.1 and 18.3% in men and women over the age of 60 years, respectively. OAB is present in approximately a third of individuals reporting nocturia and up to half of OAB sufferers have nocturia. Urinary urgency is correlated with nocturia (OR: 1.70), as is incontinence. The symptoms of OAB are suggestive of DO during the storage phase, although this is not present in approximately 30% of cases, and can be due to other forms of LUT dysfunction. Theories of causation include increased sensory afferent activity and reduced motor inhibition due to changes in CNS control mechanisms. Urgency is the defining feature of OAB and is described as "the sudden and compelling desire to void, which is difficult to defer" by the ICS. CNS disorders associated with aging, such as stroke and Parkinson's disease, are potential causes of OAB and indeed DO, and stroke has been shown to be independently associated with nocturia (OR: 2.0). An additional factor in aging women is the menopause, where urogenital atrophy due to effects of reduced estrogenization may lead to similar symptoms to OAB.
Urine Production
An overproduction of urine during the hours of sleep will logically result in an increased need to empty the bladder. This phenomenon is termed polyuria and may be global, that is, an actual increase in urine production occurring throughout the 24 h of the day, or nocturnal, a relative increase in urine production occurring during the hours of sleep. In either case, as the bladder fills more quickly, the individual is inevitably troubled by more frequent visits to the toilet, which are appreciably more bothersome during the night.
Several changes that occur with aging may contribute to urine overproduction. The urine concentrating ability of the kidneys declines with age, as demonstrated in the Baltimore longitudinal study of aging where a 20% reduction in maximum urine osmolality, a 50% decrease in the ability to conserve solute and 100% reduction in minimal urine flow rate was observed in older patients (aged 60–79 years) compared with the young (20–39 years). Additionally, aging kidneys have a reduced ability to conserve sodium, which may lead to an obligatory osmotic diuresis. Elderly individuals have also been found to have a higher basal rate of ANP and show a greater renal response to ANP than the young. The elderly may also be less sensitive to stimulants of AVP release, such as blood pressure reduction.
Global polyuria is defined as >2.8 l of urine/24 h or >40 ml/kg. A common cause is diabetes mellitus, which is consistently correlated with nocturia (OR: 1.67–2.73). The probable mechanism is high circulating blood sugar levels leading to an osmotic diuresis. Alternatively, in diabetes insipidus the kidneys fail to concentrate urine, either due to inadequate production of AVP (central diabetes insipidus) or loss of renal receptivity of the kidney to AVP, resulting in polyuria. Global polyuria may also result from excessive fluid intake, termed polydipsia, which may be behavioral or related to a psychiatric problem, such as schizophrenia.
Nocturnal polyuria (NPu) increases with age and is commonly implicated in the etiology of nocturia, yet is often unrecognized. The definition adopted by the ICS is a night time volume of >20% of the daily total in younger patients (<65 years) and >33% in the elderly (>65 years). A study of patients screened for entry into trials of nocturia therapies assessed the frequency volume charts (FVCs) of a total 1763 individuals. Using ICS definitions, NPu was present in 66–83% of patients <65 years and in 90–93% ≥65 years. The recently published results from the Krimpen study group challenge the validity of the current ICS definitions. This group performed a longitudinal study that included 1688 men aged 50–78 years assessed using FVCs with a follow-up of 6 years. Using the ICS criteria of >33%, NPu was present in 77.8% of men at baseline and 80.5% after 6.5 years. At baseline, NPu was found in 91.9% of men with nocturia (defined as ≥two voids) and in 70.1% of men without nocturia. The authors argued that because of the high prevalence of NPu in men without nocturia, the current ICS definition should be reconsidered as it has limited clinical discriminatory value. Using the authors' definition of nocturnal urine production of >90 ml/h, the total prevalence of NPu was 15%, 8% in those without nocturia and 28% in those with nocturia. There were several methodological issues with this study, such as FVCs lasting only 24 h, a high drop-out rate and selection bias. Further studies are needed to confirm these results and the validity of nocturnal urine production of >90ml/h versus the ICS definition, which is based on a relative increase in urine production in terms of clinical relevance.
The pathogenesis of NPu is incompletely understood but it is thought that age-related changes in renal function that compromise water- and sodium-conserving mechanisms are contributory. A specific dysfunction in the diurnal pattern of AVP release, resulting in insufficient circulating levels during the night time may be implicated in some elderly people.
Fluid retention in the feet and legs is independently correlated with nocturia (OR: 1.67) and is associated with conditions that lead to 'third spacing' of fluids, such as venous insufficiency and cardiac failure, which are more common in the elderly. When recumbent, this fluid redistributes centrally leading to expansion of the intravascular volume and increased nocturnal urine production. Obstructive sleep apnea (OSA) increases in prevalence with aging and is strongly associated with nocturia, an association that is confirmed by the dramatic resolution of nocturia when OSA is treated. The probable underlying mechanism is NPu resulting from increased ANP levels induced by the negative intrathoracic pressures generated in OSA.
Sleep Disturbance
The occurrence of nocturia is intimately related to the quality of sleep. Consequently, conditions that lead to sleep disturbance are frequently associated with an incidence of nocturia, in particular insomnia, depression and anxiety, pruritus, snoring, burning mouth syndrome and chronic pain. In practice, however, it is often difficult to ascertain whether the nocturia is due to convenience voids taken after waking due to a primary sleep problem or whether nocturia is itself the cause of disturbed sleep. Additionally, patients with OAB often void pre-emptively for fear of incontinence episodes.
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