Prevalent, morbid, and costly ($1.5 billion/year in 2008), nocturia is a major problem, especially for older adults. It increases the risk of falls, fractures, depression, nursing home placement, and death. Yet management of nocturia remains inadequate because its etiology is not fully understood, especially that of its most prevalent attribute: nocturnal polyuria (NP), or increased urine production during sleep. Disruption of diurnal excretory pattern, with higher nighttime urine production is common in older adults. Recent evidence suggests the impact of sleep on nocturnal urine production, but pathophysiology is not fully understood. The goal of the proposed new study is to assess the role of endogenous circadian rhythm on the diurnal variation of urine production in older adults and the impact of sleep. Urine production follows a circadian pattern in which transition from wake to sleep is followed by a pronounced decrease in excretion of water, electrolytes and other osmotically active substances. Studies in young population have established that physiological urine production follows a circadian rhythm, which is regulated by diurnal variation in secretion of hormones controlling water and salt excretion such as arginine vasopressin (AVP), renin-angiotensin-aldosterone system (RAAS), and atrial natriuretic peptide (ANP). Sleep deprivation blunts nocturnal surge of these hormones and consequently alter water and salt excretion thereby increase nocturnal urine volume (NUV) leading to NP. NP is common in older adults even in the absence of lower urinary tract symptoms, peripheral edema or fluid overload. The underlying pathophysiology of disrupted circadian pattern of urine production in older adults, and the contribution of sleep, is not known. The knowledge about circadian variations in hormonal regulation in older adults is scarce and contradictory. Therefore, aims of the present proposal are to better characterize, in the elderly: 1) the circadian rhythms of hormones regulating salt and water excretion; and 2) the impact of sleep on these rhythms. Our overall hypothesis is that sleep suppresses nocturnal urinary output via increased secretion of AVP, activated renin and ANP, and that these hormones have weak endogenous circadian rhythmicity. Thus sleep disruption associated with older age may disinhibit the physiologic dip in nocturnal in urine output, hence lead to NP. To accomplish our goals we will recruit healthy older adults ? 60 years, without insomnia or lower urinary tract symptoms (n=20) who will undergo two 24-hour studies at Clinical and Translational Research Center 6 weeks apart: 1) a constant routine protocol that removes the masking influence of sleep, posture, and other confounders, and 2) a normal sleep-wake (nychthemeral) protocol. During each 24-hour study we will collect plasma (every 2 hours 8am-7pm, and every 30 minutes 7pm-7am) to assess diurnal variation in secretion of hormones regulating salt and water excretion. Circadian rhythms will be assessed with phase and amplitude of plasma melatonin rhythms. The study will enable us to assess the diurnal variation in secretion of the renal regulatory hormones in healthy older adults and the impact of sleep. Regardless of the results, knowledge from this study will contribute substantially to current understanding of disrupted diurnal excretory pattern in older adults and potentially modifiable underlying factors. Such knowledge may also allow differentiation of different phenotypes of NP and facilitate development of more targeted therapy.
Nocturia is prevalent in older adults and it vastly reduces quality of life. Yet its treatment remains inadequate because its causes are not well understood, especially nocturnal polyuria or increased urine production a night. This study, which builds on our ongoing research, would be the first of its kind and should contribute important knowledge to guide development of better therapy for this prevalent and morbid condition.
| Tyagi, Shachi; Perera, Subashan; Clarkson, Becky D et al. (2017) Nocturnal Polyuria in Older Women with Urge Urinary Incontinence: Role of Sleep Quality, Time in Bed and Medications Used. J Urol 197:753-758 |
