Nocturia: the Complex Role of the Heart, Kidneys, and Bladder

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Mini Review – Voiding Dysfunction

Nocturia: The Complex Role of the Heart, Kidneys, and Bladder

a,* a b

Riccardo Lombardo , Andrea Tubaro , Fiona Burkhard

a b

Ospedale Sant’ Andrea, Sapienza University of Rome, Rome, Italy; Department of Urology, Inselspital University Hospital Bern, Bern, Switzerland

Article info Abstract

Article history:

We review the role of the heart, kidneys, and bladder in the pathophysiology of nocturia

Accepted July 25, 2019 and nocturnal polyuria. Lower urinary tract symptoms such as nocturia have often been

associated with lower urinary tract dysfunction. It is known that the bladder contributes

Associate Editor: to nocturia in the case of low functional capacity, urgency, and detrusor overactivity.

Heart diseases, especially arterial hypertension and congestive heart failure, are closely

Malte Rieken

related to nocturnal polyuria. The main mechanisms include renal hyperﬁltration and

elevated atrial natriuretic peptide. A number of drugs frequently used in cardiovascular

Keywords:

disorders are implicated in nocturia; diuretics, calcium channel blockers, and b-blockers

Nocturia induce nocturnal polyuria and thus nocturia, whereas alpha-blockers improve nocturia.

Among the different forms of hypertension, nondipping arterial hypertension has been

Nocturnal polyuria

associated with a higher risk of nocturnal polyuria. Besides the role of the kidneys in

Physiopathology

nocturia linked to arterial hypertension, chronic kidney disease is an independent

predictor of nocturia through an osmotic diuresis mechanism. Some evidence suggests

a close relationship between the heart (nondipping arterial hypertension), kidneys

(chronic kidney disease), and nocturia/nocturnal polyuria. These complex interactions

between the heart, kidneys, and bladder warrant a multidisciplinary approach in

patients with nocturia.

Patient summary: We review the different mechanisms that lead to nocturia and

nocturnal polyuria. The complex interactions between the heart, the kidneys, and

the bladder warrant a multidisciplinary approach in patients with nocturia. Careful

investigation of the cause of nocturia can improve its management.

* Corresponding author. Sapienza University of Rome, Via Jacini 34, Rome 00191, Italy.

E-mail address: [email protected] (R. Lombardo).

(RN), characterized by small voided volumes, or nocturnal

1. Introduction polyuria (NP). Although different definitions of NP have

been proposed, all of them assume that urine production

Nocturia is the complaint whereby an individual wakes one during the night exceeds functional bladder capacity

or more times at night to void. It is a common symptom in because of increased production of urine during sleep.

both women and men and it is considered one of the most Epidemiology suggests that the prevalence of nocturia

bothersome lower urinary tract symptoms (LUTS) [1]. Its increases with age.

prevalence increases with age and varies according to RN often depends on prostate or bladder conditions such

definitions. Nocturia involving two or more micturitions as benign prostatic enlargement/obstruction, urgency with

per night affects up to 60% of men and women older than 65 or without detrusor overactivity, reduced functional

yr [2,3]. Nocturnal voids can be due to either real nocturia bladder capacity, and chronic urinary retention, while NP

https://doi.org/10.1016/j.euf.2019.07.007

Please cite this article in press as: Lombardo R, et al. Nocturia: The Complex Role of the Heart, Kidneys, and Bladder. Eur Urol Focus

(2019), https://doi.org/10.1016/j.euf.2019.07.007

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is often determined by systemic conditions affecting water Both calcium channel blockers and diuretics are associated

and salt balance that lead to excessive production of urine at with a higher risk of NP. In addition, b-blockers decrease

all times (global polyuria) or overnight (NP) [4]. Nocturia bladder capacity and can cause nocturia if taken just before

should no longer be considered just a symptom of disorders going to bed. a1-Adrenoreceptor antagonists relieve nocturia

affecting the urinary system, and the diagnostic algorithm in selected patients and other symptoms of bladder outflow

includes a number of internal medicine conditions that obstruction in elderly men with prostatic hyperplasia. It is

every urologist must be aware of [5,6]. hypothesized that the therapeutic effect of a1-adrenorecep-

The aim of this mini-review is to examine the role of the tor antagonists on AH may decrease NP and explain the

heart, kidneys, and bladder in the causes of nocturia. positive effect on nocturia observed in some patients. Lastly,

nocturia has been proposed as a risk factor for AH. Compared

with daytime values, blood pressure (BP) in most subjects is

2. Evidence acquisition

considerably lower during the night and attenuation of this

physiological nocturnal decline is defined as nondipping AH

A systematic review of the literature using the Medline,

(NDAH). Some studies suggest that an increase in nocturnal

Scopus, and Web of Science databases for relevant articles

activity related to nocturia may explain a nondipping BP

published upto January 2019 was performed with both MeSH

profile (defined as failure of the nocturnal BP to fall by at

and free test protocols. The MeSH search was conducted by

least 10% of daytime BP) [7,8]. NDAH itself is a risk factor for

combining the following terms: “kidney”, “heart”, “bladder”

the development of end organ damage, including left ven-

“hypertension”, “chronic kidney disease”, “coronary artery

tricular hypertrophy, congestive heart failure, and microal-

disease”, “nocturia”, “nocturnal polyuria”, “arrhythmia”,

buminuria, which, as mentioned earlier, can contribute to NP,

“heart failure”, and “kidney failure”. In addition, selected

thus creating avicious loop involving nocturia, NDAH, and NP.

references from the bibliographies of the full-text manu-

scripts chosen were identified and added to the list. English

3.2. The kidneys

language text was not a specific parameter; however, only

English language publications were considered. The title and

The kidneys play a major role in patients with NP specifically

abstract for each article were reviewed for their appropriate-

related to AH, as discussed above. However, there is some

ness and relevance to the relationship to nocturia by two

evidence suggesting a direct relationship between kidney

authors (A.T. and R.L.) and a third author was involved (F.B.) in

diseases and NP. NP resulting from impaired ability to con-

the case of disagreement. Real nocturia (RN) is defined as the

complaintthattheindividualhastowakeatnightoneormore centrate urine or natriuresis makes nocturia one of the initial

presenting symptoms of chronic kidney disease (CKD). In

times to void small volumes. Nocturnal polyuria (NP) is

patients with CKD the prevalence of nocturia is as high as

defined as urine production during the night which exceeds

64.0%. Interestingly, a large-scale cohort study indicated that

functional bladder capacity.

self-reported NP is an independent risk factor for end-stage

renal disease. According to Fukuda et al [9] the main mecha-

3. Evidence synthesis nism causing nocturia in CKD is osmotic diuresis rather than

water diuresis. It has also been suggested that nocturia

3.1. The heart

reflects a high volume of fluid ingestion, which is detrimental

in patients with kidney disease because high urine volume

NP is a common symptom in patients with heart diseases. increases intratubular volume and pressure, which in turn

In a systematic review, Feldstein [7] evaluated the available inducefibrosis[9]. Moreover, Agarwalet al[10]found a strong

evidence linking RN/NP and arterial hypertension (AH) and association between CKD, NDAH, and NP, which opens new

found strong epidemiological evidence for a link. Hyper- insights into the relationship between kidney diseases and

tension appears to be related to NP through its effects on RN/NP. Although the peer-reviewed literature clearly shows a

glomerular filtration and tubular transport; the main relationship between kidney diseases, NDAH, and NP, well-

mechanisms involved are renal hyperfiltration and an designed studies to clarify the underlying mechanisms are

increase in atrial natriuretic peptide (ANP). ANP is released still lacking.

as a result of atrial stretch due to congestive heart failure

resulting from AH. Moreover, AH and the use of calcium 3.3. The bladder

antagonists (eg, amlodipine) may be associated with

peripheral edema. The nightly reabsorption of peripheral The role of the bladder in RN is mainly related to a lower

edema increases urine volume. functional bladder capacity (FBC) and overactive bladder

Another link between AH and NP is sleep apnea. (OAB) syndrome. RN caused by diminished nocturia bladder

Obstructive sleep apnea is associated with obesity, elevated capacity (NBC) is of two general types: decreased FBC and

sympathetic nervous system activity, and AH. Abnormally decreased NBC. In both conditions, the nocturnal volume

low production of antidiuretic hormone (ADH) has been urinated exceeds the bladder capacity and the patient is

implicated as one of the physiological mechanisms for NP awakened by the need to void because the bladder capacity

in obstructive sleep apnea. Besides a clear relationship is not sufficient [11]. The relation between RN and OAB has

between heart diseases and NP, the relation between been investigated in several studies [12–14]. Ge et al [14]

cardiological drugs and RN and NP should be considered. evaluated sleep disturbances and found that OAB patients

Please cite this article in press as: Lombardo R, et al. Nocturia: The Complex Role of the Heart, Kidneys, and Bladder. Eur Urol Focus

(2019), https://doi.org/10.1016/j.euf.2019.07.007

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had a greater number of nighttime urinations than controls [2] Bower WF, Whishaw DM, Khan F. Nocturia as a marker of poor

health: causal associations to inform care. Neurourol Urodyn

did (2.6 Æ 1.1 vs 0.9 Æ 0.7; p < 0.001). The odds ratio for

2017;36:697–705.

having one or more nighttime urinations was 6.9 (95%

[3] Fitzgerald MP, Litman HJ, Link CL, et al. The association of nocturia

confidence interval [CI] 1.31–36.1) in the OAB group

with cardiac disease, diabetes, body mass index, age and diuretic

(94.0% vs 76.7%; p = 0.023). The odds ratio for having two

use: results from the BACH survey. J Urol 2007;177:1385–9.

or more nighttime urinations was 41.9 (95% CI 10.7–164.8)

[4] Sakalis VI, Karavitakis M, Bedretdinova D, et al. Medical treatment of

in the OAB group (86.0% vs 13.3%; p < 0.001) [14]. Although

nocturia in men with lower urinary tract symptoms: systematic

these associations are well demonstrated in the literature,

review by the European Association of Urology guidelines panel for

the exact pathophysiological mechanisms involved are still male lower urinary tract symptoms. Eur Urol 2017;72:757–69.

a matter of debate. [5] Everaert K, Hervé F, Bosch R, et al. International Continence Society

consensus on the diagnosis and treatment of nocturia. Neurourol

Urodyn 2019;38:478–98.

3.4. The heart, kidneys, and bladder in relation to nocturia

[6] Dani H, Esdaille A, Weiss JP. Nocturia: aetiology and treatment in

adults. Nat Rev Urol 2016;13:573–83.

The above evidence clearly suggests that the heart, kid-

[7] Feldstein CA. Nocturia in arterial hypertension: a prevalent, under-

neys, and bladder are important actors in the development reported, and sometimes underestimated association. J Am Soc

of RN/NP. Family physicians often underestimate the pres- Hypertens 2013;7:75–84.

ence of RN/NP as they do not identify the symptom, which [8] Perk G, Ben-Arie L, Mekler J, et al. Dipping status may be determined

–

is always considered during a urological consultation by nocturnal urination. Hypertension 2001;37:749 52.

[9] Fukuda M, Motokawa M, Miyagi S, et al. Polynocturia in chronic

[15]. When more than two nocturnal voids are identified,

kidney disease is related to natriuresis rather than to water diuresis.

use of a bladder diary is recommended to differentiate RN

Nephrol Dial Transplant 2006;21:2172–7.

from NP. The higher the number of nocturnal voids, the

[10] Agarwal R, Light RP, Bills JE, et al. Nocturia, nocturnal activity, and

higher is the risk of NP. In cases of NP, urologists should

nondipping. Hypertension 2009;54:646–51.

consider a diagnostic algorithm that includes a number of

[11] Weiss JP, Blaivas JG. Nocturnal polyuria versus overactive bladder in

systemic conditions affecting both the heart and the kid-

nocturia. Urology 2002;60:28–32.

neys [16]. Although RN/NP is often first diagnosed in a

[12] Chow P-M, Liu S-P, Chuang Y-C, et al. The prevalence and risk factors

urological consultation, a multidisciplinary approach is of nocturia in China, South Korea, and Taiwan: results from a cross-

warranted and must be part of the core curriculum in sectional, population-based study. World J Urol 2018;36:1853–62.

urological training. [13] Wen L, Wen YB, Wang ZM, et al. Risk factors of nocturia (two or

more voids per night) in Chinese people older than 40 years.

Neurourol Urodyn 2015;34:566–70.

Conﬂicts of interest: The authors have nothing to disclose. [14] Ge TJ, Vetter J, Lai HH. Sleep disturbance and fatigue are associated

with more severe urinary incontinence and overactive bladder

symptoms. Urology 2017;109:67–73.

References [15] Bower WF, Everaert K, Ong TJ, et al. Questions to ask a patient with

nocturia. Aust J Gen Pract 2018;47:465–9.

[1] Bosch JLHR, Everaert K, Weiss JP, et al. Would a new deﬁnition and [16] Oelke M, De Wachter S, Drake MJ, et al. A practical approach to the

classiﬁcation of nocturia and nocturnal polyuria improve our man- management of nocturia. Int J Clin Pract 2017;71:e13027. http://dx.

agement of patients? ICI-RS 2014. Neurourol Urodyn 2016;35:283–7. doi.org/10.1111/ijcp.13027.

Please cite this article in press as: Lombardo R, et al. Nocturia: The Complex Role of the Heart, Kidneys, and Bladder. Eur Urol Focus

(2019), https://doi.org/10.1016/j.euf.2019.07.007