Eur J Pediatr

DOI 10.1007/s00431-016-2729-3

REVIEW

The pathophysiology of monosymptomatic nocturnal enuresis

with special emphasis on the circadian rhythm of renal physiology
L. Dossche 1 & J. Vande Walle 1 & C. Van Herzeele 1

Received: 3 February 2016 / Revised: 15 April 2016 / Accepted: 25 April 2016

# Springer-Verlag Berlin Heidelberg 2016

Abstract Nocturnal polyuria in monosymptomatic noctur-

nal enuresis (MNE) has so far mainly been attributed to a What is Known:
disturbed circadian rhythm of renal water handling. Low • Disturbance in the circadian rhythm of arginine vasopressin secretion is
vasopressin levels overnight correlate with absent maxi- related to nocturnal polyuria in children with enuresis.
mal concentrating activity, resulting in an increased noc- • Desmopressin is recommended as a treatment for monosymptomatic
nocturnal enuresis, working as a vasopressin analogue acting on V2
turnal diuresis with low urinary osmolality. Therefore, receptors in the collecting ducts of the kidney.
treatment with desmopressin is a rational choice. What is New:
U n f o r t u n a t e l y, 2 0 t o 6 0 % o f c h i l d r e n w i t h • Other renal circadian rhythms might play a role in nocturnal polyuria,
monosymptomatic enuresis are desmopressin-resistant. especially in desmopressin-resistant case.
There is increasing evidence that other disturbed circadian
rhythms might play a role in nocturnal polyuria. This re-
view focuses on renal aspects in the pathophysiology of Keywords Enuresis . Pathophysiology . Renal . Children .
nocturnal polyuria in MNE, with special emphasis on cir- Circadian rhythm
cadian rhythms. Articles related to renal circadian
rhythms and enuresis were searched through the
PubMed library with the goal of providing a concise Abbreviations
review. AVP Arginine vasopressin
Conclusion: Nocturnal polyuria can only partially be ex- DDAVP Desmopressin
plained by blunted circadian rhythm of vasopressin secretion. EBC Expected bladder capacity
Other alterations in the intrinsic renal circadian clock system FBC Functional bladder capacity
also seem to be involved, especially in desmopressin-resistant GFR Glomerular filtration rate
enuresis. ICCS International Children’s Continence Society
LUT Lower urinary tract
MVV Maximum voided volume
MNE Monosymptomatic nocturnal enuresis
NMNE Non-monosymptomatic nocturnal enuresis
NP Nocturnal polyuria

Communicated by Mario Bianchetti

Introduction on pathogenesis of monosymptomatic
* L. Dossche nocturnal enuresis
lien.dossche@ugent.be
Enuresis or Bbedwetting^ means micturition during sleep in a
1
Department of Paediatric Nephrology, Ghent University Hospital, De child of at least 5 years old, the age at which bladder control
Pintelaan 185, 9000 Ghent, Belgium should have achieved [4]. Prevalence rate is estimated at 5–

10 % at the age of 7 years and 0.5–1 % during adulthood [6,
22, 78, 80]. It occurs more frequently in boys than girls, al-
though this difference tends to diminish after the age of
10 years. Historically, it was believed that this Bbenign^ dis-
order would disappear spontaneously with aging. However, a
significant proportion of children remain enuretic when un-
treated, especially those with severe enuresis [78]. Enuresis
has a major psychological impact on both the child and its
family [7]. Therefore, patients deserve an individualised ap-
proach adjusted to the underlying pathophysiology. Moreover,
alertness for possible comorbidities are important, like bowel
dysfunction [5], psychological disorders [69] and sleep prob-
lems [13, 14], since they might play a significant role in path-
ogenesis and therapy resistance.
According to the International Children’s Continence
Society (ICCS), enuresis is classified as
monosymptomatic nocturnal enuresis (MNE) or non-
MNE. The latter is defined as enuresis concomitant with
daytime incontinence and/or lower urinary tract (LUT)
symptoms, such as urgency, holding manoeuvres or
decreased/increased voiding frequency, and is beyond
the scope of this review [46].
MNE is mainly characterized by enuresis in the ab-
sence of daytime symptoms. It occurs when there is a
mismatch between the bladder capacity and nocturnal di-
uresis, in a child that does not wake up in response to a
full bladder.
a. The role of the bladder
For a long time, voiding and bladder volume was
believed to be normal in children with MNE.
Expected bladder capacity (EBC) increases with age
at a rate of less than 30 mL/year according to the
Hjalmas formula ((age + 1) × 30 mL), reaching a max-
imum at the age of 12 [29, 37]. Clinically, an estimate
of daytime bladder capacity can be obtained by mea-
suring maximum voided volume (MVV). Home re-
cordings of fluid intake and voids using frequency/
volume charts besides MVV measurements are useful
to differentiate between MNE and non-MNE [28, 72].
However, there is growing evidence that an isolated
reduced nocturnal functional bladder capacity might
be one of the causes, despite a normal expected blad-
der capacity for age and the absence of LUT symp-
toms at daytime [63, 79]. Moreover, in a group of
children with MNE, incomplete bladder emptying oc-
curred just as frequently as complete bladder empty-
ing, during enuresis episodes [27]. The initial reports
identifying this pathology were based on cystometric
measurements overnight, leaving a doubt on the po-
tential bias of a catheter in situ [76]. However, the
Aarhus group recently confirmed this phenotype,
based on bladder diaries [Borg B, Kamperis K,
Eur J Pediatr
Rittig S Isolated reduced nocturnal bladder reservoir
function—a new type of nocturnal enuresis. Presented
at the 26th ESPU congress].
Meta-analysis of the literature on the possible role
of the bladder in the pathophysiology of MNE re-
mains difficult since the majority of studies that took
place before the ICCS classification of 2006 was used.
This resulted in an important overestimation of the
number of children with MNE, because LUT symp-
toms were previously not taken into account.
b. Central nervous system: arousal
Many parents of children with enuresis reported that
their children are Bdeep sleepers^ and very difficult to
wake up, leading to the assumption that the Babsence of
arousal^ had to be the major pathophysiological factor.
However, the importance of Bdeep sleep^ has to be
questioned for multiple reasons. There is no evidence in
the literature demonstrating that children have to pass
through a phase of nocturia to acquire night-time conti-
nence. Moreover, sleep EEG patterns failed to document
increased Bdeep^ sleep phase in enuretic children [3, 77].
Recently, an increased cortical arousal together with a
disrupted sleep architecture and a higher incidence of pe-
riodic limb movement in sleep (PLMS) was found in en-
uretic children [13, 14]. Together, the observation that an
anti-diuretic/anti-enuretic therapy (desmopressin) amelio-
rated sleep pattern and associated neurocognitive dys-
functions suggests a common central pathogenetic path-
way [70]. However, the specific role of the central ner-
vous system is not yet clear.
c. Nocturnal polyuria
Nocturnal polyuria is defined by the ICCS as nocturnal
diuresis exceeding more than 130 % of EBC. The increase
of nocturnal diuresis is classically attributed to a disturbed
circadian rhythm of vasopressin secretion, leading to de-
creased plasma level overnight [58, 61]. Therefore, treat-
ment with desmopressin (DDAVP) was suggested, a va-
sopressin analogue acting on V2 receptors in the
collecting ducts of the kidney. Because of the high re-
sponse rate in the initial studies, this therapy is recom-
mended by the International Continence Society (grade
A, level 1) for children with MNE.
However, there is increasing evidence also that oth-
er disturbed day/night rhythms are involved in patho-
genesis. The day/night rhythm of physiological mech-
anisms in humans is a well-established phenomenon,
including sleep, physical activity, secretion of hor-
mones and intermediate metabolism. The term circa-
dian is used to denote these mechanisms that occur
with an approximately 24-h rhythm. This review fo-
cuses on renal aspects in the pathophysiology of noc-
turnal polyuria in MNE, with special emphasis on cir-
cadian rhythm.
Eur J Pediatr
Circadian rhythm in kidney physiology
The circadian rhythm is driven by a self-sustained circadian
pacemaker (central clock), which is located in the suprachias-
matic nucleus of the hypothalamus in the brain.
It conducts a system of individual cellular oscillators and is
synchronised by environmental changes, also called
Bzeitgebers^, such as the light/dark cycle, temperature chang-
es and metabolic flux related to feeding [50].
Besides this central clock, there are peripheral clocks locat-
ed in nearly every cell type and tissue of the body [54].
Recently, research has revealed the role of peripheral clocks
in the kidney in the regulation of renal function and blood
pressure [65]. Despite all these insights in the circadian
rhythm, the mechanism of synchronization between the cen-
tral and peripheral clocks is still being determined. However,
neuronal (autonomous nervous system) and humoral (melato-
nin, cortisol) signals from the suprachiasmatic nucleus are
likely to play a key role [15].
A diurnal rhythm of renal functions was first described in
the nineteenth century, as significant circadian oscillations of
urinary excretion of water and urea were shown [62]. Later
studies in rodents and humans confirmed that most, if not all,
renal functions exhibit circadian oscillations. For example,
glomerular filtration rate (GFR) and renal blood flow are os-
cillating in phase with rhythms of urinary excretion of all
major electrolytes [51, 71]. The origin of renal circadian
rhythms has been attributed to the reactive response of the
kidney to circadian changes of several factors, such as secre-
tion of hormones or changes in blood pressure, entrained by
rest/activity and feeding/fasting cycles. Analysis of circulating
factors revealed that blood levels of vasopressin, aldosterone
and many other hormones responsible for maintaining water
and electrolyte balance also exhibit circadian oscillations [31].
However, even in the absence of periodic environmental stim-
uli, most of the renal excretory rhythms persist for long pe-
riods of time [43]. Moore-Ede noted that circadian cyclic ex-
cretion constituted a Bpredictive^ homeostatic system that en-
hanced the capacity of the nephron to perform its reactive
response during the times of the 24-h cycle, when there is an
increase of fluid and food intake [44]. The molecular basis of
this mechanism remained unknown until the discovery in
mouse models of molecular clockworks, working autono-
mously in each cell through a transcriptional/translational
feedback loop operated by a set of Bclock genes^ and their
encoded proteins which have been found in all tissues studied,
including the kidney [18, 21]. The discovery of the molecular
circadian timing system allowed major advance in the under-
standing of the origin of renal excretory rhythms and their
potential role in pathophysiology. Until now, clear evidence
is lacking to proof that this intrinsic clock of the kidney may
play a role in the pathogenesis of enuresis. Nevertheless, there
are many reasons to investigate this hypothesis. Increased
sodium retention in children during daytime coincides with
nocturnal polyuria in children [53]. Furthermore, a molecular
link was shown between the circadian clock gene Per1 and
ENaC, an epithelial sodium channel in the collecting duct,
suggesting a direct role of the circadian rhythm in diuresis
and sodium handling [26]. If nocturnal polyuria is partially
caused by a disturbed circadian rhythm of sodium handling,
this could explain therapy resistance to desmopressin, as it
mainly works on water balance.
Insights into nocturnal polyuria: the role of blunted
renal circadian rhythms
Nocturnal polyuria: Bthe vasopressin theory^
Impaired circadian rhythms are increasingly being identified
as a cause of nocturnal polyuria, both in patients with noctur-
nal enuresis and nocturia [25, 73]. Maturation of the circadian
rhythm of vasopressin levels in childhood influences the cir-
cadian rhythm of the urine production, resulting in a nocturnal
diuresis rate up to approximately 50 % of daytime levels. Low
vasopressin levels overnight correlate with absent maximal
concentrating activity, resulting in an increased nocturnal di-
uresis with low urinary osmolality [49, 58, 61].
Although the vasopressin theory as a cause of nocturnal
polyuria is widely accepted, we cannot deny that there are
several uncertainties.
First of all, the ICCS definition for nocturnal polyuria
based on nocturnal diuresis exceeding 130 % of EBC is only
expert opinion-based. A population-based study showed that
the 97.5th percentile line of nocturnal urine volume excluding
nocturia is similar to the current ICCS formula only around the
age of 7 to 8 years but deviates significantly at lower and
higher ages [56].
Secondly, DDAVP response does not prove that the low
vasopressin levels overnight are the primary cause leading to
nocturnal polyuria and other associated phenomena. The de-
fect circadian rhythm of AVP could also be a secondary phe-
nomenon of abnormal circadian homeostasis including neuro-
transmitters, sleep, other vasoactive hormones, blood pressure
and renal functions.
Furthermore, the circadian rhythm of diuresis is acquired in
toddlers and young children, reaching a maximum in adoles-
cents and young adults but is already regressing progressively
in adults. Consequently, adult literature on nocturia and noc-
turnal polyuria is using totally different definitions and refer-
ence values and might be related to other pathogenetic mech-
anisms [25].
Moreover, there is a night-to-night variation in nocturnal
diuresis, making nocturnal polyuria only present intermittent-
ly. Urine output on dry nights is lower than that during wet
nights [55, 64], complicating a clinical trial design to study the

pathogenesis in MNE patients, since it is impossible to predict
when a wet night will occur to perform renal function tests.
Finally, not every child with MNE has nocturnal polyuria
and not every child with nocturnal polyuria responds to
DDAVP therapy. The reported incidence of DDAVP-
resistant MNE, defined as a reduction of less than 50 % of
the number of wet nights, is varying between 20 and 60 %.
It is assumed that this large number of therapy resistance is
an overestimation, since many patients were studied in tertiary
centres or they are actually non-monosymptomatic nocturnal
enuresis (NMNE) patients, according to the new ICCS
standardisation [24, 47].
a. Desmopressin-resistant monosymptomatic enuresis
DDAVP-resistant enuresis can be subdivided into three
archetypes. Although there is a certain continuum and
some patients might have a combination of characteristics,
this subtyping helps to understand the underlying patho-
physiology and to guide a more individualised therapeutic
approach. The first type is characterized by a lack of anti-
enuretic effect despite appropriate anti-diuretic effect and
disappearing of the nocturnal polyuria. In this subtype, a
missed underlying bladder dysfunction, such as isolated
nightly bladder overactivity, remains the most likely diag-
nosis. The second and third archetypes are linked to
DDAVP-resistant nocturnal polyuria, without or with
maximal concentrated urine. DDAVP results here often
in a significant decrease of nocturnal diuresis rate, but
without reaching values lower than the bladder volume
for age.
b. Desmopressin-resistant nocturnal polyuria
Prevalence of DDAVP-resistant nocturnal polyuria is
unknown, because nocturnal diuresis rate during therapy
is rarely reported, but the incidence must definitely have
been underestimated so far.
Persistent nocturnal polyuria can be due to insufficient
or suboptimal concentrating activity or can occur despite
maximal concentrating activity. Insufficient concentrated
urine cannot be explained by a lack of circulating vaso-
pressin or DDAVP alone. Other explanations can be ab-
normalities in the vasopressin receptor, mild chronic kid-
ney disease or kidney tubulopathies, that lead to
a concentration disorder.
However, we might not underestimate a lack of adher-
ence. It is obvious that a drug can only work when the
patient takes the drug, and even in motivated parents and
children, only 70 % is adherent to the therapy [68].
Furthermore, adherence means also taking the drug at
the right moment and under the best possible circum-
stances. Advice is to take DDAVP at least 1 h before the
last void/sleeping time on an empty stomach and avoiding
fluid intake 1 h before drug administration until the next
morning [9, 74]. The poor bioavailability with large intra-
Eur J Pediatr
and interindividual variability could play also an impor-
tant role [8].
If there is persistent nocturnal polyuria despite maxi-
mal concentrating activity, this correlates not only with
increased free water clearance but also with increased
solute excretion overnight [12, 35].
Other pathogenetic mechanisms inducing nocturnal
polyuria, such as disturbed circadian rhythms in the kid-
neys, might play a role in children with DDAVP-resistant
MNE. Circadian rhythm disturbance of renal solute han-
dling, vasoactive hormones and glomerular filtration rates
were revealed in these children, but until now, none of
these mechanisms are proven causal or comorbid [16,
35, 45].
Nocturnal polyuria: Bthe non-vasopressin theory^
The importance of investigating renal circadian rhythms in
nocturnal polyuria is undeniable, especially in DDAVP-
resistant cases. There is increasing evidence for blunted renal
circadian rhythms in patients with nocturnal polyuria, for ex-
ample the renal solute handling [12, 35] and GFR [11, 16].
The hormones governing solute and water handling in the
kidney, aldosterone and angiotensin II, might also be involved
[59]. Furthermore, a higher excretion of prostaglandin E2
(PGE2) was found in children with disturbed circadian rhythm
of diuresis [41].
a. Renal solute handling
Abnormally high nocturnal excretion of solutes, in par-
ticular sodium, leading to an inverse circadian rhythm is
observed in children with nocturnal polyuria [35, 40, 59].
Several studies demonstrate a subgroup of patients with
nocturnal polyuria and increased sodium excretion [1, 12,
36, 66]. Increased solute excretion overnight can be relat-
ed to an increased 24-h sodium load or abnormal circadian
rhythm of sodium handling. A subgroup of children
showed a 24-h higher excretion of sodium, most sugges-
tive for a higher dietary intake of salt [12]. However, other
studies found an isolated higher excretion of solutes over-
night in these children, explained by the change in ion
reabsorption in the thick ascending loop of Henle [12,
45, 73].
Several suggestions to explain this phenomenon have
been considered. Hypothetically, primary sodium reten-
tion during the daytime could cause hypervolaemia at
night and thereby suppression of all vasoactive hormones
leading to high sodium excretion [19, 48]. Furthermore,
several treatments targeting decreased sodium excretion
overnights were successful in the treatment of MNE.
First of all, imipramine was demonstrated to reduce noc-
turnal polyuria by decreasing nocturnal solute excretion
Eur J Pediatr
[30]. Secondly, diclofenac associated with DDAVP was
shown to decrease nocturnal polyuria [41]. Finally, furo-
semide in the morning decreased sodium excretion over-
night, resulting in subsequent desmopressin response
[10].
Whether the higher nocturnal sodium excretion could
explain DDAVP resistance remains to be elucidated.
Moreover, DDAVP seems to have anti-natriuretic proper-
ties independent of sodium-regulating hormones [36].
Hypercalciuria has also been suggested as a mecha-
nism for nocturnal polyuria, although further research
showed that these observations were secondary to nutri-
tional intake and renal sodium handling [52, 66, 67].
b. Vasoactive hormones and prostaglandins
The hormones governing renal solute and water han-
dling (renin, aldosterone, angiotensin II and atrial natri-
uretic peptide (ANP)) could play a role in nocturnal poly-
uria. An increase of nocturnal sodium excretion in com-
bination with an attenuated rhythm in plasma angiotensin
II and mean arterial blood pressure was shown [59, 60].
Since the glomerular filtration was normal in these
studies, this was explained as a decreased tubular reab-
sorption of sodium [59]. These renal tubular changes in
electrolyte handling might be attributable to the observed
suppressed levels of plasma angiotensin II [60]. No ab-
normality in circadian rhythm of aldosterone has been
documented thus far [35]. An abnormal increase of ANP
in children with obstructive sleep apnoea (OSA) has been
observed [38]. However, unless OSA occurs, ANP has
never been related to nocturnal polyuria seen in enuresis
and does not account for a circadian rhythm in sodium
excretion [57]. A higher urinary excretion of the major
renal autacoid PGE2 was found in children with
DDAVP-resistant nocturnal enuresis [33, 35, 41].
Remarkably, PGE2 has an antagonistic effect on arginine
vasopressin, which counteracts the renal concentrating
properties [2]. Furthermore, NSAIDs and prostaglandin
synthetase blockers which reduce urinary solute excretion
by prostaglandin synthesis inhibition seem to have not
only an anti-diuretic but also anti-enuretic effect, suggest-
ing a pathophysiological role in enuresis [34]. This could
also influence GFR and renal perfusion.
The importance of a disrupted circadian rhythm of
blood pressure in children with enuresis has been shown.
Hypertension, and especially lack of night-time dipping,
coincides with nocturnal polyuria, with increased sodium
excretion, and lack of circadian rhythm of renal functions
[39]. Children with enuresis have higher blood pressures
overnight. Even more, a link between disrupted sleep and
hypertension is shown in children and adults [32, 42].
The finding of higher blood pressure overnight could
be related to night-time alternations of the autonomic ner-
vous system. Adrenergic stimulations leads to renin
release, renal vasoconstriction, GFR changes and anti-di-
uresis. Although the autonomous nervous system is only
marginally examined in children with enuresis, a para-
sympathetic hyperactivity was shown [23, 75].
However, in contrast, a sympathetic system hyperfunction
was also suggested [17]. Higher nocturnal blood pressure
hypothetically might then be induced by increased noc-
turnal sympathetic activity.
c. Glomerular filtration rate
Circadian rhythm of GFR is a well-known physiolog-
ical process in humans. GFR decreases to 15 to 30 %
overnight, independent of circulating vasoactive hor-
mones [11]. A potential role of a blunted rhythm of GFR
in MNE remains unclear because of conflicting data [11,
16, 35, 57]. Rather than a primary error, GFR hypotheti-
cally may fail to decrease overnight due to persistent mo-
bilization of functional renal reserve capacity.
Theoretically, it can be a primary phenomenon but is most
likely secondary, where mobilization of interstitial fluid
and sodium, together with an increased osmotic load,
leads to hypervolaemia. This could lead to an increased
blood pressure and hyperfiltration, all resulting in an in-
creased nocturnal osmotic excretion in these children.
A normal kidney has a functional renal reserve capacity
than can be mobilized by dopamine, amino acid perfusion,
protein load and osmotic load [20]. Although such a per-
sistent functional renal reserve capacity mobilization
overnight is a tempting theory for patients with high over-
night osmotic excretion, evidence in humans remains ab-
sent [11]. Otherwise, furosemide in the morning in
desmopressin-resistant children with maximal concentrat-
ed urine resulted in significantly lower nocturnal diuresis
rates, making this theory more likely [10]. Furthermore,
increased nocturnal blood pressure observed in enuretic
children with polyuria was speculated to be related to
blunted circadian rhythm of GFR [39].
Conclusion
For decades, nocturnal enuresis has been considered as a be-
nign maturation defect with spontaneous cure. It is now evi-
dent that enuresis is a complex disorder, involving multiple
pathogenetic factors. In primary care, it is rational to restrict to
a simple protocol, differentiating into MNE and NMNE pa-
tients, leading to a rational therapeutic approach. In MNE
patients, the treatments of choice are desmopressin and the
alarm; in NMNE, we should target the bladder. But up to
one third of patients will turn out to be therapy-resistant to
this initial approach. Bladder dysfunction has been identified
as a key factor in therapy resistance, but the involvement of
the kidney has been underestimated so far. Nocturnal polyuria

can only partially be explained by blunted circadian rhythm of
vasopressin secretion. Other alterations in the intrinsic renal
circadian clock system also seem to play a role, especially in
DDAVP-resistant nocturnal polyuria. Hypothetically, these al-
terations could cause increased nocturnal blood pressure by
changes in the autonomic nervous system with subsequent
suppression of vasopressin and sodium-regulating hormones
as well as increased GFR, resulting in increased renal excre-
tion of solutes and water [39]. Further studies are needed to
confirm this hypothesis, although studying renal circadian
rhythms in these children with DDAVP-resistant nocturnal
polyuria remains very challenging due to small study popula-
tions and difficult study design.
Author’s contributions L. Dossche performed the literature search,
drafted the initial manuscript and revised the subsequent drafts.
J. Vande Walle critically reviewed the drafts.
C. Van Herzeele conceptualized the study and critically reviewed and
revised the manuscript.
All authors approve the final manuscript as submitted.
Compliance with ethical standards
Funding This study was funded by the BAgency for Innovation by
Science and Technology in Flanders (IWT)^ through the BSAFE-
PEDRUG^ project (IWT-SBO 130033).
Conflict of interest L. Dossche declares that she has no conflict of
interest. J. Vande Walle is a lecturer, investigator and advisor for the
Ferring Pharmaceuticals (no conflict of interest). C. Van Herzeele de-
clares that she has no conflict of interest.
Ethical approval This article does not contain any studies with human
participants or animals performed by any of the authors.
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