Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 277e288

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Best Practice & Research Clinical

Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem

Renal aquaporins and water balance disorders

Hanne B. Moeller, MD PhD, Associate Professor,
Cecilia H. Fuglsang, BSc, Medical Student,
Robert A. Fenton, PhD, Professor of Molecular Cell Biology *
Department of Biomedicine and Center for Interactions of Proteins in Epithelial Transport, Aarhus University,
Denmark

a r t i c l e i n f o
Aquaporins (AQPs) are a 13 member family (AQP0-12) of proteins
Article history: that act as channels, through which water and, for some family
Available online 2 March 2016 members, glycerol, urea and other small solutes can be trans-
ported. Aquaporins are highly abundant in kidney epithelial cells
Keywords: where they play a critical role with respect to water balance. In this
aquaporin review we summarize the current knowledge with respect to the
vasopressin localization and function of AQPs within the kidney tubule, and
water balance their role in mammalian water homeostasis and the water balance
nephrogenic diabetes insipidus disorders. Overviews of practical aspects with regard to differential
NDI
diagnosis for some of these disorders, alongside treatment stra-
concentrating mechanism
tegies are also discussed.
thiazide
water retention 2016 Elsevier Ltd. All rights reserved.

Introduction

Aquaporins (AQPs), facilitate regulated water transport. In the kidney, which plays a critical role in
regulation of body water balance, numerous AQPs are expressed in the renal tubules (AQP1-8 and
AQP11). However, only AQP1-4 and AQP7 have been proposed to play any role in body water balance
and are the focus of this review (see [1] for alternative roles of AQPs in the kidney). Aided by the os-
motic gradient generated by active NaCl transport in the thick ascending limbs and countercurrent
multiplication, AQPs transport water across the tubular epithelium into the interstitium, thereby
maintaining blood osmolality under varying degrees of water intake [2]. Dysfunction of several of these

 3,
* Corresponding author. Department of Biomedicine, Aarhus University, Building 1233, Room 213, Wilhelm Meyers Alle
8000 Aarhus C, Denmark.
E-mail address: robert.a.fenton@biomed.au.dk (R.A. Fenton).

http://dx.doi.org/10.1016/j.beem.2016.02.012
1521-690X/ 2016 Elsevier Ltd. All rights reserved.
278 H.B. Moeller et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 277e288

AQPs results in clinical conditions where body water balance is altered. This review provides an
overview of what is currently known about renal AQPs and water balance disorders.

Aquaporin 1 (AQP1)

In the kidney, AQP1 is expressed constitutively in apical and basolateral membranes of renal tubular
cells in the proximal tubule and descending thin limb of Henle in long looped nephrons where it re-
absorbs the vast majority of ltered water [3]. AQP1 is also expressed in the vasa recta [4]. Although
AQP1 trafcking or expression is not altered by the antidiuretic hormone arginine vasopressin (AVP)
[5], deletion of AQP1 in mice causes severe polyuria (reviewed in [6]). However, humans lacking Colton
blood antigens have defective AQP1, and these individuals are asymptomatic and only present with a
mild urinary concentrating defect following water restriction [7]. Although the role of AQP1 in human
kidney epithelial cells appears to be relatively minor, AQP1 is also expressed in kidney endothelial cells
[4]. Of particular importance is the expression of AQP1 in the endothelium lining peritoneal capillaries
[8], where it facilitates osmotically driven water transport during peritoneal dialysis. Peritoneal dialysis
is a technique of renal-replacement therapy that is frequently used to restore water balance in patients
with end-stage renal disease (reviewed in [9]). Enhancement of AQP1 function increases water
transport across the peritoneal membrane, suggesting that pharmacological targeting of AQP1 would
be benecial in treatment of end-stage renal disease.

Aquaporin 2 (AQP2)

AQP2 is expressed in the principal cells of the kidney connecting tubule and collecting duct [10],
where its apical membrane expression is regulated by AVP. In the kidney, AVP binds to the basolateral
G-protein coupled type II AVP receptor (V2R), resulting in increased intracellular cAMP levels and
altered intracellular signaling. This altered signaling results in regulated trafcking of AQP2 to the
plasma membrane, and in the long term, increased AQP2 abundance [11,12]. Combined, these pro-
cesses greatly increase water reabsorption. As V2R-mediated regulation of AQP2 plays a pivotal role in
regulated water transport by the kidney, a large proportion of this article focuses on their role in water
balance disorders (see later).

Aquaporin 3 (AQP3)

AQP3 is localized at the basolateral membrane of collecting duct principal cells and is permeable to
both glycerol and urea [13]. Chronic AVP exposure increases AQP3 abundance [14]. Mice lacking AQP3
are polyuric, but have a partial ability to increase urine concentration in response to desmopressin
(DDAVP) (reviewed in [6]).

Aquaporin 4 (AQP4)

In the kidney, AQP4 is localized mainly at the basolateral membrane of inner medulla collecting
duct cells (IMCD) [15]. Long-term AVP exposure can increase AQP4 levels, but there are differential
effects along the collecting duct system [16]. AQP4 knockout mice have a mild urinary concentrating
defect, despite AQP4 being the major exit route for water in the IMCD (reviewed in [6]). AQP4 has the
ability to form orthogonal arrays, which are proposed to be regulated differently and have different
water permeabilities [17].

Aquaporin 7 (AQP7)

AQP7 is localized in the late proximal tubule brush border, where it facilitates glycerol and water
transport [14]. AQP7 knockout mice have no defect in urinary concentrating ability, but have increased
urinary glycerol, suggesting that the primary function of AQP7 is to scavenge glycerol from the preurine
[18]. However, mice with combined deletion of AQP1 and AQP7 have a reduced urinary concentrating
 H.B. Moeller et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 277e288 279

ability compared with AQP1 knockout mice, suggesting that the amount of water reabsorbed through
AQP7 is physiologically substantial.

The role of the V2R and AQPs in conditions with loss of body water

Diabetes insipidus (DI)

DI is a clinical condition characterized by polyuria, polydipsia and hypotonic urine (reviewed in
[19]). The main causes for DI are 1) central DI (CDI) due to decient AVP production, 2) nephrogenic DI
(NDI) due to a defective response by the kidney to AVP, 3) gestational DI due to AVP degradation, and 4)
psychogenic DI due to excessive uid intake (primary polydipsia). NDI is further classied as inherited
or acquired due to other clinical conditions or adverse effects to various drugs.

Diagnosis of DI. Measurements of urine volume and osmolality are critical for the diagnosis of DI,
although there are great variations in these parameters among patients. Although the patient history
can facilitate discrimination of the underlying cause (presentation time in life, head trauma, pregnancy
etc.), additional tests are required to make a precise diagnosis and to determine the correct therapeutic
approach. For example, MRI of the brain can aid differentiation between CDI and primary polydipsic DI.
Other tests include:

1) Desmopressin (DDAVP) challenge The administration of DDAVP can discriminate between CDI and
NDI [20]. Urine osmolality is assessed after administration of the V2R-selective agonist DDAVP to
the patient (intranasal, subcutaneous, intravenous). In normal individuals, or in CDI cases, urine
osmolality increases. Although the short duration of this test is an advantage, careful interpretation
of results in infants is required due to complicating factors (discussed in [20]) (Chapter 12).
2) Water deprivation test: Water deprivation is used to discriminate between CDI and NDI if the patient
presents with equivocal biochemical ndings [20]. Fluid is initially withheld from the patient (due
to the risk of dehydration this test should only be performed under supervision) accompanied by
frequent assessment of their hydration status (body weight, urine and plasma osmolality). This is
followed by administration of DDAVP and assessment of urine osmolality, which will increase in CDI
patients.
3) Plasma AVP and Copeptin analysis: AVP shares a precursor peptide consisting of a signal peptide,
AVP, neurophysin II and copeptin. Plasma AVP levels are measured under basal conditions, during
uid deprivation, and/or during hypertonic saline infusion alongside with measurements of
plasma and urine osmolality. If the plasma AVP levels increase with no alterations in urine
osmolality, this is indicative of NDI. If the levels of AVP are normal/high during osmotic stimu-
lation relative to plasma osmolality, the ndings indicate that the patient does not have CDI.
However, the value of measuring plasma AVP has been questioned due to various factors,
including the low half-life of AVP in isolated plasma or the overestimation of AVP levels in plasma
contaminated by platelets [21]. An alternative to measuring plasma AVP is measurement of
copeptin levels (Chapter *), which are stable in plasma and released together with AVP during
processing. Thus, copeptin is a potential marker of AVP production, with its levels in the plasma
correlating with AVP levels [21].

Practice points/research agenda

Care should be taken in the interpretation of plasma AVP levels when discriminating between
CDI and NDI.

Copeptin may in the future be an alternative to estimate AVP production, but care should be
taken in the presence of comorbidities since the correlation is distorted (e.g. in chronic kidney
disease).
280 H.B. Moeller et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 277e288

Congenital NDI
Congenital NDI is rare and present from birth. It results from loss of function mutations in the genes
encoding the V2R (AVPR2 gene) or AQP2 (AQP2 gene). In severe cases with a delayed diagnosis, suc-
cessive episodes of dehydration can cause mental retardation and, due to the polyuria, a trabeculated
bladder and hydronephrosis. Partial forms of congenital NDI exist where the patient is to some degree
able to concentrate urine. Other inherited diseases associated with NDI, so called inherited secondary
NDI, include Bartter syndrome, syndrome of apparent mineralocorticoid excess, renal Fanconi syn-
drome, distal renal tubular acidosis, cystic kidney disorders and familial hypomagnesemia with
hypercalciuria and nephrocalcinosis (reviewed in [22]).
Mutations in the AVPR2 gene: Mutations in the AVPR2 gene cause NDI [23]. As the gene is on the X
chromosome, this form of NDI is often referred to as X-linked NDI (XNDI), although females can oc-
casionally be affected due to skewed X-inactivation (reviewed in [19]) (Chapter *). More than 200
mutations in the AVPR2 have been reported [19], 90% of which cause congenital NDI in males [20].
Mutations in the V2R result in complete or partial disruption of downstream signaling, although the
mechanisms vary [24]. Gene deletions or re-arrangements in the adjacent L1CAM gene can also result
in NDI [25]. V2R-mediated signaling can also be interrupted by indirect means (discussed in [26]),
including targeting of the V2R to the primary cilia at the apical side of principal cells [27].

Practice points/research agenda

Pay attention to the clinical characteristics of female carriers since the presence of NDI in
these patients can occasionally occur.

Mutations in the AQP2 gene: 10% of congenital NDI cases are due to mutation in the AQP2
gene, with more than 50 mutations currently reported [19]. Mutations are usually inherited in
an autosomal recessive way, although dominant mutations have been observed (Chapter *).
Different mutations cause dysfunctional AQP2 by different mechanisms, including mis-sorting
of the protein or reducing water transport capacity of the channel [28].

Acquired NDI
Acquired NDI, often arising due to reduced AQP2 abundance/function, is a common complication of
other clinical conditions. For example, various drugs, antifungal agents or antibiotics have the potential
to cause NDI. These include amphotericin B, tetracyclines, dexamethasone, dopamine, ifosfamide,
ooxacin, orlistat and cisplatin (reviewed in [19]). Although rare, acquired NDI can also result from
hypergammaglobulinemia [29]. Common causes of acquired NDI include:

Lithium treatment. Lithium is a common and efcient treatment for patients with bipolar mood disor-
ders. However, lithium can be nephrotoxic and result in NDI within 8 weeks of treatment initiation. The
prevalence of lithium induced NDI (Li-NDI) varies between 20 and 87% [30]. Although upon removal of
therapy the condition is reversible, prolonged treatment can result in irreversible effects, including
chronic kidney disease (CKD) and hypercalcemia [30]. In the kidney, lithium is freely ltered; with up to
80% reabsorbed in the proximal tubule and a small fraction reabsorbed by the collecting duct [31].
Although studies in humans are limited (see below), a variety of studies in rodents have contributed to
our understanding of the molecular basis for the disease. Lithium enters the AQP2 containing collecting
duct principal cells via the apical epithelial sodium channel (ENaC) [32], resulting in a severe decrease in
AQP2 abundance [33e35]. Lithium treatment also changes the cellular composition of the collecting
duct by decreasing the fraction of principal cells relative to intercalated cells [35], a process that is
reversible upon lithium withdrawal [36]. The altered ratio of principle to intercalated cells during
lithium therapy may result from arrest of principal cell proliferation in late G2 phase [37]. Transition
 H.B. Moeller et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 277e288 281

from intercalated cells into principal cells upon lithium withdrawal has also been proposed [36]. As
treatment with rapamycin, an inhibitor of mTOR, can prevent lithium-induced proliferation [38], it is
likely that the concentrating defect in Li-NDI is not a direct consequence of collecting duct remodeling.
How lithium therapy reduces AQP2 abundance and/or causes NDI is still unclear; but the effects are
likely multifactorial. Lithium therapy affects expression of a number of proteins in the collecting duct
[39], of which some are potentially directly involved in urine concentration such as AQP3 [33] and urea
transporters [34]. Furthermore, lithium is an inhibitor of glycogen synthase kinase type 3b (Gsk3b) [39]
and Gsk3b collecting duct knockout mice have an impaired urinary concentrating ability [40]. Other
potential factors include an effect of lithium on prostaglandin PGE2 levels (reviewed in [41]). Studies in
humans on long-term treatment with lithium conrmed the effects on AQP2 abundance; e.g., subjects
treated with lithium for 4 weeks showed a decreased ability to respond to DDAVP and concentrate urine
combined with reduced urinary AQP2 and cAMP excretion [42].

Hypokalemia. Although long-term potassium deprivation decreases expression of AQP2 alongside an

increase in urine production [43], this decrease in AQP2 and the subsequent urinary concentrating
defect can precede the onset of hypokalemia in rodent models [44]. Furthermore, in humans, although
conditions associated with tubular hyperkalemia can be accompanied by urinary concentrating de-
fects, e.g. Fanconi syndrome, low plasma potassium values do not necessarily result in secondary NDI
[22]. Mechanisms underlying hypokalemia-induced NDI include reductions in the tonicity of the
medullary interstitium and changes in expression pattern of a number of transporters important for
urinary concentration such as NKCC2 and ROMK (reviewed in [45]).

Hypercalcemia. In humans, a link between hypercalcemia and NDI is supported by studies in various
animal models of hypercalcemia [46], which present with reduced AQP2 expression and increased
urine volume. The mechanism underlying the decreased AQP2 abundance is proposed to occur via the
hypercalciuria that accompanies the hypercalcemia. Hypercalciuria exposes the calcium sensing re-
ceptor (CaSR) on the apical membrane of principal cells [47] to high Ca2 concentrations. Activation of
the CaSR results in decreased sensitivity of the cells to AVP [48], resulting in decreased plasma
membrane targeting of AQP2 [49] and ultimately decreased water permeability [50]). However,
although hypercalciuric patients have impaired AQP2 targeting to the membrane following AVP
stimulation [51], patients with inactivating mutations in the CaSR do not have impaired renal water
handling (discussed in [22]).

Urinary tract obstruction. The potential for urinary tract obstruction to cause NDI is well established.
Animal models of bilateral ureteral obstruction (BUO) or unilateral ureteral obstruction (UUO) have
revealed that reduced AQP2 levels, in combination with reduced V2R, AQP1 and AQP3 levels are
responsible for the decreased ability to concentrate urine, which persists for several days after release of
the obstruction [52,53]. Although the precise mechanisms are unclear, the signicant downregulation
of AQP2 in non-obstructed kidneys points towards a role of systemic factors. In children with NDI due to
unilateral obstruction or hydronephrosis, the levels of AQP1-4 are also decreased [54,55].

Acute kidney injury (AKI). AKI (also known as acute renal failure, ARF) is the abrupt loss of kidney
function, resulting in the retention of urea and other nitrogenous waste products and in the dysre-
gulation of extracellular volume and electrolytes. By denition, AKI patients must satisfy either; 1)
serum creatinine increases 26 mmol/L within 48 h, or 2) serum creatinine increases 1.5 fold from a
known reference value, or 3) urine output is < 0.5 ml/kg/hr for more than 6 consecutive hours [56]. The
condition is heterogeneous and risk factors for AKI include sepsis, critical illness, circulatory shock and
nephrotoxic drugs [57]. Although AKI per se is a water retaining condition, NDI is a complication
following an AKI episode, with an increased urine volume that does not respond to AVP treatment [58].
In various animal models of AKI, e.g. renal ischemia and reperfusion, or renal ischemia with contra-
lateral nephrectomy, AQP levels in the collecting duct are consistently and signicantly reduced e.g.
[59,60]. Although the mechanisms behind reduced AQP2 abundance are unclear a variety of systemic
and inammatory factors are likely to play a role [61].
282 H.B. Moeller et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 277e288

Chronic kidney disease (CKD). CKD, also known as chronic kidney failure, is the gradual loss of kidney
function. CKD is dened by abnormalities in various markers of kidney damage, including albuminuria,
urine sediment abnormalities, electrolyte abnormalities, abnormalities detected by histology or im-
aging, history of kidney transplantation, or a GFR <60 mL/min per 1.73 m2 for a duration of more than 3
months [62]. The condition has a heterogeneous etiology and risk factors for CKD include diabetes
mellitus, hypertension, polycystic kidney disease and glomerulonephritis, among others. In a common
model of CKD, the 5/6 nephrectomy, the expression of AQP1-3 are decreased [63], likely as a result of
reduced V2R levels [64] and compromised V2R-mediated signaling [65]. In various patient groups with
CKD there is an abnormal response in the V2R-cAMP-AQP2 axis resulting in reduced renal concen-
trating capacity [66].

Current treatment strategies for NDI

Detailed treatment strategies for congenital NDI have recently been extensively reviewed [26,67].
Classical and potential treatment strategies to relieve NDI symptoms and prevent hypernatraemic
dehydration [20] include:

1) Regulating salt and water intake. Sufcient intake of water is required to replace the water loss in
patients with NDI, whereas limiting salt intake reduces the kidneys solute load and the obligatory
water excretion required to remove it.
2) Thiazides and Amiloride. The diuretics act mainly via inhibiting NaCl reabsorption in the distal
convoluted tubule via the NaCl cotransporter NCC, and the collecting duct via ENaC. The decreased
NaCl reabsorption leads to hypervolemia, activation of the Renin Angiotensin Aldosterone System
(RAAS) and increased NaCl reabsorption in the proximal tubule, which is consequently followed by
water reabsorption via AQP1. The net effect is a decreased load of prourine reaching the collecting
duct, making this segment less important for water reabsorption. As amiloride inhibits the function
of ENaC and thus cellular uptake of lithium, amiloride therapy is encouraged for treatment of Li-
NDI [20]. Indeed, amiloride increases urine concentrating capacity in lithium-treated patients or in
animal models of Li-NDI e.g. [32,68].
3) Indomethacin. Indomethacine is a cyclooxygenase (COX) inhibitor that decreases the production of
PGE2, which under certain conditions can antagonize the effects of AVP (reviewed in [41]). Patients
treated with indomethacin or indomethacin combined with thiazides have an increased urine
concentrating capacity [69].

Practice points/research agenda

The current treatment for NDI includes ensuring access to free water, correction of hyper-
natremia if present, limiting dietary salt intake, and pharmacological treatment with diuretics
and indomethacin.

Future or potential treatment strategies for NDI

Most strategies focus on by-passing or enhancing the function of the V2R to promote AQP2 traf-
cking. Potential strategies have been discussed in detail [19,67] and include:

1) Phosphodiesterase (PDE) inhibitors. PDE inhibitors prevent the breakdown of cAMP or cGMP, which
can both stimulate AQP2 trafcking. Selective cGMP PDE5 inhibition by sildenal citrate [70,71], or
PDE4 inhibition by rolipram [72] have been proposed.
2) Statins. Statins inhibit cholesterol synthesis and are used for the treatment of hypercholesterolemia.
Statins also enhance AQP2 plasma membrane abundance [73,74] and urinary concentrating defects
 H.B. Moeller et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 277e288 283

associated with CDI [73] or BUO [75]. Fluvastatin treatment in combination with secretin
dramatically improved urine concentration in mice with XNDI [76].
3) Prostaglandin receptor agonists. Activation of the PGE2-specic receptors EP2 and EP4 increases
AQP2 trafcking and limits water loss in CDI and NDI models [77,78].
4) V2R agonists and antagonists (chaperones). Chaperones function to rescue misfolded V2R, allowing
them to reach the plasma membrane and initiate signaling and attempt have been made e.g. with
Conivaptan [79] or SR49059 [80]. Cell permeable V2R agonists aim to activate the intracellular V2R
to initiate signaling [81].

Practice points/research agenda:

Due to the common entrance of lithium and sodium into the principal cell via ENaC channels,
amiloride, a blocker of ENaC, should be considered for treatment of Li-NDI and should be
further examined for the possible prevention of NDI in the treatment of patients.

Studies in humans are needed to determine if there is a role for statins in the treatment of
NDI.

The role of the V2R and AQPs in conditions with gain of body water

A variety of conditions exist where, in most cases, non-osmotic stimulation of AVP release results in
alterations of renal AQPs, water retention and hyponatremia (see [45] for extensive review). Common
causes of water retention in which AQPs play a role include:

Syndrome of inappropriate ADH secretion (SIADH)

SIADH is common in hospitalized patients, with causes ranging from neurological diseases,
neoplasia and lung diseases, through to the use of a wide variety of medications [82]. AVP levels are
abnormally high, resulting in water reabsorption by the kidney and potentially life-threatening
hyponatremia [83]. In a rat model of SIADH, AQP2 levels were markedly increased and accompa-
nied by hyponatremia [84], but these effects could be normalized using a V2R antagonist. This
suggests that V2R mediated signaling and subsequent AQP2 translocation to the membrane play a
central role in the development of water retention and hyponatremia in SIADH. Most SIADH patients
show release of AVP that is totally unrelated to plasma osmolality, e.g. ectopic AVP production by
neoplasms [85]. In some cases, the effects of SIADH are limited by the phenomenon of AVP escape, a
mechanism by which the kidney is able to escape AVP-induced antidiuresis by reducing AQP2 levels,
allowing free water excretion despite inappropriate secretion of AVP [86]. The mechanisms behind
AVP escape are unclear, but likely involve a complex interplay between endocrine, paracrine and
mechanical factors [87].

Congestive heart failure (CHF)

CHF results from an inability of the heart to keep a sufcient blood ow, leading to activation of
neurohumoral and renal compensatory mechanisms [88]. CHF is characterized by high levels of AVP,
which contribute to increased extracellular volume and the development of hyponatremia [89]. The
increased levels of AQP2, accompanied by greater membrane accumulation of AQP2 observed in the
kidneys from rat models of CHF link AQP2 to the observed water retention [90]. Higher levels of urinary
AQP2 in CHF patients compared to healthy subjects suggest a similar mechanism in humans [91]. V2R
antagonists (see later) can normalize AQP2 levels and increase diuresis in animal models of CHF and
patients e.g. [92,93].
284 H.B. Moeller et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 277e288

Practice points/research agenda

V2 receptor antagonists should be utilized with caution as they have shown no improvement
in long-term outcomes in patients when comparing to placebo treated.

Hepatic cirrhosis

Cirrhosis of the liver is a late stage of liver disease resulting from long-term damage to the tissue.
Patients with cirrhosis often suffer from hyponatremia, believed to be the consequence of a decrease in
systemic vascular resistance leading to the non-osmotic stimulation of AVP release [89]. V2R antago-
nists increase solute-free water excretion in cirrhotic rats [94], but a role for AQPs in cirrhotic hypo-
natremia and volume expansion is controversial, with varying results in both animal models and
patients. For example, AQP2-4 levels were decreased in a chronic common bile duct ligation model
[95], whereas in a carbon tetrachloride-induced cirrhosis model performed by the same group AQP3
and AQP1 levels were increased and plasma membrane AQP2 abundance was enhanced [96]. Similarly
in cirrhotic patients, some have found an increased urinary excretion of AQP2 that correlates with the
severity of the disease [97], whereas others have found no alterations or decreased AQP2 levels in the
urine from cirrhotic patients [91].

Practice points/research agenda

Patients presenting with symptoms that might be due to low plasma sodium or with sig-
nificant hyponatremia need appropriate evaluation and therapy (see Chapter 3).

Vaptans (conivaptan, tolvaptan) should be used with caution due to increased mortality in
patients treated with satavaptan and increased risk of liver or kidney failure when treating
patients with tolvaptan (see Chapter 4).

The role of AQPs in hepatic cirrhosis needs to be clarified.

Pregnancy

In pregnancy, similar to hepatic cirrhosis, peripheral arterial vasodilation followed by decreased

blood pressure can activate a variety of systems, including the sympathetic nervous system and the
RAAS, leading to non-osmotic AVP release, water and sodium retention and decreased plasma osmo-
lality [89]. The degradation of AVP during pregnancy is increased by placental vasopressinase [98].
Although studies in pregnant rats have failed to detect consistent rises in plasma AVP levels [99,100],
AQP2 levels are signicantly increased. In an experimental model, this increase in AQP2 levels can be
prevented by the use of a V2R antagonist [100].

Practice points/research agenda:

The role of AVP-mediated stimulation of AQP2 for the water retention during pregnancy
needs to be clarified

Current treatment strategies for water retaining disorders

Fluid restriction combined with oral intake of urea or with loop diuretics is often used initially for
treatment of euvolemic or hypervolemic chronic hyponatremia. Lithium therapy has also been used
successfully for some patients with SIADH. Other therapeutic strategies include:
 H.B. Moeller et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 277e288 285

1) Demeclocycline. Demeclocycline is a tetracycline-like antibiotic that causes water diuresis and is

currently used to treat hyponatremia in patients with SIADH, where it can restore plasma sodium
concentrations to normal levels [101]. The aquaretic effect of demeclocycline is due to a reduction in
AVP stimulated cAMP generation and a subsequent reduction in AQP2 gene transcription [102].
2) Vasopressin-receptor antagonists (Vaptans). Promising new drugs for the treatment of AQP2-
mediated hyponatremia are the so called vaptans, which directly block the action of AVP at its
V1a, V1b or V2 receptors (see Chapter *). In both animal models of SIADH, CHF or liver cirrhosis, and
in patients with euvolemic or hypervolemic hyponatremia due to a variety of causes, vaptans are
able to increase diuresis and correct hyponatremia (reviewed in [45]), but their clinical use is
dependent on etiology of the hyponatremia and still a subject of debate [103].

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