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Renal aquaporins and water balance disorders
Best Practice & Research Clinical Endocrinology & Metabolism xxx (2016) 1e12
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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 Article history: Available online xxx Keywords: aquaporin vasopressin water balance nephrogenic diabetes insipidus NDI concentrating mechanism thiazide water retention
Aquaporins (AQPs) are a 13 member family (AQP0-12) of proteins that act as channels, through which water and, for some family members, glycerol, urea and other small solutes can be transported. Aquaporins are highly abundant in kidney epithelial cells where they play a critical role with respect to water balance. In this review we summarize the current knowledge with respect to the localization and function of AQPs within the kidney tubule, and their role in mammalian water homeostasis and the water balance disorders. Overviews of practical aspects with regard to differential diagnosis for some of these disorders, alongside treatment strategies are also discussed. © 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 osmotic 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: [email protected] (R.A. Fenton). http://dx.doi.org/10.1016/j.beem.2016.02.012 1521-690X/© 2016 Elsevier Ltd. All rights reserved.
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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 reabsorbs the vast majority of filtered water [3]. AQP1 is also expressed in the vasa recta [4]. Although AQP1 trafficking 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 beneficial 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 trafficking of AQP2 to the plasma membrane, and in the long term, increased AQP2 abundance [11,12]. Combined, these processes 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 Please cite this article in press as: Moeller HB, et al., Renal aquaporins and water balance disorders, Best Practice & Research Clinical Endocrinology & Metabolism (2016), http://dx.doi.org/10.1016/ j.beem.2016.02.012
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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 deficient 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 fluid intake (primary polydipsia). NDI is further classified 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 findings [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 fluid 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 stimulation relative to plasma osmolality, the findings 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).
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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, successive 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 syndrome, 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 occasionally 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, ofloxacin, 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 efficient treatment for patients with bipolar mood disorders. However, lithium can be nephrotoxic and result in NDI within 8 weeks of treatment initiation. The prevalence of lithium induced NDI (Liþ-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 filtered; 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 Please cite this article in press as: Moeller HB, et al., Renal aquaporins and water balance disorders, Best Practice & Research Clinical Endocrinology & Metabolism (2016), http://dx.doi.org/10.1016/ j.beem.2016.02.012
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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 Liþ-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 confirmed 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 defects, 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 receptor (CaSR) on the apical membrane of principal cells [47] to high Ca2þ 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 significant 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 dysregulation of extracellular volume and electrolytes. By definition, 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 contralateral nephrectomy, AQP levels in the collecting duct are consistently and significantly reduced e.g. [59,60]. Although the mechanisms behind reduced AQP2 abundance are unclear a variety of systemic and inflammatory factors are likely to play a role [61].
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Chronic kidney disease (CKD). CKD, also known as chronic kidney failure, is the gradual loss of kidney function. CKD is defined by abnormalities in various markers of kidney damage, including albuminuria, urine sediment abnormalities, electrolyte abnormalities, abnormalities detected by histology or imaging, 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 concentrating 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. Sufficient 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 LiþNDI [20]. Indeed, amiloride increases urine concentrating capacity in lithium-treated patients or in animal models of Liþ-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 hypernatremia 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 trafficking. 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 trafficking. Selective cGMP PDE5 inhibition by sildenafil 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 Please cite this article in press as: Moeller HB, et al., Renal aquaporins and water balance disorders, Best Practice & Research Clinical Endocrinology & Metabolism (2016), http://dx.doi.org/10.1016/ j.beem.2016.02.012
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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-specific receptors EP2 and EP4 increases AQP2 trafficking 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 accompanied 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 sufficient blood flow, 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]. Please cite this article in press as: Moeller HB, et al., Renal aquaporins and water balance disorders, Best Practice & Research Clinical Endocrinology & Metabolism (2016), http://dx.doi.org/10.1016/ j.beem.2016.02.012
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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 antagonists increase solute-free water excretion in cirrhotic rats [94], but a role for AQPs in cirrhotic hyponatremia 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 significant 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 osmolality [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 significantly 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: Please cite this article in press as: Moeller HB, et al., Renal aquaporins and water balance disorders, Best Practice & Research Clinical Endocrinology & Metabolism (2016), http://dx.doi.org/10.1016/ j.beem.2016.02.012
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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 AQP2mediated 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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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 Article history: Available online xxx Keywords: aquaporin vasopressin water balance nephrogenic diabetes insipidus NDI concentrating mechanism thiazide water retention
Aquaporins (AQPs) are a 13 member family (AQP0-12) of proteins that act as channels, through which water and, for some family members, glycerol, urea and other small solutes can be transported. Aquaporins are highly abundant in kidney epithelial cells where they play a critical role with respect to water balance. In this review we summarize the current knowledge with respect to the localization and function of AQPs within the kidney tubule, and their role in mammalian water homeostasis and the water balance disorders. Overviews of practical aspects with regard to differential diagnosis for some of these disorders, alongside treatment strategies are also discussed. © 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 osmotic 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: [email protected] (R.A. Fenton). http://dx.doi.org/10.1016/j.beem.2016.02.012 1521-690X/© 2016 Elsevier Ltd. All rights reserved.
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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 reabsorbs the vast majority of filtered water [3]. AQP1 is also expressed in the vasa recta [4]. Although AQP1 trafficking 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 beneficial 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 trafficking of AQP2 to the plasma membrane, and in the long term, increased AQP2 abundance [11,12]. Combined, these processes 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 Please cite this article in press as: Moeller HB, et al., Renal aquaporins and water balance disorders, Best Practice & Research Clinical Endocrinology & Metabolism (2016), http://dx.doi.org/10.1016/ j.beem.2016.02.012
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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 deficient 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 fluid intake (primary polydipsia). NDI is further classified 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 findings [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 fluid 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 stimulation relative to plasma osmolality, the findings 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).
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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, successive 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 syndrome, 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 occasionally 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, ofloxacin, 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 efficient treatment for patients with bipolar mood disorders. However, lithium can be nephrotoxic and result in NDI within 8 weeks of treatment initiation. The prevalence of lithium induced NDI (Liþ-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 filtered; 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 Please cite this article in press as: Moeller HB, et al., Renal aquaporins and water balance disorders, Best Practice & Research Clinical Endocrinology & Metabolism (2016), http://dx.doi.org/10.1016/ j.beem.2016.02.012
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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 Liþ-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 confirmed 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 defects, 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 receptor (CaSR) on the apical membrane of principal cells [47] to high Ca2þ 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 significant 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 dysregulation of extracellular volume and electrolytes. By definition, 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 contralateral nephrectomy, AQP levels in the collecting duct are consistently and significantly reduced e.g. [59,60]. Although the mechanisms behind reduced AQP2 abundance are unclear a variety of systemic and inflammatory factors are likely to play a role [61].
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Chronic kidney disease (CKD). CKD, also known as chronic kidney failure, is the gradual loss of kidney function. CKD is defined by abnormalities in various markers of kidney damage, including albuminuria, urine sediment abnormalities, electrolyte abnormalities, abnormalities detected by histology or imaging, 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 concentrating 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. Sufficient 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 LiþNDI [20]. Indeed, amiloride increases urine concentrating capacity in lithium-treated patients or in animal models of Liþ-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 hypernatremia 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 trafficking. 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 trafficking. Selective cGMP PDE5 inhibition by sildenafil 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 Please cite this article in press as: Moeller HB, et al., Renal aquaporins and water balance disorders, Best Practice & Research Clinical Endocrinology & Metabolism (2016), http://dx.doi.org/10.1016/ j.beem.2016.02.012
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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-specific receptors EP2 and EP4 increases AQP2 trafficking 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 accompanied 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 sufficient blood flow, 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]. Please cite this article in press as: Moeller HB, et al., Renal aquaporins and water balance disorders, Best Practice & Research Clinical Endocrinology & Metabolism (2016), http://dx.doi.org/10.1016/ j.beem.2016.02.012
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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 antagonists increase solute-free water excretion in cirrhotic rats [94], but a role for AQPs in cirrhotic hyponatremia 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 significant 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 osmolality [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 significantly 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: Please cite this article in press as: Moeller HB, et al., Renal aquaporins and water balance disorders, Best Practice & Research Clinical Endocrinology & Metabolism (2016), http://dx.doi.org/10.1016/ j.beem.2016.02.012
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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 AQP2mediated 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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