body water homeostasis: clinical disorders of urinary...

Review

Body Water Homeostasis: Clinical Disorders of UrinaryDilution and Concentration

Robert W. SchrierDepartment of Medicine, University of Colorado School of Medicine, Denver, Colorado

J Am Soc Nephrol 17: 1820–1832, 2006. doi: 10.1681/ASN.2006030240

T he discovery of the aquaporin-1 (AQP1) water channelby Agre and colleagues (1,2), which led to the NobelPrize in 2003, has revolutionized the understanding of

body fluid water regulation by the kidney. Moreover, the iden-tification of other water channels in the kidney, namely AQP2,3, and 4, along with urea and ion transporters, has allowed amuch improved understanding of urinary dilution and concen-tration in health and disease at the cellular and molecular levels(3–8).

The AQP have provided a pathway for water movementacross cellular membranes that could not be explained by sim-ple diffusion through the lipid bilayers of cell membranes.AQP1 has been found to be expressed constitutively on boththe apical and the basolateral membranes of the proximal tu-bule and descending limb of Henle’s loop. This water channelis not under control of vasopressin but is important in urinaryconcentration. Water efflux through these channels in the de-scending limb is an important factor in the countercurrentconcentrating mechanism, and diminished maximal urinaryosmolality has been shown in AQP1 knockout mice (9) andhumans without the AQP1 gene (10).

AQP2, 3, and 4 are expressed in the cortical and medullarycollecting duct (Figure 1) (11). AQP2 is found exclusively in theprincipal cells of the collecting tubule and collecting duct and isknown to be regulated by arginine vasopressin (AVP). AQP3and 4 are located on the basolateral membrane of the principalcells in the collecting duct. AQP3 knockout mice exhibit sub-stantial polyuria secondary to vasopressin-resistant nephro-genic diabetes insipidus (NDI) (12). AQP3 is regulated by AVP.AQP4 predominates on the basolateral membrane of the innermedulla and is not regulated by AVP. AQP4 knockout micealso exhibit an NDI that is less severe than that observed in theAQP3 knockout mice (13). Whereas AQP3 and AQP4 constitutethe exit channels for water movement across the basolateralmembrane of the collecting duct, AQP2 is the water channel forwater reabsorption across the apical membrane of the principalcells of the collecting duct. These transgenic mouse models of

AQP deletion/mutation are of importance not only for kidneyfunction but also for other epithelia (14).

AVP regulates AQP2 in both an acute (short term) (15) andchronic (long term) manner (16,17). The short-term regulationby AVP involves trafficking of vesicles that contain AQP2 to theapical membrane with resultant increased water permeability.Suppression of plasma AVP reverses this exocytosis of AQP2,and the vesicles are retrieved from the membrane (endocytosis)into the cytoplasm. Both the short- and long-term regulation ofAQP2 by AVP is initiated by activation of the V2 receptor onthe basolateral membrane of the collecting duct. The binding ofAVP to the V2 receptor, which is coupled to a guanine-nucle-otide–binding protein Gs, results in activation of adenylyl cy-clase. This results in an increase in intracellular cAMP concen-tration that mediates the activation of protein kinase A (PKA).Activated PKA phosphorylates the serine 256 residue at theC-terminus of AQP2 protein (18,19). The phosphorylated AQP2then is translocated to the collecting duct apical membrane,thus constituting short-term regulation of AQP2. The long-termregulation of AQP2 is mediated by the cAMP response elementin the 5� flanking region of the AQP2 gene in response to AVPstimulation (20,21). The AQP2 transcription and protein expres-sion involves the phosphorylation of the cAMP response el-ement–binding protein. In contrast to the involvement of PKAactivation in the short-term regulation of AQP2, there is somein vivo evidence for PKA-independent long-term regulation ofAQP2 expression by AVP (22). There also is recent in vitro (23)and in vivo (24) evidence for AQP2 regulation by hyperosmo-lality independent of AVP. The in vivo experiments were per-formed in Brattleboro rats, which have no detectable circulatoryAVP.

Disorders of water balance can lead to either clinically rele-vant hyponatremia or hypernatremia. Hyponatremia is muchmore common and is the most frequent fluid and electrolytedisturbance in hospitalized patients. When defined as plasmasodium concentration �135 mEq/L, the prevalence of hypona-tremia in hospitalized patients may be as high as 15 to 30%.Studies indicate that 40 to 75% of these cases are hospitalacquired (25,26). It is clear that hyponatremia may occur in thepresence of an increase in total body sodium, a decrease in totalbody sodium, or a near-normal total body sodium (Figure 2). Inany of these three circumstances, hyponatremia has occurredbecause of a relatively greater amount of total body water ascompared with total body solute. Recent advances of the mech-

Published online ahead of print. Publication date available at www.jasn.org.

Address correspondence to: Dr. Robert W. Schrier, Department of Medicine,University of Colorado School of Medicine, 4200 East Ninth Avenue B-173,Denver, CO 80262. Phone: 303-315-8059; Fax: 303-315-2685; E-mail:[email protected]

Copyright © 2006 by the American Society of Nephrology ISSN: 1046-6673/1707-1820

anisms of impaired urinary diluting capacity that lead to thesehyponatremic disorders are discussed.

HypothyroidismAdvanced primary hypothyroidism can lead to hyponatre-

mia, most frequently associated with myxedema. Milder formsof hypothyroidism can lead to a decrease in renal blood flow,glomerular filtration, and a decrease in maximal solute-free

water excretion. However, these defects generally are not ofsufficient magnitude to lead to hyponatremia in associationwith a normal fluid intake. With normal fluid intake, hypona-tremia generally results from the inability to decrease urineosmolality below plasma rather than a defect in maximal sol-ute-free water excretion. The failure to dilute the urine belowplasma generally is due to a failure to suppress maximally theantidiuretic hormone AVP (27). The failure of some hypothy-roid patients to suppress plasma AVP during an acute waterload was reported initially by Skowsky et al. (28).

Recently, experimental studies in rats with advanced hypo-thyroidism (serum total T4 0.6 � 0.02 ng/dl) further examinedurinary dilution and maximal solute-free water excretion (29).There was a significant decrease in cardiac index and heart ratein these hypothyroid animals that was normalized with l-thyroxine replacement. During an acute water load, these hy-pothyroid animals exhibited a significantly lower urine flowand higher urinary osmolality than either control animals orhypothyroid animals that were treated with l-thyroxine. Thehypothyroid animals also had significantly higher plasma AVPconcentrations despite a lower plasma osmolality that normal-ized with l-thyroxine treatment. The impaired water excretionalso was associated with an upregulation of AVP-mediatedAQP2 expression and membrane trafficking in the inner me-dulla (Figure 3). Taken together, these results suggested a majorrole of nonosmotic AVP release in the hyponatremia associatedwith advanced hypothyroidism. Studies therefore were under-taken with a vasopressin V2 receptor antagonist (OPC-31260) inthese animals with advanced hypothyroidism. Minimal urinaryosmolality in hypothyroid rats that were treated with the V2

Figure 1. Nephron sites of aquaporin (AQP) water channels(blue), ion transporters (black), and urea transporters (green).ROMK, renal outer medullary potassium channel; UT, ureatransporter.

Figure 2. Diagnostic and therapeutic approach to the hypovolemic, euvolemic, and hypervolemic hyponatremic patient.

J Am Soc Nephrol 17: 1820–1832, 2006 Body Water Homeostasis 1821

receptor antagonist was normalized as compared with un-treated hypothyroid rats (97 versus 430 mOsm/kg H2O; P �

0.0001). Maximal solute-free water excretion in the hypothyroidrats significantly increased but did not reach euthyroid values.These experimental results therefore support the pivotal role ofthe baroreceptor-mediated nonosmotic AVP release in the hy-ponatremia associated with advanced hypothyroidism. Thesubmaximal solute-free water excretion would not be of clinicalsignificance unless other factors, such as diuretics or large fluidintakes, intervene.

Of interest, a defect in maximal urinary concentration wasobserved at a somewhat less prolonged stage of experimentalhypothyroidism (30). Maximal urinary osmolality with fluiddeprivation was associated with decreased Na-K-2Cl expres-sion and diminished medullary osmolality. Even though AQP2expression was decreased, the failure to exhibit a differencebetween the diminished urinary and medullary osmolality sug-gested that the primary mediator of the concentrating defectwas a decrease in the Na-K-2Cl co-transporter expression andtherefore impaired countercurrent concentration rather thanthe decreased AQP2 expression. This urine-concentrating de-

fect in hypothyroidism would be of clinical relevance only inpatients who were undergoing excessive extrarenal fluid losses(e.g., diarrhea).

Addison’s Disease and HypopituitarismPrimary adrenal insufficiency (Addison’s disease) involves

deficiency of glucocorticoid and mineralocorticoid hormones,both of which can be associated with hyponatremia. Hypopi-tuitarism is associated with only glucocorticoid deficiency, be-cause the renin-angiotensin-aldosterone system is intact. Al-though secondary hypothyroidism is associated withhypopituitarism, in contrast to primary hypothyroidism, theseverity generally is not sufficient to be associated with hypo-natremia. Therefore, the hyponatremia that is related to hypop-ituitarism generally is due to glucocorticoid deficiency ratherthan thyroid deficiency.

Mineralocorticoid deficiency that is associated with primaryadrenal insufficiency exhibits a different pathophysiology thanglucocorticoid deficiency in causing hyponatremia. Because al-dosterone increases potassium and hydrogen ion secretion,hyperkalemia and nonanion gap metabolic acidosis is charac-

Figure 3. Effects in control (CTL) and hypothyroid (HT) and thyroid (T) replaced rats on urine flow (A), urine osmolality (B),plasma vasopressin (AVP; C), and inner medullary AQP2 plasma membrane (PM)/intracellular vesical (ICV) densitometry ratio(D). Reprinted from reference (27), with permission.

1822 Journal of the American Society of Nephrology J Am Soc Nephrol 17: 1820–1832, 2006

teristic of primary but not secondary adrenal insufficiency as aresult of hypopituitarism. The mineralocorticoid deficiency alsois responsible for the sodium chloride wasting and extracellularfluid volume depletion in primary adrenal insufficiency. Selec-tive mineralocorticoid deficiency has been studied in adrena-lectomized animals that received replacement glucocorticoidhormone (31–33). With isolated mineralocorticoid hormone de-ficiency and hyponatremia, plasma AVP concentrations werenot suppressed and collecting duct AQP2 and 3 expressionswere upregulated. Outer medullary Na-K-2Cl co-transporterand Na-K-ATPase were decreased in mineralocorticoid animals(32). Administration of AVP V2 antagonist in these animalssignificantly improved urinary dilution, but a modest defect inmaximal solute-free water excretion remained (33). This latterdefect relates to effects of extracellular fluid volume depletion,including decreased GFR and increased proximal tubular so-dium reabsorption with resultant diminished fluid delivery tothe distal diluting segment of the nephron. Avoidance of neg-ative sodium balance in mineralocorticoid-deficient rats nor-malized Na-K-2Cl co-transporter, Na-K-ATPase, and collectingduct AQP2 and 3 (32). It also is of interest that high sodiumchloride intake may correct not only the hyponatremia but alsothe hyperkalemia and metabolic acidosis in Addison’s disease,thereby supporting an important role for mineralocorticoiddeficiency.

If hyponatremia persists in primary adrenal insufficiencydespite avoiding negative sodium balance, then the hyponatre-mia is due to glucocorticoid deficiency. The mechanisms ofhyponatremia with glucocorticoid deficiency are different thanwith mineralocorticoid deficiency. Glucocorticoid deficiencydoes not cause a negative sodium balance, and in fact a positivesodium balance may occur. The absence of glucocorticoid hor-mone, however, has major effects on systemic hemodynamics,including a decrease in cardiac index with an inadequate re-sponse of systemic vascular resistance to maintain mean arte-rial pressure (34). These systemic effects result in several con-sequences. The resultant decrease in stretch on the arterialbaroreceptors in the carotid sinus and aortic arch removes thetonic vagal and glossopharyngeal inhibition on the central re-lease of AVP. Elevated plasma AVP concentrations have beendemonstrated in glucocorticoid-deficient animals (33,35) andpatients with hypopituitarism (36) despite a degree of hypos-molality that would maximally suppress AVP in normal indi-viduals. The messenger RNA for AVP in the hypothalamus alsohas been shown to be increased during glucocorticoid defi-ciency (37). AVP-synthesizing neurons terminate in the medianeminence of the hypothalamus; therefore, a role for ACTH alsocould be involved in the nonosmotic AVP stimulation that isassociated with glucocorticoid deficiency. There also is evi-dence of a central effect of glucocorticoid hormone in the hy-pothalamus whereby hypo-osmolality does not maximally sup-press AVP synthesis during glucocorticoid deficiency (38). Ineither case, the importance of this nonosmotic stimulation ofAVP in glucocorticoid deficiency was documented using pep-tide and nonpeptide vasopressin V2 receptor antagonists,which profoundly reversed the water retention (33,35).

A recent molecular analysis of the impaired diluting capacity

with glucocorticoid deficiency was undertaken in adrenalecto-mized rats that received replacement physiologic concentra-tions of mineralocorticoid hormone (35). As compared withadrenalectomized rats that received replacement of both min-eralocorticoid and glucocorticoid hormone, during an acutewater load, the glucocorticoid-deficient animals exhibitedhigher plasma AVP concentrations, diminished solute-free wa-ter excretion, and increased protein expression in the innermedulla of AQP2, phosphorylated AQP2, and apical mem-brane trafficking of AQP2. The administration of a nonpeptidevasopressin V2 receptor antagonist reversed these events (Fig-ure 4).

There also was insight into AVP-independent effects on wa-ter excretion during glucocorticoid deficiency. Pair feeding dur-ing glucocorticoid deficiency was associated with an upregula-tion of the Na�-K�-2Cl� co-transporter, Na�/H� exchangerisoform 3, and cortical � and � subunits of the epithelial sodiumchannel and sodium retention (35). These events, along with theeffect of a decrease in renal perfusion pressure, would lead todecreased fluid delivery to the distal nephron diluting seg-ments and attenuate maximal solute-free water excretion. ThisAVP-independent effect on maximal water excretion probablywould not be of clinical significance except in the circumstanceof large increases in water intake.

Of interest, maximal urinary concentration also was dimin-ished in glucocorticoid-deficient rats after 36 h of fluid depri-vation (34). The concentrating defect involved primarily animpairment of the countercurrent concentrating mechanismwith comparable diminutions in medullary and urinary osmo-lalities. With the fluid deprivation, lower expression of the ureatransporter and ion transporters (e.g., Na-K-2Cl) in the outermedulla seemed to account for the diminished medullary os-motic gradient.

Primary Polydipsia or Compulsive WaterDrinking

The renal capacity to excrete solute-free water is substantial(27), yet the average daily fluid intake for hyponatremic pa-tients is only 2.4 L (39). The delivery of tubular fluid to thedistal diluting segment of the nephron is estimated to be ap-proximately 20% of glomerular filtrate. The diluting segmentbegins with the water-impermeable ascending limb of Henle’sloop and in the absence of vasopressin includes virtually theremainder of the nephron, i.e., connecting tubule, collectingtubule, and cortical and medullary collecting ducts. With a GFRof 100 ml/min, 140 L of filtrate occurs daily. If 20% of thisfiltrate reaches the distal diluting segment and plasma AVP ismaximally suppressed, then 28 L of solute-free water theoreti-cally could be excreted. Therefore, the normal capacity to ex-crete solute-free water may approximate 1 L/h if administeredconsistently over 24 h. Patients with primary polydipsia, how-ever, ingest their water intake mostly during their awake hoursof the day. Even so, individuals who have primary polydipsiaand normal renal, endocrine, cardiac, and hepatic function andare not volume depleted or taking diuretics do not becomehyponatremic from drinking up to 10 to 12 L of water per day.Their plasma osmolalities, however, may be in the lower nor-


mal range (275 to 285 mOsm/kg H2O). If any of the abovecircumstances intervene, then patients with primary polydipsiaare in danger of developing “water intoxication” with severecentral nervous system symptoms, including headache, nausea,vomiting, decreased mentation, confusion, obtundation, sei-zures, and even cerebral hernia, cardiopulmonary arrest, anddeath. Pure water intoxication rarely can occur without anintervening event with massive water intake, e.g., drinkingdirectly from a faucet or with an open hose in the stomach.

Psychiatric patients in hospital frequently have polydipsia,because of dry mouth from medications with anticholinergicproperties and/or delusions (e.g., “water cleanses the soul”). Infact, another term that has been used for primary polydipsiahas been psychogenic water drinking. In 1973, acute psychoseswith hyponatremia mimicking the syndrome of antidiureticsyndrome first was described (40). Subsequently, hyponatremiaand water intoxication with failure to suppress plasma AVPhave been described with psychotic disorders, such as schizo-phrenia (41). Psychiatric patients also have a high incidence ofsmoking, and nicotine is a very potent acute stimulus for AVPrelease (42,43).

Recently, molecular and cellular events were analyzed in a

unique rat model of primary polydipsia in which the samedaily food intake was ingested in control animals with adlibitum water intake and polyuric rats that drank 100 ml/d (44).This model therefore allowed assessment of the renal effects ofpolyuria at comparable electrolyte, caloric, and protein intakes.As compared with controls, serum osmolality was lower in thepolydipsic rats (293 versus 277 mOsm/kg H2O; P � 0.04) as wasurine osmolality (1365 versus 139 mOsm/kg H2O; P � 0.001).As occurs in humans after 10 d of increased water intake (45),a form of AVP-resistant NDI emerged after 10 d in the poly-dipsic rats. With 36 h of fluid deprivation, the polydipsic ani-mals exhibited significantly higher urine output associatedwith a lower urine osmolality despite significant higher plasmaAVP concentrations (Figure 5). The ion and urea transporterswith potential to alter the integrity of the countercurrent con-centrating mechanism were unaltered, including outer medul-lary Na-K-2Cl, Na-K-ATPase, and inner medullary urea trans-porter, in polydipsic as compared with control rats. The AQP1water channel expression, which if mutated can cause a con-centrating defect (9,10), also was no different in the polydipsicanimals. What was remarkably different was a highly signifi-cant suppression of AQP2 protein expression in the outer and

Figure 4. Effect of V2 receptor antagonist (OPC) in glucocorticoid-deficient rats to reverse the impaired water excretion (A) andurinary dilution (B) as well as the increased AQP2 (C) and phosphorylated AQP2 expression (D). Reprinted from reference (33),with permission.


inner medulla. The AQP2 expression in the membrane fraction,as an index of trafficking to the collecting duct membrane, wasdecreased. The AQP3 protein abundance in the outer medullaalso was significantly diminished in the polydipsic rats. Afterthe 36-h fluid deprivation, the medullary osmolalities in thecontrol and polydipsic rats were no different, even though thepolydipsic rats demonstrated a significant decrease in maximalurinary osmolality. This failure of osmotic equilibration be-tween the medullary interstitium and urine in the polydipsicrats supported a critical role of the downregulation of AQP2and, possibly, AQP3 in the impaired urine-concentrating capac-ity associated with polydipsia.

PregnancyA decrease in plasma osmolality of 8 to 10 mOsm/kg H2O is

an early occurrence in normal pregnancy. Sodium and waterretention occurs during pregnancy with an expansion of extra-cellular fluid ranging from 30 to 50% (46). Water retentionexceeds the sodium retention in normal pregnancy and thus thefall in plasma osmolality and sodium concentration. Recentstudies have shown that systemic arterial vasodilation occursearly in the first trimester of pregnancy (47). The mediator(s) ofthis decrease in vascular resistance is(are) not well defined, butsome experimental results indicate a role of estrogen-mediatednitric oxide (48) and relaxin (49). In any case, the standardresponses to arterial underfilling secondary to arterial vasodi-

lation also occur in pregnancy. There is a compensatory rise incardiac output and stimulation of the renin-angiotensin-aldo-sterone system that attenuates the vasodilation-mediated fall inBP during the first trimester (47). In other circumstances ofarterial vasodilation, such as cirrhosis or a large arteriovenousfistula, the activation of arterial baroreceptors is accompaniedby the nonosmotic release of AVP (50,51). In pregnancy, plasmaAVP concentrations are still detectable in the presence of adegree of hypo-osmolality that normally would suppress AVPrelease, i.e., 1 to 2% decrease in plasma osmolality. The hypo-osmolality of pregnancy has been termed a “resetting” of thehypothalamic osmoreceptor threshold to a lower level (52) butmay be due merely to the nonosmotic release of AVP thatoccurs with arterial vasodilation (50,51). It also is of interest thatearly in pregnancy, there is an increase in thirst and fluid intakedespite a fall in plasma osmolality, which normally suppressesthirst. This also is compatible with a nonosmotic stimulation ofthirst as a result of arterial underfilling.

Arterial underfilling as a result of arterial vasodilation, asoccurs in cirrhosis and pregnancy, is associated with compen-satory increases in total blood volume and cardiac output.Moreover, arterial vasodilation stimulates the nonosmotic AVPrelease and activates the renin-angiotensin-aldosterone axis, asoccurs in cirrhosis and pregnancy. These hormonal responsesalso compensate for arterial underfilling, at the expense ofhyponatremia and edema (50,51,53).

Figure 5. During 36 h of water deprivation, rats with polydipsia (POLY) demonstrated increased urine output (A), decreased urineosmolality (B), increased plasma AVP (C), and decreased AQP2 expression as compared with control (CTL) rats (D). Reprintedfrom reference (44), with permission.


With the discovery of the renal water channels, i.e., AQP,body water regulation in pregnancy could be investigated inmore depth. Pregnancy in the rat exhibits most of the charac-teristics of human pregnancy and therefore has been the stan-dard experimental model. Studies therefore were undertaken inpregnant rats to examine the effect on renal AQP (54). If thenonosmotic release of AVP secondary to arterial vasodilation isinvolved in the water retention in pregnancy (55), then vaso-pressin-mediated upregulation and trafficking of AQP2 shouldbe demonstrable. Alternatively, if pregnancy “resets” the os-motic threshold for AVP release, then the regulation of theAQP2 around this reset osmostat should mimic the nonpreg-nant state. As compared with nonpregnant littermates, preg-nant rats were found to have in the first trimester a profoundupregulation of inner medullary AQP2 mRNA and proteinexpression that persisted throughout the pregnancy (Figure 6).In the pregnant rats, there also was an increase in AQP2 in themembrane fraction, indicating increased AQP2 trafficking tothe apical membrane of the collecting duct. It is known that theeffect of AVP on AQP2 protein expression and trafficking ismediated by vasopressin V2 receptor. Studies therefore wereundertaken with a nonpeptide V2 receptor antagonist in preg-nant and nonpregnant animals. The AQP2 protein expressionand apical membrane location by immunofluorescence werereturned to the nonpregnant state during the V2 receptor an-tagonist administration to pregnant rats (53). These experimen-tal results therefore strongly support a role of the nonosmoticAVP release in regulation AQP2 expression and trafficking inpregnancy. This was supported further by the observation thatincreased urinary AQP2 occurs during pregnancy (56). It must

be remembered, however, that the antidiuretic effect of oxy-toxin also is mediated via the V2 receptor on the basolateralmembrane of the collecting duct and therefore could be acontributing factor in the water retention of pregnancy (57). Italso has been shown that circulating vasopressinase from theplacenta, which increases AVP degradation, can uncover orcause diabetes insipidus in pregnancy (58).

Cardiac FailureAdvanced heart failure frequently is associated with hypo-

natremia. In fact, hyponatremia has been found to be a riskfactor for poor survival for patients with congestive heart fail-ure (59). The pathogenesis of the hyponatremia of cardiac fail-ure initially seemed not to involve AVP, primarily because thebioassay for antidiuretic hormone was relatively insensitive.With the development of the RIA to measure plasma AVP,studies were undertaken to examine the cause of hyponatremiain patients with heart failure. In the first study, the hypo-osmolality in patients with heart failure was of a degree thatwould maximally suppress plasma AVP in normal individuals,yet 30 (81%) of 37 patients had detectable plasma AVP by RIA(60). Therefore, the term nonosmotic AVP release emerged todescribe hyponatremic patients with heart failure and otheredematous disorders. There also is evidence for increased AVPsynthesis in the hypothalamus in experimental heart failure(61). Hyponatremia may occur both in low-output cardiac fail-ure (e.g., ischemic or nonischemic cardiomyopathy) and inhigh-output cardiac failure (e.g., thyrotoxicosis, beriberi, largearteriovenous fistula) (62). This apparent dilemma is under-standable because arterial underfilling with baroreceptor-me-diated AVP stimulation can occur with either a decrease incardiac output or systemic arterial vasodilation as occurs withhigh-output cardiac failure (50,51,53).

With the discovery of water channels, investigations wereundertaken to examine whether increased plasma AVP in car-diac failure would be associated with increased renal AQP2protein expression and trafficking to the apical membrane ofthe collecting duct (63,64). As in humans, plasma AVP in-creased in advanced cardiac failure in rats despite hypo-osmo-lality (63). In these animals with heart failure secondary tocoronary artery ligation, AQP2 expression and membrane traf-ficking were increased in the inner medulla of the kidney(63,64). Administration of a nonpeptide V2 receptor antagonistto these animals with heart failure reversed the increased ex-pression and trafficking of AQP2 (63). Support for this relation-ship between nonosmotic AVP and AQP2 expression has beendemonstrated by studies in patients with heart failure by mea-surement of urinary AQP2 (65). Approximately 3 to 6% ofAQP2 can be measured by RIA or Western immunoblotting inthe urine. In patients with New York Heart Association class IIor III heart failure, a V2 receptor antagonist caused a solute-freewater diuresis and increased plasma sodium concentration.Urinary AQP2 decreased in these patients during the V2 recep-tor antagonist administration (Figure 7) (65), thus indicatingthat less of this water channel reached the apical membrane ofthe collecting duct. An orally active, nonpeptide vasopressin V2receptor antagonist was shown recently in patients with cardiac

Figure 6. Inner medulla AQP2 protein expression (densitometryabove and immunoblots below) in nonpregnant (NP) rats andfirst-trimester (P7), second-trimester (P14), and third-trimester(P20) pregnant rats. Glycosylated (36 to 45 kD) and nonglyco-sylated (29 kD) expression is shown. Reprinted from reference(54), with permission.


failure to cause a substantial loss of body weight over 30 d oftreatment (66). Acute reversal of water retention with anothernonpeptide V2 antagonist also was shown recently (67). Car-diac afterload reduction with either hydralazine or an angio-tensin-converting enzyme inhibitor in patients with cardiacfailure increased cardiac output, thereby attenuating arterialunderfilling. This was associated with an increase in solute-freewater excretion in association with a decrease in plasma andplatelet AVP concentration (68).

CirrhosisHyponatremia frequently occurs in decompensated patients

with cirrhosis and ascites (69), whereas patients with compen-sated cirrhosis and no ascites rarely are hyponatremic (70).Hyponatremia also is a risk factor for poor survival in patientswith cirrhosis (71). As with heart failure, not until measurementof plasma AVP by RIA was the nonosmotic AVP incriminatedin the hyponatremia of cirrhosis (72). Early in cirrhosis, portalhypertension is associated with an increased splanchnic bloodflow (73). The associated decrease in systemic vascular resis-tance causes arterial underfilling and baroreceptor-mediatedincrease in AVP release (74). An increase in AVP synthesis inthe hypothalamus also has been found in experimental cirrho-sis (75). The increase in plasma AVP and water excretion incirrhosis were shown to correlate directly with plasma norepi-nephrine and renin activity (76). This observation providesevidence that cirrhosis activates the sympathetic and renin-angiotensin systems, as well as the nonosmotic stimulation ofAVP, during arterial underfilling as a result of arterial vasodi-lation. Increased AQP2 expression and trafficking also havebeen shown to be present in experimental cirrhosis (77), afinding that is compatible with the observed increased urinaryexcretion of AQP2 in patients with cirrhosis (78). VasopressinV2 receptor antagonists also have been shown to increase sol-

ute-free water excretion in patients with cirrhosis (79) andexperimental cirrhosis (80). These effects on the nonosmoticstimulation of AVP and AQP2 seem to be manifest with moresevere cirrhosis, because milder experimental forms of cirrhosis(e.g., bile duct ligation, inhalation of carbon tetrachloride) didnot show these changes (81,82).

There are several candidates as mediators of the splanchnicvasodilation and arterial underfilling in cirrhosis. Recent evi-dence, however, indicates a prominent role of endothelial andinducible nitric oxide synthesis (83). In this regard, 7 d oftreatment with a nonspecific nitric oxide synthase inhibitor at adose to reverse the arterial vasodilation and thus the hyperdy-namic circulation of experimental cirrhosis was found to sup-press plasma AVP, increase solute-free water diuresis, andcorrect the hyponatremia (84).

NDI: Genetic and AcquiredNDI is when the kidney does not respond normally to the

antidiuretic effect of AVP. NDI can be due to genetic or ac-quired causes. The cellular and molecular defects that cause theabsolute or relative renal unresponsiveness to vasopressin mayinvolve impairment of the water permeability across the col-lecting duct, the generation of the medullary osmotic gradientfor water transport, or both.

Congenital NDIThe genetic or congenital NDI can be due primarily to mu-

tations in two areas. The most common defect relates to muta-tions of the vasopressin V2 receptor on the basolateral mem-brane of the collecting duct. More than 180 mutations of the V2receptor have been found in chromosome region Xq28 (Figure8), and together these abnormalities account for 90% of patients

Figure 7. Effect of V2 antagonist (VPA-985) in patients withchronic heart failure (New York Heart Association II and III) todecrease urinary AQP2 excretion in a dose-dependent manneras compared with placebo during day �1. Day �1 was thecontrol day. T, time in hours. Reprinted from reference (65),with permission.

Figure 8. Diagram showing the type 2 vasopressin receptor (V2receptor) protein and identifying putative disease-causing mu-tations in the arginine vasopressin receptor 2 gene (circles).Mutations are present in the extracellular, transmembrane, andcytoplasmic domains of the V2 receptor. The numbers 1 and371 refer to amino acids 1 and 371, respectively. COOH, car-boxy-terminus of the protein; NH2, amino-terminus of the pro-tein. Reprinted from reference (11), with permission.


with congenital NDI (85). Studies suggest that most mutationsinvolve protein misfolding, which traps the V2 receptor intra-cellularly, thereby not allowing the receptor to translocate tothe basolateral membrane of the collecting duct (86). Therefore,the adenylate cyclase-cAMP signaling pathway, which medi-ates AQP2 expression and trafficking to the apical membrane,is not activated. Recent in vivo studies indicate that nonpeptideV2, V1, and V1/V2 receptor antagonists may allow some of themutant V2 receptors to be transported to the basolateral mem-brane and to function normally (87). These antagonists act aschaperones for the misfolded V2 receptors to reach the mem-brane. A recent study in patients with NDI demonstrated anapproximate decrease in daily urine flow from 12 to 8 L and anincrease in urinary osmolality from 98 to 170 mOsm/kg usingsuch a receptor antagonist (88). This variety of congenital NDIhas an X-linked recessive mode of inheritance, and affectedmale individuals cannot concentrate their urine in response tovasopressin. Heterozygous female individuals generally areasymptomatic but may have a modest degree of polyuria andpolydipsia. In contrast, male individuals may have up to 20 L ofurine every day. The need to drink sufficient water to maintainwater balance, therefore, is challenging and certainly affects thequality of life of the individual. Before genetic screening ofnewborns in affected families, dehydration and mental retar-dation frequently developed. Now affected individuals whoreceive adequate water intake progress to normal adulthoodwithout any mental or physical retardation.

Another cause of congenital NDI involves mutations of theAQP2 gene in chromosome region 12q13 (89). This accounts for10% of families with congenital NDI. Currently, more than 30such mutations have been identified (Figure 9). In the autoso-mal recessive variety, the mutant AQP2 proteins are trapped inthe endoplasmic reticulum, whereas the autosomal dominantvarieties are mutations of the carboxy terminus.

Acquired NDIHypokalemia and hypercalcemia are electrolyte disorders

that may be associated with polyuria and polydipsia as a resultof a defect in the renal response of vasopressin to concentratethe urine maximally. Experimental studies in rats have beenundertaken to study the mechanisms involved. A potassium-deficient diet for 11 d caused hypokalemic-related NDI (90),and 7 d of vitamin D (dihydrotachysterol) caused hypercalce-mic-related NDI (91). In both experimental models, there was adownregulation of AQP2 expression in the inner medulla. Inthe hypercalcemic model, there also was a decrease in theNa-K-2Cl co-transporter in the outer medulla. As the initiatorof the countercurrent concentrating mechanism for generationof the corticomedullary osmotic gradient, this decrease in theNa-K-2Cl co-transporter no doubt also contributed to the ac-quired NDI.

Polyuria secondary to NDI also may accompany bilateralurinary tract obstruction, in part due to the resultant volumeexpansion and urea retention. Experimental studies, however,have shown that unilateral ureteral obstruction, which avoidsthese sequelae of bilateral ureteral obstruction, also causes NDI(92). As with the above electrolyte disorders, AQP2 downregu-lation has been demonstrated to be associated with acquiredNDI related to urinary tract obstruction. Lithium also has beendemonstrated in experimental animals to be associated withdownregulation of AQP2 expression and trafficking (93). Lith-ium therapy has been a worldwide, effective treatment forbipolar affective disorder for many years. Therefore, under-standing the mechanism for the NDI that is associated with thismedication is important, particularly because it occurs in ap-proximately 20% of treated patients. In this regard, recent invitro and in vivo experiments suggest that the effect of lithium todownregulate AQP2 may occur independent of adenylyl cy-clase activity (94,95).

A vasopressin-resistant urine-concentrating defect is one ofthe earliest abnormalities associated with acute renal failure.This variety of acquired NDI also seems to involve an inabilityto establish a high medullary solute content, i.e., the osmoticdriving force for water reabsorption. Moreover, AQP1, 2, and 3expression has been shown to be reduced in rats with botholiguric and nonoliguric ischemic acute renal failure (96). Sim-ilar results have been found in the 5/6 nephrectomy–inducedmodel of chronic renal failure (97). In patients with advancedchronic renal failure, vasopressin-resistant hypotonic urine hasbeen described (98). This finding suggests a defect in watertransport across the medullary collecting duct, because abso-lute impairment of the countercurrent concentrating mecha-nism still would be associated with an isotonic, not hypotonic,medullary interstitium. In contrast to congenital NDI, the poly-uria of acquired NDI generally is of a moderate degree (e.g., 3to 4 L/24 h). The thirst mechanism generally protects againsthypernatremia in NDI states unless age (newborn, elderly) orillness restricts availability of fluid intake.

ConclusionThe ability to analyze the renal water channels and ion and

urea transporters has allowed for the better understanding of

Figure 9. Diagram showing the AQP2 protein and identifyingputative disease-causing mutations in AQP2 (circles). Muta-tions are present in the extracellular, transmembrane, and cy-toplasmic domains of AQP2. The numbers 1 and 271 refer toamino acids 1 and 271, respectively. Reprinted from reference(11), with permission.


several clinical disorders with impaired urinary dilutionand/or concentration.

AcknowledgmentsThis work was supported by National Institutes of Health grant DK

19928.I appreciate the assistance of Jan Darling in the preparation of the

manuscript. Most important, I acknowledge Peter Agre, MD, and hisassociates, whose discovery of the first mammalian water channel hasallowed much of this work to be undertaken.

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