Body Water Homeostasis: Clinical Disorders of Urinary Dilution and Concentration
Robert W. Schrier
Department of Medicine, University of Colorado School of Medicine, Denver, Colorado
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: robert.schrier{at}uchsc.edu
The discovery of the aquaporin-1 (AQP1) water channel by Agreand colleagues (1,2), which led to the Nobel Prize in 2003,has revolutionized the understanding of body fluid water regulationby the kidney. Moreover, the identification of other water channelsin the kidney, namely AQP2, 3, and 4, along with urea and iontransporters, has allowed a much improved understanding of urinarydilution and concentration in health and disease at the cellularand molecular levels (3–8).
The AQP have provided a pathway for water movement across cellularmembranes that could not be explained by simple diffusion throughthe lipid bilayers of cell membranes. AQP1 has been found tobe expressed constitutively on both the apical and the basolateralmembranes of the proximal tubule and descending limb of Henle’sloop. This water channel is not under control of vasopressinbut is important in urinary concentration. Water efflux throughthese channels in the descending limb is an important factorin the countercurrent concentrating mechanism, and diminishedmaximal urinary osmolality has been shown in AQP1 knockout mice(9) and humans without the AQP1 gene (10).
AQP2, 3, and 4 are expressed in the cortical and medullary collectingduct (Figure 1) (11). AQP2 is found exclusively in the principalcells of the collecting tubule and collecting duct and is knownto be regulated by arginine vasopressin (AVP). AQP3 and 4 arelocated on the basolateral membrane of the principal cells inthe collecting duct. AQP3 knockout mice exhibit substantialpolyuria secondary to vasopressin-resistant nephrogenic diabetesinsipidus (NDI) (12). AQP3 is regulated by AVP. AQP4 predominateson the basolateral membrane of the inner medulla and is notregulated by AVP. AQP4 knockout mice also exhibit an NDI thatis less severe than that observed in the AQP3 knockout mice(13). Whereas AQP3 and AQP4 constitute the exit channels forwater movement across the basolateral membrane of the collectingduct, AQP2 is the water channel for water reabsorption acrossthe apical membrane of the principal cells of the collectingduct. These transgenic mouse models of AQP deletion/mutationare of importance not only for kidney function but also forother epithelia (14).
Figure 1. Nephron sites of aquaporin (AQP) water channels (blue), ion transporters (black), and urea transporters (green). ROMK, renal outer medullary potassium channel; UT, urea transporter.
AVP regulates AQP2 in both an acute (short term) (15) and chronic(long term) manner (16,17). The short-term regulation by AVPinvolves trafficking of vesicles that contain AQP2 to the apicalmembrane with resultant increased water permeability. Suppressionof plasma AVP reverses this exocytosis of AQP2, and the vesiclesare retrieved from the membrane (endocytosis) into the cytoplasm.Both the short- and long-term regulation of AQP2 by AVP is initiatedby activation of the V2 receptor on the basolateral membraneof the collecting duct. The binding of AVP to the V2 receptor,which is coupled to a guanine-nucleotide–binding proteinGs, results in activation of adenylyl cyclase. This resultsin an increase in intracellular cAMP concentration that mediatesthe activation of protein kinase A (PKA). Activated PKA phosphorylatesthe serine 256 residue at the C-terminus of AQP2 protein (18,19).The phosphorylated AQP2 then is translocated to the collectingduct apical membrane, thus constituting short-term regulationof AQP2. The long-term regulation of AQP2 is mediated by thecAMP response element in the 5' flanking region of the AQP2gene in response to AVP stimulation (20,21). The AQP2 transcriptionand protein expression involves the phosphorylation of the cAMPresponse element–binding protein. In contrast to the involvementof PKA activation in the short-term regulation of AQP2, thereis some in vivo evidence for PKA-independent long-term regulationof AQP2 expression by AVP (22). There also is recent in vitro(23) and in vivo (24) evidence for AQP2 regulation by hyperosmolalityindependent of AVP. The in vivo experiments were performed inBrattleboro rats, which have no detectable circulatory AVP.
Disorders of water balance can lead to either clinically relevanthyponatremia or hypernatremia. Hyponatremia is much more commonand is the most frequent fluid and electrolyte disturbance inhospitalized patients. When defined as plasma sodium concentration<135 mEq/L, the prevalence of hyponatremia in hospitalizedpatients may be as high as 15 to 30%. Studies indicate that40 to 75% of these cases are hospital acquired (25,26). It isclear that hyponatremia may occur in the presence of an increasein total body sodium, a decrease in total body sodium, or anear-normal total body sodium (Figure 2). In any of these threecircumstances, hyponatremia has occurred because of a relativelygreater amount of total body water as compared with total bodysolute. Recent advances of the mechanisms of impaired urinarydiluting capacity that lead to these hyponatremic disordersare discussed.
Advanced primary hypothyroidism can lead to hyponatremia, mostfrequently associated with myxedema. Milder forms of hypothyroidismcan 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 of sufficient magnitude to leadto hyponatremia in association with a normal fluid intake. Withnormal fluid intake, hyponatremia generally results from theinability to decrease urine osmolality below plasma rather thana defect in maximal solute-free water excretion. The failureto dilute the urine below plasma generally is due to a failureto suppress maximally the antidiuretic hormone AVP (27). Thefailure of some hypothyroid patients to suppress plasma AVPduring an acute water load was reported initially by Skowskyet al. (28).
Recently, experimental studies in rats with advanced hypothyroidism(serum total T4 0.6 ± 0.02 ng/dl) further examined urinarydilution and maximal solute-free water excretion (29). Therewas a significant decrease in cardiac index and heart rate inthese hypothyroid animals that was normalized with l-thyroxinereplacement. During an acute water load, these hypothyroid animalsexhibited a significantly lower urine flow and higher urinaryosmolality than either control animals or hypothyroid animalsthat were treated with l-thyroxine. The hypothyroid animalsalso had significantly higher plasma AVP concentrations despitea lower plasma osmolality that normalized with l-thyroxine treatment.The impaired water excretion also was associated with an upregulationof AVP-mediated AQP2 expression and membrane trafficking inthe inner medulla (Figure 3). Taken together, these resultssuggested a major role of nonosmotic AVP release in the hyponatremiaassociated with advanced hypothyroidism. Studies therefore wereundertaken with a vasopressin V2 receptor antagonist (OPC-31260)in these animals with advanced hypothyroidism. Minimal urinaryosmolality in hypothyroid rats that were treated with the V2receptor antagonist was normalized as compared with untreatedhypothyroid rats (97 versus 430 mOsm/kg H2O; P < 0.0001).Maximal solute-free water excretion in the hypothyroid ratssignificantly increased but did not reach euthyroid values.These experimental results therefore support the pivotal roleof the baroreceptor-mediated nonosmotic AVP release in the hyponatremiaassociated with advanced hypothyroidism. The submaximal solute-freewater excretion would not be of clinical significance unlessother factors, such as diuretics or large fluid intakes, intervene.
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.
Of interest, a defect in maximal urinary concentration was observedat a somewhat less prolonged stage of experimental hypothyroidism(30). Maximal urinary osmolality with fluid deprivation wasassociated with decreased Na-K-2Cl expression and diminishedmedullary osmolality. Even though AQP2 expression was decreased,the failure to exhibit a difference between the diminished urinaryand medullary osmolality suggested that the primary mediatorof the concentrating defect was a decrease in the Na-K-2Cl co-transporterexpression and therefore impaired countercurrent concentrationrather than the decreased AQP2 expression. This urine-concentratingdefect in hypothyroidism would be of clinical relevance onlyin patients who were undergoing excessive extrarenal fluid losses(e.g., diarrhea).
Primary adrenal insufficiency (Addison’s disease) involvesdeficiency of glucocorticoid and mineralocorticoid hormones,both of which can be associated with hyponatremia. Hypopituitarismis associated with only glucocorticoid deficiency, because therenin-angiotensin-aldosterone system is intact. Although secondaryhypothyroidism is associated with hypopituitarism, in contrastto primary hypothyroidism, the severity generally is not sufficientto be associated with hyponatremia. Therefore, the hyponatremiathat is related to hypopituitarism generally is due to glucocorticoiddeficiency rather than thyroid deficiency.
Mineralocorticoid deficiency that is associated with primaryadrenal insufficiency exhibits a different pathophysiology thanglucocorticoid deficiency in causing hyponatremia. Because aldosteroneincreases potassium and hydrogen ion secretion, hyperkalemiaand nonanion gap metabolic acidosis is characteristic of primarybut not secondary adrenal insufficiency as a result of hypopituitarism.The mineralocorticoid deficiency also is responsible for thesodium chloride wasting and extracellular fluid volume depletionin primary adrenal insufficiency. Selective mineralocorticoiddeficiency has been studied in adrenalectomized animals thatreceived replacement glucocorticoid hormone (31–33). Withisolated mineralocorticoid hormone deficiency and hyponatremia,plasma AVP concentrations were not suppressed and collectingduct AQP2 and 3 expressions were upregulated. Outer medullaryNa-K-2Cl co-transporter and Na-K-ATPase were decreased in mineralocorticoidanimals (32). Administration of AVP V2 antagonist in these animalssignificantly improved urinary dilution, but a modest defectin maximal solute-free water excretion remained (33). This latterdefect relates to effects of extracellular fluid volume depletion,including decreased GFR and increased proximal tubular sodiumreabsorption with resultant diminished fluid delivery to thedistal diluting segment of the nephron. Avoidance of negativesodium balance in mineralocorticoid-deficient rats normalizedNa-K-2Cl co-transporter, Na-K-ATPase, and collecting duct AQP2and 3 (32). It also is of interest that high sodium chlorideintake may correct not only the hyponatremia but also the hyperkalemiaand metabolic acidosis in Addison’s disease, thereby supportingan important role for mineralocorticoid deficiency.
If hyponatremia persists in primary adrenal insufficiency despiteavoiding negative sodium balance, then the hyponatremia is dueto glucocorticoid deficiency. The mechanisms of hyponatremiawith glucocorticoid deficiency are different than with mineralocorticoiddeficiency. Glucocorticoid deficiency does not cause a negativesodium balance, and in fact a positive sodium balance may occur.The absence of glucocorticoid hormone, however, has major effectson systemic hemodynamics, including a decrease in cardiac indexwith an inadequate response of systemic vascular resistanceto maintain mean arterial pressure (34). These systemic effectsresult in several consequences. The resultant decrease in stretchon the arterial baroreceptors in the carotid sinus and aorticarch removes the tonic vagal and glossopharyngeal inhibitionon the central release of AVP. Elevated plasma AVP concentrationshave been demonstrated in glucocorticoid-deficient animals (33,35)and patients with hypopituitarism (36) despite a degree of hyposmolalitythat would maximally suppress AVP in normal individuals. Themessenger RNA for AVP in the hypothalamus also has been shownto be increased during glucocorticoid deficiency (37). AVP-synthesizingneurons terminate in the median eminence of the hypothalamus;therefore, a role for ACTH also could be involved in the nonosmoticAVP stimulation that is associated with glucocorticoid deficiency.There also is evidence of a central effect of glucocorticoidhormone in the hypothalamus whereby hypo-osmolality does notmaximally suppress AVP synthesis during glucocorticoid deficiency(38). In either case, the importance of this nonosmotic stimulationof AVP in glucocorticoid deficiency was documented using peptideand nonpeptide vasopressin V2 receptor antagonists, which profoundlyreversed the water retention (33,35).
A recent molecular analysis of the impaired diluting capacitywith glucocorticoid deficiency was undertaken in adrenalectomizedrats that received replacement physiologic concentrations ofmineralocorticoid hormone (35). As compared with adrenalectomizedrats that received replacement of both mineralocorticoid andglucocorticoid hormone, during an acute water load, the glucocorticoid-deficientanimals exhibited higher plasma AVP concentrations, diminishedsolute-free water excretion, and increased protein expressionin the inner medulla of AQP2, phosphorylated AQP2, and apicalmembrane trafficking of AQP2. The administration of a nonpeptidevasopressin V2 receptor antagonist reversed these events (Figure 4).
Figure 4. Effect of V2 receptor antagonist (OPC) in glucocorticoid-deficient rats to reverse the impaired water excretion (A) and urinary dilution (B) as well as the increased AQP2 (C) and phosphorylated AQP2 expression (D). Reprinted from reference (33), with permission.
There also was insight into AVP-independent effects on waterexcretion during glucocorticoid deficiency. Pair feeding duringglucocorticoid deficiency was associated with an upregulationof the Na+-K+-2Cl– co-transporter, Na+/H+ exchanger isoform3, and cortical and subunits of the epithelial sodium channeland sodium retention (35). These events, along with the effectof a decrease in renal perfusion pressure, would lead to decreasedfluid delivery to the distal nephron diluting segments and attenuatemaximal solute-free water excretion. This AVP-independent effecton maximal water excretion probably would not be of clinicalsignificance except in the circumstance of large increases inwater intake.
Of interest, maximal urinary concentration also was diminishedin glucocorticoid-deficient rats after 36 h of fluid deprivation(34). The concentrating defect involved primarily an impairmentof the countercurrent concentrating mechanism with comparablediminutions in medullary and urinary osmolalities. With thefluid deprivation, lower expression of the urea transporterand ion transporters (e.g., Na-K-2Cl) in the outer medulla seemedto account for the diminished medullary osmotic gradient.
The renal capacity to excrete solute-free water is substantial(27), yet the average daily fluid intake for hyponatremic patientsis only 2.4 L (39). The delivery of tubular fluid to the distaldiluting segment of the nephron is estimated to be approximately20% of glomerular filtrate. The diluting segment begins withthe water-impermeable ascending limb of Henle’s loop andin the absence of vasopressin includes virtually the remainderof the nephron, i.e., connecting tubule, collecting tubule,and cortical and medullary collecting ducts. With a GFR of 100ml/min, 140 L of filtrate occurs daily. If 20% of this filtratereaches the distal diluting segment and plasma AVP is maximallysuppressed, then 28 L of solute-free water theoretically couldbe excreted. Therefore, the normal capacity to excrete solute-freewater may approximate 1 L/h if administered consistently over24 h. Patients with primary polydipsia, however, ingest theirwater intake mostly during their awake hours of the day. Evenso, individuals who have primary polydipsia and normal renal,endocrine, cardiac, and hepatic function and are not volumedepleted or taking diuretics do not become hyponatremic fromdrinking up to 10 to 12 L of water per day. Their plasma osmolalities,however, may be in the lower normal range (275 to 285 mOsm/kgH2O). If any of the above circumstances intervene, then patientswith primary polydipsia are in danger of developing "water intoxication"with severe central nervous system symptoms, including headache,nausea, vomiting, decreased mentation, confusion, obtundation,seizures, and even cerebral hernia, cardiopulmonary arrest,and death. Pure water intoxication rarely can occur withoutan intervening 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 anticholinergic propertiesand/or delusions (e.g., "water cleanses the soul"). In fact,another term that has been used for primary polydipsia has beenpsychogenic water drinking. In 1973, acute psychoses with hyponatremiamimicking the syndrome of antidiuretic syndrome first was described(40). Subsequently, hyponatremia and water intoxication withfailure to suppress plasma AVP have been described with psychoticdisorders, such as schizophrenia (41). Psychiatric patientsalso have a high incidence of smoking, and nicotine is a verypotent acute stimulus for AVP release (42,43).
Recently, molecular and cellular events were analyzed in a uniquerat model of primary polydipsia in which the same daily foodintake was ingested in control animals with ad libitum waterintake and polyuric rats that drank 100 ml/d (44). This modeltherefore allowed assessment of the renal effects of polyuriaat comparable electrolyte, caloric, and protein intakes. Ascompared with controls, serum osmolality was lower in the polydipsicrats (293 versus 277 mOsm/kg H2O; P < 0.04) as was urineosmolality (1365 versus 139 mOsm/kg H2O; P < 0.001). As occursin humans after 10 d of increased water intake (45), a formof AVP-resistant NDI emerged after 10 d in the polydipsic rats.With 36 h of fluid deprivation, the polydipsic animals exhibitedsignificantly higher urine output associated with a lower urineosmolality despite significant higher plasma AVP concentrations(Figure 5). The ion and urea transporters with potential toalter the integrity of the countercurrent concentrating mechanismwere unaltered, including outer medullary Na-K-2Cl, Na-K-ATPase,and inner medullary urea transporter, in polydipsic as comparedwith control rats. The AQP1 water channel expression, whichif mutated can cause a concentrating defect (9,10), also wasno different in the polydipsic animals. What was remarkablydifferent was a highly significant suppression of AQP2 proteinexpression in the outer and inner medulla. The AQP2 expressionin the membrane fraction, as an index of trafficking to thecollecting duct membrane, was decreased. The AQP3 protein abundancein the outer medulla also was significantly diminished in thepolydipsic rats. After the 36-h fluid deprivation, the medullaryosmolalities in the control and polydipsic rats were no different,even though the polydipsic rats demonstrated a significant decreasein maximal urinary osmolality. This failure of osmotic equilibrationbetween the medullary interstitium and urine in the polydipsicrats supported a critical role of the downregulation of AQP2and, possibly, AQP3 in the impaired urine-concentrating capacityassociated with polydipsia.
Figure 5. During 36 h of water deprivation, rats with polydipsia (POLY) demonstrated increased urine output (A), decreased urine osmolality (B), increased plasma AVP (C), and decreased AQP2 expression as compared with control (CTL) rats (D). Reprinted from reference (44), with permission.
A decrease in plasma osmolality of 8 to 10 mOsm/kg H2O is anearly occurrence in normal pregnancy. Sodium and water retentionoccurs during pregnancy with an expansion of extracellular fluidranging from 30 to 50% (46). Water retention exceeds the sodiumretention in normal pregnancy and thus the fall in plasma osmolalityand sodium concentration. Recent studies have shown that systemicarterial vasodilation occurs early in the first trimester ofpregnancy (47). The mediator(s) of this decrease in vascularresistance is(are) not well defined, but some experimental resultsindicate a role of estrogen-mediated nitric oxide (48) and relaxin(49). In any case, the standard responses to arterial underfillingsecondary to arterial vasodilation also occur in pregnancy.There is a compensatory rise in cardiac output and stimulationof the renin-angiotensin-aldosterone system that attenuatesthe vasodilation-mediated fall in BP during the first trimester(47). In other circumstances of arterial vasodilation, suchas cirrhosis or a large arteriovenous fistula, the activationof arterial baroreceptors is accompanied by the nonosmotic releaseof AVP (50,51). In pregnancy, plasma AVP concentrations arestill detectable in the presence of a degree of hypo-osmolalitythat normally would suppress AVP release, i.e., 1 to 2% decreasein plasma osmolality. The hypo-osmolality of pregnancy has beentermed a "resetting" of the hypothalamic osmoreceptor thresholdto a lower level (52) but may be due merely to the nonosmoticrelease of AVP that occurs with arterial vasodilation (50,51).It also is of interest that early in pregnancy, there is anincrease in thirst and fluid intake despite a fall in plasmaosmolality, which normally suppresses thirst. This also is compatiblewith a nonosmotic stimulation of thirst as a result of arterialunderfilling.
Arterial underfilling as a result of arterial vasodilation,as occurs in cirrhosis and pregnancy, is associated with compensatoryincreases in total blood volume and cardiac output. Moreover,arterial vasodilation stimulates the nonosmotic AVP releaseand activates the renin-angiotensin-aldosterone axis, as occursin cirrhosis and pregnancy. These hormonal responses also compensatefor arterial underfilling, at the expense of hyponatremia andedema (50,51,53).
With the discovery of the renal water channels, i.e., AQP, bodywater regulation in pregnancy could be investigated in moredepth. Pregnancy in the rat exhibits most of the characteristicsof human pregnancy and therefore has been the standard experimentalmodel. Studies therefore were undertaken in pregnant rats toexamine the effect on renal AQP (54). If the nonosmotic releaseof AVP secondary to arterial vasodilation is involved in thewater retention in pregnancy (55), then vasopressin-mediatedupregulation and trafficking of AQP2 should be demonstrable.Alternatively, if pregnancy "resets" the osmotic threshold forAVP release, then the regulation of the AQP2 around this resetosmostat should mimic the nonpregnant state. As compared withnonpregnant littermates, pregnant rats were found to have inthe first trimester a profound upregulation of inner medullaryAQP2 mRNA and protein expression that persisted throughout thepregnancy (Figure 6). In the pregnant rats, there also was anincrease in AQP2 in the membrane fraction, indicating increasedAQP2 trafficking to the apical membrane of the collecting duct.It is known that the effect of AVP on AQP2 protein expressionand trafficking is mediated by vasopressin V2 receptor. Studiestherefore were undertaken with a nonpeptide V2 receptor antagonistin pregnant and nonpregnant animals. The AQP2 protein expressionand apical membrane location by immunofluorescence were returnedto the nonpregnant state during the V2 receptor antagonist administrationto pregnant rats (53). These experimental results thereforestrongly support a role of the nonosmotic AVP release in regulationAQP2 expression and trafficking in pregnancy. This was supportedfurther by the observation that increased urinary AQP2 occursduring pregnancy (56). It must be remembered, however, thatthe antidiuretic effect of oxytoxin also is mediated via theV2 receptor on the basolateral membrane of the collecting ductand therefore could be a contributing factor in the water retentionof pregnancy (57). It also has been shown that circulating vasopressinasefrom the placenta, which increases AVP degradation, can uncoveror cause diabetes insipidus in pregnancy (58).
Figure 6. Inner medulla AQP2 protein expression (densitometry above and immunoblots below) in nonpregnant (NP) rats and first-trimester (P7), second-trimester (P14), and third-trimester (P20) pregnant rats. Glycosylated (36 to 45 kD) and nonglycosylated (29 kD) expression is shown. Reprinted from reference (54), with permission.
Advanced heart failure frequently is associated with hyponatremia.In fact, hyponatremia has been found to be a risk factor forpoor survival for patients with congestive heart failure (59).The pathogenesis of the hyponatremia of cardiac failure initiallyseemed not to involve AVP, primarily because the bioassay forantidiuretic hormone was relatively insensitive. With the developmentof the RIA to measure plasma AVP, studies were undertaken toexamine the cause of hyponatremia in patients with heart failure.In the first study, the hypo-osmolality in patients with heartfailure was of a degree that would maximally suppress plasmaAVP in normal individuals, yet 30 (81%) of 37 patients had detectableplasma AVP by RIA (60). Therefore, the term nonosmotic AVP releaseemerged to describe hyponatremic patients with heart failureand other edematous disorders. There also is evidence for increasedAVP synthesis in the hypothalamus in experimental heart failure(61). Hyponatremia may occur both in low-output cardiac failure(e.g., ischemic or nonischemic cardiomyopathy) and in high-outputcardiac failure (e.g., thyrotoxicosis, beriberi, large arteriovenousfistula) (62). This apparent dilemma is understandable becausearterial underfilling with baroreceptor-mediated AVP stimulationcan occur with either a decrease in cardiac output or systemicarterial vasodilation as occurs with high-output cardiac failure(50,51,53).
With the discovery of water channels, investigations were undertakento examine whether increased plasma AVP in cardiac failure wouldbe associated with increased renal AQP2 protein expression andtrafficking to the apical membrane of the collecting duct (63,64).As in humans, plasma AVP increased in advanced cardiac failurein rats despite hypo-osmolality (63). In these animals withheart failure secondary to coronary artery ligation, AQP2 expressionand membrane trafficking were increased in the inner medullaof the kidney (63,64). Administration of a nonpeptide V2 receptorantagonist to these animals with heart failure reversed theincreased expression and trafficking of AQP2 (63). Support forthis relationship between nonosmotic AVP and AQP2 expressionhas been demonstrated by studies in patients with heart failureby measurement of urinary AQP2 (65). Approximately 3 to 6% ofAQP2 can be measured by RIA or Western immunoblotting in theurine. 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. UrinaryAQP2 decreased in these patients during the V2 receptor antagonistadministration (Figure 7) (65), thus indicating that less ofthis water channel reached the apical membrane of the collectingduct. An orally active, nonpeptide vasopressin V2 receptor antagonistwas shown recently in patients with cardiac failure to causea substantial loss of body weight over 30 d of treatment (66).Acute reversal of water retention with another nonpeptide V2antagonist also was shown recently (67). Cardiac afterload reductionwith either hydralazine or an angiotensin-converting enzymeinhibitor in patients with cardiac failure increased cardiacoutput, thereby attenuating arterial underfilling. This wasassociated with an increase in solute-free water excretion inassociation with a decrease in plasma and platelet AVP concentration(68).
Figure 7. Effect of V2 antagonist (VPA-985) in patients with chronic heart failure (New York Heart Association II and III) to decrease urinary AQP2 excretion in a dose-dependent manner as compared with placebo during day +1. Day –1 was the control day. T, time in hours. Reprinted from reference (65), with permission.
Hyponatremia frequently occurs in decompensated patients withcirrhosis and ascites (69), whereas patients with compensatedcirrhosis and no ascites rarely are hyponatremic (70). Hyponatremiaalso is a risk factor for poor survival in patients with cirrhosis(71). As with heart failure, not until measurement of plasmaAVP by RIA was the nonosmotic AVP incriminated in the hyponatremiaof cirrhosis (72). Early in cirrhosis, portal hypertension isassociated with an increased splanchnic blood flow (73). Theassociated decrease in systemic vascular resistance causes arterialunderfilling and baroreceptor-mediated increase in AVP release(74). An increase in AVP synthesis in the hypothalamus alsohas been found in experimental cirrhosis (75). The increasein plasma AVP and water excretion in cirrhosis were shown tocorrelate directly with plasma norepinephrine and renin activity(76). This observation provides evidence that cirrhosis activatesthe sympathetic and renin-angiotensin systems, as well as thenonosmotic stimulation of AVP, during arterial underfillingas a result of arterial vasodilation. Increased AQP2 expressionand trafficking also have been shown to be present in experimentalcirrhosis (77), a finding that is compatible with the observedincreased urinary excretion of AQP2 in patients with cirrhosis(78). Vasopressin V2 receptor antagonists also have been shownto increase solute-free water excretion in patients with cirrhosis(79) and experimental cirrhosis (80). These effects on the nonosmoticstimulation of AVP and AQP2 seem to be manifest with more severecirrhosis, 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. Recentevidence, however, indicates a prominent role of endothelialand inducible nitric oxide synthesis (83). In this regard, 7d of treatment with a nonspecific nitric oxide synthase inhibitorat a dose to reverse the arterial vasodilation and thus thehyperdynamic circulation of experimental cirrhosis was foundto suppress plasma AVP, increase solute-free water diuresis,and correct the hyponatremia (84).
NDI is when the kidney does not respond normally to the antidiureticeffect of AVP. NDI can be due to genetic or acquired causes.The cellular and molecular defects that cause the absolute orrelative renal unresponsiveness to vasopressin may involve impairmentof the water permeability across the collecting duct, the generationof the medullary osmotic gradient for water transport, or both.
Congenital NDI
The genetic or congenital NDI can be due primarily to mutationsin two areas. The most common defect relates to mutations ofthe vasopressin V2 receptor on the basolateral membrane of thecollecting duct. More than 180 mutations of the V2 receptorhave been found in chromosome region Xq28 (Figure 8), and togetherthese abnormalities account for 90% of patients with congenitalNDI (85). Studies suggest that most mutations involve proteinmisfolding, which traps the V2 receptor intracellularly, therebynot allowing the receptor to translocate to the basolateralmembrane of the collecting duct (86). Therefore, the adenylatecyclase-cAMP signaling pathway, which mediates AQP2 expressionand trafficking to the apical membrane, is not activated. Recentin vivo studies indicate that nonpeptide V2, V1, and V1/V2 receptorantagonists may allow some of the mutant V2 receptors to betransported to the basolateral membrane and to function normally(87). These antagonists act as chaperones for the misfoldedV2 receptors to reach the membrane. A recent study in patientswith NDI demonstrated an approximate decrease in daily urineflow from 12 to 8 L and an increase in urinary osmolality from98 to 170 mOsm/kg using such a receptor antagonist (88). Thisvariety of congenital NDI has an X-linked recessive mode ofinheritance, and affected male individuals cannot concentratetheir urine in response to vasopressin. Heterozygous femaleindividuals generally are asymptomatic but may have a modestdegree of polyuria and polydipsia. In contrast, male individualsmay have up to 20 L of urine every day. The need to drink sufficientwater to maintain water balance, therefore, is challenging andcertainly affects the quality of life of the individual. Beforegenetic screening of newborns in affected families, dehydrationand mental retardation frequently developed. Now affected individualswho receive adequate water intake progress to normal adulthoodwithout any mental or physical retardation.
Figure 8. Diagram showing the type 2 vasopressin receptor (V2 receptor) protein and identifying putative disease-causing mutations in the arginine vasopressin receptor 2 gene (circles). Mutations are present in the extracellular, transmembrane, and cytoplasmic domains of the V2 receptor. The numbers 1 and 371 refer to amino acids 1 and 371, respectively. COOH, carboxy-terminus of the protein; NH2, amino-terminus of the protein. Reprinted from reference (11), with permission.
Another cause of congenital NDI involves mutations of the AQP2gene in chromosome region 12q13 (89). This accounts for 10%of families with congenital NDI. Currently, more than 30 suchmutations have been identified (Figure 9). In the autosomalrecessive variety, the mutant AQP2 proteins are trapped in theendoplasmic reticulum, whereas the autosomal dominant varietiesare mutations of the carboxy terminus.
Figure 9. Diagram showing the AQP2 protein and identifying putative disease-causing mutations in AQP2 (circles). Mutations are present in the extracellular, transmembrane, and cytoplasmic domains of AQP2. The numbers 1 and 271 refer to amino acids 1 and 271, respectively. Reprinted from reference (11), with permission.
Acquired NDI
Hypokalemia and hypercalcemia are electrolyte disorders thatmay be associated with polyuria and polydipsia as a result ofa defect in the renal response of vasopressin to concentratethe urine maximally. Experimental studies in rats have beenundertaken to study the mechanisms involved. A potassium-deficientdiet for 11 d caused hypokalemic-related NDI (90), and 7 d ofvitamin D (dihydrotachysterol) caused hypercalcemic-relatedNDI (91). In both experimental models, there was a downregulationof AQP2 expression in the inner medulla. In the hypercalcemicmodel, there also was a decrease in the Na-K-2Cl co-transporterin the outer medulla. As the initiator of the countercurrentconcentrating mechanism for generation of the corticomedullaryosmotic gradient, this decrease in the Na-K-2Cl co-transporterno doubt also contributed to the acquired NDI.
Polyuria secondary to NDI also may accompany bilateral urinarytract obstruction, in part due to the resultant volume expansionand urea retention. Experimental studies, however, have shownthat unilateral ureteral obstruction, which avoids these sequelaeof bilateral ureteral obstruction, also causes NDI (92). Aswith the above electrolyte disorders, AQP2 downregulation hasbeen demonstrated to be associated with acquired NDI relatedto urinary tract obstruction. Lithium also has been demonstratedin experimental animals to be associated with downregulationof AQP2 expression and trafficking (93). Lithium therapy hasbeen a worldwide, effective treatment for bipolar affectivedisorder for many years. Therefore, understanding the mechanismfor the NDI that is associated with this medication is important,particularly because it occurs in approximately 20% of treatedpatients. In this regard, recent in vitro and in vivo experimentssuggest that the effect of lithium to downregulate AQP2 mayoccur independent of adenylyl cyclase 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, and3 expression has been shown to be reduced in rats with botholiguric and nonoliguric ischemic acute renal failure (96).Similar results have been found in the 5/6 nephrectomy–inducedmodel of chronic renal failure (97). In patients with advancedchronic renal failure, vasopressin-resistant hypotonic urinehas been described (98). This finding suggests a defect in watertransport across the medullary collecting duct, because absoluteimpairment of the countercurrent concentrating mechanism stillwould be associated with an isotonic, not hypotonic, medullaryinterstitium. In contrast to congenital NDI, the polyuria ofacquired NDI generally is of a moderate degree (e.g., 3 to 4L/24 h). The thirst mechanism generally protects against hypernatremiain NDI states unless age (newborn, elderly) or illness restrictsavailability of fluid intake.
The ability to analyze the renal water channels and ion andurea transporters has allowed for the better understanding ofseveral clinical disorders with impaired urinary dilution and/orconcentration.
Acknowledgments
This work was supported by National Institutes of Health grantDK 19928.
I appreciate the assistance of Jan Darling in the preparationof the manuscript. Most important, I acknowledge Peter Agre,MD, and his associates, whose discovery of the first mammalianwater channel has allowed much of this work to be undertaken.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Introduction
Hypothyroidism
and 
subunits of the epithelial sodium channel and sodium retention (35). These events, along with the effect of a decrease in renal perfusion pressure, would lead to decreased fluid delivery to the distal nephron diluting segments and attenuate maximal solute-free water excretion. This AVP-independent effect on maximal water excretion probably would not be of clinical significance except in the circumstance of large increases in water intake. 
