Arginine vasopressin resistance (nephrogenic diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation

INTRODUCTION — Arginine vasopressin V2 resistance (AVP-R), previously called nephrogenic diabetes insipidus [1], refers to a decrease in urinary concentrating ability that results from resistance to the action of arginine vasopressin (AVP, also known as antidiuretic hormone [ADH]). This problem can reflect resistance at the AVP site of action in the collecting tubules, or interference with the countercurrent mechanism due, for example, to medullary injury or to decreased sodium chloride reabsorption in the medullary aspect of the thick ascending limb of the loop of Henle (figure 1) [2]. (See "Evaluation of patients with polyuria".)

The etiologies, clinical manifestations, and postdiagnostic evaluation of AVP-R are reviewed in this topic. Related issues are discussed separately:

●Evaluation of patients with polyuria and diagnosis of AVP-R (see "Evaluation of patients with polyuria")

●Treatment of AVP-R (see "Arginine vasopressin resistance (nephrogenic diabetes insipidus): Treatment")

●Arginine vasopressin deficiency (AVP-D, previously called central diabetes insipidus) (see "Arginine vasopressin deficiency (central diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation" and "Arginine vasopressin deficiency (central diabetes insipidus): Treatment")

EPIDEMIOLOGY — AVP-R, in its mildest form, is relatively common since almost all patients who are older adults, acutely or chronically ill, or have acute or chronic kidney disease have a reduction in maximum concentrating ability [2]. As an example, the maximum urine osmolality that can be achieved may fall from the normal value of 800 to 1200 mosmol/kg down to 350 to 600 mosmol/kg in these settings [2]. In chronic kidney disease, this defect is due in part to increased solute excretion per functioning nephron and probably also to decreased expression of mRNA for the V2 vasopressin receptor [2,3].

By contrast, AVP-R that is clinically significant (ie, polyuria >3L/day or >40 to 50 mL/kg/day) is a rare disease. (See "Evaluation of patients with polyuria".)

The true incidence and prevalence of AVP-R are unknown. However, it is thought to be less prevalent than arginine vasopressin deficiency (AVP-D, previously called central diabetes insipidus), which is estimated to be present in 1 of 25,000 individuals.

Both age of presentation and sex differences in prevalence depend on the etiology. In adults, the most common causes of AVP-R severe enough to produce polyuria are chronic lithium ingestion and hypercalcemia, with no clear sex dimorphism. In children, the most common cause is hereditary AVP-R (ie, genetic), with a median age at diagnosis of seven months and a male predominance due to residence of the vasopressin V2 receptor gene on the X-chromosome [4].

In one study that followed the general population of Quebec, Canada for a 10-year period (1988 to 1997), the incidence of X-linked AVP-R was approximately 9 per million male live births (ie, four cases in 454,629 male live births) [5]. Although this esimate may reflect the incidence of this disorder worldwide, a population genetic event such as a founder effect can lead to a higher incidence regionally. As an example, the incidence of AVP-R due to the W71X AVPR2 mutation was 58 cases per million male live births in the Canadian maritime provinces of Nova Scotia and New Brunswick; the incidence is also higher in Utah [6].

Hereditary AVP-R due to mutations in the AQP2 gene is thought to be even less common than AVP-R due to AVPR2 mutations [7,8].

PATHOPHYSIOLOGY — The pathophysiology of AVP-R depends upon the etiology but, in nearly all cases, involves disruption of the AVP-stimulated signaling cascade in the principal cells of the kidney collecting duct (figure 1).

With genetic etiologies, there are inactivating mutations of either the gene encoding the AVP V2 receptor (AVPR2) or the aquaporin 2 water channel (AQP2). The first results in insufficient generation of G-protein-stimulated cyclic adenosine monophosphate (cAMP) to activate insertion of AQP2 channels into the apical membrane; the second results in insufficient insertion of biologically active AQP2 channels into the apical membrane despite elevated intracellular cAMP levels.

Most of the medication-induced (lithium) and metabolic (hypercalcemia, hypokalemia) etiologies appear to produce autophagy and dysfunction of AQP2 water channels. Functional etiologies are due to down-regulation of AQP2 synthesis and protein abundance in the principal cells of the collecting duct. These are each described in more detail below. (See 'Etiologies' below.)

ETIOLOGIES

Medication-induced

Lithium toxicity — Polyuria due to impaired urinary concentrating ability occurs in up to 20 percent of patients treated with chronic lithium therapy; an additional 30 percent have a subclinical impairment in concentrating ability. These adverse effects are mediated by lithium entry into the principal cells in the collecting tubule via the epithelial sodium channel (ENaC) [9]. Here, lithium inhibits signaling pathways that involve glycogen synthase kinase type 3 beta (GSK3beta), resulting in dysfunction of the aquaporin 2 (AQP2) water channel (figure 2) [9]. Lithium may also impair generation of cAMP, leading to decreased insertion of that water channel into the apical membrane [10].

A more detailed discussion of the pathogenesis, clinical manifestations, and management of lithium-induced AVP-R is presented separately. (See "Renal toxicity of lithium", section on 'Arginine vasopressin resistance (nephrogenic diabetes insipidus)'.)

Other medications — AVP-R can be caused by a number of medications other than lithium. These include [11-17]:

●Cidofovir and foscarnet, which are used to treat cytomegalovirus infection in patients with human immunodeficiency virus (HIV) infection

●Vasopressin V2 receptor antagonists, which induce a transient state of AVP-R that can be used to treat hyponatremia and autosomal dominant polycystic kidney disease

●Amphotericin B

●Demeclocycline

●Ifosfamide

●Ofloxacin

●Orlistat

●Didanosine

Medication-induced AVP-R is typically reversible, at least in part [16].

Metabolic

Hypercalcemia — A renal concentrating defect may become clinically apparent if the plasma calcium concentration is persistently above 11 mg/dL (2.75 mmol/L) [2], although most patients who present with hypercalcemia-induced AVP-R have calcium concentrations above 12 mg/dL (3 mmol/L). (See "Clinical manifestations of hypercalcemia", section on 'Arginine vasopressin resistance'.)

The mechanism by which these changes occur is incompletely understood. Calcium deposition in the medulla with secondary tubulointerstitial injury may play an important role [18]. In addition, activation of the calcium-sensing receptor can directly impair concentrating ability by affecting both the loop of Henle and the collecting tubules [19] (see "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia"):

●Calcium-sensing receptors are expressed on the basolateral membrane in the thick ascending limb of the loop of Henle. Activation of these receptors by calcium reduces sodium chloride and calcium reabsorption in the thick ascending limb, an effect that appears to be mediated by the generation of a P450 arachidonic acid metabolite (possibly 20-HETE), which then induces closure of the luminal potassium channel [20]. Inhibition of loop sodium chloride reabsorption impairs generation of the medullary osmotic gradient that is essential for urinary concentration [19].

●Hypercalcemia also enhances the generation of prostaglandin E2, which can contribute to the impairment in sodium chloride reabsorption in the thick ascending limb [21,22]. This response may be mediated by angiotensin II-induced activation of phospholipase A2 and prostaglandin H synthase 1 [22]. In hypercalcemic rats, the associated polyuria can be abolished by the administration of losartan, an angiotensin II receptor blocker [22].

●Calcium-sensing receptors are also expressed on the luminal membrane of the cells of the inner medullary collecting duct (IMCD) (figure 2). By reducing calcium and sodium reabsorption in the loop of Henle, hypercalcemia is associated with an increase in calcium delivery to the luminal IMCD calcium-sensing receptors; their activation reduces the AVP-induced increase in water permeability due to inhibition of signaling pathways that involve GSK3beta, similar to lithium (figure 2) [21,23-25].

Hypercalcemia may also impair water reabsorption by autophagic degradation of AQP2 [26]. In a rodent study, a large decrease in AQP2 expression was observed in the inner medulla and cortex of hypercalcemic rats compared with control animals [27]. This was associated with an increase in urine output and a reduction in urine osmolality.

The concentrating defect induced by hypercalcemia is generally reversible with restoration of a normal serum calcium concentration. However, the defect may persist in patients in whom interstitial nephritis has induced permanent medullary damage.

Hypokalemia — Persistent severe hypokalemia (plasma potassium concentration usually below 3 mEq/L) can impair urinary concentrating ability (figure 2). As with hypercalcemia, both decreased collecting tubule responsiveness to AVP (which may be mediated by decreased expression of AQP2) and diminished sodium chloride reabsorption in the thick ascending limb have been demonstrated in experimental animals [28-30]. Downregulation of urea transporters may also contribute to the impairment of urinary concentrating ability induced by potassium depletion [31] (see "Hypokalemia-induced kidney dysfunction", section on 'Impaired urinary concentrating ability'). In addition, enhanced autophagic degradation of proteins, most notably AQP2, has been demonstrated to be an early event in hypokalemia-induced AVP-R [32].

The concentrating defect is generally less severe than with lithium toxicity or hypercalcemia, and symptomatic polyuria and polydipsia are uncommon [2]. When these symptoms do occur, direct stimulation of thirst (via an unknown mechanism) may play a contributory role [33].

Kidney disease — Symptomatic AVP-R can be seen in a variety of kidney diseases, including unilateral or bilateral urinary tract obstruction [34,35], sickle cell disease or trait, autosomal dominant polycystic kidney disease and medullary cystic kidney disease [36,37], renal amyloidosis [38], and Sjögren's disease [39]. In the last two conditions, amyloid deposits in and lymphocytic infiltration around the collecting tubules are presumably responsible for the decline in AVP responsiveness. (See "Sickle cell disease effects on the kidney" and "Autosomal dominant polycystic kidney disease (ADPKD): Kidney manifestations", section on 'Concentrating defect' and "Autosomal dominant tubulointerstitial kidney disease" and "Renal amyloidosis" and "Kidney disease in primary Sjögren's disease" and "Clinical manifestations and diagnosis of urinary tract obstruction (UTO) and hydronephrosis", section on 'Prognosis'.)

A decline in urinary concentrating ability is also common in patients with acute or chronic kidney disease. A variety of factors contribute including decreased tubular responsiveness to AVP [40,41], and interference with the countercurrent mechanism in diseases affecting the renal medulla, such as chronic pyelonephritis and analgesic abuse nephropathy. In addition, the decrease in the number of functioning nephrons in patients with acute or chronic kidney disease means that each remaining nephron must excrete a larger proportion of the total solute load. The net result is an osmotic diuresis that limits the ability to concentrate the urine [42,43]. Despite the impairment in concentrating ability, patients with acute or chronic kidney disease do not usually develop polyuria for at least two reasons: the glomerular filtration rate, and therefore the filtered fluid load, is substantially reduced; and the urine osmolality is usually isosmotic or only slightly hypoosmotic to plasma [41].

Hereditary AVP-R — Hereditary AVP-R is an uncommon disorder resulting in variable degrees of resistance to AVP [44-48]. There are two different receptors for AVP: the V1 (AVPR1, including V1a and V1b, receptors) and V2 (AVPR2) receptors. The AVPR2 gene is located on the X chromosome (Xq-28).

Activation of the V1 receptors induces vasoconstriction and enhancement of prostaglandin release [2], while the V2 receptors mediate the antidiuretic response as well as peripheral vasodilation and the release of factor VIIIc and von Willebrand factor from endothelial cells (figure 3) [49].

There are also several congenital polyuric-polydipsic Bartter-like syndromes associated with urinary concentrating defects of varying severity. (See 'Other genetic disorders' below and "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations".)

Vasopressin V2 receptor gene mutations — Approximately 90 percent of cases of hereditary AVP-R have X-linked inheritance [50,51]. They are due to mutations in the AVPR2 gene, which encodes for a dysfunctional vasopressin V2 receptor.

Several hundred putative disease-causing AVPR2 mutations have been identified in ancestrally independent families. Most of these mutant proteins are misfolded, trapped in the endoplasmic reticulum and unable to reach the basolateral cell surface of the principal cells of the collecting ducts to engage circulating vasopressin [45]. In patients with AVPR2 mutations, the antidiuretic, vasodilator, and coagulation factor responses to AVP are impaired, while the vasoconstrictor and prostaglandin effects are intact [49].

The X-linked inheritance means that males tend to have more pronounced polyuria. Female carriers are usually asymptomatic because they have a normal gene on the second X chromosome. However, occasional females have severe polyuria. The presumed mechanism is that X chromosome inactivation is skewed in such a way that the normal X chromosome is preferentially inactivated, leaving the mutant X chromosome dominantly expressed in the kidney [52,53].

Although heterozygous female individuals may be asymptomatic most of the time, they may develop polyuria during pregnancy when vasopressinases released from the placenta markedly increase the clearance of endogenous AVP. (See "Polyuria and diabetes insipidus of pregnancy".)

There is no specific therapy for X-linked AVP-R due to mutations in the AVPR2 gene. However, studies in a mouse model in which the V2 vasopressin receptors were deleted showed that activation of kidney EP4 prostaglandin E2 receptors with a selective agonist could compensate for the lack of functional V2 receptors and could markedly reduce all of the manifestations of the disease, including the polyuria and alterations in kidney morphology [54]. In the same mouse model, metformin, an adenosine monophosphate kinase activator, also increased urine osmolality, probably bypassing the V2 receptor and directly phosphorylating AQP2 [55]. In addition, nonpeptide vasopressin receptor agonists have been identified that can activate the mutant V2 receptors at their intracellular sites [56]. These and other treatment issues in patients with AVP-R are discussed elsewhere. (See "Arginine vasopressin resistance (nephrogenic diabetes insipidus): Treatment", section on 'Treatment'.)

Aquaporin-2 gene mutation — A second form of hereditary AVP-R is caused by a defect in the AQP2 gene that encodes the AVP-sensitive water channels in the collecting tubule cells. This variant may have autosomal recessive or autosomal dominant modes of inheritance [46,48,50,52,57-65].

AQP2 channels are normally stored in the cytosol. Under the influence of AVP, the AQP2 water channels are phosphorylated at Ser 256, Ser 264, and Ser 269 [66,67] and redistributed to the apical (luminal) membrane, thereby allowing water to be reabsorbed down the favorable concentration gradient from the tubular fluid into the hypertonic medullary interstitium [61,62,68]. (See "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'Regulation of plasma tonicity'.)

In one kindred, the autosomal dominant form of AVP-R was mediated by lack of phosphorylation of the AQP2 water channel [69]. Such defects impair trafficking of the water channels, preventing their fusion with the luminal membrane, and decrease channel function [46,50,58,64].

Inherited defects of the AQP2 water channel can be distinguished clinically from the more common V2 receptor defect by evaluating, in male patients, the extrarenal responses to AVP: vasodilation and release of factor VIIIc and von Willebrand factor from endothelial cells [64,70]. These responses are intact in patients with defective water channels and impaired in patients with defective V2 receptors. Molecular genetic testing is also available [48,52].

Other genetic disorders

●Bardet-Biedl syndrome – Bardet-Biedl syndrome is an autosomal recessive disorder that is characterized by obesity and a number of other abnormalities, including hypogenitalism in males, intellectual disability, retinal dystrophy, polydactyly, kidney malformations (particularly calyceal abnormalities), hypertension, and, over time, progressive chronic kidney disease [71,72].

Polyuria and polydipsia are among the most common and earliest symptoms [71]. A urinary concentration defect can be detected when kidney function is near normal and in the absence of major cyst formation [73]. Bardet-Biedl-derived renal epithelial cells are nonciliated, and the vasopressin V2 receptor, which is activated by AVP in normal individuals, is present in the primary cilium [73]. In in vitro studies, these cells did not respond to luminal vasopressin and did not activate luminal AQP2.

●Bartter syndrome – There are several congenital polyuric-polydipsic Bartter syndromes associated with AVP-R of varying severity [50,74-76]. These patients have various degrees of polyuria that may be poorly investigated and confused with "pure" hereditary AVP-R [47]. However, patients with "pure" AVP-R handle sodium and potassium normally in contrast to patients with Bartter syndrome, who have renal sodium and potassium wasting. In addition, Bartter syndrome may start prenatally, with polyhydramnios frequently leading to prematurity; in some cases caused by mutations in MAGED2, the antenatal Bartter syndrome may be transient [76]. (See 'Hereditary AVP-R' above and "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations", section on 'Clinical manifestations'.)

The presence of Bartter syndrome can also be distinguished from "pure" hereditary AVP-R in part by sequencing the carboxyl terminus or the last exons of SLC12A1 and KCNJ1 (which are two of the five genes underlying Bartter syndrome) [47]. This approach may be informative because most mutations in SLC12A1 and KCNJ1 are found in the carboxyl terminus or in the last exon and, as a consequence, are amenable to rapid DNA sequencing.

●Other – Other inherited disorders with a mild, moderate, or severe inability to concentrate the urine include nephronophthisis [77,78], cystinosis [79], familial hypomagnesemia with hypercalciuria and nephrocalcinosis [80], and the syndrome of apparent mineralocorticoid excess, in which the polyuria is presumed to be due to chronic hypokalemia, as described above [81,82]. (See "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Renal disease' and "Cystinosis", section on 'Kidney manifestations' and "Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)" and 'Hypokalemia' above and "Hypomagnesemia: Causes of hypomagnesemia".)

The ARC syndrome (arthrogryposis-renal dysfunction-cholestasis), a rare autosomal recessive multisystem disorder caused by mutations in VPS33B [83] and VIPAR [84], is also associated with renal tubular dysfunction, medullary nephrocalcinosis, and AVP-R.

Functional — As noted above, many etiologies of AVP-R (eg, lithium, hypercalcemia, kidney disease) involve reduced abundance of AQP2 water channels in principal cells, which are essential for maximal AVP-stimulated urine concentration. Transcriptomic and proteomic analyses indicate that several mechanisms contribute to the decreased AQP2 abundance in these pathological conditions, including oxidative stress, apoptosis/autophagy, and inflammatory signaling [85].

However, in addition to these pathological causes of decreased AQP2 protein in principal cells of the collecting duct, some physiological conditions that chronically reduce stimulation of vasopressin V2 receptors by circulating AVP can produce a down-regulation of AQP2 synthesis, leading to decreased AQP2 abundance resulting in AVP-R. This is because AVP-mediated stimulation of adenylyl cyclases, elevation of intracellular cAMP, and activation of protein kinase A not only increases trafficking of AQP2 water channels to the apical membrane of principal cells but also promotes AQP2 transcription [86,87]. Thus, in the absence of AVP activation of vasopressin V2 receptors in the kidney, AQP2 levels in the kidney are reduced by as much as any of the pathological conditions causing clinically significant AVP-R, such as lithium or hypercalcemia. This has importance clinically for situations where plasma AVP levels are chronically absent or suppressed.

●Arginine vasopressin deficiency (AVP-D) – AVP-D is a state of chronic AVP deficiency. When complete, this leads to hypotonic polyuria and polydipsia. (See "Arginine vasopressin deficiency (central diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation".)

In experimental animals, the chronic absence of vasopressin leads to decreased AQP2 synthesis. Consequently, in Brattleboro rats with genetic AVP-D, AQP2 levels in the collecting duct after AVP administration are 68 percent lower than in the non-deficient parent strain [88]. Following sustained AVP infusion by osmotic minipumps, collecting duct AQP2 levels in the AVP-deficient rats gradually rise, reaching levels equivalent to the parent strain after five days. Similarly, in some patients with newly diagnosed AVP-D, it may take several days to reach maximal levels of urine osmolality after administration of desmopressin.

●Primary polydipsia – Primary polydipsia is a disorder characterized by increased intake of fluids with secondary polyuria. Although pathophysiologically distinct from AVP-D, both disorders share the same characteristic of absent or low plasma AVP levels. In AVP-D, this is because of absent neurohypophyseal AVP secretion. In primary polydipsia, the increased fluid intake leads to decreased plasma osmolality and, consequently, suppression of neurohypophyseal AVP secretion.

Consequently, like in patients with chronic AVP-D, the response to vasopressin is also temporarily diminished in patients with primary polydipsia. When desmopressin is administered after water deprivation as a diagnostic test to determine the cause of polyuria, patients with primary polydipsia respond with a much lower urine osmolality than is found in healthy individuals deprived of water. However, with time, the urine becomes more concentrated, and if water intake is not curtailed, polydipsic patients are susceptible to desmopressin-induced hyponatremia.

On the other hand, when water intake is abruptly reduced or curtailed in individuals with chronic primary polydipsia (eg, after admission to the hospital), they can become mildly dehydrated. Blunted urine concentrating ability may lead to an erroneous diagnosis of partial AVP-D.

Pregnancy — Gestational arginine vasopressin disorder is an uncommon condition during the second half of pregnancy in which AVP is degraded by placental vasopressinase [89,90]. Gestational AVP disorder is neither truly AVP-D (since AVP is produced normally by the neurohypophysis) nor AVP-R (since the kidneys remain capable of responding to AVP, and in fact do respond to exogenous desmopressin, which is resistant to vasopressinase). This disorder is discussed in detail separately. (See "Polyuria and diabetes insipidus of pregnancy".)

CLINICAL MANIFESTATIONS — Patients with untreated AVP-R typically present with polyuria, nocturia, and, due to the initial elevation in serum sodium and osmolality, polydipsia.

Children with hereditary AVP-R are at high risk for hypernatremia, hypovolemia, hypotension, and shock, beginning as early as their first hours of life; many examples of these dramatic cases have been reported [91]. Although rare, such cases are simple to recognize, and early diagnosis is essential to prevent catastrophic outcomes.

In addition to polydipsia and polyuria, these patients can have other clinical findings such as food aversion and motor developmental delay (eg, delay in independent walking). As a result of these symptoms, other diagnostic tests, such as imaging studies, are sometimes performed that require temporary cessation of oral intake. In a patient who has not been recognized as having hereditary AVP-R, this can lead to rapid onset of severe hypernatremia and neurologic injury.

As an example, in the experience of one of the authors, a 20-month-old boy with polydipsia and polyuria (approximately 3 litres per day) who had food aversion and motor developmental delay was scheduled for magnetic resonance imaging (MRI). Despite having been diagnosed with AVP-R, oral intake was withheld prior to the procedure without intravenous fluids. The MRI was delayed, and after approximately eight hours with no fluid intake, his neurologic status deteriorated. Laboratory testing at the time revealed a plasma sodium of 174 mmol/L. The emergency response team administered two boluses of 20 ml/kg isotonic saline and the boy became unresponsive. A subsequent test revealed a plasma sodium of 198 mmol/L. A subsequent MRI showed diffuse white matter abnormalities consistent with osmotic demyelination syndrome.

In adults with acquired AVP-R, resistance to AVP is typically partial, rather than complete as seen in patients with hereditary AVP-R. The urine in adults with acquired AVP-R is normally most concentrated in the morning due to lack of fluid ingestion overnight and increased AVP secretion during the late sleep period [92]. As a result, the first manifestation of a mild to moderate loss of concentrating ability is often nocturia. However, nocturia is not diagnostic of a defect in concentrating ability, since it can also be caused by other factors such as drinking before going to bed or, in males, by prostatic hypertrophy, which is characterized by urinary frequency rather than polyuria.

The serum sodium level in untreated patients with AVP-R is often in the high normal range, which provides the stimulus for thirst to replace urinary water losses [93]. Moderate to severe hypernatremia can develop when thirst is impaired, or cannot be expressed, or if there is limited access to water. This can occur in infants, young children, and neurologically impaired adults who cannot independently access free water, and in the postoperative period in patients with unrecognized AVP-R.

Patients with AVP-R may also have manifestations related to the underlying cause, such as lithium toxicity, hypercalcemia, and hypokalemia. If severe hypernatremia develops rapidly, profound neurological disturbances can occur, called hypernatremic encephalopathy.

Partial AVP-R can be exacerbated or first become apparent during pregnancy since catabolism of AVP is increased by vasopressinases released from the placenta [89,94]. (See "Polyuria and diabetes insipidus of pregnancy".)

DIAGNOSIS AND POSTDIAGNOSTIC EVALUATION

Confirming the diagnosis — In patients who have symptoms consistent with an arginine vasopressin disorder (eg, polyuria, nocturia, and polydipsia not resulting from uncontrolled diabetes mellitus or another obvious cause), the approach to confirming the diagnosis of AVP-R is as follows (see "Evaluation of patients with polyuria", section on 'When the cause is not obvious'):

●Establish the presence of polyuria and a water diuresis – Patients with confirmed polyuria (ie, urine output >3 L/day, or >40 to 50 mL/kg/day, usually assessed with a 24-hour urine collection) may have a solute diuresis or a water diuresis (algorithm 1). In such patients, a urine osmolality <300 mosmol/kg confirms the presence of a water diuresis. A urine osmolality >600 mosmol/kg confirms the presence of a solute diuresis. In patients with an intermediate urine osmolality (ie, between 300 and 600 mosmol/kg), the total daily solute excretion is calculated (which is equal to the urine osmolality multiplied by the total urine volume on a 24-hour specimen). If the total daily solute excretion is <1000 mosmol, then the patient has a water diuresis. (See "Evaluation of patients with polyuria", section on 'Determining if further testing is necessary'.)

●Establishing the presence of AVP resistance – Patients with polyuria and a water diuresis may have AVP-D, AVP-R, or primary polydipsia. These three disorders can be distinguished using plasma copeptin (only if reliable assays are available) (algorithm 2), or with a water restriction test and assessing the response to desmopressin (algorithm 3). These procedures are discussed in detail elsewhere. (See "Evaluation of patients with polyuria", section on 'Water restriction (or hypertonic saline) test'.)

Postdiagnostic evaluation to determine the etiology — Once the diagnosis of AVP-R has been confirmed, the next step is to determine its cause. Among patients with a physiologic diagnosis of AVP-R, a generally accepted approach is as follows:

●Cause is often apparent – In many cases, the etiology of AVP-R is apparent from the history (eg, a patient with long-term use of lithium for bipolar disorder) or from routine laboratory studies (eg, hypercalcemia, severe hypokalemia, advanced chronic kidney disease).

●When the cause is not apparent – Rarely, the cause of AVP-R is not apparent from the routine history, physical exam, and laboratory testing. In all such patients, particularly in children, genotyping should be performed to evaluate for mutations in the AVP V2 receptor (AVPR2) gene and the aquaporin 2 water channel (AQP2) gene. Genetic testing should be performed even in the absence of a family history of polyuria because spontaneous (ie, non-germline) mutations may occur. Genetic testing may also uncover other mutations associated with polyuria (eg, Bartter syndrome).

If no candidate mutations are discovered, then all medications that could be associated with AVP-R should be discontinued, if possible. (See 'Other medications' above.)

If the patient is not taking a potentially causative medication or if polyuria persists after discontinuing a potentially causative medication, then the diagnosis of AVP-R should be reevaluated. (See "Evaluation of patients with polyuria", section on 'Patients with a normal serum sodium'.)

It should be noted that "idiopathic" AVP-R is much less common than "idiopathic" AVP-D. If a diagnosis of AVP-R is confirmed, then the patient should be followed carefully over time to identify potential latent conditions responsible for the disorder.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fluid and electrolyte disorders in adults".)

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SUMMARY

●Definition and pathophysiology – Arginine vasopressin V2 resistance (AVP-R), previously called nephrogenic diabetes insipidus, refers to a decrease in urinary concentrating ability that results from resistance to the action of arginine vasopressin (AVP, also known as antidiuretic hormone [ADH]). This problem can reflect resistance at the AVP site of action in the collecting tubules, or interference with the countercurrent mechanism due, for example, to medullary injury or to decreased sodium chloride reabsorption in the medullary aspect of the thick ascending limb of the loop of Henle (figure 1). (See 'Introduction' above and 'Pathophysiology' above.)

●Epidemiology – AVP-R that is clinically significant (ie, with polyuria >3L/day or >40 to 50 mL/kg/day) is a rare disease. Both age of presentation and sex differences in prevalence depend on the etiology. In adults, the most common causes of AVP-R severe enough to produce polyuria are chronic lithium ingestion and hypercalcemia, with no clear sex dimorphism. In children, the most common cause is hereditary AVP-R (ie, genetic), with a median age at diagnosis of seven months and a male predominance due to residence of the vasopressin V2 receptor gene on the X-chromosome. (See 'Epidemiology' above.)

●Etiology – AVP-R may be acquired, due to medications (ie, lithium or other agents), metabolic disorders (ie, hypercalcemia, hypokalemia), or certain types of kidney disease, or may be hereditary, due to mutations in the AVPR2 gene (which encodes the vasopressin V2 receptor) or in the AQP2 gene (which encodes the AVP-sensitive water channels in the collecting tubule cells). (See 'Etiologies' above.)

●Clinical manifestations – Patients with untreated AVP-R typically present with polyuria, nocturia, and, due to the initial elevation in serum sodium and osmolality, polydipsia. (See 'Clinical manifestations' above.)

Children with hereditary AVP-R are at high risk for hypernatremia, hypovolemia, hypotension, and shock, beginning as early as their first hours of life. In addition to polydipsia and polyuria, these patients can have other clinical findings such as food aversion and motor developmental delay. In adults with acquired AVP-R, resistance to AVP is typically partial, rather than complete as seen in patients with hereditary AVP-R. The first manifestation of a mild to moderate loss of concentrating ability is often nocturia.

The serum sodium level in untreated patients with AVP-R is often in the high normal range. Moderate to severe hypernatremia can develop when thirst is impaired, or cannot be expressed, or if there is limited access to water. This can occur in infants, young children, and neurologically impaired adults who cannot independently access free water, and in the postoperative period in patients with unrecognized AVP-R.

●Confirming the diagnosis – In normonatremic patients who have symptoms consistent with an AVP disorder, the diagnosis is confirmed by, initially, establishing the presence of a water diuresis and (algorithm 1), subsequently, distinguishing AVP-R from arginine vasopressin V2 deficiency (AVP-D, formerly called central diabetes insipidus) and primary polydipsia (algorithm 2 and algorithm 3). (See 'Confirming the diagnosis' above.)

●Etiologic evaluation – Once the diagnosis of AVP-R has been confirmed, the next step is to determine its cause. Among patients with a physiologic diagnosis of AVP-R, a generally accepted approach is as follows:

•Cause apparent – In many cases, the etiology of AVP-R is apparent from the history (eg, a patient with long-term use of lithium for bipolar disorder) or from routine laboratory studies (eg, hypercalcemia, severe hypokalemia, advanced chronic kidney disease).

•Cause not apparent – Rarely, the cause of AVP-R is not apparent from the routine history, physical exam, and laboratory testing. In all such patients, particularly in children, genotyping should be performed to evaluate for mutations in AVPR2 gene and the AQP2 gene. If no candidate mutations are discovered, then all medications that could be associated with AVP-R should be discontinued, if possible.