Version May 2024
INTRODUCTION — Arginine vasopressin 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 antidiuretic hormone (ADH, also known as arginine vasopressin [AVP]). This problem can reflect resistance at the ADH 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".)
AVP-R, in its mild form, is relatively common since almost all patients who are older adults, sick, 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 to decreased expression of mRNA for the V2 vasopressin receptor [2,3].
The clinical manifestations and causes of AVP-R will be reviewed here. The treatment of AVP-R, the diagnostic approach to polyuria, and the clinical manifestations and causes of arginine vasopressin deficiency (AVP-D, previously called central diabetes insipidus) are discussed separately:
●(See "Arginine vasopressin resistance (nephrogenic diabetes insipidus): Treatment".)
●(See "Evaluation of patients with polyuria".)
CLINICAL MANIFESTATIONS — Patients with moderate to severe AVP-R or AVP-D typically present with polyuria, nocturia, and polydipsia. Polyuria is arbitrarily defined as a urine output exceeding 3 L/day in adults or 2 L/m2 in children.
Causes of polyuria other than AVP-R and AVP-D include primary polydipsia and increased solute excretion due to one or more of the following: glucosuria in uncontrolled diabetes mellitus, glucosuria resulting from administration of sodium-glucose cotransporter 2 (SGLT2) inhibitors [4,5], urea with a high-protein diet or after urea administration to treat hyponatremia [6], or sodium chloride and urea in a postobstructive diuresis. In addition, glucosuria can contribute to polyuria in patients with severe AVP-R or AVP-D when hyperglycemia is induced by the administration of large volumes of intravenous dextrose in water. (See "Evaluation of patients with polyuria", section on 'Solute (osmotic) diuresis'.)
The urine is normally most concentrated in the morning due to lack of fluid ingestion overnight and increased vasopressin secretion during the late sleep period [7]. 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 men, by prostatic hypertrophy, which is characterized by urinary frequency rather than polyuria.
The serum sodium in untreated patients with AVP-R is often in the high normal range to provide the stimulus for thirst to replace the urinary water losses. Moderate to severe hypernatremia can develop when thirst is impaired or cannot be expressed. This can occur in patients with central nervous system lesions who also have hypodipsia or adipsia, 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. (See "Etiology and evaluation of hypernatremia in adults", section on 'Adipsic diabetes insipidus'.)
Patients with AVP-R may also have manifestations related to the underlying cause, such as lithium toxicity, hypercalcemia, and hypokalemia.
CAUSES — The most common causes of antidiuretic hormone (ADH, also known as arginine vasopressin [AVP]) resistance severe enough to produce polyuria are hereditary AVP-R in children, and chronic lithium ingestion and hypercalcemia in adults. Acquired causes are often at least partially reversible with cessation of the offending drug or correction of hypercalcemia [8].
Hereditary AVP-R — Hereditary AVP-R is an uncommon disorder resulting in variable degrees of resistance to ADH [9-13]. There are two different receptors for ADH: the V1 (AVPR1) 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's factor from endothelial cells (figure 2) [14].
There are also several congenital polyuric-polydipsic Bartter-like syndromes associated with urinary concentrating defects of varying severity. (See 'Other inherited 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 [15,16]. They are due to mutations in the AVPR2 gene, which encodes for a dysfunctional vasopressin V2 receptor (V2R).
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 [10]. In patients with AVPR2 mutations, the antidiuretic, vasodilator, and coagulation factor responses to ADH are impaired, while the vasoconstrictor and prostaglandin effects are intact [14].
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 [17,18].
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 ADH. (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 [19]. In the same mouse model, metformin, an adenosine monophosphate kinase activator, also increased urine osmolality, probably bypassing the V2 receptor and directly phosphorylating aquaporin-2 [20]. In addition, nonpeptide vasopressin receptor agonists have been identified that can activate the mutant V2 receptors at their intracellular sites [21]. 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 aquaporin-2 gene that encodes the ADH-sensitive water channels in the collecting tubule cells. This variant may have autosomal recessive or autosomal dominant modes of inheritance [11,13,15,17,22-30].
Aquaporin-2 channels are normally stored in the cytosol. Under the influence of ADH, the aquaporin-2 water channels are phosphorylated at Ser-256, Ser-264, and Ser-269 [31,32] 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 [26,27,33]. (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 aquaporin-2 water channel [34]. Such defects impair trafficking of the water channels, preventing their fusion with the luminal membrane, and decrease channel function [11,15,23,29].
Inherited defects of the aquaporin-2 water channel can be distinguished clinically from the more common V2 receptor defect by evaluating, in male patients, the extrarenal responses to ADH: vasodilation and release of factor VIIIc and von Willebrand's factor from endothelial cells [29,35]. These responses are intact in patients with defective water channels and impaired in patients with defective V2 receptors. Molecular genetic testing is also available [13,17].
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) [36]. At cytotoxic concentrations, lithium inhibits signaling pathways that involve glycogen synthase kinase type 3 beta (GSK3beta), resulting in dysfunction of the aquaporin-2 water channel (figure 3) [36]. GSK3beta knock-out mice have a reduced response to vasopressin administration [37]. (See "Renal toxicity of lithium", section on 'Arginine vasopressin resistance (nephrogenic diabetes insipidus)'.)
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]. This defect, which is generally reversible with correction of the hypercalcemia, may be associated with reductions both in sodium chloride reabsorption in the thick ascending limb of the loop of Henle, thereby interfering with the countercurrent mechanism, and in the ability of ADH to increase collecting tubule water permeability [38-40]. (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 [41]. In addition, activation of the calcium-sensing receptor can directly impair concentrating ability by affecting both the loop of Henle and the collecting tubules [42]. (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 [43]. Inhibition of loop sodium chloride reabsorption impairs generation of the medullary osmotic gradient that is essential for urinary concentration [42].
Hypercalcemia also enhances the generation of prostaglandin E2, which can contribute to the impairment in sodium chloride reabsorption in the thick ascending limb [39,44]. This response may be mediated by angiotensin II-induced activation of phospholipase A2 and prostaglandin H synthase-1 [44]. In hypercalcemic rats, the associated polyuria can be abolished by the administration of losartan, an angiotensin II receptor blocker [44].
●Calcium-sensing receptors are also expressed on the luminal membrane of the cells of the inner medullary collecting duct (IMCD) (figure 3). 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 antidiuretic hormone-induced increase in water permeability [45].
Studies in patients with familial hypocalciuric hypercalcemia have demonstrated the importance of hypercalciuria and/or the calcium-sensing receptor in the concentrating defect associated with hypercalcemia. The primary defect in this disorder is an inactivating mutation of the calcium-sensing receptors leading to a reduction in urinary calcium excretion. Affected patients have normal concentrating ability despite persistent hypercalcemia [46]. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)
Hypercalcemia may also impair water reabsorption by autophagic degradation of aquaporin-2 [47]. In a rodent study, a large decrease in aquaporin-2 expression was observed in the inner medulla and cortex of hypercalcemic rats compared to control animals [48]. 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 3). As with hypercalcemia, both decreased collecting tubule responsiveness to ADH (which may be mediated by decreased expression of aquaporin-2) and diminished sodium chloride reabsorption in the thick ascending limb have been demonstrated in experimental animals [49-51]. Downregulation of urea transporters may also contribute to the impairment of urinary concentrating ability induced by potassium depletion [52] (see "Hypokalemia-induced kidney dysfunction", section on 'Impaired urinary concentrating ability'). In addition, enhanced autophagic degradation of proteins, most notably aquaporin-2, has been demonstrated to be an early event in hypokalemia-induced AVP-R [53].
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 [54].
Other — AVP-R has been described in a number of other clinical settings.
Kidney disease — Symptomatic AVP-R can be seen in a variety of kidney diseases, including release of bilateral urinary tract obstruction [55], sickle cell disease or trait, autosomal dominant polycystic kidney disease and medullary cystic kidney disease [56,57], renal amyloidosis [58], and Sjögren's disease [59]. In the last two conditions, amyloid deposits in and lymphocytic infiltration around the collecting tubules are presumably responsible for the decline in ADH 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 ADH [60,61], 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 [62,63]. 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 [61].
Drugs — AVP-R can be caused by a number of drugs other than lithium. These include cidofovir and foscarnet which are used to treat cytomegalovirus infection in HIV-infected patients [64,65], and 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 [66-68], amphotericin B, demeclocycline, ifosfamide, ofloxacin, orlistat, and didanosine [8,69]. Drug-induced AVP-R is typically reversible, at least in part [8].
Pregnancy — An unusual form of transient ADH resistance occurs in selected women during the second half of pregnancy, a disorder that has been called gestational diabetes insipidus [70,71]. (See "Maternal adaptations to pregnancy: Renal and urinary tract physiology".)
Craniopharyngioma surgery — Craniopharyngioma has been associated with arginine vasopressin deficiency (AVP-D, previously called central diabetes insipidus) both before surgery and particularly after surgery [72]. (See "Arginine vasopressin deficiency (central diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation".)
A different mechanism is responsible in at least some patients who develop early polyuria following transfrontal surgery for craniopharyngioma. In this setting, the increase in urine output may result from the release of an ADH precursor from the hypothalamus that competes for but does not activate the antidiuretic vasopressin V2 receptors [73]. These patients initially have high ADH levels by immunoassay, but little or no biological activity and a diminished response to exogenous hormone replacement. Thus, they behave as if they have AVP-R.
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 [74,75].
Polyuria and polydipsia are among the most common and earliest symptoms [74]. A urinary concentration defect can be detected when kidney function is near normal and in the absence of major cyst formation [76]. Bardet-Biedl derived renal epithelial cells are nonciliated and the vasopressin V2 receptor, which is activated by ADH in normal individuals, is localized in the primary cilium [76]. In in vitro studies, these cells did not respond to luminal vasopressin and did not activate luminal aquaporin-2.
Bartter syndrome — There are several congenital polyuric-polydipsic Bartter syndromes associated with AVP-R of varying severity [15,77-79]. These patients have various degrees of polyuria that may be poorly investigated and confused with "pure" hereditary AVP-R [12]. 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 [79]. (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) [12]. 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 inherited disorders — Other inherited disorders with a mild, moderate, or severe inability to concentrate the urine include nephronophthisis [80,81], cystinosis [82], familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) [83], and the syndrome of apparent mineralocorticoid excess in which the polyuria is presumed to be due to chronic hypokalemia, as described above [84,85] (see "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Renal disease' and "Cystinosis", section on 'Renal manifestations' and "Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)" and 'Hypokalemia' above and "Hypomagnesemia: Causes of hypomagnesemia", section on 'Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)' and "Hypomagnesemia: Causes of hypomagnesemia"). The ARC syndrome (arthrogryposis-renal dysfunction-cholestasis), a rare autosomal recessive multisystem disorder caused by mutations in VPS33B [86] and VIPAR [87], is also associated with renal tubular dysfunction, medullary nephrocalcinosis, and AVP-R.
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
●Arginine vasopressin resistance (AVP-R, previously called nephrogenic diabetes insipidus) refers to a decrease in urinary concentrating ability that results from resistance to the action of antidiuretic hormone (ADH, also known as arginine vasopressin [AVP]). This problem can reflect resistance at the ADH 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.)
●Patients with moderate to severe AVP-R or arginine vasopressin deficiency (AVP-D, previously called central diabetes insipidus) typically present with polyuria, nocturia, and polydipsia. The first manifestation of a mild to moderate loss of concentrating ability is often nocturia. (See 'Clinical manifestations' above.)
●The most common causes of AVP-R in children are genetic mutations; in adults, AVP-R is most often due to drugs, hypercalcemia, and hypokalemia. (See 'Causes' above.)
●Mutations in the vasopressin V2 receptor (V2R) gene, which is X-linked, and the aquaporin-2 gene, which is autosomal, are the two most frequent causes of hereditary AVP-R. (See 'Hereditary AVP-R' above.)
●Acquired symptomatic AVP-R occurring in adults is usually due to lithium toxicity or hypercalcemia (figure 3). The polyuria in these settings is at least partially reversible with cessation of lithium or correction of the hypercalcemia. (See 'Lithium toxicity' above and 'Hypercalcemia' above.)
●Less frequent causes of AVP-R include a variety of genetic and acquired conditions, including:
•Kidney diseases such as bilateral urinary tract obstruction, sickle cell disease or trait, renal amyloidosis, and Sjögren's disease. (See 'Kidney disease' above.)
•Use of cidofovir, foscarnet, vasopressin V2 receptor (V2R) antagonists, amphotericin B, demeclocycline, ifosfamide, ofloxacin, orlistat, and didanosine. (See 'Drugs' above.)
•Pregnancy, which is associated with release of a vasopressinase from the placenta. (See 'Pregnancy' above.)
•Craniopharyngioma surgery. (See 'Craniopharyngioma surgery' above.)
•Bardet-Biedl syndrome, Bartter syndrome, nephronophthisis, cystinosis, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and the syndrome of apparent mineralocorticoid excess. (See 'Bardet-Biedl syndrome' above and 'Bartter syndrome' above and 'Other inherited disorders' above.)
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