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Treatment of nephrogenic diabetes insipidus

Author: Daniel G Bichet, MD
Section Editors: Richard H Sterns, MD, Tej K Mattoo, MD, DCH, FRCP
Deputy Editor: John P Forman, MD, MSc

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Aug 2022. | This topic last updated: Oct 13, 2021.

INTRODUCTION

Nephrogenic diabetes insipidus (nephrogenic DI) results from partial or complete

resistance of the kidney to the effects of antidiuretic hormone (ADH). As a result, patients
with this disorder are not likely to have a good response to hormone administration (as
desmopressin [dDAVP]) or to drugs that increase either the renal response to ADH or ADH
secretion.

Nephrogenic DI can be hereditary or acquired. In adults, a concentrating defect severe

enough to produce polyuria due to nephrogenic DI is most often due to chronic lithium use
or hypercalcemia and less frequently to other conditions that impair tubular function, such
as Sjögren's syndrome [1]. Release of ureteral obstruction is often associated with a
diuresis, but this is short lived and does not require specific therapy other than
maintenance fluids. (See "Clinical manifestations and causes of nephrogenic diabetes
insipidus" and "Clinical manifestations and diagnosis of urinary tract obstruction (UTO) and
hydronephrosis", section on 'Prognosis'.)

Hereditary nephrogenic DI, which is largely an X-linked disease, may also be seen by
internists since early recognition and treatment in infancy has led to survival to adulthood
[2-4]. In addition, affected women may be carriers with few or no symptoms until
pregnancy or other stress.

In infants with hereditary nephrogenic DI, treatment is aimed at minimizing the polyuria
and avoiding hypernatremia and volume depletion. In adults, therapy is usually aimed at
correcting the underlying disorder or discontinuing an offending drug. In hypercalcemic
patients, for example, normalization of the plasma calcium concentration usually leads to
amelioration of polyuria. By contrast, lithium-induced nephrogenic DI may be irreversible if

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the patient already has severe tubular injury and a marked concentrating defect [5]. (See
"Renal toxicity of lithium".)

The approach to the treatment of polyuria in patients with nephrogenic DI will be reviewed
here. The causes of nephrogenic DI, the diagnostic approach to polyuria, and the treatment
of central DI are discussed separately:

● (See "Clinical manifestations and causes of nephrogenic diabetes insipidus".)

● (See "Evaluation of patients with polyuria".)

● (See "Treatment of central diabetes insipidus".)

TREATMENT

The urine output in patients with nephrogenic DI can be lowered with a low-salt, low-
normal protein diet, diuretics, and nonsteroidal antiinflammatory drugs (NSAIDs). In
infants, early recognition is of immediate clinical significance because treatment can avert
the physical and intellectual disabilities that results from repeated episodes of dehydration
and hypernatremia. (See "Evaluation of patients with polyuria".)

In adults, the decision to undertake treatment must be based upon the individual patient's
intolerance of the polyuria and polydipsia since, in almost all patients, the thirst mechanism
is sufficient to maintain the plasma sodium in the high-normal range. The treatment of
patients with hypernatremia is discussed separately. (See "Treatment of hypernatremia in
adults".)

Special considerations in hereditary disease — Given their inability to independently

respond to increased thirst, infants and very young children should be offered water every
two hours during the day and night. In severe cases, continuous gastric feeding may be
required. However, the ingestion of large quantities of water may exacerbate physiologic
gastroesophageal reflux in infants and toddlers, which may require treatment. Appetite and
growth should be monitored closely. (See "Management of gastroesophageal reflux
disease in children and adolescents".)

The high urine flow associated with hereditary nephrogenic DI induces dilatation of the
urinary tract (hydronephrosis) and bladder in ≥50 percent of cases [6-8]. A rare complication
is progressive loss of kidney function and possible end-stage kidney disease, probably
related to voluntary retention of urine leading to bladder dysfunction [9-11]. These
problems may also occur with other causes of massive urine volumes, most commonly
seen with primary polydipsia [9].

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Decreasing urine flow with the interventions discussed below [12], and frequent voiding
and "double voiding" (to empty the bladder entirely), are important preventive measures.
This approach should be taught to children once they are old enough, and should be
continued in adulthood, to prevent severe dilatation of the urinary tract.

Special considerations in patients requiring intravenous fluids — Patients, particularly

children, with nephrogenic DI who have extrarenal fluid losses (eg, diarrhea, vomiting, and
fever) frequently require intravenous fluids [13]. Both 5 percent dextrose in water and one-
quarter isotonic (0.22 percent) saline are usually well tolerated, but a replacement fluid that
has a higher osmolality than the urine (eg, one-half isotonic [0.45 percent] saline) can
produce hypernatremia, even though it may have a lower osmolality as compared with
plasma. As an example, a patient who has a maximal urine osmolality of 100 mosmol/kg will
need to excrete 1.54 liters of urine for each liter of 0.45 percent saline received in order to
excrete the osmotic load, resulting in a net loss of 0.54 liters of water. However, if hypotonic
fluids are administered at a rate higher than the urine output, hyponatremia can ensue.
These considerations should be taken into account in order to prevent complications in
patients with nephrogenic DI requiring intravenous fluids [14].

Decreased dietary solute — When the urine osmolality is fixed, as in nephrogenic DI, the
urine output is determined by solute excretion. Suppose that the maximum urine osmolality
is 150 mosmol/kg. In this setting, the daily urine volume will be 5 liters if solute excretion is
in the normal range at 750 mosmol/day, but only 3 liters if solute excretion is lowered to 450
mosmol/day by dietary modification.

These observations provide the rationale for the use of a low-salt, low-protein diet to
diminish the urine output in nephrogenic DI [1,15]. The reduction in urine output will be
directly proportional to the decrease in solute intake and excretion. Restriction of salt
intake to ≤100 mEq/day (2.3 g sodium) and protein intake to ≤1.0 g/kg may be reasonable
goals, but such diets are not easy to achieve and maintain. Furthermore, protein restriction
in infants and young children may be harmful and is not advised. (See "Patient education:
Low-sodium diet (Beyond the Basics)".)

Although most children with nephrogenic DI are underweight and relatively short during
the first years of life, their height and weight become progressively normal during school-
age years [16]. These growth observations could be related, in part, to limited caloric intake
and decreased dietary solute during the first years of life.

Diuretics — Thiazide diuretics in combination with a low-solute diet can diminish the

degree of polyuria in patients with nephrogenic DI [1,17-19]. The potassium-sparing diuretic
amiloride also may be helpful, both by its additive effect with the thiazide diuretic [20] and,
with reversible lithium-induced disease, by possibly allowing lithium to be continued (see
below) [21].
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A thiazide diuretic (such as hydrochlorothiazide, 25 mg once or twice daily) acts by inducing

mild volume depletion. As little as a 1 to 1.5 kg weight loss can reduce the urine output by
more than 50 percent (eg, from 10 L/day to below 3.5 L/day in a study of patients with
nephrogenic DI on a severely sodium-restricted diet [9 mEq/day]) [17].

This effect is presumably mediated by a hypovolemia-induced increase in proximal sodium

and water reabsorption, thereby diminishing water delivery to the antidiuretic hormone
(ADH)-sensitive sites in the collecting tubules and reducing the urine output. Diuretic
therapy can lead to a variety of usually mild electrolyte complications. (See "Time course of
loop and thiazide diuretic-induced electrolyte complications" and "Causes of hypokalemia in
adults", section on 'Diuretics' and "Diuretic-induced hyperuricemia and gout".)

The initial natriuresis and therefore the later antipolyuric response can be enhanced by
combination therapy with amiloride (or other potassium-sparing diuretic) [21]. This regimen
has an additional benefit since amiloride partially blocks the potassium wasting induced by
the thiazide.

Amiloride may be particularly beneficial in patients with reversible lithium nephrotoxicity,

given its site and mechanism of action [22,23]. If amiloride is used, a small contraction of
extracellular fluid volume may ensue, and it may be necessary to decrease the dose of
lithium chronically administered and to measure plasma concentrations at frequent
intervals until a new steady state is achieved. This drug closes the sodium channels in the
luminal membrane of the collecting tubule cells [24]. These channels constitute the
mechanism by which filtered lithium normally enters these cells and then interferes with
their response to ADH [20]. The permeability for lithium of the epithelial sodium channel
(ENaC) is 1.5- to 2-fold higher than that for sodium [25]. Whereas sodium is extruded from
the interior of the cell to the blood compartment by the sodium pump (Na-K-ATPase)
located at the basolateral membrane, lithium is a poor substrate for the sodium pump. As a
consequence, toxic intracellular levels could build up quickly in all cells expressing ENaC at
their plasma membrane and exposed to therapeutic concentrations of lithium (0.6 to 1.2
mmol/L) (see "Renal toxicity of lithium"). Glycogen synthase kinase 3 (GSK-3 beta) is
inhibited by lithium and is probably the common molecular target for the primary and
secondary toxic effects of lithium [26,27].

Acetazolamide monotherapy is as effective as the combination of hydrochlorothiazide and

amiloride in reducing polyuria in an animal model of lithium-induced nephrogenic DI but
has fewer side effects [28]. Human data are limited, although acetazolamide was used
successfully in a patient with lithium-induced nephrogenic DI and produced an increase in
urine osmolality from 250 to 339 mosmol/kg H2O [29].

A loop diuretic, although also capable of inducing mild volume depletion, is not as likely to
lower the urine output in nephrogenic DI. These agents decrease sodium chloride
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reabsorption in the medullary thick ascending limb of the loop of Henle, thereby decreasing
the accumulation of NaCl in the medullary interstitium that is essential for the production
of a concentrated urine. Thus, a loop diuretic induces relative ADH resistance, an effect that
is counterproductive in nephrogenic DI.

Nonsteroidal antiinflammatory drugs — The efficacy of NSAIDs in this setting is

dependent upon inhibition of renal prostaglandin synthesis. In normal subjects,
prostaglandins antagonize the action of ADH and NSAIDs increase concentrating ability
[30,31]. If, for example, normal subjects are given a submaximal dose of ADH, the ensuing
rise in urine osmolality can be increased by more than 200 mosmol/kg if the patient has
been pretreated with an NSAID [30]. The net effect in patients with DI may be a 25 to 50
percent reduction in urine output [18,19,32], a response that is partially additive to that of a
thiazide diuretic [19,21].

This approach is particularly beneficial in patients with polyuria due to complex congenital
polyuric-polydipsic Bartter-like syndromes, in whom prostaglandins appear to be
pathogenetically important. (See "Inherited hypokalemic salt-losing tubulopathies:
Pathophysiology and overview of clinical manifestations".)

Not all NSAIDs are equally effective in a given patient; as an example, indomethacin appears
to have a greater effect than ibuprofen [18]. A variety of complications may ensue with
long-term use of NSAIDs. (See "Nonselective NSAIDs: Overview of adverse effects".)

Exogenous ADH — Most patients with nonhereditary nephrogenic DI have partial rather

than complete resistance to antidiuretic hormone (ADH). It is therefore possible that
attaining supraphysiologic hormone levels will increase the kidney effect of ADH to a
clinically important degree. In some patients with nephrogenic DI, exogenous ADH has
been found to increase the urine osmolality by 40 to 45 percent, an effect that would be
expected to produce a similar decline in urine volume [22,33,34].

In addition to nonhereditary nephrogenic DI, some cases of hereditary nephrogenic DI may

respond to exogenous ADH.

Thus, desmopressin may be tried in patients who have persistent symptomatic polyuria
after implementation of the above regimen. One case report of a patient with lithium-
induced nephrogenic DI suggested that benefit may be more likely if desmopressin is
combined with an NSAID [35].

Experimental approaches — Most patients with congenital X-linked nephrogenic DI have

defective V2 vasopressin receptors that are unable to properly fold intracellularly and, as a
consequence, do not transfer to the cell surface where the receptors could respond to
circulating vasopressin. Several new approaches to treatment of this disorder are being

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investigated: V2 receptor chaperones and V2 receptor bypass. (See "Clinical manifestations

and causes of nephrogenic diabetes insipidus", section on 'Vasopressin V2 receptor gene
mutations'.)

V2 receptor chaperones — In in vitro systems, the administration of selective, cell-

permeable nonpeptide V2 and V1a receptor antagonists were able to rescue mutant V2
receptors, presumably acting intracellularly to promote proper folding and maturation
[36,37]. This resulted in the expression of functional cell surface V2 receptors, suggesting
that such a therapeutic approach may be effective in patients.

In a pilot study, a nonpeptide V1a receptor antagonist was administered to five men with
nephrogenic DI (each with one of three identified mutations in the AVPR2 gene that codes
for the V2 receptor) [37]. This resulted in an increase in urine osmolality from a mean of 100
to 150 mosmol/kg and reductions in urine volume from 12 to 8 L/day and in water intake
from 11 to 7 L/day. Nonpeptide V2 agonists have also been demonstrated experimentally to
rescue misfolded AVPR2 mutations responsible for X-linked nephrogenic DI [38,39].

Most mutations in aquaporin-2 (the vasopressin-sensitive water channel) that are

associated with nephrogenic DI result in proteins being retained in the intracellular space
[40]. Research to find chaperone-like molecules to help direct these proteins to the cell
surface is ongoing [41].

V2 receptor bypass — The antidiuretic activity of the V2 receptor is mediated by the

activation of a G protein-signaling cascade that leads to increased intracellular cyclic
adenosine monophosphate (AMP) and the trafficking of aquaporin-2 to the cell membrane.
The collecting duct also expresses two prostaglandin E2 receptors (EP2 and EP4) and a
beta-3 adrenergic receptor; similar to the V2 receptor-signaling cascade, these receptors
can increase intracellular cyclic AMP [42-44]. Prostaglandin E2 and beta-3 adrenergic
signaling through these receptors increases the apical membrane abundance and
phosphorylation of aquaporin-2.

Thus, stimulation of prostaglandin E2 receptors EP2 and EP4, and stimulation of beta-3
adrenergic receptors, may be a way of bypassing the need for V2 receptor signaling. In a
mouse model of X-linked nephrogenic DI, for example, ONO-AE1-329, a selective agonist of
the EP4 prostaglandin E2 receptor in the collecting tubule cells, increased urine osmolality
from 150 to 500 mosmol/kg H2O [45]. In addition, a beta-3 adrenergic receptor agonist
increased urine osmolality in a murine model of nephrogenic DI from 150 to 250
mosmol/kg H2O [46].

The phosphodiesterase inhibitor, sildenafil, has also shown similar effects in a single case
report, improving the urine osmolality in a patient with X-linked nephrogenic DI [47].

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Metformin may also transiently increase urine osmolality in rodent models, although there
is a rapid return to basal values [48]. Fluconazole may have similar effects [49].

Adenosine monophosphate-activated protein kinase (AMPK) has been shown to

phosphorylate aquaporin-2 and increase the urine concentration in animal models of
nephrogenic DI [50].

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".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces
are longer, more sophisticated, and more detailed. These articles are written at the 10th to
12th grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Diabetes insipidus (The Basics)")

SUMMARY AND RECOMMENDATIONS

Nephrogenic diabetes insipidus (nephrogenic DI) results from partial or complete

resistance of the kidney to the effects of antidiuretic hormone (ADH). In adults, a
concentrating defect severe enough to produce polyuria due to nephrogenic DI is most
often due to chronic lithium use or hypercalcemia and less frequently to other conditions
that impair tubular function, such as Sjögren's syndrome. In infants, congenital
nephrogenic DI is most common. (See "Clinical manifestations and causes of nephrogenic
diabetes insipidus".)

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If a cause can be identified, we recommend correcting the underlying disorder (eg,

hypercalcemia) or discontinuing the offending drug, if feasible. Lithium-induced
nephrogenic DI may be irreversible if tubular injury is severe and there is a marked
concentrating defect. (See "Renal toxicity of lithium".)

There are usually no adverse medical effects of polyuria, although, as noted above, the
functional hydronephrosis in congenital nephrogenic DI rarely leads to significant kidney
injury [9]. As a result, the only indication for therapy in adults is to relieve the patient's
symptoms.

Initial therapy — Therapy of the polyuria in nephrogenic DI consists of the following

sequential approach:

● All adult patients should be instructed to take a low-sodium, low-protein diet, as

tolerated, and all infants and young children should be provided a low-sodium diet.
The reduction in urine output will be directly proportional to the fall in solute
excretion. As a result, the efficacy of solute restriction will depend directly upon
patient compliance. (See 'Decreased dietary solute' above.)

● In all patients who have significant polyuria, we recommend frequent and "double-
voiding" to avoid bladder dilatation and dysfunction.

● In all children, and in adults with symptomatic polyuria persisting despite a low-solute
diet, we recommend starting a thiazide diuretic (eg, hydrochlorothiazide 25 mg once
daily to a usual maximum of 25 mg twice daily in adults and appropriate dosing in
children) (Grade 1A). (See 'Diuretics' above.)

The preferred initial therapy is similar in children with polyuria due to complex
congenital polyuric-polydipsic Bartter-like syndromes, in whom we recommend
nonsteroidal antiinflammatory drugs (NSAIDs) (Grade 1B). (See 'Nonsteroidal
antiinflammatory drugs' above and "Inherited hypokalemic salt-losing tubulopathies:
Pathophysiology and overview of clinical manifestations".)

● We suggest adding amiloride if the urine output is insufficiently reduced (Grade 2B).
We recommend amiloride as part of primary therapy to prevent progression of, or
possibly improve, lithium-induced DI in patients in whom lithium is continued (Grade
1B). (See 'Diuretics' above.)

In patients taking lithium, a low-sodium diet and the use of thiazide and/or amiloride may
increase the plasma level of lithium. Thus, frequent measurements of lithium and a
decrease in the daily lithium dose may be necessary when initiating such treatments.

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● If symptomatic polyuria persists, we suggest adding indomethacin if there are no

contraindications (Grade 2B). (See 'Nonsteroidal antiinflammatory drugs' above.)

● In patients who cannot be treated with NSAIDs or who have persistent symptomatic
polyuria after the addition of NSAIDs, we suggest a trial of desmopressin (Grade 2B).
(See 'Exogenous ADH' above.)

Hereditary disease — There are special considerations in the management of hereditary

nephrogenic DI, particularly in infants and young children (see 'Special considerations in
hereditary disease' above):

● In infants and very young children, we recommend offering water every two hours,
with the goal of avoiding severe dehydration and hypernatremia (Grade 1B). If
gastroesophageal reflux becomes problematic, we recommend appropriate
management. (See "Management of gastroesophageal reflux disease in children and
adolescents".)

● In all children, we recommend implementation of measures to decrease urine flow, as

discussed above, and frequent and "double voiding," with the goal of avoiding
dilatation of the urinary tract and bladder (Grade 1C). We suggest continuing these
preventive measures to avoid dilatation of the urinary tract in adulthood.

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Topic 2382 Version 17.0

Contributor Disclosures
Daniel G Bichet, MD Grant/Research/Clinical Trial Support: Amicus Therapeutics [Fabry]; Otsuka
Pharmaceuticals [ADPKD]; Sanofi Genzyme [Fabry]; Takeda Canada [Fabry].
Consultant/Advisory Boards:
Amicus Therapeutics [Fabry]; Otsuka Pharmaceuticals [ADPKD]; Sanofi Genzyme [Fabry].
Speaker's
Bureau: Amicus Therapeutics [Fabry]; Otsuka Pharmaceuticals [ADPKD]; Sanofi Genzyme [Fabry].
All of

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9/26/22, 8:27 PM Treatment of nephrogenic diabetes insipidus - UpToDate

the relevant financial relationships listed have been mitigated. Richard H Sterns, MD No relevant
financial relationship(s) with ineligible companies to disclose. Tej K Mattoo, MD, DCH,
FRCP Consultant/Advisory Boards: Alnylam Pharmaceuticals [Primary hyperoxaluria].
All of the relevant
financial relationships listed have been mitigated. John P Forman, MD, MSc No relevant financial
relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

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