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Nephrogenic Diabetes Insipidus


L. Aimee Hechanova

, MD, Texas Tech University Health Sciences Center, El Paso

Reviewed/Revised May 2022 | Modified Sep 2022

Nephrogenic diabetes insipidus (NDI) is an inability to concentrate urine due to impaired renal tubule response to vasopressin (ADH), which leads to excretion of large amounts of dilute urine. It can be inherited or occur secondary to conditions that impair renal concentrating ability. Symptoms and signs include polyuria and those related to dehydration and hypernatremia. Diagnosis is based on measurement of urine osmolality changes after water deprivation and administration of exogenous vasopressin. Treatment consists of adequate free water intake, thiazide diuretics, nonsteroidal anti-inflammatory drugs, and a low-salt, low-protein diet.

NDI is characterized by inability to concentrate urine in response to vasopressin. Argininevasopressin deficiency is characterized by lack of vasopressin. Either type of diabetes insipidus may be complete or partial.

Etiology of NDI

NDI can be

  • Inherited

  • Acquired

Inherited NDI

The most common inherited NDI is an X-linked trait with variable penetrance in heterozygous females that affects the argininevasopressin (AVP) receptor 2 gene. Heterozygous females may have no symptoms or a variable degree of polyuria and polydipsia, or they may be as severely affected as males.

In rare cases, NDI is caused by an autosomal recessive or autosomal dominant mutation that affects the aquaporin-2 gene and can affect both males and females.

Acquired NDI

Acquired NDI can occur when disorders (many of which are tubulointerstitial diseases Overview of Tubulointerstitial Diseases Tubulointerstitial diseases are clinically heterogeneous disorders that share similar features of tubular and interstitial injury. In severe and prolonged cases, the entire kidney may become... read more ) or drugs disrupt the medulla or distal nephrons and impair urine concentrating ability, making the kidneys appear insensitive to vasopressin. These disorders include the following:

Acquired NDI can also be idiopathic. A mild form of acquired NDI can occur in any patient who is older or sick or who has acute or chronic renal insufficiency.

In addition, certain clinical syndromes can resemble NDI:

  • The placenta can secrete vasopressinase during the 2nd half of pregnancy (a syndrome called gestational diabetes insipidus).

  • After pituitary surgery, some patients secrete an ineffective ADH precursor rather than vasopressin.

Symptoms and Signs of NDI

Generation of large amounts of dilute urine (3 to 20 L/day) is the hallmark. Patients typically have a good thirst response, and serum sodium remains near normal. However, patients who do not have good access to water or who cannot communicate thirst (eg, infants, older patients with dementia) typically develop hypernatremia Hypernatremia Hypernatremia is a serum sodium concentration > 145 mEq/L (> 145 mmol/L). It implies a deficit of total body water relative to total body sodium, caused by water intake being less than water... read more due to extreme dehydration. Hypernatremia may cause neurologic symptoms, such as neuromuscular excitability, confusion, seizures, or coma. Ureteral dilation is rare but can occur in severe cases with high urine volumes.

Diagnosis of NDI

  • 24-hour urine volume and osmolality

  • Serum electrolytes

  • Water deprivation test

Initial testing includes 24-hour urine collection (without fluid restriction) for volume and osmolality, and serum electrolytes.

Patients with NDI excrete > 50 mL/kg of urine/day (polyuria). If urine osmolality is < 300 mOsm/kg (300 mmol/L; known as water diuresis), argininevasopressin deficiency or NDI is likely. With NDI, urine osmolality is typically < 200 mOsm/kg (200 mmol/L) despite clinical signs of hypovolemia (normally, urine osmolality is high in patients with hypovolemia). If osmolality is > 300 mOsm/kg (300 mmol/L), solute diuresis is likely. Glucosuria and other causes of solute diuresis must be excluded.

Serum sodium is mildly elevated (142 to 145 mEq/L, or 142 to 145 mmol/L) in patients with adequate free water intake but can be dramatically elevated in patients who do not have adequate access to free water.

Water deprivation test

The diagnosis is confirmed by a water deprivation test, which assesses the maximum urine concentrating ability and response to exogenous vasopressin.

During the test, urine volume and osmolality are measured hourly and serum osmolality is measured every 2 hours. After 3 to 6 hours of water deprivation, the maximal osmolality of urine in patients with NDI is abnormally low (< 300 mOsm/kg, or 300 mmol/L). NDI can be distinguished from argininevasopressin deficiency (lack of vasopressin) by administering exogenous vasopressin (aqueous vasopressin 5 units subcutaneously or desmopressin 10 mcg intranasally) and measuring urine osmolality. In patients with argininevasopressin deficiency, urine osmolality increases 50 to 100% over the 2 hours after administration of exogenous vasopressin (15 to 45% in partial argininevasopressin deficiency). Patients with NDI usually have only a minimal rise in urine osmolality (< 50 mOsm/kg [50 mmol/L]; up to 45% in partial NDI).

Prognosis for NDI

Infants with inherited NDI may develop brain damage with permanent intellectual disability if treatment is not started early. Even with treatment, physical growth is often delayed in affected children presumably because of frequent dehydration. All complications of NDI except for ureteral dilation are preventable with adequate water intake.

Treatment of NDI

  • Adequate free water intake

  • Restriction of dietary salt and protein

  • Correction of the cause

  • Sometimes a thiazide diuretic, a nonsteroidal anti-inflammatory drug (NSAID), or amiloride

Treatment consists of ensuring adequate free water intake; providing a low-salt, low-protein diet; and correcting the cause or stopping any likely nephrotoxin. Serious sequelae are rare if patients can drink at will.

If symptoms persist despite these measures, drugs can be given to lower urine output. Thiazide diuretics (eg, hydrochlorothiazide 25 mg orally once or twice/day) can paradoxically reduce urine output by diminishing water delivery to vasopressin-sensitive sites in the collecting tubules. NSAIDs (eg, indomethacin) or amiloride can also help.

Key Points

  • Patients with NDI are unable to concentrate urine due to impaired renal tubule response to vasopressin.

  • They typically pass large volumes of dilute urine, are appropriately thirsty and have near-normal serum sodium levels.

  • Minimize preventable neurologic sequelae by considering inherited NDI in infants with polyuria or affected family members.

  • Measure 24-hour urine volume and osmolality and serum electrolytes.

  • Confirm the diagnosis with a water deprivation test.

  • Ensure adequate free water intake, restrict dietary salt and protein, and use a thiazide diuretic or amiloride as needed.

Drugs Mentioned In This Article

Drug Name Select Trade
Arginine, Nutricia SHS L-Arginine, R-Gene
Pitressin, Vasostrict
Eskalith, Eskalith CR, Lithobid
Amphocin, Fungizone
AK-Dex, Baycadron, Dalalone, Dalalone D.P, Dalalone L.A, Decadron, Decadron-LA, Dexabliss, Dexacort PH Turbinaire, Dexacort Respihaler, DexPak Jr TaperPak, DexPak TaperPak, Dextenza, DEXYCU, DoubleDex, Dxevo, Hemady, HiDex, Maxidex, Ocu-Dex , Ozurdex, ReadySharp Dexamethasone, Simplist Dexamethasone, Solurex, TaperDex, ZCORT, Zema-Pak, ZoDex, ZonaCort 11 Day, ZonaCort 7 Day
Floxin, Ocuflox
alli, Xenical
DDAVP, Minirin, Nocdurna, Noctiva, Stimate
Esidrix, Ezide, HydroDIURIL, Microzide, Oretic, Zide
Indocin, Indocin SR, TIVORBEX
NOTE: This is the Professional Version. CONSUMERS: View Consumer Version
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