(See also Central Diabetes Insipidus.)
NDI is characterized by inability to concentrate urine in response to vasopressin. Central diabetes insipidus is characterized by lack of vasopressin. Either type of diabetes insipidus may be complete or partial.
Etiology
NDI can be
Inherited NDI
The most common inherited NDI is an X-linked trait with variable penetrance in heterozygous females that affects the arginine vasopressin (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) 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:
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Nephronophthisis and medullary cystic kidney disease complex
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Sickle cell nephropathy
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Release of obstructing periureteral fibrosis
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Bardet-Biedl syndrome
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Certain cancers (eg, myeloma, sarcoma)
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Many drugs, especially lithium, but also others (eg, demeclocycline, amphotericin B, dexamethasone, dopamine, ifosfamide, ofloxacin, orlistat)
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Possibly chronic hypokalemic nephropathy
Acquired NDI can also be idiopathic. A mild form of acquired NDI can occur in any patient who is elderly or sick or who has acute or chronic renal insufficiency.
In addition, certain clinical syndromes can resemble NDI:
Symptoms and Signs
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, elderly patients with dementia) typically develop hypernatremia due to extreme dehydration. Hypernatremia may cause neurologic symptoms, such as neuromuscular excitability, confusion, seizures, or coma.
Diagnosis
NDI is suspected in any patient with polyuria. In infants, polyuria may be noticed by the caregivers; if not, the first manifestation may be dehydration.
Initial testing includes 24-h 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), central diabetes insipidus 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 h. After 3 to 6 h 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 central diabetes insipidus (lack of vasopressin) by administering exogenous vasopressin (aqueous vasopressin 5 units sc or desmopressin 10 mcg intranasally) and measuring urine osmolality. In patients with central diabetes insipidus, urine osmolality increases 50 to 100% over the 2 h after administration of exogenous vasopressin (15 to 45% in partial central diabetes insipidus). 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
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
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 po once/day or bid) 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
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Patients with NDI are unable to concentrate urine due to impaired renal tubule response to vasopressin.
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They typically pass large volumes of dilute urine, are appropriately thirsty and have near-normal serum sodium levels.
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Minimize preventable neurologic sequelae by considering inherited NDI in infants with polyuria or affected family members.
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Measure 24-h urine volume and osmolality and serum electrolytes.
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Confirm the diagnosis with a water deprivation test.
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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 |
|---|---|
hydrochlorothiazide |
MICROZIDE |
demeclocycline |
No US brand name |
dexamethasone |
OZURDEX |
indomethacin |
INDOCIN |
desmopressin |
DDAVP, STIMATE |
vasopressin |
VASOSTRICT |
ifosfamide |
IFEX |
amiloride |
MIDAMOR |
ofloxacin |
FLOXIN OTIC |
orlistat |
ALLI, XENICAL |
lithium |
LITHOBID |
