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) 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:
Nephronophthisis and medullary cystic kidney disease complex
Sickle cell nephropathy
Release of obstructing periureteral fibrosis
Bardet-Biedl syndrome
Certain cancers (eg, myeloma, sarcoma)
Possibly chronic hypokalemic nephropathy
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 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
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-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 vasopressinargininevasopressin 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
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.
vasopressin
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.
