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Nephrogenic Diabetes Insipidus

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by James I. McMillan, MD

Nephrogenic diabetes insipidus (NDI) is an inability to concentrate urine due to impaired renal tubule response to ADH (vasopressin), 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 ADH. Treatment consists of adequate free water intake, thiazide diuretics, NSAIDs, and a low-salt, low-protein diet.

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

Etiology

NDI can be

  • Inherited

  • Acquired

Inherited NDI

The most common inherited disorder is an X-linked trait that affects the arginine vasopressin (AVP) receptor 2 gene. 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. Except with the autosomal dominant form, patients who are homozygous are completely unresponsive to ADH. Patients who are heterozygous have normal or slightly impaired responsiveness to ADH. Rarely, heterozygous females have some laboratory abnormalities although they have no symptoms.

Acquired NDI

Acquired NDI can occur when disorders (some of them heritable) or drugs disrupt the medulla or distal nephrons and impair urine concentrating ability, making the kidneys appear insensitive to ADH. These disorders include the following:

  • Autosomal dominant polycystic kidney disease

  • Nephronophthisis and medullary cystic kidney disease complex

  • Sickle cell nephropathy

  • Release of obstructing periureteral fibrosis

  • Medullary sponge kidney

  • Pyelonephritis

  • Hypercalcemia

  • Amyloidosis

  • Sj√∂gren syndrome

  • Bardet-Biedl syndrome

  • Certain cancers (eg, myeloma, sarcoma)

  • Many drugs, especially lithium, but also others (eg, demeclocycline, amphotericin B, dexamethasone, dopamine, ifosfamide, ofloxacin, orlistat)

  • 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:

  • 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 ADH.

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 Na 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 from extreme dehydration. Hypernatremia may cause neurologic symptoms, such as neuromuscular excitability, confusion, seizures, or coma.

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.

Diagnosis

  • 24-h urine volume and osmolality

  • Serum electrolytes

  • Water deprivation test

NDI is suspected in any patient with polyuria (see also Polyuria). In infants, polyuria may be noticed by the mother; 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 (water diuresis), central or nephrogenic diabetes insipidus is likely. With NDI, urine osmolality is typically < 200 mOsm/kg despite clinical signs of hypovolemia (normally, urine osmolality is high in patients with hypovolemia). If osmolality is > 300 mOsm/kg, solute diuresis is likely. Glucosuria and other causes of solute diuresis must be excluded.

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

The diagnosis is confirmed by a water deprivation test (see Central Diabetes Insipidus : Diagnosis), which assesses the maximum urine concentrating ability and response to exogenous ADH. After 3 to 6 h of water deprivation (measuring urine volume and osmolality hourly and serum osmolality every 2 h), the maximal osmolality of urine in patients with NDI is abnormally low (< 300 mOsm/kg). NDI can be distinguished from central diabetes insipidus (lack of ADH) by administering exogenous ADH (aqueous vasopressin 5 units sc or desmopressin 10 mcg intranasally) and measuring urine osmolality. In patients with central diabetes insipidus (see Central Diabetes Insipidus), urine osmolality increases 50 to 100% over the 2 h after administration of exogenous ADH (15 to 45% in partial central diabetes insipidus). Patients with NDI usually have only a minimal rise in urine osmolality (< 50 mOsm/kg; up to 45% in partial NDI).

Treatment

  • Adequate free water intake

  • Restriction of dietary salt and protein

  • Correction of the cause

  • Sometimes a thiazide diuretic, an 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 (hydrochlorothiazide 25 mg po once/day or bid) can paradoxically reduce urine output by diminishing water delivery to ADH-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 ADH

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

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

  • Measure 24 h 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
  • VASOSTRICT
  • R-GENE 10
  • IFEX
  • FLOXIN OTIC
  • No US brand name
  • OZURDEX
  • ALLI, XENICAL
  • LITHOBID
  • DDAVP, STIMATE
  • MICROZIDE
  • MIDAMOR
  • INDOCIN

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