Nephrogenic diabetes insipidus

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor in Chief: Cafer Zorkun, M.D., Ph.D. [2]

Diabetes insipidus is the excretion of abnormally large volumes (i.e., >50 mL/kg body weight in 24 hours) of dilute urine (i.e., specific gravity <1.010 or osmolality <300 mOsm/kg).

Nephrogenic diabetes insipidus (NDI) is characterized by inability to concentrate the urine, which results in polyuria (excessive urine production) and polydipsia (excessive thirst). Affected untreated infants usually have poor feeding and failure to thrive, and rapid onset of severe dehydration with illness, hot environment, or the withholding of water. Short stature and secondary dilatation of the ureters and bladder from the high urine volume is common in untreated individuals.

The clinical diagnosis of NDI relies upon demonstration of subnormal ability to concentrate the urine despite the presence of the antidiuretic hormone, pituitary-derived arginine vasopressin (AVP). The two genes associated with NDI are AVPR2 (X-linked) and AQP2 (autosomal recessive and autosomal dominant). Molecular genetic testing of the AVPR2 gene detects approximately 95% of disease-causing mutations in individuals with X-linked NDI; molecular genetic testing of the AQP2 gene detects about 95% of disease-causing mutations in individuals with autosomal recessive NDI. Such testing is clinically available.

Management by a team (nutritionist, pediatric nephrologist / endocrinologist, clinical geneticist); provide free access to drinking water and to toilet facilities; reduce polyuria (and thus polydipsia) up to 50% without inducing hypernatremia by use of one of the following: thiazide diuretics (i.e., hydrochlorothiazide, chlorothiazide), dietary restriction of sodium, nonsteroidal anti-inflammatory drugs (NSAIDs); in individuals with dehydration or shock, establish whether the deficit is primarily in free water (through water deprivation or excessive urine, stool, or sweat) or in extracellular fluid (bleeding, fluid extravasation) to avoid inappropriate treatment of dehydration with normal saline (0.9% NaCl); treat hydronephrosis, hydroureter, and megacystis with medical management to reduce urine output and continuous or intermittent bladder catheterization when post-void urinary bladder residuals are significant; when ‘NPO’ (nothing per ora), individuals with NDI must have intravenous replacement of their usual oral intake of water as 2.5% dextrose in water. Surveillance: monitoring of growth in infants and children; periodic measurement of serum sodium concentration to identify unrecognized hyperosmolality and early dehydration; annual renal ultrasound evaluation to monitor for hydronephrosis and megacystis.

• Agents/circumstances to avoid: Restriction of water intake. Testing of relatives at risk: evaluation of at-risk infants as early as possible to allow for prompt diagnosis and treatment to reduce morbidity from hypernatremia, dehydration, and dilation of the urinary tract.
• Genetic counseling: NDI is most commonly inherited in an X-linked manner (~90% of individuals). NDI can also be inherited in an autosomal recessive manner (~9% of individuals) or in an autosomal dominant manner (~1% of individuals). The risks to sibs and offspring depend upon the mode of inheritance and the carrier status of the parents, which can be established in most families using molecular genetic testing. Prenatal testing is available for at-risk pregnancies in which the disease-causing mutation(s) have been identified in an affected family member.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor in Chief: Cafer Zorkun, M.D., Ph.D. [2]

The name “nephrogenic diabetes insipidus” was coined by Williams and Henry in 1947. In the literature the name “nephrogenic diabetes insipidus” has been used synonymously with the terms “vasopressin- or ADH-resistant diabetes insipidus” or “diabetes insipidus renalis.”

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor in Chief: Cafer Zorkun, M.D., Ph.D. [2]

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Nephrogenic diabetes insipidus (NDI) is characterized by inability to concentrate the urine, which results in polyuria (excessive urine production) and polydipsia (excessive thirst). Affected untreated infants usually have poor feeding and failure to thrive, and rapid onset of severe dehydration with illness, hot environment, or the withholding of water. Short stature and secondary dilatation of the ureters and bladder from the high urine volume is common in untreated individuals.

• AVPR2. A gain-of-function mutation in AVPR2 was reported to produce an abnormality called “nephrogenic syndrome of inappropriate antidiuresis” [Feldman et al 2005, Knoers 2005].
• AQP2. No other phenotypes are known to be associated with mutations in AQP2.

X-linked and recessive NDI are similar with respect to initial symptoms and, with a few exceptions, age of onset.

In the minority of individuals with X-linked NDI and a V2 receptor mutation resulting in partial insensitivity to AVP or DDAVP, the disease onset may be later in childhood. Thus, three families had the missense mutation D85N associated with decreased ligand-binding affinity and decreased coupling to Gs, and one had the missense mutation G201D associated with a decreased number of cell surface AVPR2 receptors [Sadeghi et al 1997]. An individual representing a simplex case (a single affected individual in a family) had the mutation P322S, which was able to partly activate the Gs/adenylyl cyclase system [Ala et al 1998].

Nephrogenic diabetes insipidus (NDI) may be transmitted in an X-linked recessive manner (90% of families), an autosomal recessive manner (~9% of families), or an autosomal dominant manner (~1% of families).

• The father of an affected male will not have NDI nor will he be a carrier of the mutation.

• Women who have an affected son and another affected male relative are obligate heterozygotes.

• A positive family history consistent with X-linked inheritance is observed in about half of X-linked cases [Arthus et al 2000].

• Pedigree analysis reveals that in about half of families with an affected male, he represents a simplex case (i.e., an affected individual with no known family history of NDI); several possibilities regarding his mother’s carrier status need to be considered:

• The proband has a de novo disease-causing mutation in the AVPR2 gene and his mother is not a carrier;

• His mother has a de novo disease-causing mutation in the AVPR2 gene, either (a) as a “germline mutation” (i.e., present at the time of her conception and therefore in every cell of her body) or (b) as “germline mosaicism” (i.e., in some of her germ cells only);

• His maternal grandmother has a de novo disease-causing mutation in the AVPR2 gene.

• The risk to sibs depends upon the genetic status of the proband’s mother.

• If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will usually not be affected.

• If the disease-causing mutation cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because the possibility of germline mosaicism exists.

All the daughters of an affected male are carriers; none of his sons will be affected.

Carrier testing by molecular analysis of at-risk female relatives is available if the mutation has been identified in the proband.

• The parents are obligate heterozygotes and, therefore, carry a single copy of a disease-causing mutation in the AQP2 gene.
• Heterozygotes are asymptomatic.

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

• The offspring of an individual with autosomal recessive NDI are obligate heterozygotes (carriers) for a disease-causing mutation in the AQP2 gene.

Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier testing by molecular analysis for at-risk family members is available once the mutations have been identified in the proband.

• The proportion of individuals with autosomal dominant NDI who have an affected parent is unknown because the number of reported cases is small.

• A proband with autosomal dominant NDI may have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo mutations is unknown.

• The risk to sibs depends upon the genetic status of the proband’s parent.

• If a parent of a proband is affected, the risk to the sibs is 50%.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

• Each child of an individual with autosomal dominant NDI has a 50% chance of inheriting the AQP2 mutation.

• The risk to other family members depends upon the status of the proband’s parents. If a parent is found to be affected, his or her family members are at risk.

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Nephrogenic DI (NDI) is most common in its acquired forms, meaning that the defect was not present at birth. These acquired forms have numerous potential causes. The most obvious cause is a kidney or systemic disorder, including amyloidosis,^[1] polycystic kidney disease,^[2] electrolyte imbalance,^[3][4] or some other kidney defect.^[1]

The major causes of acquired NDI that produce clinical symptoms (e.g. polyuria) in the adult are lithium toxicity and hypercalcemia. Chronic lithium ingestion – appears to affect the tubules by entering the collecting tubule cells through sodium channels, accumulating and interfering with the normal response to ADH (ADH Resistance) in a mechanism that is not yet fully understood. Hypercalcemia causes natriuresis (increased sodium loss in the urine) and water diuresis, in part by its effect through the calcium-sensing receptor (CaSR).

Osmotic

Other causes of acquired NDI include: hypokalemia, post-obstructive polyuria, sickle cell disease/trait, amyloidosis, Sjogren syndrome, renal cystic disease, Bartter syndrome and various drugs (Amphotericin B, Orlistat, Ifosfomide, Ofloxacin, Cidofovir, Vaptanes).

In addition to kidney and systemic disorders, nephrogenic DI can present itself as a side-effect to some medications. The most common and well known of these drugs is lithium,^[5] although there are numerous other medications that cause this effect with lesser frequency.^[1]

This form of DI can also be hereditary:

Type	OMIM	Gene	Locus
NDI1	304800	AVPR2	Usually, the hereditary form of nephrogenic DI is the result of an X-linked genetic defect which causes the vasopressin receptor (also called the V2 receptor) in the kidney to not function correctly.[1][6]
NDI2	125800	AQP2	In more rare cases, a mutation in the “aquaporin 2” gene impede the normal functionality of the kidney water channel, which results in the kidney being unable to absorb water. This mutation is often inherited in an autosomal recessive manner although dominant mutations are reported from time to time [1][7]

Cardiovascular	No underlying causes
Chemical/Poisoning	No underlying causes
Dental	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	Streptozocin
Ear Nose Throat	No underlying causes
Endocrine	No underlying causes
Environmental	No underlying causes
Gastroenterologic	No underlying causes
Genetic	No underlying causes
Hematologic	No underlying causes
Iatrogenic	No underlying causes
Infectious Disease	No underlying causes
Musculoskeletal/Orthopedic	No underlying causes
Neurologic	No underlying causes
Nutritional/Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	No underlying causes
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal/Electrolyte	No underlying causes
Rheumatology/Immunology/Allergy	No underlying causes
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	No underlying causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor in Chief: Cafer Zorkun, M.D., Ph.D. [2]

Diabetes insipidus is the excretion of abnormally large volumes (i.e., >50 mL/kg body weight in 24 hours) of dilute urine (i.e., specific gravity <1.010 or osmolality <300 mOsm/kg) [Robertson 1988, Robertson 1995]. In addition to inherited forms of nephrogenic diabetes insipidus (NDI), causes of diabetes insipidus include the following:

• Deficiency in synthesis of the antidiuretic hormone arginine vasopressin (AVP) in the supraoptic nuclei or secretion by the posterior pituitary (also called neurogenic, hypothalamic, cranial, central, or vasopression-responsive diabetes insipidus).

• Acquired causes include trauma, malignancy, granulomatous disease, infection, vascular disease, and autoimmune disease.

• Autosomal dominant neurogenic diabetes insipidus is caused by mutations in the gene encoding prepro-arginine-vasopressin-neurophysin II (prepro-AVP-NPII) [Rittig et al 1996].

• Acquired nephrogenic diabetes insipidus is much more common than the hereditary form of NDI, is usually less severe, and is associated with down-regulation of AQP2 [Bichet 1998]. Known causes include lithium treatment; hypokalemia; hypercalcemia; vascular, granulomatous, and cystic kidney disease; infection; and urinary tract obstruction [Khanna et al 2006]. Rarer reported causes include antibiotics and antifungal, antineoplastic, and antiviral agents [Garofeanu et al 2005].

• Primary polydipsia may result from mental illness (called psychogenic polydipsia or compulsive water drinking) or disturbance of the thirst mechanism (called dipsogenic diabetes insipidus). The presence of plasma osmolarity greater than 295 mOsm/kg or serum sodium concentration greater than 143 mEq/L in the context of ad libitum fluid intake effectively excludes primary polydipsia.

• Diabetes mellitus. Polyuria associated with diabetes mellitus is associated with glucose in the urine and increased urine specific gravity.

• Other. Because of the nonspecific nature of the presenting signs of NDI, infants with NDI may go undiagnosed or be misdiagnosed while under care for failure to thrive, unexplained fever, urinary reflux, or other symptoms.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor in Chief: Cafer Zorkun, M.D., Ph.D. [2]

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The exact prevalence of NDI is not known but it is assumed to be rare. The most recent estimate of the prevalence of NDI in Quebec, Canada is 8.8:1,000,000 males [Arthus et al 2000]. In the Dutch population of about 16 million, 40 affected families are known.

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Occasionally, the presenting sign is hydronephrosis, hydroureter, or megacystis.

Dehydrated individuals who have not been diagnosed to have NDI or who are unable to communicate their complaints run the risk of being improperly treated with IV administration of normal saline, especially in emergency situations. This may exacerbate hypernatremia. Prolonged, unrecognized, or repeated episodes of hypernatremic dehydration may result in seizures, permanent brain damage, developmental delay, and mental retardation. With early diagnosis and proper management, intelligence and life span are usually normal.

Chronic excretion of large volumes of urine in untreated persons results in hydronephrosis, hydroureter, and megacystis (huge bladder). Some degree of urinary tract distension may be seen on ultrasound examination even in infants [Yoo et al 2006].

Potential complications of urinary tract dilatation are rupture of the urinary tract, infection, intractable pain, improper bladder function, and/or kidney failure. These complications may occur as early as the second decade of life [Shalev et al 2004]. Lifestyle is substantially affected by the need to have constant access to potable water and by the increased frequency of urination. The unavailability of restroom facilities, even for a short time, is a problem in societies in which public urination is taboo. School and other social or group activities may be disrupted.

Delayed developmental milestones are common in children with nephrogenic diabetes insipidus.

Affected individuals are almost always less than 50^th percentile for height; most are more than one standard deviation below the mean. Failure to thrive or short stature may result from unsuccessful management or inadequate nutrition related to polydipsia. Catch-up growth does not occur later in childhood [van Lieburg et al 1999].

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