Patients usually have good thirst response which allows for proper rehydration and, therefore, maintenance of normal serum levels. However, children and elderly patients with critical illness or dementia who may not communicate thirst effectively may present with hypernatremia. In turn, hypernatremia causes confusion, coma, and uninhibited neuromuscular excitation leading to convulsions. Infants with NDI may present with cognitive impairments, failure to thrive, and growth retardation.
Entire Body System
- Short Stature in Children
The reduced caloric and dietary solute intake may cause weight reduction and short stature in children in the first few years of treatment. Thiazide diuretics are also indicated in treatment. [symptoma.com]
We report a novel AVPR2 mutation in a Turkish 18 month-old boy with skeletal anomalies. [ncbi.nlm.nih.gov]
- Intermittent Fever
Here, we report a case of congenital NDI presented with bilateral hydronephrosis.A 15-year-old boy complaining a history of intermittent fever was admitted to Peking Union Medical College Hospital. He voided 10 to 15 L of urine daily. [ncbi.nlm.nih.gov]
Awareness of the primary signs of NDI, polyuria, and polydipsia would facilitate early diagnosis and treatment to prevent its severe complications. [ncbi.nlm.nih.gov]
- Failure to Thrive
For 70%, drug choice was determined by severity of failure to thrive (FTT). [ncbi.nlm.nih.gov]
A one-year-boy presented with constipation, fever, failure to thrive and developmental delay from the neonatal period. Investigations revealed persistent hypernatremia and deranged renal functions. [ncbi.nlm.nih.gov]
Disease definition Nephrogenic diabetes insipidus (NDI) is characterized by polyuria with polydipsia, recurrent bouts of fever, constipation, and acute hypernatremic dehydration after birth that may cause neurological sequelae. [orpha.net]
Infants affected by the inherited forms of the disease usually show failure to thrive, fever, constipation, and episodes of severe hypernatremic dehydration with risk of neurological sequels. [em-consulte.com]
"The presenting complaints were unexplained fever, failure to gain weight, and constipation. The bouts of dehydration are usually not associated with acidosis. [encyclopedia.com]
- Abdominal Mass
The boy presented at 5 months with failure to thrive, polyuria, hypernatremia and abdominal mass. Analysis of leukocyte DNA showed a novel missense mutation (Q174H) of the AVPR2 gene, which was not present in his mother. [ncbi.nlm.nih.gov]
- Altered Mental Status
This presents as altered mental status and the condition can be life-threatening Shock: Very severe form of dehydration may progress to the development of a state of shock. [dovemed.com]
The cause is generally due to severe dehydration and volume depletion due to the combination of natriuresis and water diuresis accompanied by elevated lithium levels, altered mental status, and subsequent poor oral intake. [emedicine.medscape.com]
- Neurologic Manifestation
Neurologic manifestations of acute water intoxication are usually not observed until the plasma sodium concentration has fallen to less than 125 mEq per liter. They include nausea, emesis, muscular twitching, grand mal seizures, and coma. [gps.org]
Polyuria will continue as long as the patient is able to drink. If the patient is unable to drink and is still unable to concentrate the urine, then hypernatremia will ensue with its neurologic symptoms. [en.wikipedia.org]
Polyuria, renal tubular acidosis and finally chronic renal failure are the most frequent adverse effects. The occurrence of an overt nephrogenic diabetes insipidus (NDI) limits Li usage and imposes suspension. [ncbi.nlm.nih.gov]
The patient has severe symptoms like deep polyuria nocturia, polydipsia, and fatigue. He was given arginine vasopressin treatment while he was a child. However, he could not get well due to his nephrogenic type of illness. [ncbi.nlm.nih.gov]
All suffered either from enuresis nocturna or nocturia. [doi.org]
DI, in general, will present with complaints of polyuria, nocturia, and thirst. The patient will not be dehydrated if he or she has free access to water. Serum electrolytes and renal and liver function may be within normal limits. [clinicaladvisor.com]
She (S-1) presented with clitoromegaly at 3 month of age, and polydipsia and polyuria at 13 month of age. [ncbi.nlm.nih.gov]
If nephrogenic diabetes insipidus is suspected in a patient, investigations required to confirm the diagnosis include a 24-hour urine collection for volume and osmolality, serum electrolyte levels, and a water deprivation test.
If urine osmolality is < 300 mOsm/kg after a 24-hour collection, diabetic insipidus (central or nephrogenic) is likely. If osmolality is greater than 300mOsm/kg, solute diuresis is likely and the causes of solute diuresis such as diabetes mellitus should be investigated and excluded.
The diagnosis can be confirmed by a water deprivation test. Water deprivation tests assess the maximum concentrating ability of the kidneys and their response to ADH. The test involves depriving a patient of water for 3 to 6 hours, within which period the urine is collected for measurement of volume every hour and osmolality every 2 hours. In nephrogenic diabetes insipidus, the maximal urine osmolality is usually low (<300 mOsm/kg).
Distinguishing nephrogenic diabetes insipidus from central diabetes insipidus involves the administration of exogenous ADH, such as desmopressin 10 mcg intranasally or aqueous vasopressin 5 units subcutaneously. After two hours of administering exogenous ADH, urine osmolality is measured. In central diabetes insipidus, urine osmolality increases by 50-100%, while minimal increase in urine osmolality is recorded in nephrogenic diabetes insipidus.
Treatment consists of adequate intake of free water, treatment of the underlying etiology and dietary salt and protein restriction. Diuretics and NSAIDs are supportive treatment options.
In infants, young children, and the elderly, who may not respond well to thirst, adequate free water intake should be ensured. Additionally, adequate nutrition should be ensured in these patients because of the risk of malnutrition.
A reduction in urine volume can be achieved by reducing dietary solute intake. Therefore, a low-salt and low-protein diet is recommended for patients with nephrogenic diabetes insipidus  . However, a low protein diet is not recommended in infants and young children. The reduced caloric and dietary solute intake may cause weight reduction and short stature in children in the first few years of treatment .
Thiazide diuretics are also indicated in treatment. Thiazide diuretics used in combination with dietary solute restriction reduces polyuria in nephrogenic diabetes insipidus    . Additionally, amiloride, a potassium-sparing diuretic is indicated in the treatment of nephrogenic diabetes insipidus. Amiloride is employed for its synergistic effects with thiazide diuretics (both prevent potassium depletion caused by thiazides) and for its beneficial effects in patients with reversible lithium-induced NDI    . However, with amiloride, the dose of lithium being administered should be reduced since there is a little chance of reduction of extracellular fluid volume.
Amiloride acts by closing the luminal sodium channels in the collecting tubules . These sodium channels usually allow for the entry of lithium into cells, causing a defective response of the cells to ADH . These channels are up to two times more permeable to lithium than sodium . Lithium in the cells primarily targets and inhibits glycogen synthase kinase 3, so this inhibition mediates the toxic effects of lithium use .
Loop diuretics are contraindicated in nephrogenic diabetes insipidus because of their counterproductive effects. Loop diuretics inhibit sodium reabsorption in the thick ascending limb of the loop of Henle, thereby reducing the sodium chloride gradient in the medullary interstitium responsible for water reabsorption.
Prostaglandins counter the effects of ADH and NSAIDs inhibit prostaglandin synthesis, hence the indication of NSAIDs in the treatment of nephrogenic diabetes insipidus  . Treatment of patients with NSAIDs before the administration of ADH achieves a net reduction in urine output of 25-50%   . Patients with polyuria resulting from congenital polyuric-polydipsic Bartter-like syndromes benefit most from NSAID therapy because these conditions have prostaglandin as a key pathogenic entity. The NSAIDs vary in their effects on urine output reduction; indomethacin is more efficient than ibuprofen in reducing urine output .
The clinical outcome of nephrogenic diabetes insipidus is generally good, however, it depends on the underlying etiology. In some cases of prolonged lithium use, certain irreversible features may occur.
A common complication of NDI is dilatation of the urinary tract (dilatation of the ureter and hydronephrosis)   . Rarely, the disease may ultimately result in renal failure and end-stage renal disease   .
Mortality occurs most commonly among children and the elderly and may be a result of severe dehydration, fever, cardiovascular collapse, and hypernatremia. Mortality is rare in adults because of the ease of rehydration.
Nephrogenic diabetes insipidus may be acquired or genetic. The most common hereditary form is an X-linked disease characterized by a mutation of the arginine vasopressin (AVP) receptor 2 gene. Other genetic forms involve the autosomal recessive or dominant inheritance of genetic mutations of the aquaporin-2 genes. Excluding the autosomal dominant disease, all homozygous forms of these genetic disorders present with complete unresponsiveness to ADH, while the heterozygous forms show no clinical manifestations.
Acquired causes of the disease include diseases and drugs which impair the concentrating ability of the kidneys. These disorders include the autosomal dominant polycystic kidney disease, sickle cell nephropathy, pyelonephritis, hypercalcemia, amyloidosis, myeloma, sarcoma, medullary sponge kidney, chronic hypokalemic nephropathy, and drugs such as lithium, demeclocycline, ofloxacin, amphotericin B, dopamine, dexamethasone, and orlistat. NDI may also be idiopathic.
Certain clinical syndromes mimic neurogenic diabetes insipidus and include gestational diabetes insipidus (in which the placenta secretes vasopressinase which degrades ADH) and post-pituitary surgery, whereby a functionally ineffective ADH precursor is secreted instead of ADH.
Childhood-onset disease is mostly due to genetic defects, the most common of which include the X-linked hereditary NDI resulting from defects in the AVPR2 gene, and the autosomal dominant and recessive disorders due to mutations in the aquaporin-2 genes. Adult-onset disease is almost always acquired and most commonly results from hypercalcemia and lithium toxicity.
The prevalence of diabetes insipidus in the United States is about 3 in 100,000 population . Both central and nephrogenic diabetes insipidus show no sexual or ethnic predilections. The inherited forms constitute 1-2% of all cases of diabetes insipidus (central and nephrogenic). Furthermore, there is an estimated incidence rate of 1 in 20 million births for genetic nephrogenic diabetes insipidus caused by a mutation in the aquaporin-2 genes .
The hallmark of nephrogenic diabetes insipidus is an impaired response of the kidneys to ADH; however, ADH secretion remains normal. The problem is usually due to a defective response to ADH of the collecting tubules or a defect in the renal countercurrent mechanism.
In elderly individuals and critically ill patients, there may be a mild reduction in renal concentrating ability. However, the symptoms are milder compared to the manifestations of NDI.
The acquired forms of nephrogenic diabetes insipidus can be prevented by eliminating the risk factors for the underlying disease or prescribing alternative medications or lower doses of the offending drugs.
Lithium, for example, causes NDI in a dose-dependent pattern, therefore, the lowest therapeutic dose of lithium is prescribed to prevent it. Additionally, patients on lithium should undergo baseline and routine renal function, thyroid function, electrolyte, and liver function tests.
Diabetes insipidus (DI) is defined as the excessive passage of dilute (<300mOsm/kg) urine in large volumes (>3 L/24 h).
Diabetes insipidus can be classified into central and nephrogenic diabetes insipidus. Central or neurogenic diabetes insipidus is characterized by an impaired secretion of antidiuretic hormone (ADH), also called arginine vasopressin. This results in an impaired urine-concentrating ability of the kidney. Nephrogenic diabetes insipidus (NDI) is characterized by an impaired response or resistance to ADH by the kidney cells  in the presence of normal ADH secretion.
Nephrogenic DI can result from genetic disorders or may occur following certain acquired diseases. Hereditary forms of NDI are rare and include mutations in the genes coding for aquaporin receptor-2 and arginine vasopressin receptors . The hereditary forms of the disease usually have an early onset, presenting as early as the first few days of neonatal life.
Common secondary causes of NDI include polycystic kidney disease, sickle cell nephropathy, amyloidosis, and chronic hypokalemic nephropathy. Medications such as lithium and orlistat are also implicated in NDI.
The clinical features include polyuria, polydipsia, and nocturia. The severe dehydration which may result from the excessive fluid loss may cause confusion, coma, and renal impairment. Death usually results from cardiovascular compromise.
Diagnosis requires the exclusion of differential diagnoses such as primary polydipsia and glycosuria, and diabetes mellitus. Tests necessary for the diagnosis include serum electrolytes, 24-hour urine collection for volume and osmolality, and a water deprivation test. The water deprivation test is the confirmatory test for nephrogenic diabetes insipidus.
Treatment involves the correction or treatment of the underlying disease, reduction of urine output, and rehydration. Rehydration may be via the intravenous route in severe dehydration or by adequate oral intake of free water. Reduction of urine output can be attained by maintaining a low-salt, low-protein diet with pharmacologic intervention, including the administration of thiazide diuretics, amiloride, and non-steroidal antiinflammatory drugs (NSAIDs).
Diabetes insipidus can be classified into two types, based on the organ from which the problem emanates. These are central diabetes insipidus and nephrogenic diabetes insipidus (NDI). Central diabetes insipidus is caused by the brain's inability to produce and secrete a hormone called anti-diuretic hormone (ADH). This hormone is responsible for the absorption of excess water from the urine. Nephrogenic diabetes insipidus implies that the problem is not from the brain, but the kidneys. In this condition, ADH is produced, but the kidneys are unresponsive to it, therefore causing excess urine production and water loss.
Nephrogenic diabetes insipidus can be caused by genetic disorders or other diseases or drugs. The genetic disorders involved cause defects in the genes which code for the ADH receptors and the water channels in the kidneys. Diseases which could cause NDI include pyelonephritis, multiple myeloma, and polycycystic kidney disease. Drugs which could cause the disease include lithium, amphoterin B, dexamethasone, dopamine, and ofloxacin. Lithium is the most common drug which causes the disease.
Generally, once the underlying factor is controlled, NDI can be successfully treated. However, in some cases of chronic lithium use, a permanent damage might have been established. Death results from severe dehydration and heart failure and it usually occurs among children and the elderly because of the difficulty in communicating dehydration.
The cardinal features include excessive urination (polyuria), excessive thirst (polydipsia), and frequent urination at night (nocturia). There is a critical chemical in the blood called sodium: excess sodium in the blood occurs in dehydrated patients and when it is severe, it may cause confusion and coma.
Because there are a number of conditions which could present similarly to diabetes insipidus, several investigations are necessary to confirm the diagnosis. These include measurement of urine volume and its solute content after a 24-hour urine collection, measurement of blood levels of certain chemicals called electrolytes including potassium and sodium, and assessing the volume and solute content of urine after the patient has been deprived of water for about 6 hours; the latter is referred to as the water-deprivation test.
Treatment involves the correction or treatment of the underlying disease, adequate intake of free water, and restriction of salt and protein in diet.
Certain drugs are administered to reduce urine volume, thirst, and to improve the kidney's ability to concentrate the urine. Rehydration is very important in the management of a patient with NDI to prevent the complications of dehydration.
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