About nephrogenic diabetes insipidus
What is nephrogenic diabetes insipidus?
Nephrogenic diabetes insipidus (NDI) is a rare kidney disorder that may be inherited or acquired. NDI is not related to the more common diabetes mellitus (sugar diabetes), in which the body does not produce or properly use insulin. NDI is a distinct disorder caused by complete or partial resistance of the kidneys to arginine vasopressin (AVP). Vasopressin is an antidiuretic hormone used by the kidney to manage water balance in the body. NDI causes chronic excessive thirst (polydipsia), excessive urine production (polyuria), and potentially dehydration. If left untreated, repeated episodes of severe dehydration may develop, eventually resulting in serious complications. Most cases of hereditary NDI are inherited as X-linked recessive disorders. Rare cases are inherited as an autosomal recessive or dominant disorder. Two different genes have been identified that cause hereditary NDI. NDI may also be acquired during life as a result of drug use (e.g., lithium therapy), kidney disease, obstruction of the tubes that carry urine from the kidneys to the bladder (ureters), and prolonged metabolic imbalances such as low levels of potassium in the blood (hypokalemia) or high levels of calcium in the blood (hypercalcemia). NDI may also be a temporary complication associated with pregnancy.
What are the symptoms for nephrogenic diabetes insipidus?
The symptoms of NDI can vary from one person to another. Some individuals may be more severely affected than others. The acquired form is almost always less severe than the hereditary forms. In hereditary NDI, symptoms usually appear shortly after birth and most children are diagnosed within the first year of life. In autosomal dominant NDI, symptoms tend to appear later in life, sometimes not until adulthood. The acquired form of NDI most often occurs in adults and the onset of symptoms may be slow.
The two main symptoms of NDI are chronic excessive thirst (polydipsia) and excessive urine production (polyuria). Excessive urination at night (nocturia) also occurs. Some infants may present with vomiting, retching, unexplained fevers, lethargy, and irritability. Constipation, diarrhea and poor feeding may also occur. As a result, some infants may fail to grow or gain weight at the expected rate (failure to thrive). In some patients, these symptoms may be mild and underappreciated.
Infants and adults with NDI may rapidly develop dehydration following low water intake, a hot environment, or concurrent illness. Infants with NDI may experience repeated episodes of dehydration, which can result in weakness, confusion, dry mucous membranes, dry skin, and weight loss. If left untreated, severe dehydration may develop. Repeated episodes of severe dehydration may result in significant abnormalities including seizures, brain damage, developmental delays, and physical and mental disability. However, with proper diagnosis and prompt treatment, intelligence and development are usually normal.
Because of the chronic excretion of large amounts of urine, additional symptoms may develop as affected individuals age including bedwetting at night (nocturnal enuresis), abnormal accumulation of urine in the kidneys (hydronephrosis), swelling (distention) of the ureters with urine due to blockage (hydroureter), and an abnormally large bladder (megacystis). Some individuals develop widening (dilatation) of the urinary tract.
Adults with NDI may also develop orthostatic hypotension, a condition in which there is a dramatic decrease in blood pressure upon standing or sitting. Orthostatic hypotension can result in dizziness or momentary loss of consciousness (syncope).
Many individuals with NDI attain an adult height that is just below normal or where would be expected otherwise. This may result from unsuccessful management or inadequate nutrition during childhood (e.g. failure to thrive).
What are the causes for nephrogenic diabetes insipidus?
A variety of factors can cause acquired NDI. A common cause is chronic use of the drug lithium. Less common causes include protein malnutrition, a variety of kidney diseases, obstruction of the urinary tract, and prolonged metabolic imbalances specifically as low levels of potassium in the blood (hypokalemia) or high levels of calcium in the blood (hypercalcemia). Other drugs such as certain antibiotics, antivirals, antifungals, or antineoplastic drugs have been reported to potentially cause acquired NDI. During pregnancy, some women may develop a temporary (transient) form of NDI.
In most cases of hereditary NDI inheritance is X-linked recessive. In rare cases, inheritance is autosomal recessive or dominant. Some cases may occur randomly as the result of a spontaneous genetic change (i.e., new mutation).
X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
Although most females who carry the mutated gene usually do not develop the clinical symptoms (asymptomatic) of NDI, some females do develop certain symptoms such as varying degrees of excessive thirst and excessive urination. This occurs because of a process known as marked skewing of X chromosome inactivation. In this process, the X chromosome carrying the normal gene is inactivated instead of the X chromosome with the mutated gene.
The X-linked recessive form of NDI is caused by disruptions or changes (mutations) of the AVPR2 gene on the X chromosome.
Approximately 10% of cases of hereditary NDI are inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Less than 1% of cases hereditary NDI are inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Most (but not all) patients with autosomal recessive and dominant NDI are caused by mutations of the aquaporin-2 (AQP2) gene.
The symptoms of NDI result from the inability of the kidneys to reabsorb water. Water within the body normally flows through the kidneys where it is reabsorbed through structures called nephrons – tubular filters that collect urine containing water and waste products. The water is filtered out and eventually returned the body. The amount of water retained is determined by the antidiuretic hormone, arginine vasopressin. This hormone works with a protein coating the cells of nephrons called a vasopressin-2 receptor (V2R). The V2R protein recognizes vasopressin in the body. Vasopressin and V2Rs bind together to begin a complex chemical process that manages water intake by the kidneys. As part of this process, another protein known as aquaporin-2 (AQP2) is activated to serve as a passageway or water channel through which water crosses the cell membrane.
The V2R protein is encoded by the AVPR2 gene, which is abnormal in individuals with the X-linked form of this disorder. An abnormal AVPR2 gene results in abnormal V2Rs that are trapped within cells (intracellular) and do not reach the cell surface. A few abnormal V2Rs do reach the cell surface, but they fail to recognize or bind with vasopressin, thereby preventing the proper reabsorption of water.
Individuals with autosomal recessive or dominant NDI generally have mutations of the AQP2 gene, which encodes the water channel protein aquaporin-2. An abnormal AQP2 gene results in abnormal aquaporin-2. Abnormal aquaporin-2 proteins result in abnormal water channels that prevent enough water from passing through the cell membranes.
If the kidneys do not properly reabsorb water, the water is lost through frequent urination. The urine of individuals with NDI is weak or dilute, meaning that the urine has too much water in it.
What are the treatments for nephrogenic diabetes insipidus?
The treatment of NDI is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, kidney specialists (nephrologists), endocrinologists, nutritionists, and other health care professionals may need to systematically and comprehensively plan an individual’s treatment.
The mainstay of therapy is ensuring proper fluid intake and reducing urine output. Specific treatments include dietary modifications and the administration of certain drugs. Adequate water intake is essential for individuals with NDI in order to prevent dehydration. Infants may require periodic offerings of water. If the child cannot consume enough water to match their urine output, they may require a feeding tube to be placed into the stomach or intestine.
Children, parents and adults should take precautions to ensure affected individuals have access to drinking water and toilet facilities. Heavy sleepers may need to be awakened during the night to drink water and to urinate. Parents should work with school officials and teachers to ensure that proper provisions are in place for their children. Affected individuals are encouraged to wear medic alert bracelets or some similar form of identification that indicates that they have NDI.
Dietary modifications and drug therapy are used to decrease urine output. Individuals with NDI may be placed on a very low sodium diet (0.5 g/d) because sodium contributes to water loss. Drugs that affect how much water is excreted in the urine (diuretics) may also be used. Diuretics, which include hydrochlorthiazide or chlorothiazide, inhibit the amount of salt absorbed by the kidneys, thereby reducing water loss. These drugs may be used alone or in combination with other drugs such as indomethacin or amiloride. Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) that can increase urine concentration and reduce urine output. Indomethacin, which may also be used alone, may be associated with adverse side effects such as gastrointestinal bleeding. Amiloride is a diuretic that helps the body maintain potassium levels, which may drop with hydrochlorthiazide therapy.
For individuals with acquired NDI treating the underlying cause (e.g., correcting metabolic imbalances or discontinuing drug use) can reverse the kidneys resistance to vasopressin. However, this reversal may take weeks. In some cases caused by the use of drugs such as lithium, it may take years for the kidneys to respond to vasopressin again or it can become irreversible.
Individuals with NDI undergoing surgery that requires no food or drink for a period of time preceding the surgery should consult with their physicians. Affected individuals will require proper hydration, usually via an IV, before and/or during surgery.
Genetic counseling is recommended for affected individuals and their families with the inherited forms of the disorder. Other treatment is symptomatic and supportive.
What are the risk factors for nephrogenic diabetes insipidus?
As this disease is hereditary, risk begins from the defected male gene, which can pass through women in their children.
- Infants are usually born with Nephrogenic Diabetes due to hereditary mutations of genes from parents.
- Problems with a part of your brain that controls thirst can also cause diabetes insipidus
- Certain chronic diseases and drugs for the same given during the first few months lead to this form of diabetes in the body.
- It also occurs due to an imbalance of required minerals in a body: calcium and potassium levels.
- Damage to your hypothalamus or your pituitary glands as a result of surgery, infection, inflammation, a tumor, or a head injury may also cause diabetes insipidus.
- Damage to brain hormone sending signals, thirst-regulating signals, and the rarest of them all: damage to the placental enzyme.
- Other risk factors include using medicines, especially those used to treat bipolar disorder, low levels of potassium in your blood, high levels of calcium in your blood, a blocked urinary tract, an inherited gene mutation, and chronic kidney disease, though rarely.
Is there a cure/medications for nephrogenic diabetes insipidus?
Most of the time, the child born with Nephrogenic Diabetes Insipidus leads a neutral life with extra care towards diet and water intake surveillance.
This form of diabetes is usually seen in infants with slow growth and poor eating habits resulting in them being underweight.
- Detection in infants: By analyzing the frequency of getting a fever, dehydration, vomiting, and heavy diapers with frequent urination.
- Genetic Testing: Tests on parents’ and newborn babies’ genes are conducted to understand the mutations of their copies.
- 24-Hour Urine Collection: Tests to check the salts in urine collected for 24 hours without fluid restriction.
- Water Deficiency Test: This test helps in assessing maximum urine concentrating ability and response to ADH.
Diabetes is not a curable disease, but a diabetic patient can lead a neutral life with necessary preventions included in the lifestyle.
- Anti-Inflammatory Medicines with no steroids present in them can help in reducing urination and balancing ADH levels.
- Lower levels of salts and proteins help in demeaning the frequency of urination.
- Apart from steroid-less medicines, water pills can also be taken orally and used for normalizing kidney functioning.
Pains in Muscles,Vomiting,Weakness,Laziness and Tiredness,Lots of Thirst
Excessive urine production,Dehydration, Kidney defects for life,Delayed growth,Weight loss