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.