Nephrogenic Diabetes Insipidus: Clinical Symptoms, Pathogenesis, Genetics and Treatment
| Title: | Nephrogenic Diabetes Insipidus: Clinical Symptoms, Pathogenesis, Genetics and Treatment |
|---|---|
| Authors: | Monnens, Leo A.H.; Knoers, Nine |
| Publisher: | Pediatric Nephrology |
| Date Published: | September 01, 1992 |
| Reference Number: | 255 |
This review summarizes various aspects of the inherited kidney disorder nephrogenic diabetes insipidus (NDI). The clinical manifestations of the disease are presented. The important role of the genetic localization of the NDI gene to the X-chromosome long arm, in region Xq28, for carrier detection and early (prenatal) diagnosis of the disorder is emphasized. Following an overview of the cellular physiology involved in the antidiuretic action of vasopressin, possible mechanisms in the pathogenesis of NDI are discussed. We hypothesize that NDI is most probably due to the absence or abnormality of the renal V2 receptor. This assumption is strengthened by recent findings in receptor studies, which indicate a general V2 receptor defect in NDI, and in experiments with somatic cell hybrid cell lines, which are consistent with a co-localization of the genes for NDI and for the V2 receptor in the Xq28 region. Finally, the efficacy of the combination amiloride-hydrochlorothiazide, compared with the indomethacin-hydrochlorothiazide regimen, in the treatment of NDI is presented and the advantages of the former combination are discussed.
This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
Polyuria (chronic passage of large volumes of urine) and polydipsia (chronic, excessive thirst) are NDI's primary symptoms. When inherited, the defect in NDI is present from birth and manifests in the first weeks of life. At this point, in addition to polyuria and polydipsia, the symptoms include constipation, fever, irritability, failure to thrive, vomiting, poor feeding and poor weight gain. Bouts of severe dehydration may occur, especially if the disorder goes undiagnosed and untreated. This could lead to high blood sodium levels, physical and mental retardation, and even death. Malnutrition and cerebral edema (from giving the infant too much water in the attempt to rehydrate him) also could inflict mental retardation.
As the NDI child grows, his psychological development can also be influenced by his increased water desires and the need to urinate frequently, which compete with normal playing and learning. NDI patients are often characterized by short attention spans, hyperactivity, distractibility and restlessness. Further, they grow susceptible to distention and functional obstruction of the kidneys, bladders and the tubes which lead from kidney to bladder.
NDI is most commonly inherited as an X-linked recessive disease. This means that females carry the gene for NDI on one of their two X chromosomes. The female carrier is less likely to have NDI symptoms because on one of her X chromosomes there is a normal version of the mutated gene responsible for NDI. This normal gene is able to function and thus masks the presence of the mutated NDI gene on her other X chromosome. Males have only one X chromosome, which they inherit from their mother. If the son should inherit the X chromosome that carries the NDI gene, he will express the symptoms of NDI. So, females can carry the NDI gene and pass it on to their sons, who exhibit its symptoms.
There is a strong suspicion and rapidly accumulating laboratory evidence that the vasopressin-2 receptor (V2R) gene is the gene responsible for X-linked NDI. Normally, AVP binds with V2R and this sets off the following molecular sequence: the bound AVP/V2R couples with a G-protein. This activates adenylyl cyclase, which catalyzes the formation of an important metabolic regulator called cAMP. cAMP activates protein kinase A, which initiates a series of as yet incompletely known molecular steps that induce water transporting proteins called aquaporin-2 (AQP2) to insert themselves in the apex of the membranes of the principal cells of the kidney collecting duct. The inserted AQP2s increase the cells' ability to absorb water and this is what allows the kidney collecting ducts to reabsorb water, concentrate urine and help balance body water.
The defect in NDI could occur at any one of the steps in this molecular sequence, but some of the steps are less likely than others. If the defect was in the G-protein, it should lead to resistance to many other hormones than just AVP. But NDI is characterized by resistance to AVP only. The same holds true for the enzyme adenylyl cyclase. It is possible that the fault may be with cAMP as a strain of NDI mice have exhibited an enzyme that rapidly breaks down cAMP, perhaps breaking it down before it can carry out its function. The cAMP-dependent protein kinase could qualify as an NDI-causing candidate as one of its subunits is specific for the kidney cells sensitive to AVP.
However, laboratory research has indicated that the most likely cause for most cases of inherited NDI lies in an abnormality in the V2R, the receptor that AVP must bind with to initiate the urine concentrating process. V2Rs exist both within and outside of the kidney. In the kidney, they bind with AVP to initiate urine concentration. Outside the kidney, they bind with AVP to initiate dilation of blood vessels and release of blood factors associated with blood coagulation. NDI patients, when injected with a synthetic analog of AVP called DDAVP, do not show any antidiuretic, vasodilating or coagulation responses, whereas people without NDI do show responses in these areas.
Further, V2R binding activity was measured in laboratory cell cultures carrying different fragments of the X chromosome. In those cultures carrying the fragment of the X chromosome known to be the site where the NDI causing gene is located, V2R binding activity and an increase of cAMP was observed. This finding added to other findings which locate the V2R gene at the same location as the NDI causing gene, indicating that the mutated V2R gene is the NDI causing gene. (Though there have been some initial studies indicating that there may be another gene that, when mutated, also causes NDI.)
The treatment of choice for NDI consists of a low sodium diet in conjunction with hydrochlorothiazide diuretics in combination with amiloride. However, the prolonged use of thiazides can lead to low blood levels of potassium. Amiloride does not deplete potassium levels, which helps counterbalance thiazide-induced potassium loss. The antidiuretic action of hydrochlorothiazide and amiloride are additive, probably because they work on different parts of the kidneys. This combination of drugs appears to have only minor long-term side effects.