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Nephrogenic Diabetes Insipidus

Jeff M. Sands, MD; and Daniel G. Bichet, MD
[+] Article and Author Information

From Emory University School of Medicine, Atlanta, Georgia, and Université de Montréal, Montréal, Québec, Canada.


Acknowledgments: The authors thank Danielle Binette for providing graphical expertise.

Grant Support: By National Institutes of Health grants R01-DK41707, R01-DK63657, and P01-DK61521 (Dr. Sands) and by the Canadian Institutes of Health Research (MOP81581) and the Kidney Foundation of Canada (Dr. Bichet). Dr. Bichet also holds a Canada Research Chair in Genetics of Renal Diseases.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Jeff M. Sands, MD, Renal Division, Emory University School of Medicine, 1639 Pierce Drive, NE, WMB Room 338, Atlanta, GA 30322; e-mail, jeff.sands@emory.edu.

Current Author Addresses: Dr. Sands: Renal Division, Emory University School of Medicine, 1639 Pierce Drive, NE, WMB Room 338, Atlanta, GA 30322.

Dr. Bichet: Department of Medicine and Groupe d'étude des protéines membranaires, Université de Montréal, Research Center, Hôpital du Sacré-Coeur de Montréal, 5400 Boulevard Gouin West, Montréal, Québec H4J 1C5, Canada.


Ann Intern Med. 2006;144(3):186-194. doi:10.7326/0003-4819-144-3-200602070-00007
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During the past decade, our understanding of NDI has improved tremendously. The cloning of key genes led to advances in our knowledge of the cellular mechanisms involved in water reabsorption. Before the cloning of these key genes, it was known that water is reabsorbed across the collecting duct when it is stimulated by vasopressin (the collecting duct is impermeable to water in the absence of vasopressin) and when the kidney medulla is hypertonic. It was also known that the causes of NDI generally fall into 2 categories: defects in the ability of the collecting duct to respond to vasopressin and reabsorb water, and defects in the establishment of the medullary osmotic gradient needed to reabsorb water. However, the cellular mechanisms were not known, and it was not possible to screen individuals and families for disease-causing mutations, provide genetic counseling, and initiate appropriate therapy before the onset of clinical symptoms.

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Figure 1.
Water deprivation test.DI

The diagram shows the typical response after water deprivation in healthy individuals, in patients with complete or partial central diabetes insipidus ( ), in patients with complete or partial nephrogenic DI, and in patients with primary or psychogenic polydipsia. The 200 mmol/kg straight line is for schematic representation because patients with full phenotype (either central or nephrogenic DI) have a urine osmolality less than 100 mmol/kg. See text for additional details. dDAVP = desmopressin.

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Figure 2.
Urine-concentrating mechanism.

Diagram of the loop of Henle, distal tubule, and collecting duct showing the names and locations of the major transport proteins involved in the urine-concentrating mechanism. See text for additional details. AQP = aquaporin; ClC-K1 = chloride channel; NCC/TSC = Na-Cl cotransporter; NKCC2/BSC1 = Na-K-2Cl cotransporter; ROMK = renal outer medullary potassium channel; UT = urea transporter.

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Figure 3.
Water reabsorption in principal cells of the collecting duct.V2RACcAMPPKAAQP

Vasopressin binds to the type 2 vasopressin receptor ( ) on the basolateral membrane, activates adenylyl cyclase ( ), increases intracellular cyclic adenosine monophosphatase ( ), and stimulates protein kinase A ( ) activity. Cytoplasmic vesicles carrying aquaporin ( ) water channel proteins are inserted into the luminal membrane in response to vasopressin, thereby increasing the water permeability of this membrane. When vasopressin stimulation ends, water channels are retrieved by an endocytic process and water permeability returns to its low basal rate. The AQP3 and AQP4 water channels are expressed on the basolateral membrane and complete the transcellular pathway for water reabsorption. pAQP2 = phosphorylated aquaporin-2.

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Figure 4.
Type 2 vasopressin receptor.circles2

Diagram showing the type 2 vasopressin receptor (V2 receptor) protein and identifying putative disease-causing mutations in the arginine vasopressin receptor 2 gene ( ). Mutations are present in the extracellular, transmembrane, and cytoplasmic domains of the V2 receptor. The numbers 1 and 371 refer to amino acids 1 and 371, respectively. COOH = carboxy-terminus of the protein; NH = amino-terminus of the protein.

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Figure 5.
The aquaporin-2 protein.circles2

Diagram showing the aquaporin-2 (AQP2) protein and identifying putative disease-causing mutations in AQP2 ( ). Mutations are present in the extracellular, transmembrane, and cytoplasmic domains of AQP2. The numbers 1 and 271 refer to amino acids 1 and 271, respectively. COOH = carboxy-terminus of the protein; NH = amino-terminus of the protein.

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Figure 6.
Thick ascending limb.NKCC2/BSC1ROMKClC-Kb

Diagram showing the transport pathways involved in transepithelial NaCl reabsorption in a thick ascending limb cell from the loop of Henle. The Bartter syndrome results from recessive mutations in the genes that encode the Na-K-2Cl cotransporter ( ), the renal outer medullary potassium channel ( ), the chloride channel ( ), and Barttin; these are named types I to IV, respectively. A fifth type of the Bartter syndrome has recently been shown to be a digenic disorder that results from loss-of-function mutations in the genes that encode the ClC-Ka and ClC-Kb chloride channels. Normally, potassium is recycled back into the tubule lumen by ROMK, thereby maintaining a lumen-positive gradient that drives the paracellular reabsorption of calcium, magnesium, potassium, and ammonium. In addition, paracellin-1 is needed for the paracellular transport of calcium and magnesium. In the Bartter syndrome, regardless of subtype, a lumen-positive voltage cannot be generated, thereby preventing paracellular reabsorption of positively charged ions.

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