Polyuria and Diabetes Insipidus

CHAPTER

43

Polyuria and Diabetes Insipidus Daniel G. Bichet Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada

Diabetes insipidus is a disorder characterized by the excretion of abnormally large volumes (⬎30 ml/kg body weight/ day for an adult patient) of dilute urine (⬍250 mmol/kg). Four basic defects can be involved. The most common, a deficient secretion of the antidiuretic hormone (ADH) arginine vasopressin (AVP), is referred to as neurogenic (or central, neurohypophyseal, cranial, or hypothalamic) diabetes insipidus. Diabetes insipidus can also result from renal insensitivity to the antidiuretic effect of AVP, which is referred to as nephrogenic diabetes insipidus (NDI). Excessive water intake can result in polyuria, which is referred to as primary polydipsia: It can be due to an abnormality in the thirst mechanism, referred to as dipsogenic diabetes insipidus; it can also be associated to a severe emotional cognitive dysfunction, referred to as psychogenic polydipsia. Finally, increased metabolism of vasopressin during pregnancy is referred to as gestational diabetes insipidus.

AVP and its corresponding carrier protein, neurophysin II, are synthesized as a composite precursor by the magnocellular and parvocellular neurons described previously. The precursor is packaged into neurosecretory granules and transported axonally in the stalk of the posterior pituitary (34). On route to the neurohypophysis, the precursor is processed into the active hormone. Prepro-vasopressin has 164 amino acids and is encoded by the 2.5-kb AVP gene located in chromosome region 20p13 (148). The AVP gene (coding for AVP and neurophysin II) and the OXT gene (coding for oxytocin and neurophysin I) are located in the same chromosome region, at a very short distance from each other (12 kb in humans) in headto-head orientation. Data from transgenic mouse studies indicate that the intergenic region between the OXT and the AVP genes contains the critical enhancer sites for cellspecific expression in the magnocellular neurons (34). It is phylogenetically interesting to note that cis and trans components of this specific cellular expression have been conserved between the Fugu isotocin (the homolog of mammalian oxytocin) and rat oxytocin genes (188). Exon 1 of the AVP gene encodes the signal peptide, AVP, and the NH2-terminal region of NPII. Exon 2 encodes the central region of NPII, and exon 3 encodes the COOH-terminal region of NPII and the glycopeptide. Pro-vasopressin is generated by the removal of the signal peptide from prepro-vasopressin and the addition of a carbohydrate chain to the glycopeptide. Additional posttranslation processing occurs within neurosecretory vesicles during transport of the precursor protein to axon terminals in the posterior pituitary, yielding AVP, NPII, and glycopeptide (Fig. 2). The AVP-NPII complex forms tetramers that can self-associate to form higher oligomers (Fig. 3) (36). In the posterior pituitary, AVP is stored in vesicles. Exocytotic release is stimulated by minute increases in serum osmolality (hypernatremia, osmotic regulation) and by more pronounced decreases of extracellular fluid (hypovolemia, nonosmotic regulation). Oxytocin and neurophysin I are released from the posterior pituitary by the suckling response in lactating females. The neuropeptides oxytocin and vasopressin are involved in new fascinating studies of the neurobiology of attachment (81) and central vasopressin and oxytocin receptors may regulate the autonomic expression of fear (79).

ARGININE VASOPRESSIN Synthesis Nonapeptides of the vasopressin family are the key regulators of water homeostasis in amphibia, reptiles, birds, and mammals. Since these peptides reduce urinary output, they are also referred to as antidiuretic hormones. Oxytocin and AVP (Fig. 1) are synthesized in separate populations of magnocellular neurons of the supraoptic and paraventricular nuclei (151). Oxytocin is most recognized for its key role in parturition and milk letdown in mammals (199). The axonal projections of AVP- and oxytocinproducing neurons from supraoptic and paraventricular nuclei reflect the dual function of AVP and oxytocin as hormones and as neuropeptides, in that they project their axons to several brain areas and to the neurohypophysis. Another pathway from parvocellular neurons to the hypophysial portal system transports high concentration of AVP to the anterior pituitary gland. AVP produced by this pathway together with the corticotropin-releasing hormone are two major hypothalamic secretagogues regulating the secretion of adrenocorticotropic hormone by the anterior pituitary (90). Seldin and Giebisch’s The Kidney

1225

Copyright © 2008, Elsevier Inc. All rights reserved.

1226

SECTION III

•

Regulation and Disorders of Water Homeostasis

ARGININE VASOPRESSIN

Q4

OXYTOCIN L8 Q4

P7

N5

G9

R8

I3

C6 C6

N5

P7

F3 G9 C1

Y2

C1

Y2

FIGURE 1 Contrasting structures of arginine-vasopressin (AVP) and oxytocin (OT). The peptides differ only by two amino acids (F3 → I3 and R8 → L8 in AVP and OT, respectively). The conformation of AVP was obtained from Mouillac B, Chini B, Balestre MN, et al. The binding site of neuropeptide vasopressin V1a receptor. Evidence for a major localization within transmembrane regions. J Biol Chem 1995;270:25771–25777; and the conformation of OT was obtained from the Protein Data Bank (PDB Id 1XY1).

Osmotic and Nonosmotic Stimulation The regulation of AVP release from the posterior pituitary is dependent primarily on two mechanisms involving the osmotic and nonosmotic pathways (160). The osmotic regulation of AVP is dependent on osmoreceptor cells. Although magnocellular neurons are themselves osmosensitives, they require input from the lamina terminalis to respond fully to osmotic challenges. Neurons in the lamina terminalis are also osmosensitive and because the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) lie outside the blood–brain barrier, they can integrate this information with endocrine signals borne by circulating hormones, such as angiotensin

AVP (2,5 kb; 20p13)

II (ANG II), relaxin, and atrial natriuretic peptide (ANP). While circulating ANG II and relaxin excite oxytocin and vasopressin magnocellular neurons, ANP inhibits vasopressin neurons. In addition to an angiotensinergic path from the SFO, the OVLT and the median preoptic nucleus provide direct glutaminergic and GABAergic projections to the hypothalamo-neurohypophysial system. Nitric oxide and apelin may also modulate neurohormone release (50). In magnocellular neurons, stretch-inactivating cationic channels transduce osmotically evoked changes in cell volume and results in functionally relevant changes in membrane potential; hypertonicity will trigger a membrane depolarization of these cells and AVP secretion (29,

Exon 1

Prepro-vasopressin (164 a.a.)

AVP

Exon 2

Gly-Lys-Arg Neurophysin II (cleavage site)

Exon 3

Arg

Glycopeptide

Signal peptide

*

Provasopressin

AVP

Gly-Lys-Arg

Neurophysin II

3 products from the prohormone

AVP

NH2

Neurophysin II

Arg

Glycopeptide

Glycopeptide

*addition of a carbohydrate chain

FIGURE 2

Structure of the human vasopressin (AVP) gene and prohormone.

CHAPTER 43

30). Recent studies demonstrate that a variant of the transient receptor potential vanilloid type-1 (Trpv1) channel is expressed in osmosensitive neurons of the SON. Knockout mice (Trpv1⫺/⫺) showed a pronounced serum hyperosmolality under basal conditions and abnormal AVP responses to osmotic stimulation in vivo. These results suggest that the Trpv1 gene encodes a central component of the osmoreceptor (175). Cell volume is decreased most readily by substances that are restricted to the extracellular fluid, such as hypertonic saline or hypertonic mannitol, which not only enhance osmotic water movement from the cells but also very effectively stimulate AVP release. In contrast, hypertonic urea, which moves rapidly into the cells, neither readily alters cell volume nor effectively stimulates AVP

A NH2 49

61

75

65

23

59

78

11 25

71 82 69

37 29

COOH 32

B

13

39

•

Polyuria and Diabetes Insipidus

1227

release (207). The osmoreceptor cells are very sensitive to changes in extracellular fluid osmolality. With fluid deprivation a 1% increase in extracellular fluid osmolality stimulates AVP release, whereas with water ingestion a 1% decrease in extracellular fluid osmolality suppresses AVP release. AVP release can also be caused through a nonosmotic mechanism (Fig. 4). Large decrements in blood volume or blood pressure (⬎10%) sensed by stretch and baroreceptors in the central venous and arterial system stimulate AVP release. A variety of hypothalamic neurotransmitters, including monoamines and neuropeptides, are involved in the control of AVP release (105). Noradrenaline in the supraoptic nuclei, as well as in the paraventricular nuclei, has a primary excitatory effect on AVP release, most probably mediated through ␣1-adrenergic receptors (146). ANG II is also a potent stimulant of AVP release (59). It is of note that knockout mice with loss-of-function of angiotensinogen (a precursor peptide of ANG II) or of the angiotensin receptor type 1A, do not demonstrate obvious alterations in thirst or in water balance (83, 135, 179). Mice that lack the gene encoding the angiotensin receptor type 2 have a mild impairment in drinking response to water deprivation (74). ␤-adrenergic receptors (105) and opioid receptors (157) may be involved in the inhibition of AVP release. The osmotic stimulation of AVP release by dehydration or hypertonic saline infusion, or both, is regularly used to test the AVP secretory capacity of the posterior pituitary. This secretory capacity can be assessed directly by comparing the plasma AVP concentration measured sequentially during a dehydration procedure with the normal values and then correlating the plasma AVP with the

FIGURE 3

A: Three-dimensional structure of a bovine peptide– neurophysin monomer complex. The structure of each chain is 12% helix and 40% ␤ sheet. The chain is folded into two domains as predicted by disulfide-pairing studies. The amino-terminal domain begins in a long loop (residues 1–10), then enters a four-stranded (residues 11–13, 19–23, 25–29, and 32–37) antiparallel ␤ sheet (sheet I; four shaded arrows), followed by a three-turn 310-helix (residues 39-49) and another loop (residues 50–58). The carboxyl-terminal domain is shorter, consisting of only a four-stranded (residues 59–61, 65–69, 71–75, and 78–82) antiparallel ␤ sheet (sheet II; four cross-hatched arrows) (36). The arginine-vasopressin molecule (balls and sticks model) is shown in the peptide-binding pocket of the neurophysin monomer. The strongest interactions in this binding pocket are salt bridge interactions between the ␣NH3⫹ group of the peptide, the ␥-COO⫺ group of GluNP47 (residue number 47 of the neurophysin molecule), and the side chain of ArgNP8. The ␥-COO⫺ group of GluNP47 plays a bifunctional role in the peptide-binding pocket: (a) it directly interacts with the hormone; (b) it interacts with other neurophysin residues to establish the correct, local structure of the peptide-neurophysin complex. ArgNP8 and GluNP47 are conserved in all neurophysin sequences from mammals to invertebrates. B: Ribbon drawing (Midas) of the dimer neurophysin-oxytocin. The bound oxytocin sits in binding pockets located at the end of a three-turn 310-helix. (From Rose JP, Wu CK, Hsiao CD, et al. Crystal structure of the neurophysin-oxytocin complex. Nat Struct Biol 1996;3:163–169, with permission.) See color insert.

1228

SECTION III

•

Regulation and Disorders of Water Homeostasis

B

Neurogenic diabetes insipidus

A

Nephrogenic diabetes insipidus

B

3 2 1

100

10

1

Detection limit

0 120 125 130 135 140 145 Plasma sodium (mEq/l)

10 20 30 40 50 60 % fall in mean arterial blood pressure

FIGURE 4 Osmotic and nonosmotic stimulation of arginine-vasopressin (AVP). A: The relationship between plasma AVP (PAVP) and plasma sodium (PNa) in 19 healthy subjects is described by the gray area, which includes the 99% confidence limits of the regression line PNa/PAVP. The osmotic threshold for AVP release is about 280 to 285 mmol/kg or 136 mEq of sodium per liter. AVP secretion should be abolished when plasma sodium is lower than 135 mEq/l (15). B: Increase in plasma AVP during hypotension. Note that a large diminution in blood pressure in healthy humans induces large increments in AVP. (From Vokes T, Robertson GL. Physiology of secretion of vasopressin. In: Czernichow P, Robinson AG, eds. Diabetes Insipidus in Man. Basel: S. Karger; 1985:127–155, with permission.)

urinary osmolality measurements obtained simultaneously (Fig. 5) (206). The AVP release can also be assessed indirectly by measuring plasma and urine osmolalities at regular intervals during the dehydration test (125). The maximum urinary osmolality obtained during dehydration is compared with the maximum urinary osmolality obtained after the administration of vasopressin or 1-desamino-8-D-arginine vasopressin (dDAVP; Pitressin: 5 units subcutaneously [SQ ] in adults; 1 unit SQ in children; or dDAVP 1-4 ␮g intravenously during 5 to 10 minutes). The nonosmotic stimulation of AVP release can be used to assess the vasopressin secretory capacity of the posterior pituitary in a rare group of patients with the essential hyponatremia and hypodipsia syndrome. Although some of these patients may have partial central diabetes insipidus, they respond normally to nonosmolar AVP release signals such as hypotension, emesis, and hypoglycemia (19). In all other cases of suspected central diabetes insipidus, these nonosmotic stimulation tests will not give additionnal clinical information (10). Cellular Actions of Vasopressin The neurohypophyseal hormone AVP has multiple actions, including the inhibition of diuresis, contraction of smooth muscle, platelet aggregation, stimulation of liver glycogenolysis, modulation of adrenocorticotropic hormone release from the pituitary, and central regulation of somatic and higher functions (thermoregulation, blood pressure, autonomic expression of fear, neurobiology of attachment) (79, 81, 88). These multiple actions of AVP could be explained by the interaction of AVP with at least three types of

10

1000 Normal

Urine osmolality (mOsmol/kg)

4

Plasma arginine vasopressin (pg/ml)

1000

5

Increase in plasma arginine-vasopressin (pg/mL)

Plasma arginine-vasopressin (pg/mL)

A

5

0

Normal

500

0 280

295

310

Plasma osmolality (mOsmol/kg)

0

5

10

Plasma arginine vasopressin (pg/ml)

FIGURE 5 A: Schematic diagram of the relationship between plasma arginine-vasopressin (AVP) and plasma osmolality during hypertonic saline infusion. In patients with neurogenic diabetes insipidus, plasma AVP is almost always subnormal relative to plasma osmolality. In contrast, patients with primary polydipsia or nephrogenic diabetes insipidus (NDI) have values within the normal range (light gray area). B: Relationship between urine osmolality and plasma AVP during a dehydration test. Patients with NDI have hypotonic urine despite high plasma AVP. In contrast, patients with neurogenic diabetes insipidus or primary polydipsia have values within the normal range (dark gray area). (From Zerbe RL, Robertson GL. Disorders of ADH. Med North Am 1984;13:1570–1574, with permission.)

G-protein–coupled receptors: The V1a (vascular hepatic) and V1b (anterior pituitary) receptors act through phosphatidylinositol hydrolysis to mobilize calcium (130), and the V2 (kidney) receptor is coupled to adenylate cyclase (88). The first step in the action of AVP on water excretion is its binding to V2 receptors on the basolateral membrane of the collecting duct cells (Fig. 6). The human V2 receptor gene, AVPR2, is located in chromosome region Xq28 and has three exons and two small introns (26, 172). The sequence of the complementary DNA (cDNA) predicts a polypeptide of 371 amino acids with a structure typical of guanine-nucleotide (G) protein–coupled receptors with seven transmembrane, four extracellular, and four cytoplasmic domains (Fig. 7) (194). The activation of the V2 receptor on renal collecting tubules stimulates adenylyl cyclase by the way of the stimulatory G-protein (Gs ) and promotes the cyclic adenosine monophosphate (cAMP)–mediated incorporation of the water channels aquaporin-2 (AQP2) into the luminal surface of these cells. This process is the molecular basis of the vasopressin-induced increase in the osmotic water permeability of the apical membrane of the collecting tubule. The human AQP2 gene is located in chromosome region 12q13 and has four exons and three introns (51, 52, 168). It is predicted to code for a polypeptide of 271 amino acids that is organized into two repeats oriented at 180 degrees to each other and has six membranespanning domains, both terminal ends located intracellularly, and conserved Asn-Pro-Ala boxes (Fig. 8). These features are characteristic of the major intrinsic protein family (168). AQP2 is detectable in urine, and changes in urinary excretion of this protein can be used as an index of the action of

CHAPTER 43

•

Polyuria and Diabetes Insipidus

1229

Outer and inner medullary collecting duct

Gi +

Syntaxin 4

Endocytic retrieval

V2 receptor

AQP3 Recycling vesicle

AVP AQP2

C

Ac

tin

fila

ATP C2

C C

AKAP

AP AK

C

Actin filament motor

G␣s PDEs

Endocytic vesicle associated PKA AKAP

AQP2 H 2O

Adenylyl cyclase

Exocytic insertion

C1

C

cAMP C

m

en

t

Microtubule

Luminal

Microtubule motor

Basolateral AQP4

FIGURE 6

Schematic representation of the effect of arginine-vasopressin (AVP) to increase water permeability in the principle cells of the collecting duct. AVP is bound to the V2 receptor (a G-protein–linked receptor) on the basolateral membrane. The basic process of G-protein–coupled receptor signaling consists of three steps: A hepta-helical receptor that detects a ligand (in this case, AVP) in the extracellular milieu, a G-protein (Gⴤs) that dissociates into ␣ subunits bound to GTP and ␤␥ subunits after interaction with the ligand-bound receptor, and an effector (in this case, adenylyl cyclase) that interacts with dissociated G-protein subunits to generate small-molecule second messengers. AVP activates adenylyl cyclase, increasing the intracellular concentration of cAMP. The topology of adenylyl cyclase is characterized by two tandem repeats of six hydrophobic transmembrane domains separated by a large cytoplasmic loop and terminates in a large intracellular tail. The dimeric structure (C1 and C2) of the catalytic domains is represented. Conversion of ATP to cAMP takes place at the dimer interface. Two aspartate residues (in C1) coordinate two metal cofactors (Mg2⫹ or Mn2⫹, small black circles), which enable the catalytic function of the enzyme (183). Adenosine is the large open circle and the three phosphate groups (ATP) are the three small open circles. Protein kinase A (PKA) is the target of the generated cAMP. The binding of cAMP to the regulatory subunits of PKA induces a conformational change, causing these subunits to dissociate from the catalytic subunits. These activated subunits (C) as shown here are anchored to an aquaporin-2 (AQP2)–containing endocytic vesicle via san A-kinase anchoring protein (AKAP). The local concentration and distribution of the cAMP gradient is limited by phosphodiesterase (PDE). Cytoplasmic vesicles carrying the water channel proteins (represented as homotetrameric complexes) are fused to the luminal membrane in response to AVP, thereby increasing the water permeability of this membrane. The dissociation of AKAP from the endocytic vesicle is not represented. Microtubules and actin filaments are necessary for vesicle movement toward the membrane. When AVP is not available, AQP2 water channels are retrieved by an endocytic process, and water permeability returns to its original low rate. AQP3 and AQP4 water channels are expressed constitutively at the basolateral membrane. From (25), with permission.

vasopressin on the kidney (93). AQP2 is exclusively present in principle cells of inner medullary collecting duct cells and is diffusely distributed in the cytoplasm in the euhydrated condition, whereas apical staining of AQP2 is intensified in the dehydrated condition or after vasopressin administration (65, 133, 134). AVP also increases the water reabsorptive capacity of the kidney by regulating the urea transporter variants UT-A1/3, which are present in the inner medullary collecting duct, predominantly in its terminal part (57). AVP also increases the permeability of principle collecting duct cells to sodium. In summary, as stated elegantly by Ward and colleagues (192), in the absence of AVP stimulation, collecting duct epithelia exhibit very low permeabilities to sodium urea and

water. These specialized permeability properties permit the excretion of large volumes of hypotonic urine formed during intervals of water diuresis. In contrast, AVP stimulation of the principle cells of the collecting ducts leads to selective increases in the permeability of the apical membrane to water (Pf ), urea (Purea), and Na (PNa). These actions of vasopressin in the distal nephron are possibly modulated by prostaglandins E2 and by the luminal calcium concentration. High levels of E-prostanoid (EP3) receptors are expressed in the kidney. However, mice lacking EP3 receptors for prostaglandin E2 were found to have quasinormal regulation of urine volume and osmolality in response to various physiological stimuli (60). An apical calcium/polycation receptor protein expressed in the terminal portion of the inner

FIGURE 7

Schematic representation of the V2 receptor and identification of 184 putative disease-causing AVPR2 mutations. Predicted amino acids are given as the one-letter amino-acid code. Solid symbols indicate missense or nonsense mutations; a number indicates more than one mutation in the same codon; other types of mutations are not indicated on the figure. The extracellular, transmembrane, and cytoplasmic domains are defined according to Mouillac B, Chini B, Balestre MN, et al. The binding site of neuropeptide vasopressin V1a receptor. Evidence for a major localization within transmembrane regions. J Biol Chem 1995;270:25771–25777. There are 90 missense, 18 nonsense, 45 frameshift deletion or insertion, seven in-frame deletion or insertions, four splice sites, 19 large deletion mutations, and one complex mutation. See http://www.medicine.mcgill.ca/nephros for a list of mutations.

2

W E 3

L

35

G51

61

73

I 67 N68

S 10 F9

4

H 66

R11

T72 V

65

70

G 78

A

A12

S R5

I

A8

C 79

G 64

A

74

C 75

L 76

A V 71

V 77

P69

H 80

V 81

S 82

V 83

V13

87

S63

85

A 86

L 84

103

L

L 95 G 96

130

A 129

Q

252

R

260

H

150

151

251

V

261

S

E

146

153

R

249

263

Q

E250 R

262

P

152

R

145

I

T138

131

V

142

V

139

L

F

143

L

D

2 253

R

254

R

255

Q

Pa⫺ S 256

257

V

258

E

259

L

149

T

132

T

128

127

F136 L135

140

147

148

S

A

144

C

Q

133

V 137

L 141

L

E134

Intracellular

88

A 92 V 90 A 91 F Y 89 A

F14

62

R

A 97

102

A

106

G

A

174

L 175

G

248

E

264

S

154

G

I164

156

247

E

265

L

155

E

157

N

P

246

W

266

P

244

T

243

D

225

P

242

P

241

E

FIGURE 8 A: Schematic representation of aquaporin-2 (AQP2) and identification of 38 putative disease-causing AQP2 mutations. Solid symbols indicate missense or nonsense mutations; a number indicates more than one mutation in the same codon; other types of mutations are not indicated on the figure.The locations of the NPA boxes (Asparagine, N; Proline, P; Alanine, A) and the protein kinase A phosphorylation site (Pa) are indicated. The extracellular, transmembrane, and cytoplasmic domains are defined according to Deen PMT, Verdijk MAJ, Knoers NVAM, et al. Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine. Science 1994;264:92–95. Solid symbols indicate the location of the missense or nonsense mutations. There are 28 missense, two nonsense, six frameshift deletion or insertion, and two splice-site mutations. 217

L

239

G

237

238

K

L

V236

235

A

234

L

233

221

R

232

E

240

L

S

231

222

V

230

L

229

S

228

K

227

A

P226

223

224

F

L

201

202

V210

Y

199

D

D200 H W

L214 218

L

211

207

G G

215

219

Y

G

212

A

208

P

203

204

F

197

F198

K

196

G

T195

194

V

193

V

V

192

A

205

W

P191

216

220

N

S

I 213

209

206

L

I

190

A

COOH

271

A

270

189

L

K

269

T

271

268

G

245

D

267

R

T

163

S 159

F166

L170

162

L 158

G

161

165

G A

168

169

A

L

173

H177

178

Y

I 176 172

H V

P160

167

S

G171

T126

179

T

125

180

181

C

182

S

183

M

184

N

P185

T

N123

122

S

121

L

120

A

NPA box

P109

I 107 E

119

N

T108

110

V98 A 99

105

101

A

Q 93 L 94

100

L104 G

I

6

I 52

F48

I44

H

A15

7

60

H

E16

NPA box

G49

A 45

G53 L55 Q 57 V56 A 58 G L59

L 50

46

L 42 M

T54

A 47

Q43

V41

S40

L T20 L 21 22 A 19 F17 L18

F25

F26

L32

L 28 G 29

31

A

P

A37 Q36

L38 P39

118

V

G

117

S124

A

111

D

I112

116

L

188

S

•

NH2⫺ M 1

1

34

F23 V24

G27

S30

N33

W

Extracellular

A

R113

114

G

D115

A

187

R 186

A

2

CHAPTER 43 Polyuria and Diabetes Insipidus

1231

1232

SECTION III

•

Regulation and Disorders of Water Homeostasis

medullary collecting duct of the rat has been shown to reduce AVP-elicited osmotic water permeability when luminal calcium concentration rises (165). This possible link between calcium and water metabolism may play a role in the pathogenesis of renal stone formation (165).

THE BRATTLEBORO RAT WITH AUTOSOMAL RECESSIVE NEUROGENIC DIABETES INSIPIDUS The classical animal model for studying diabetes insipidus has been the Brattleboro rat with autosomal recessive neurogenic diabetes insipidus. di/di rats are homozygous for a 1-bp deletion (G) in the second exon, which results in a frameshift mutation in the coding sequence of the carrier neurophysin II (NPII) (Fig. 9) (169). The polyuric symptoms are also observed in heterozygous di/n rats. Homozygous Brattleboro rats may still demonstrate some V2 antidiuretic effect since the administration of a selective nonpeptide V2 antagonist (SR121463A, 10 mg/kg intraperitoneal) induced a further increase in urine flow rate (200 to 354 ⫾ 42 ml/24 hours) and a decline in urinary osmolality (170 to 92 ⫾ 8 mmol/kg) (173). Oxytocin, which is present at enhanced plasma concentrations in Brattleboro rats, may be responsible for the antidiuretic activity observed (5, 40). Oxytocin is not stimulated by increased plasma osmolality in humans. The Brattleboro rat model is therefore not strictly comparable with the rarely observed human cases of autosomal recessive neurogenic diabetes insipidus (45, 198).

AQP4, AQP3 and AQP4, CLCNK1, NKCC2, NFAT5, AVPR2, or AGT have been engineered (39, 109–112, 122, 139, 180, 202, 205). Angiotensinogen (AGT)–deficient mice are characterized by both concentrating and diluting defects secondary to a defective renal papillary architecture (139). As reviewed by Rao and Verkman (147) extrapolation of data in mice to humans must be made with caution. For example, the maximum osmolality of mouse (⬍ 3000 mOsm/kg H2O) is much greater than that of human urine (1000 mOsmol/kg H2O) and normal serum osmolality in mice is 330 to 345 mOsmol/kg H2O, substantially greater than that in humans (280–290 mOsm/kg H2O). Protein expression patterns and thus the interpretation of phenotype studies may also be species-dependent. For example, AQP4 is expressed in both proximal tubule and collecting duct in mouse but only in collecting duct in rat and human (147). The Aqp3, Aqp4, Clcnk1 and Agt knockout mice have no identified human counterparts. Of interest, AQP1-null humans have no obvious symptoms (145). Knockout mice deficient in AVPR2, AQP2, NKCC2, or ROMK suffer from severe dehydration and die during their first week of life. Adult conditional and tissue-specific AQP2-knockout mice survived (161, 203). Ethylnitrosourea-mutagenized mice heterozygous for the F204V mutation in the Aqp2 gene have been described (107) and mice from the Jackson Laboratory with congenital progressive hydronephrosis bear the S256L mutation in Aqp2 which affects its phosphorylation and apical membrane accumulation (123).

QUANTITATING RENAL WATER EXCRETION KNOCKOUT MICE WITH URINARY CONCENTRATION DEFECTS A useful strategy to establish the physiological function of a protein is to determine the phenotype produced by pharmacological inhibition of protein function or by gene disruption. Transgenic knockout mice deficient in AQP1, AQP2, AQP3, Deleted in Brattleboro rat

GGA AGC GGA GGC CGC TGC GCT GCC Gly Ser Gly Gly Arg Cys Ala Ala GGG AGC GGG GGC CGC TGC GCC GCC Gly Ser Gly Gly Arg Cys Ala Ala 62 63 64 65 66 67 68 69

Diabetes insipidus is characterized by the excretion of abnormally large volumes of hypo-osmotic urine (⬍ 250 mmol/kg). This definition excludes osmotic diuresis, which occurs when excess solute is being excreted, as with glucose in the polyuria of diabetes mellitus. Other agents that produce osmotic diuresis are mannitol, urea, glycerol, contrast media, and loop diuretics. Osmotic diuresis should be considered when solute excretion exceeds 60 mmol/hour. The quantification of water excretion (free-water clearance, osmolar clearance, free electrolyte water reabsorption, effective water clearance) is described elsewhere in this textbook.

Rat

Human

CLINICAL CHARACTERISTICS OF DIABETES INSIPIDUS DISORDERS Neurogenic Diabetes Insipidus

FIGURE 9 Neurophysin II genomic and amino acid sequence showing the 1-bp (G) deleted in the Brattleboro rat. The human sequence (GenBank entry M11166) is also shown. It is almost identical to the rat prepro sequence. In the Brattleboro rat, G1880 is deleted with a resultant frameshift after 63 amino acids (amino acid-1 is the first amino acid of neurophysin II).

COMMON FORMS Failure to synthesize or secrete vasopressin normally limits maximal urinary concentration and, depending on the severity of the disease, causes varying degrees of polyuria

CHAPTER 43

and polydipsia. Experimental destruction of the vasopressinsynthesizing areas of the hypothalamus (supraoptic and paraventricular nuclei) causes a permanent form of the disease. Similar results are obtained by sectioning the hypophyseal hypothalamic tract above the median eminence. Sections below the median eminence, however, produce only transient diabetes insipidus. Lesions to the hypothalamicpituitary tract are frequently associated with a three-stage response in experimental animals and in humans (189): (1) An initial diuretic phase lasting from a few hours to 5 to 6 days; (2) a period of antidiuresis unresponsive to fluid administration. This antidiuresis is probably due to vasopressin release from injured axons and may last from a few hours to several days (because urinary dilution is impaired during this phase, continued water administration can cause severe hyponatremia); and (3) a final period of diabetes insipidus. The extent of the injury determines the completeness of the diabetes insipidus and, as already discussed, the site of the lesion determines whether the disease will be permanent. Twenty-five percent of patients studied after transsphenoidal surgery developed spontaneous isolated hyponatremia, 20% developed diabetes insipidus, and 46% remained normonatremic. Normonatremia, hyponatremia, and diabetes insipidus were associated with increasing degrees of surgical manipulation of the posterior lobe and pituitary stalk during surgery (140). Central diabetes insipidus observed after transphenoidal surgery is often transient and only 2% of patients need a long-term treatment with dDAVP (131). The causes of central diabetes insipidus in adults and in children are listed in Table 1 (47, 71, 114, 128). Rare causes of central diabetes insipidus include leukemia, thrombotic thrombocytopenic purpura, pituitary apoplexy, sarcoidosis (58) and Wegener granulomatosis, xanthoma

•

Polyuria and Diabetes Insipidus

disseminatum (137), septooptico dysplasia and agenesis of the corpus callosum (121), metabolic (anorexia nervosa), lymphocytic hypophysitis (80), necrotizing infundibulohypophysitis (2). Maghnie et al. (114) studied 79 patients with central diabetes insipidus. Additional deficits in anterior pituitary hormones were documented in 61% of patients, a median of 0.6 years (range, 01–18.0 years) after the onset of diabetes insipidus. The most frequent abnormality was growth hormone deficiency (59%), followed by hypothyroidism (28%), hypogonadism (24%), and adrenal insufficiency (22%). Seventy-five percent of the patients with Langerhans cell histiocytosis had an anterior pituitary hormone deficiency that was first detected a median of 3.5 years after the onset of diabetes insipidus (114). None of the patients with central diabetes insipidus secondary to AVP mutations developed anterior pituitary hormone deficiencies

RARE FORMS Autosomal Dominant and Recessive Neurogenic Diabetes Insipidus Lacombe (100) and Weil (195) described a familial non–Xlinked form of diabetes insipidus without any associated mental retardation. The descendants of the family described by Weil were later found to have autosomal dominant neurogenic diabetes insipidus (35, 55, 196). Neurogenic diabetes insipidus (OMIM 125700) (141) is a well-characterized entity, secondary to mutations in AVP (OMIM 192340) (141). Patients with autosomal dominant neurogenic diabetes insipidus retain some limited capacity to secrete AVP during severe dehydration, and the polyuropolydipsic symptoms usually appear after the first year of life (152) when the

Etiology of Hypothalamic Diabetes Insipidus in Children and Adults

TABLE 1

a

Primary brain tumor Before surgery After surgery Idiopathic (isolated or familial) Histiocytosis Metastatic cancerb Traumac Postinfectious disease

1233

Children (%)

Children and young adults (%)

Adults (%)

49.5 33.5 16 29 16 2.2 2.2

22

30 13 17 25 8 17 -

58 12 2.0 6.0

Data from Czernichow P, Pomarede R, Brauner R, Rappaport R. Neurogenic diabetes insipidus in children. In: Czernichow P, Robinson AG (eds.). Frontiers of Hormone Research. Basel, Switzerland: S. Karger, 1985:190–20; Greger NG, Kirkland RT, Clayton GW, Kirkland JL. Central diabetes insipidus. 22 years’ experience. Am J Dis Child 1986;140:551–554; Moses AM, Blumenthal SA, Streeten DHP. Acid-base and electrolyte disorders associated with endocrine disease: pituitary and thyroid. In: Arieff AI, de Fronzo RA (eds.). Fluid, Electrolyte and Acid-Base Disorders. New York: Churchill Livingstone, 1985:851–892; Maghnie M, Cosi G, Genovese E, et al. Central diabetes insipidus in children and young adults. N Engl J Med 2000;343:998–1007. a Primary malignancy: craniopharyngioma, dysgerminoma, meningioma, adenoma, glioma, astrocytoma. bSecondary: metastatic from lung or breast, lymphoma, leukemia, dysplastic pancytopenia. cTrauma could be severe or mild.

1234

SECTION III

•

Regulation and Disorders of Water Homeostasis

infant’s demand for water is more likely to be understood by adults. More than 50 AVP mutations segregating with autosomal dominant or autosomal recessive neurohypophyseal diabetes insipidus have been described (41) (see http:// www.medicine.mcgill.ca/nephros for a list of mutations). The mechanisms by which a mutant allele causes neurohypophyseal diabetes insipidus could involve the induction of magnocellular cell death as a result of the accumulation of AVP precursors within the endoplasmic reticulum (84, 164, 176). This hypothesis could account for the delayed onset of the disease. In addition to the “misfolding neurotoxicity” caused by mutant AVP precursors, the interaction between the wildtype and the mutant precursors suggests that a dominant-negative mechanism may also contribute to the pathogenesis of autosomal dominant diabetes insipidus (85). The absence of symptoms in infancy in autosomal dominant neurohypophyseal diabetes insipidus is in sharp contrast with NDI secondary to mutations in AVPR2 or in AQP2, in which the polyuropolydipsic symptoms are present during the first week of life. Of interest, errors in protein folding represent the underlying basis for many inherited diseases (44, 185, 197) and are also pathogenic mechanisms for AVP, AVPR2, and AQP2 mutants. Why AVP-misfolded mutants are cytotoxic to AVP-producing neurons is an unresolved issue. Protein misfolding, an “unfolded protein response” in cells, and the accumulation of excess misfolded protein leading to apoptotic cell death are well documented for autosomal dominant retinitis pigmentosa (94). Three families with autosomal recessive neurohypophyseal diabetes insipidus in which the patients were homozygous or compound heterozygotes for AVP mutations have been identified (45, 198). Two of these families are characterized phenotypically by severe and early onset (in the first 3 months of life) with polyuria, polydipsia, and dehydration. As a consequence, early hereditary diabetes insipidus can be neurogenic or nephrogenic. Wolfram Syndrome Wolfram syndrome, also known as DIDMOAD, is an autosomal recessive neurodegenerative disorder accompanied by insulin-dependent diabetes mellitus and progressive optic atrophy. The acronym DIDMOAD describes the following clinical features of the syndrome: diabetes insipidus, diabetes mellitus, optic atrophy, and sensorineural deafness. An unusual incidence of psychiatric symptoms has also been described in patients with this syndrome. These included paranoid delusions, auditory or visual hallucinations, psychotic behavior, violent behavior, organic brain syndrome typically in the late or preterminal stages of their illness, progressive dementia, and severe learning disabilities or mental retardation or both. Patients with Wolfram syndrome develop diabetes mellitus and bilateral optical atrophy mainly in the first decade of life, the diabe-

tes insipidus is usually partial and of gradual onset, and the polyuria can be wrongly attributed to poor glycemic control. Furthermore, a severe hyperosmolar state can occur if untreated diabetes mellitus is associated with an unrecognized posterior pituitary deficiency. The dilatation of the urinary tract observed in the DIDMOAD syndrome may be secondary to chronic high urine flow rates and, perhaps, to some degenerative aspects of the innervation of the urinary tract. The gene responsible for Wolfram syndrome located in chromosome region 4p16.1, encodes a putative 890–amino acid transmembrane protein referred as wolframin. Wolframin is an endoglycosidase H–sensitive glycoprotein, which localizes primarily in the endoplasmic reticulum of a variety of neurons including neurons in the supraoptic nucleus and neurons in the lateral magnocellular division of the paraventricular nucleus (53, 181). Disruption of the Wfs1 gene in mice cause progressive ␤ cell loss and impaired stimulus-secretion coupling in insulin secretion but central diabetes insipidus is not observed in Wfs⫺/⫺ mice (82).

SYNDROME OF HYPERNATREMIA AND HYPODIPSIA Some patients with the hypernatremia and hypodipsia syndrome may have partial central diabetes insipidus. These patients also have persistent hypernatremia that is not due to any apparent extracellular volume loss, absence or attenuation of thirst, and a normal renal response to AVP. In almost all the patients studied, the hypodipsia has been associated with cerebral lesions in the vicinity of the hypothalamus. It has been proposed that in these patients there is a “resetting” of the osmoreceptor because their urine tends to become concentrated or diluted at inappropriately high levels of plasma osmolality. However, using the regression analysis of plasma AVP concentration versus plasma osmolality, it has been shown that in some of these patients the tendency to concentrate and dilute urine at inappropriately high levels of plasma osmolality is due solely to a marked reduction in sensitivity or a gain in the osmoregulatory mechanism (78). This finding is compatible with the diagnosis of partial central diabetes insipidus. In other patients, however, plasma AVP concentrations fluctuate in a random manner, bearing no apparent relationship to changes in plasma osmolality. Such patients frequently display large swings in serum sodium concentration and frequently exhibit hypodipsia. It appears that most patients with “essential hypernatremia” fit one of these two patterns (Fig. 10). Both of these groups of patients consistently respond normally to nonosmolar AVP release signals, such as hypotension, emesis, hypoglycemia, or all three. These observations suggest that (1) the osmoreceptor may be anatomically as well as functionally separate from the nonosmotic efferent pathways and neurosecretory neurons for vasopressin and a hypothalamic lesion may impair the osmotic release of AVP while the nonosmotic re-

CHAPTER 43

Plasma arginine-vasopressin (pg/mL)

6

PATIENT A

5 4 3 2

PAVP ⫽ 0.04 (POsm⫺279) r ⫽ 0.79, p⬍0.01

1 0 6

PATIENT B

5

•

Polyuria and Diabetes Insipidus

1235

some region 12q13, that is, the vasopressin-sensitive water channel. When studied in vitro, most AVPR2 mutations lead to receptors that are trapped intracellularly and are unable to reach the plasma membrane. A minority of the mutant receptors reaches the cell surface but are unable to bind AVP or to trigger an intracellular cAMP signal. Similarly, AQP2 mutant proteins are trapped intracellularly and cannot be expressed at the luminal membrane. AVPR2 and AQP2-trafficking defects are correctable by chemical chaperones

4 3 r ⫽ 0.14 N.S.

2 1 0

270 280 290 300 310 320 330 340 350 360 370 380 Plasma osmolality (mOsm/kg)

FIGURE 10

Plasma arginine vasopressin (PAVP) as a function of “effective” plasma osmolality (POsm) in two patients with adipsic hypernatremia. Open circles indicate values obtained on admission; filled squares indicate those obtained during forced hydration; filled triangles indicate those obtained after 1 to 2 weeks of ad libitum water intake; gray areas indicate range of normal values. (From Robertson GL. The physiopathology of ADH secretion. In: Tolis G, Labrie F, Martin JB, Naftolin F, eds. Clinical Neuroendocrinology: A Pathophysiological Approach. New York: Raven Press; 1979:247–260, with permission).

lease of AVP remains intact; and (2) the osmoreceptor neurons that regulate vasopressin secretion are not totally synonymous with those that regulate thirst, although they appear to be anatomically close if not overlapping. Nephrogenic Diabetes Insipidus In NDI, the kidney is unable to concentrate urine despite normal or elevated concentrations of the antidiuretic hormone arginine vasopressin. In congenital NDI, the obvious clinical manifestations of the disease, that is polyuria and polydipsia, are present at birth and need to be immediately recognized to avoid severe episodes of dehydration. It is clinically useful to distinguish two types of hereditary NDI: A “pure” type characterized by loss of water only and a complex type characterized by loss of water and ions. Patients who have congenital NDI and mutations in the AVPR2 or AQP2 genes have a pure NDI phenotype with loss of water but normal conservation of sodium, potassium, chloride, and calcium. Patients with inactivating mutations in genes (SLC12A1, KCNJ1, CLCNKB, CLCNKA and CLCNKB in combination, or BSND) that encode the membrane proteins of the thick ascending limb of the loop of Henle have a complex polyuropolydipsic syndrome with loss of water, sodium, chloride, calcium, magnesium, and potassium. Most (⬎ 90%) of pure congenital NDI patients have mutations in the AVPR2 gene, the Xq28 gene coding for the vasopressin V2 (antidiuretic) receptor. In less than 10% of the families studied, congenital NDI has an autosomal recessive inheritance and mutations have been identified in the AQP2 gene located in chromo-

LOSS-OF-FUNCTION MUTATIONS OF AVPR2 X-linked NDI (OMIM 304800) (141) is secondary to AVPR2 mutations, which result in a loss of function or dysregulation of the V2 receptor (64). Males who have an AVPR2 mutation have a phenotype characterized by early dehydration episodes, hypernatremia, and hyperthermia as early as the first week of life. Dehydration episodes can be so severe that they lower arterial blood pressure to a degree that is not sufficient to sustain adequate oxygenation to the brain, kidneys, and other organs. Mental and physical retardation and renal failure are the classical “historic” consequences of a late diagnosis and lack of treatment. Heterozygous females exhibit variable degrees of polyuria and polydipsia because of skewed X chromosome inactivation (4, 136). Clinical Characteristics The historic clinical characteristics include hypernatremia, hyperthermia, mental retardation, and repeated episodes of dehydration in early infancy (46, 61, 193, 200). Mental retardation, a consequence of repeated episodes of dehydration, was prevalent in the Crawford and Bode study (46), in which only nine (11%) of 82 patients had normal intelligence. Early recognition and treatment of X-linked NDI with an abundant intake of water allows a normal lifespan with normal physical and mental development (132). Two characteristics suggestive of X-linked NDI are the familial occurrence and the confinement of mental retardation to male patients. It is then tempting to assume that the family described in 1892 by McIlraith (124) and discussed by Reeves and Andreoli (150) was an X-linked NDI family. Crawford and Bode (46) clearly describe the early symptoms of the nephrogenic disorder and its severity in infancy. The first manifestations of the disease can be recognized during the first week of life. The infants are irritable, cry almost constantly, and, although eager to suck, will vomit milk soon after ingestion unless prefed with water. The history given by the mothers often include persistent constipation, erratic unexplained fever, and failure to gain weight. Although the patients characteristically show no visible evidence of perspiration, increased water loss during fever or in warm weather exaggerates the symptoms. Unless the condition is recognized early, children experience frequent bouts of hypertonic dehydration, sometimes complicated by convulsions or

1236

SECTION III

•

Regulation and Disorders of Water Homeostasis

death; mental retardation is a frequent consequence of these episodes. The intake of large quantities of water, combined with the patient’s voluntary restriction of dietary salt and protein intake, lead to hypocaloric dwarfism beginning in infancy. Frequently, lower urinary tract dilatation and obstruction, probably secondary to the large volume of urine produced (178), develop in affected children. Dilatation of the lower urinary tract is also seen in primary polydipsic patients and in patients with neurogenic diabetes insipidus (31, 66). Chronic renal insufficiency may occur by the end of the first decade of life and could be the result of episodes of dehydration with thrombosis of the glomerular tufts (46). History In 1989, we observed that the administration of dDAVP, a V2-receptor agonist, increased plasma cAMP concentrations in healthy subjects but had no effect in 14 male patients with X-linked NDI (17). Intermediate responses were observed in obligate carriers of the disease, corresponding to half of the normal receptor response. On the basis of these results, we predicted that the defective gene in these patients with X-linked NDI was likely to code for a defective V2 receptor (17). Since that time, a number of experimental results have confirmed our hypothesis: (1) The NDI locus was mapped to the distal region of the long arm of the X chromosome Xq28 (18, 91, 95, 186); (2) the V2 receptor was identified as a candidate gene for NDI (87); (3) the human V2 receptor was cloned (26); and (4) 184 putative diseasecausing mutations have now been identified in the V2 receptor and the list of mutations is still expanding (Fig. 7). Population Genetics of AVPR2 Mutations X-linked NDI is generally a rare disease in which the affected male patients do not concentrate their urine after administration of AVP (22). Because this form is a rare, recessive Xlinked disease, female individuals are unlikely to be affected, but heterozygous female individuals can exhibit variable degrees of polyuria and polydipsia because of skewed X chromosome inactivation. In Quebec, the incidence of this disease among male individuals was estimated to be approximately 8.8 in 1,000,000 male live births (4). A founder effect of two particular AVPR2 mutations (20), one in Ulster Scot immigrants (the Hopewell mutation, W71X) and one in a large Utah kindred (the Cannon pedigree), result in an elevated prevalence of X-linked NDI in their descendants in certain communities in Nova Scotia, Canada, and Utah, United States (20). These founder mutations have now spread all over the North American continent. We have identified the W71X mutation in 42 affected male individuals who reside predominantly in the Maritime Provinces of Nova Scotia and New Brunswick and the L312X mutation in eight affected males who reside in the central United States. We know of 98 living affected male individuals of the Hopewell kindred and 18 living affected male individuals of the Cannon pedigree.

To date, 184 putative disease-causing AVPR2 mutations have been published in 287 NDI families (Fig. 7). We propose that all families with hereditary diabetes insipidus should have their molecular defect identified. The molecular identification underlying X-linked NDI is of immediate clinical significance because early diagnosis and treatment of affected infants can avert the physical and mental retardation that results from repeated episodes of dehydration. Affected premature male infants may experience less severe polyuric symptoms and may need only increased hydration during their first week without a need for hydrochlorothiazide treatment. Water should be offered every 2 hours day and night, and temperature, appetite, and growth should be monitored. Admission to hospital may be necessary for continuous gastric feeding. The voluminous amounts of water kept in patients’ stomachs will exacerbate physiological gastrointestinal reflux in infants and toddlers, and many affected boys frequently vomit. These young patients often improve with the absorption of an H2 blocker and with metoclopramide (which could induce extrapyramidal symptoms) or with domperidone, which seems to be better tolerated and efficacious. As mentioned previously, all polyuric states (whether neurogenic, nephrogenic, or psychogenic) can induce large dilatations of the urinary tract and bladder (31, 46, 66), and bladder function impairment has been well documented in patients who bear AVPR2 or AQP2 mutations (174, 184). Of interest, in mice with congenital progressive hydronephrosis (cph) homozygote for the S266L mutation (Aqp2) the congenital obstructive uropathy is likely a result of the polyuria (123). Chronic renal failure secondary to bilateral hydronephrosis has been observed as a long-term complication in these patients. Renal and abdominal ultrasound should be done annually, and simple recommendations, including frequent urination and “double voiding” could be important to prevent these consequences. Expression Studies Classification of the defects of naturally occurring mutant human V2 receptors can be based on a similar scheme to that used for the LDL receptor. Mutations have been grouped according to the function and subcellular localization of the mutant protein whose cDNA has been transiently transfected in a heterologous expression system (77). Using this classification, type 1 mutant V2 receptors reach the cell surface but display impaired ligand binding and are consequently unable to induce normal cAMP production. The presence of mutant V2 receptors on the surface of transfected cells can be determined pharmacologically. By carrying out saturation binding experiments using tritiated AVP, the number of cell surface mutant V2 receptors and their apparent binding affinity can be compared with that of the wildtype receptor. In addition, the presence of cell surface receptors can be assessed directly by using immunodetection strategies to visualize epitope-tagged receptors in whole-cell immunofluorescence assays.

CHAPTER 43

Type 2 mutant receptors have defective intracellular transport. This phenotype is confirmed by carrying out, in parallel, immunofluorescence experiments on cells that are intact (to demonstrate the absence of cell surface receptors) or permeabilized (to confirm the presence of intracellular receptor pools). In addition, protein expression is confirmed by Western blot analysis of membrane preparations from transfected cells. It is likely that these mutant type 2 receptors accumulate in a pre-Golgi compartment, because they are initially glycosylated but fail to undergo glycosyltrimming maturation. Type 3 mutant receptors are ineffectively transcribed and lead to unstable mRNA, which are rapidly degraded. This subgroup seems to be rare, since Northern blot analysis of cells expressing mutant V2 receptors showed mRNA of normal quantity and molecular size. Most of the AVPR2 mutants that we and other investigators have tested are type 2 mutant receptors. They did not reach the cell membrane and were trapped in the interior of the cell (12, 75, 127, 201). Other mutant G-protein–coupled receptors (170) and gene products that cause genetic disorders are also characterized by protein misfolding. Mutations that affect the folding of secretory proteins; integral plasma membrane proteins; or enzymes destined to the endoplasmic reticulum, Golgi complex, and lysosomes results in loss-of-function phenotypes irrespective of their direct impact on protein function because these mutant proteins are prevented from reaching their final destination (162). Folding in the endoplasmic reticulum is the limiting step: Mutant proteins which fail to correctly fold are retained initially in the endoplasmic reticulum and subsequently often degraded. Key proteins involved in the urine countercurrent mechanisms are good examples of this basic mechanism of misfolding. AQP2 mutations responsible for autosomal recessive NDI are characterized by misrouting of the misfolded mutant proteins and are trapped in the endoplasmic reticulum (182). Mutants that encode other renal membrane proteins that are responsible for Gitelman syndrome (98), Bartter syndrome (73, 143), and cystinuria (38) are also retained in the endoplasmic reticulum. The AVPR2 missense mutations are likely to impair folding and to lead to rapid degradation of the misfolded polypeptide and not to the accumulation of toxic aggregates (as is the case for AVP mutants), because the other important functions of the principle cells of the collecting duct (where AVPR2 is expressed) are entirely normal. These cells express the epithelial sodium channel (ENac). Decreased function of this channel results in a sodium-losing state (27). This has not been observed in patients with AVPR2 mutations. By contrast, another type of conformational disease is characterized by the toxic retention of the misfolded protein. The relatively common Z mutation in ␣1-antitrypsin deficiency not only causes retention of the mutant protein in the endoplasmic reticulum but also affects the secondary structure by insertion of the reactive center loop of one molecule into a destabilized ␤ sheet of a second molecule (108). These polymers clog up the endoplasmic reticulum of hepatocytes and

•

Polyuria and Diabetes Insipidus

1237

lead to cell death and juvenile hepatitis, cirrhosis, and hepatocarcinomas in these patients (103). If the misfolded protein/traffic problem that is responsible for so many human genetic diseases can be overcome and the mutant protein transported out of the endoplasmic reticulum to its final destination, these mutant proteins could be sufficiently functional (44). Therefore, using pharmacological chaperones or pharmacoperones to promote escape from the endoplasmic reticulum is a possible therapeutic approach (11, 162, 185). We used selective nonpeptide V2 and V1 receptor antagonists to rescue the cell-surface expression and function of naturally occurring misfolded human V2 receptors (127). Because the beneficial effect of nonpeptide V2 antagonists could be secondary to prevention and interference with endocytosis, we studied the R137H mutant previously reported to lead to constitutive endocytosis (6). We found that the antagonist did not prevent the constitutive ␤-arresting-promoted endocytosis (12). These results indicate that as for other AVPR2 mutants, the beneficial effects of the treatment result from the action of the pharmacological chaperones. In clinical studies, we administered a nonpeptide vasopressin antagonist SR49059 to five adult patients who have NDI and bear the del62-64, R137H, and W164S mutations. SR49059 significantly decreased urine volume and water intake and increased urine osmolality whereas sodium, potassium, and creatinine excretions and plasma sodium levels were constant throughout the study (13). This new therapeutic approach could be applied to the treatment of several hereditary diseases resulting from errors in protein folding and kinesis (44, 185). Because most human gene-therapy experiments using viruses to deliver and integrate DNA into host cells are potentially dangerous (68), other treatments are being actively pursued. Schöneberg and colleagues (167) used aminoglycoside antibiotics because of their ability to suppress premature termination codons (116). They demonstrated that geneticin, a potent aminoglycoside antibiotic, increased AVPstimulated cAMP in cultured collecting duct cells prepared from E242X mutant mice. The urine concentrating ability of heterozygous mutant mice was also improved.

LOSS-OF-FUNCTION MUTATIONS OF AQP2 (OMIM 222000, 125800, 107777) On the basis of desmopressin infusion studies and phenotypic characteristics of both male and female individuals who are affected with NDI, a non–X-linked form of NDI with a postreceptor (post-cAMP) defect was suggested (32, 96, 101, 141). A patient who presented shortly after birth with typical features of NDI but who exhibited normal coagulation and normal fibrinolytic and vasodilatory responses to desmopressin was shown to be a compound heterozygote for two missense mutations (R187C and S217P) in the AQP2 gene (51). To date, 38 putative disease-causing AQP2 mutations have been identified in 40 NDI families (Fig. 8). The oocytes of the African clawed frog (Xenopus laevis) have provided a

1238

SECTION III

•

Regulation and Disorders of Water Homeostasis

most useful experimental system for studying the function of many channel proteins. This convenient expression system was key to the discovery of AQP1 by Agre (1) because frog oocytes have very low permeability and survive even in freshwater ponds. Control oocytes are injected with water alone; test oocytes are injected with various quantities of synthetic transcripts from AQP1 or AQP2 DNA (cRNA). When subjected to a 20-mOsm osmotic shock, control oocytes have exceedingly low water permeability but test oocytes become highly permeable to water. These osmotic water permeability assays demonstrated an absence or very low water transport for all of the cRNA with AQP2 mutations. Immunofluorescence and immunoblot studies demonstrated that these recessive mutants were retained in the endoplasmic reticulum. AQP2 mutations in autosomal recessive NDI, which are located throughout the gene result in misfolded proteins that are retained in the endoplasmic reticulum. In contrast, the dominant mutations reported to date are located in the region that codes for the carboxyl terminus of AQP2 (92, 99, 120). Dominant AQP2 mutants form heterotetramers with wildtype AQP2 and are misrouted.

COMPLEX POLYUROPOLYDIPSIC SYNDROME In contrast to a pure NDI phenotype, with loss of water but normal conservation of sodium, potassium, chloride, and calcium, in Bartter syndrome, patients’ renal wasting starts prenatally and polyhydramnios often leads to prematurity. Bartter syndrome (OMIM 601678, 241200, 607364, and 602522) refers to a group of autosomal recessive disorders caused by inactivating mutations in genes (SLC12A1, KCNJ1, CLCNKB, CLCNKA and CLCNKB in combination, or BSND) that encode membrane proteins of the thick ascending limb of the loop of Henle (for review see 23, 24). Although Bartter syndrome and Bartter mutations are commonly used as a diagnosis, it is likely, as explained by Jeck et al. (89), that the two patients with a mild phenotype originally described by Dr. Bartter had Gitelman syndrome, a thiazide-like, salt-losing tubulopathy with a defect in the distal convoluted tubule (89). As a consequence, salt-losing tubulopathy of the furosemide type is a more physiologically appropriate definition. Thirty percent of the filtered sodium chloride is reabsorbed in the thick ascending limb of the loop of Henle through the apically expressed sodium-potassium-chloride cotransporter NKCC2 (encoded by the SLC12A1 gene), which uses the sodium gradient across the membrane to transport chloride and potassium into the cell. The potassium ions must be recycled through the apical membrane by the potassium channel ROMK (encoded by the KCNJ1 gene). In the large experience of Seyberth and colleagues (142), who studied 85 patients with a hypokalemic saltlosing tubulopathy, all 20 patients with KCNJ1 mutations (except one) and all 12 patients with SLC12A1 mutations were born as preterm infants after severe polyhydramnios.

Of note, polyhydramnios is never seen during a pregnancy that leads to infants bearing AVPR2 or AQP2 mutations. The most common causes of increased amniotic fluid include maternal diabetes mellitus, fetal malformations and chromosomal aberrations, twin-to-twin transfusion syndrome, rhesus incompatibility, and congenital infections (117). Postnatally, polyuria was the leading symptom in 19 of the 32 patients. Renal ultrasound revealed nephrocalcinosis in 31 of these patients. These patients with complex polyuropolydipsic disorders are often poorly recognized and may be confused with pure NDI. As a consequence, congenital polyuria does not suggest automatically AVPR2 or AQP2 mutations, and polyhydramnios, salt wasting, hypokalemia, and nephrocalcinosis are important clinical and laboratory characteristics that should be assessed. In patients with Bartter syndrome (salt-losing tubulopathy/furosemide type), the dDAVP test will only indicate a partial type of NDI. The algorithm proposed by Peters et al. (142) is useful since most mutations in SLC12A1 and KCNJ1 are found in the carboxyl terminus or in the last exon and, as a consequence, are amenable to rapid DNA sequencing.

ACQUIRED NEPHROGENIC DIABETES INSIPIDUS Acquired NDI is much more common than congenital NDI but it is rarely as severe. The ability to produce hypertonic urine is usually preserved even though there is inadequate concentrating ability of the nephron. Polyuria and polydipsia are therefore moderate (3–4 l/d). The more common causes of acquired NDI are listed in Table 2. Lithium administration has become the most frequent cause; 54% of 1105 unselected patients on chronic lithium therapy, NDI developed (28). Nineteen percent of these patients had polyuria, as defined by a 24-hour urine output exceeding 3 l. The mechanism whereby lithium causes polyuria has been extensively studied. Lithium inhibits adenylyl cyclase in a number of cell types including renal epithelia (42, 43). The concentration of lithium in urine of patients on well-controlled lithium therapy (i.e., 10–40 mOsmol/l) is sufficient to exert this effect. Measurement of adenylyl cyclase activity in membranes isolated from a cultured pig kidney cell line (LLC-PK1) revealed that lithium in the concentration range of 10 mOsmol/l interfered with the hormonestimulated guanyl nucleotide regulatory unit (Gs) (69). The effect of chronic lithium therapy has been studied in rat kidney membranes prepared from the inner medulla. It caused a marked downregulation of AQP2, only partially reversed by cessation of therapy, dehydration, or dDAVP treatment, consistent with clinical observations of slow recovery from lithium-induced urinary concentrating defects (118). Downregulation of AQP2 has also been shown to be associated with the development of severe polyuria resulting from other causes of acquired NDI (hypokalemia) (119), release of bilateral ureteral obstruction (63), and hypercalciuria (166)). Thus,

CHAPTER 43

TABLE 2

Causes of Nephrogenic Diabetes Insipidus

Narrow definition of NDI: water permeability of the collecting duct not increased by AVP Congenital (idiopathic) Hypercalcemia Hypokalemia Drugs: Lithium Nonpeptide vasopressin receptor (V2) antagonists Demeclocycline Amphotericin B Methoxyflurane Diphenylhydantoin Nicotine Alcohol Broad definition of NDI: defective medullary countercurrent function Renal failure, acute or chronic (especially interstitial nephritis or obstruction) Medullary damage: Sickle-cell anemia and trait Amyloidosis Sjögren syndrome Sarcoidosis Hypercalcemia Hypokalemia Protein malnutrition Cystinosis (Modified from Magner PO, Halperin ML. Polyuria-a pathophysiological approach. Med North America 1987;15:2987–2997, with permission).

AQP2 expression is severely downregulated in both congenital (93) and acquired NDI. More studies will be needed to determine whether nonpeptide vasopressin agonists, permeable cAMP-like compounds or other signaling molecules will be able to restore AQP2 expression and function (106). For patients on long-term lithium therapy, amiloride has been proposed to prevent the uptake of lithium in the collecting ducts, thus preventing the inhibitory effect of intracellular lithium on water transport (9). Primary Polydipsia Primary polydipsia is a state of hypotonic polyuria secondary to excessive fluid intake. Primary polydipsia was extensively studied by Barlow and de Wardener in 1959 (7); however, the understanding of the pathophysiology of this disease has made little progress. Barlow and de Wardener (7) described seven women and two men who were compulsive water drinkers; their ages ranged from 48 to 59 years, except for one patient was 24 years old. Eight of these patients had histories of previous psychological disorders, which ranged from delusions, depression, and agitation to frank hysterical behavior. The other patient appeared normal. The consumption of water fluctuated irregularly from hour to hour or from day to day; in some patients, there were remissions and relapses lasting several months or longer. In eight of the patients, the mean plasma osmolality was significantly lower than normal. Vasopressin tannate in oil made most of these patients feel ill; in one, it caused overhydration. In four patients, the fluid in-

•

Polyuria and Diabetes Insipidus

1239

take returned to normal after electroconvulsive therapy or a period of continuous narcosis; the improvement in three was transient, but in the fourth it lasted 2 years. Polyuric female subjects might be heterozygous for de novo or previously unrecognized AVPR2 mutations, may bear AQP2 mutations and may be classified as compulsive water drinkers (158). Therefore, the diagnosis of compulsive water drinking must be made with care and may represent our ignorance of yet undescribed pathophysiological mechanisms. Robertson (158) has described under the name “dipsogenic diabetes insipidus” a selective defect in the osmoregulation of thirst. Three studied patients had, under basal conditions of ad libitum water intake, thirst, polydipsia, polyuria, and high-normal plasma osmolality. They had a normal secretion of AVP, but osmotic threshold for thirst was abnormally low. These dipsogenic diabetes insipidus cases might represent up to 10% of all patients with diabetes insipidus (158). Diabetes Insipidus and Pregnancy PREGNANCY IN A PATIENT KNOWN TO HAVE DIABETES INSIPIDUS An isolated deficiency of vasopressin without a concomitant loss of hormones in the anterior pituitary does not result in altered fertility, and with the exception of polyuria and polydipsia, gestation, delivery, and lactation are uncomplicated (3). Patients may require increasing dosages of dDAVP. The increased thirst may be due to a resetting of the thirst osmostat (49). Increased polyuria also occurs during pregnancy in patients with partial NDI (86). These patients may be obligatory carriers of the NDI gene (62) or may be homozygotes, compound heterozygotes, or may have dominant AQP2 mutations. SYNDROMES OF DIABETES INSIPIDUS THAT BEGIN DURING GESTATION AND REMIT AFTER DELIVERY Barron et al. (8) described three pregnant women in whom transient diabetes insipidus developed late in gestation and subsequently remitted postpartum. In one of these patients, dilute urine was present despite of high plasma concentrations of AVP. Hyposthenuria in all three patients was resistant to administered aqueous vasopressin. Because excessive vasopressinase activity was not excluded as a cause of this disorder, Barron et al. labeled the disease vasopressin resistant rather than NDI. A well-documented case of enhanced activity of vasopressinase has been described in a woman in the third trimester of a previously uncomplicated pregnancy (54). She had massive polyuria and markedly elevated plasma vasopressinase activity. The polyuria did not respond to large intravenous doses of AVP but responded promptly to dDAVP, a vasopressinaseresistant analogue of AVP. The polyuria disappeared with the disappearance of the vasopressinase. It is suggested that pregnancy may be associated with several different forms of diabetes insipidus, including central, nephrogenic, and vasopressinase mediated (33, 76, 86).

1240

SECTION III

•

Regulation and Disorders of Water Homeostasis

INVESTIGATION OF A PATIENT WITH POLYURIA

Indirect Tests for Diabetes Insipidus The measurement of urinary osmolality after dehydration and dDAVP administration is usually referred to as “indirect testing” because AVP secretion is indirectly assessed through changes in urinary osmolalities (125). The patient is main-

1400 1200 Urine osmolality (mOsmol/kg)

Plasma sodium and osmolality are maintained within normal limits (136–143 mOsmol/l for plasma sodium; 275–290 mOsmol/kg for plasma osmolality) by a thirst-AVP-renal axis. Thirst and AVP release, both stimulated by increased osmolality, is a “double-negative” feedback system (104). Even when the AVP component of this double-negative regulatory feedback system is lost, the thirst mechanism still preserves the plasma sodium and osmolality within the normal range, but at the expense of pronounced polydipsia and polyuria. Thus, the plasma sodium concentration or osmolality of an untreated patient with diabetes insipidus may be slightly greater than the mean normal value, but these small increases have no diagnostic significance. Theoretically, it should be relatively easy to differentiate between neurogenic diabetes insipidus, NDI, and primary polydipsia by comparing the osmolality of urine obtained during dehydration with that of urine obtained after the administration of dDAVP. Patients with neurogenic diabetes insipidus should reveal a rapid increase in urinary osmolality, whereas it should increase normally in response to moderate dehydration in patients with primary polydipsia. However, for several reasons, these distinctions may not be as clear as one might expect (156). First, chronic polyuria resulting from any cause interferes with the maintenance of the medullary concentration gradient and this “wash-out” effect diminishes the maximum concentrating ability of the nephron. The extent of the blunting varies in direct proportion to the severity of the polyuria. Hence, for any given basal urine output, the maximum urine osmolality achieved in the presence of saturating concentrations of AVP is depressed to the same extent in patients with primary polydipsia, neurogenic diabetes insipidus or NDI (Fig. 11). Second, most patients with neurogenic diabetes insipidus maintain a small, but detectable, capacity to secrete AVP during severe dehydration, and urinary osmolality may then increase to greater than the plasma osmolality. Third, patients referred to as partial diabetes insipidus (either neurogenic or nephrogenic) and patients with acquired NDI have an incomplete response to AVP and are able to concentrate their urine to varying degrees in a dehydration test. Finally, all polyuric states (whether neurogenic, nephrogenic or psychogenic) can induce large dilatations of the urinary tract and bladder (31, 66). As a consequence, the urinary bladder of these patients has an increased residual capacity and changes in urinary osmolality induced by diagnostic maneuvers might be difficult to demonstrate.

Neurogenic diabetes insipidus Primary polydipsia Nephrogenic diabetes insipidus

1000 2 litres 800

4 litres 6 litres

600

8 litres 10 litres

400

12 litres 200 16 litres 0 0.5

1.0

5

10

50

⬎50

Plasma arginine vasopressin (pg/ml)

FIGURE 11

Schematic diagram of the relationship between urine osmolality and plasma vasopressin in patients with polyuria of diverse cause and severity. The shaded area represents the normal range. For each of the three categories of polyuria, the relationship is described by a family of sigmoid curves that differ in height. These differences in height reflect differences in maximum concentrating capacity due to “wash-out” of the medullary concentration gradient. They are proportional to the severity of the underlying polyuria (indicated in litres at the right-handed side of each plateau) and are largely independent of the cause. The three categories of diabetes insipidus differ principally in the submaximal or ascending portion of the dose-response curve. In patients with neurogenic diabetes insipidus, this part of the curve lies to the left of normal, reflecting increased sensitivity to the antidiuretic effects of very low concentrations of plasma vasopressin. In contrast, in patients with neurogenic diabetes insipidus, this part of the curve lies to the right of normal, reflecting decreased sensitivity to the antidiuretic effects of normal concentrations of plasma vasopressin. In primary polydipsia, this relationship is relatively normal. (From Robertson GL. Diagnosis of diabetes insipidus. In: Czernichow P, Robinson AG (eds.). Frontiers of Hormone Research. Basel: Karger, 1985:176–189, with permission.)

tained on a complete fluid-restriction regimen until urinary osmolality reaches a plateau, as indicated by an hourly increase of less than 30 mOsmol/kg for at least 3 successive hours. After measuring the plasma osmolality, 2 ␮g dDAVP are administered subcutaneously. Urinary osmolality is measured 30 and 60 minutes later. The last urinary osmolality value obtained before the dDAVP injection and the highest value obtained after the injection are compared. In patients with severe neurogenic diabetes insipidus, urinary osmolality after dehydration is usually low (⬍200 mOsmol/kg) and increases more than 50% after dDAVP administration. In patients with severe NDI, urinary osmolality after dehydration is also low (⬍200 mOsmol/kg) but does not increase after dDAVP administration (⬍20%). Urinary osmolality increases to variable degrees (10% to 50%) after dDAVP administration to patients with partial neurogenic or partial nephrogenic diabetes insipidus. In patients with primary polydipsia, maximum urinary osmolality will be obtained

CHAPTER 43

after dehydration (⬎295 mOsmol/kg) and does not increase after dDAVP administration (⬍10%). Alternatively, plasma sodium and plasma and urinary osmolalities can be measured at the beginning of the dehydration procedure and at regular intervals (usually hourly) thereafter depending on the severity of the polyuria (14). For example, an 8-year-old patient (body weight 31 kg) with a clinical diagnosis of congenital NDI (later found to bear an AVPR2 mutation) continued to excrete large volumes of urine (300 ml/h) during a short 4-hour dehydration test. During this time, the patient suffered from severe thirst, his plasma sodium was 155 mOsmol/l, plasma osmolality was 310 mOsmol/kg, and urinary osmolality was 85 mOsmol/kg. The patient received 1 ␮g of dDAVP intravenously and was allowed to drink water. Repeated urinary osmolality measurements demonstrated a complete urinary resistance to dDAVP. It would have been dangerous and unnecessary to prolong the dehydration further in this young patient. Thus, the usual prescription of overnight dehydration should not be used in patients, and especially children, with severe polyuria and polydipsia (more than 30 ml/kg body weight per day). Great care should be taken to avoid any severe hypertonic state, arbitrarily defined as plasma sodium greater than 155 mOsmol/l.

•

Polyuria and Diabetes Insipidus

1241

and indirect testing of AVP function have been discussed by Stern and Valtin (177). The diagnosis of primary polydipsia remains one of exclusion and the cause could be psychogenic (7) or inappropriate thirst (158, 159). Psychiatric patients with polydipsia and hyponatremia have unexplained defects in urinary dilution, the osmoregulation of water intake or the secretion of vasopressin (70). Therapeutic Trial of dDAVP In selected patients with an uncertain diagnosis, a closely monitored therapeutic trial of dDAVP (10 ␮g intranasally twice a day for 2 to 3 days) may be used to distinguish partial NDI from partial neurogenic diabetes insipidus or primary polydipsia. If dDAVP at this dosage causes a significant antidiuretic effect, NDI is effectively excluded. If polydipsia and polyuria are abolished and plasma sodium does not go below the normal range, the patient probably has neurogenic diabetes insipidus. Conversely, if dDAVP causes a reduction in urine output without reduction in water intake and hyponatremia appears, the patient probably has primary polydipsia. Since fatal water intoxication is a remote possibility, the dDAVP trial should be closely monitored. The methods of differential diagnosis of diabetes insipidus are described in Table 3.

Direct Tests of Diabetes Insipidus The two approaches of Zerbe and Robertson are used (206), although they are expensive, time-consuming, and difficult to do on young patients. In the first approach, during the dehydration test, plasma is collected hourly and assayed for AVP. The results are plotted on a nomogram depicting the normal relationship between plasma sodium or osmolality and plasma AVP in normal individuals (Fig. 5A). If the relationship goes below the normal range, the disorder is diagnosed as neurogenic diabetes insipidus. In the second approach: NDI can be differentiated from primary polydipsia by analyzing the relationship between plasma AVP and urinary osmolality at the end of the dehydration period (Fig. 5B). However, definitive differentiation might be impossible because a normal or even supranormal AVP response to increased plasma osmolality occurs in polydipsic patients. None of the patients with psychogenic or other forms of severe polydipsia studied by Robertson showed any evidence of pituitary suppression (156). In a comparison of diagnoses based on indirect versus direct tests of AVP function in 54 patients with polyuria of diverse cause, Robertson (156) found that the indirect test was reliable only for patients with severe defects. Three patients with severe NDI and 16 of 17 patients with severe neurogenic diabetes insipidus were accurately diagnosed. However, the error rate of the indirect test was about 50% in diagnosing partial neurogenic diabetes insipidus, partial NDI, or primary polydipsia in patients who were able to concentrate their urine to varying degrees when water deprived. The benefits of combined direct

Carrier Detection, Perinatal Testing, and Early Treatment The identification of mutations in the genes that cause hereditary diabetes insipidus allows the early diagnosis and management of at-risk members of families with identified mutations. We encourage physicians who follow families with autosomal neurogenic, X-linked and autosomal NDI to recommend mutation analysis before the birth of an infant because early diagnosis and treatment can avert the physical and mental retardation associated with episodes of dehydration. Diagnosis of X-linked NDI was accomplished by mutation testing of cultured amniotic cells (n ⫽ 6), chorionic villus samples (n ⫽ 7), or cord blood obtained at birth (n ⫽ 31) in 44 of our patients. Twenty-one males were found to bear mutant sequences, 16 males were not affected, and five females were not carriers. These affected patients were immediately given abundant water intake, a lowsodium diet, and hydrochlorothiazide. They never experienced episodes of dehydration, and their physical and mental development is normal. Gene analysis is also important for the identification of nonobligatory female carriers in families with X-linked NDI. Most females heterozygous for a mutation in the V2 receptor do not have clinical symptoms: Few are severely affected (4, 138, 187). Mutation detection in families with inherited neurogenic diabetes insipidus provides a powerful clinical tool for early diagnosis and management of subsequent cases, especially in early childhood, when diagnosis is difficult and the clinical risks are the greatest (126).

1242

SECTION III

•

Regulation and Disorders of Water Homeostasis

TABLE 3

Differential Diagnosis of Diabetes Insipidus

1. Measure plasma osmolality and/or sodium concentration under conditions of ad libitum fluid intake. If plasma osmolality is ⬎295 mOsmol/kg and sodium is ⬎143 mOsmol/l, the diagnosis of primary polydipsia is excluded and the work-up should proceed to step (5) and/or (6) to distinguish between NDI and neurogenic diabetes insipidus. Otherwise: 2. Perform a dehydration test. If urinary concentration does not occur before plasma osmolality reaches 295 mOsmol/kg and/or sodium reaches 143 mOsmol/l, the diagnosis of primary polydipsia is again excluded and the work-up should proceed to step (5) and/or (6). Otherwise: 3. Determine the ratio of urine to plasma osmolality at the end of the dehydration test. If it is ⬍1.5, the diagnosis of primary polydipsia is again excluded and the work-up should proceed to step (5) and/or (6). Otherwise: 4. Perform a hypertonic saline infusion with measurement of plasma AVP and osmolality at intervals during the procedure. If the relationship between these two variables falls below the normal range, the diagnosis of neurogenic diabetes insipidus is established (Fig. 51-5A). Otherwise: 5. Perform a dDAVP infusion test. If urine osmolality increases by ⬍150 mOsmol/kg above the value obtained at the end of the dehydration test, the diagnosis of NDI is established. Alternatively: 6. Measure urine osmolality and plasma AVP at the end of the dehydration test. If the relationship falls below the normal range, the diagnosis of NDI is established (Fig. 51-5B). Data from Robertson GL. Differential diagnosis of polyuria. Annu Rev Med 1988;39:425–442.

Neurogenic diabetes insipidus (central or Wolfram) is easily treated with dDAVP (21). All complications of congenital NDI are prevented by an adequate water intake. Thus, patients should be provided with unrestricted amounts of water from birth to ensure normal development. In addition to a lowsodium diet, the use of diuretics (thiazides) or indomethacin may reduce urinary output. This advantageous effect has to be weighed against the side effects of these drugs (thiazides: electrolyte disturbances; indomethacin: reduction of the glomerular filtration rate and gastrointestinal symptoms).

RADIOIMMUNOASSAY OF AVP AND OTHER LABORATORY DETERMINATIONS Radioimmunoassay of AVP Three developments were basic to the elaboration of a clinically useful radioimmunoassay for plasma AVP (153, 154): (1) the extraction of AVP from plasma with petrol-ether and acetone and the subsequent elimination of nonspecific immunoreactivity; (2) the use of highly specific and sensitive rabbit antiserum; and (3) the use of a tracer (125I-AVP) with high specific activity. These same extraction procedures are still widely used (15, 16, 48, 191), and commercial tracers (125IAVP) and antibodies are available. AVP can also be extracted from plasma by using Sep-Pak C18 cartridges (72, 102, 204). Blood samples collected in chilled 7-ml lavenderstoppered tubes containing ethylenediaminetetraacetic acid are centrifuged at 4°C, 1000 g (3000 rpm in a usual laboratory centrifuge), for 20 minutes. This 20-minute centrifugation is mandatory for obtaining platelet-poor plasma samples because a large fraction of the circulating vasopressin is associated with the platelets in humans (16, 144). The tubes may be kept for 2 hours on slushed ice before centrifugation. Plasma is then separated, frozen at ⫺20°C and extracted within 6 weeks of sampling. Details for sample preparation (Table 4) and assay procedure (Table 5) can be found in writings by Bichet and colleagues (15, 16). An AVP radioimmunoassay should be validated by demonstrating (1) a good correlation between

plasma sodium or osmolality and plasma AVP during dehydration and infusion of hypertonic saline solution (Fig. 4); and (2) the inability to obtain detectable values of AVP in patients with severe central diabetes insipidus. Plasma AVP immunoreactivity may be elevated in patients with diabetes insipidus following hypothamic surgery (171). In pregnant patients, the blood contains high concentrations of cystine aminopeptidase, which can (in vitro) inactivate enormous quantities (ng ⫻ mL⫺1 ⫻ min⫺1) of AVP. However, phenanthrolene effectively inhibits these cystine aminopeptidases (Table 6). Aquaporin-2 Measurements Urinary AQP2 excretion could be measured by radioimmunoassay (93) or quantitative Western analysis (56) and could provide an additional indication of the responsiveness of the collecting duct to AVP. Plasma Sodium, Plasma, and Urine Osmolality Measurements of plasma sodium, plasma, and urinary osmolality should be immediately available at various intervals during dehydration procedures. Plasma sodium is easily measured by flame photometry or with a sodium-specific electrode (113). Plasma and urinary osmolalities are also reliTABLE 4

Arginine Vasopressin Measurements: Sample Preparation

4 oC – Blood in EDTA tubes Centrifugation 1,000 g ⫻ 20 min. Plasma frozen -20oC Extraction: 2 mL acetone ⫹ 1 mL plasma 1,000 g x 30 min 4o C Supernatant ⫹ 5 mL of petrol-ether 1,000 g ⫻ 20 min 4oC Freeze -80o C Throw nonfrozen upper phase Evaporate lower phase to dryness Store desiccated samples at -20o C

CHAPTER 43

TABLE 5

Arginine Vasopressin Measurements: Assay Procedure

Day 1

Day 4 Day 7

Assay set-up 400 ␮L/tube (200 ␮L sample or standard ⫹ 200 ␮L of antiserum or buffer) Incubation 80 hours, 4oC 125 I-AVP 100 ␮L/tube 1,000 cpm/tube Incubation 72 hours, 4oC Separation dextran ⫹ charcoal

ably measured by freezing point depression instruments with a coefficient of variation at 290 mmol/kg of less than 1%. At variance with published data (16, 206), we have found that plasma and serum osmolalities are equivalent (i.e., similar values are obtained). Blood taken in heparinized tubes is easier to handle because the plasma can be more readily removed after centrifugation. The tube used (greenstoppered tube) contains a minuscule concentration of lithium and sodium, which does not interfere with plasma sodium or osmolality measurements. Frozen plasma or urinary samples can be kept for further analysis of their osmolalities because the results obtained are similar to those obtained immediately after blood sampling, except in patients with severe renal failure. In the latter patients, plasma osmolality measurements are increased after freezing and thawing but the plasma sodium values remain unchanged. Plasma osmolality measurements can be used to demonstrate the absence of unusual osmotically active substances (e.g., glucose and urea in high concentrations, mannitol, ethanol) (67). With this information, plasma or serum sodium measurements are sufficient to assess the degree of dehydration and its relationship to plasma AVP. Nomograms describing the normal plasma sodium/plasma AVP relationship (Fig. 4) are equally as valuable as classic nomograms describing the relationship between plasma osmolality and effective osmolality (i.e., plasma osmolality minus the contribution of “ineffective” solutes: glucose and urea).

MAGNETIC RESONNANCE IMAGING IN PATIENTS WITH DIABETES INSIPIDUS Magnetic resonance imaging (MRI) permits visualization of the anterior and posterior pituitary glands and the pituitary stalk. The pituitary stalk is permeated by numerous capillary loops of the hypophyseal–portal blood system. TABLE 6

Measurements of Arginine Vasopressin Levels in Pregnant Patients

1,10-phenanthroline monohydrate (Sigma) solubilized with several drops of glacial acetic acid 0.1 mL/10 mL of blood Data from Davison JM, Gilmore EA, Durr J, et al. Altered osmotic thresholds for vasopressin secretion and thirst in human pregnancy. Am J Physiol 1984;246:F105–109.

•

Polyuria and Diabetes Insipidus

1243

This vascular structure also provides the principle blood supply to the anterior pituitary lobe, because there is no direct arterial supply to this organ. In contrast, the posterior pituitary lobe has a direct vascular supply. Therefore, the posterior lobe can be more rapidly visualized in a dynamic mode after administration of a gadolinium (gadopentate dimeglumine) as contrast material during MRI. The posterior pituitary lobe is easily distinguished by a round, highintensity signal (the posterior pituitary “bright spot”) in the posterior part of the sella turcica on T1-weighted images. This round, high-intensity signal is usually absent in patients with central diabetes insipidus, but a systemic evaluation of well-characterized patients with autosomal dominant central diabetes insipidus has not been done. MRI is reported to be the best technique with which to evaluate the pituitary stalk and infundibulum in patients with idiopathic polyuria. A thickening or enlargement of the pituitary stalk may suggest an infiltrative process destroying the neurohypophyseal tract (149).

TREATMENT In most patients with complete hypothalamic diabetes insipidus, the thirst mechanism remains intact. Thus, hypernatremia does not develop in these patients and they suffer only from the inconvenience associated with marked polyuria and polydipsia. If hypodipsia develops or access to water is limited, then severe hypernatremia can supervene. The treatment of choice for patients with severe hypothalamic diabetes insipidus is dDAVP, a synthetic, long-acting vasopressin analogue, with minimal vasopressor activity but a large antidiuretic potency. The usual intranasal daily dose is between 5 and 20 ␮g. To avoid the potential complication of dilutional hyponatremia, which is exceptional in these patients as a result of an intact thirst mechanism, dDAVP can be withdrawn at regular intervals to allow the patients to become polyuric. Aqueous vasopressin (Pitressin) or dDAVP (4.0 ␮g/1-ml ampule) can be used intravenously in acute situations such as after hypophysectomy or for the treatment of diabetes insipidus in the brain-dead organ donor. Pitressin tannate in oil and nonhormonal antidiuretic drugs are somewhat obsolete and now rarely used. For example, chlorpropamide (250–500 mg daily) appears to potentiate the antidiuretic action of circulating AVP, but troublesome side effects of hypoglycemia and hyponatremia do occur. The treatment of congenital NDI has been reviewed by Knoers and Monnens (97). An abundant unrestricted water intake should always be provided, and affected patients should be carefully followed during their first years of life. Water should be offered every 2 hours day and night, and temperature, appetite, and growth should be monitored. The parents of these children easily accept setting their alarm clock every 2 hours during the night. Hospital admission may be necessary to allow continuous gastric feeding. A

1244

SECTION III

•

Regulation and Disorders of Water Homeostasis

low-osmolar and low-sodium diet, hydrochlorothiazide (1–2 mg/kg/d) alone or with amiloride, and indomethacin (0.75– 1.5 mg/kg) substantially reduce water excretion and are helpful in the treatment of children. Many adult patients receive no treatment.

Acknowledgments The author work cited in this chapter was supported by the Canadian Institutes of Health Research, the Kidney Foundation of Canada, and the Fonds de la Recherche en Santé du Québec. D.G.B. holds a Canada Research Chair in Genetics of Renal Diseases. We thank our coworkers, Marie-Françoise Arthus, Joyce Crumley, Mary Fujiwara, Michèle Lonergan, and Kenneth Morgan; and many colleagues who contributed families and ideas to our work. Typing and computer graphics expertise have been done by Danielle Binette.

References 1. Agre P. Aquaporin water channels (Nobel Lecture). Angew Chem Int Ed Engl 2004;43: 4278–4290. 2. Ahmed SR, Aiello DP, Page R, et al. Necrotizing infundibulo-hypophysitis: a unique syndrome of diabetes insipidus and hypopituitarism. J Clin Endocrinol Metab 1993;76:1499–1504. 3. Amico JA. Diabetes insipidus and pregnancy. In: Czernichow P, Robinson AG, eds. Frontiers of Hormone Research. Basel, Switzerland: Karger; 1985: 266–277. 4. Arthus M-F, Lonergan M, Crumley MJ, et al. Report of 33 novel AVPR2 mutations and analysis of 117 families with X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol 2000;11:1044–1054. 5. Balment RJ, Brimble MJ, Forsling ML. Oxytocin release and renal actions in normal and Brattleboro rats. Ann N Y Acad Sci US 1982;394:241–253. 6. Barak LS, Oakley RH, Laporte SA, Caron MG. Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus. Proc Natl Acad Sci U S A 2001;98:93–98. 7. Barlow ED, de Wardener HE. Compulsive water drinking. Q J Med New Series 1959;28: 235–258. 8. Barron WM, Cohen LH, Ulland LA, et al. Transient vasopressin-resistant diabetes insipidus of pregnancy. N Engl J Med 1984;310:442–444. 9. Batlle DC, von Riotte AB, Gaviria M, Grupp M. Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy. N Engl J Med 1985;312:408–414. 10. Baylis PH, Gaskill MB, Robertson GL. Vasopressin secretion in primary polydipsia and cranial diabetes insipidus. Q J Med 1981;50:345–358. 11. Bernier V, Lagace M, Bichet DG, Bouvier M. Pharmacological chaperones: potential treatment for conformational diseases. Trends Endocrinol Metab 2004;15:222–228. 12. Bernier V, Lagace M, Lonergan M, et al. Functional rescue of the constitutively internalized V2 vasopressin receptor mutant R137H by the pharmacological chaperone action of SR49059. Mol Endocrinol 2004;18:2074–2084. 13. Bernier V, Morello JP, Zarruk A, et al. Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol 2006;17:232–243. 14. Bichet D. Nephrogenic diabetes insipidus. In: Davison A, Cameron J, Grünfeld J, et al., eds. Oxford Textbook of Clinical Nephrology. New York: Oxford University Press; 1998: 1095– 1109. 15. Bichet DG, Kortas C, Mettauer B, et al. Modulation of plasma and platelet vasopressin by cardiac function in patients with heart failure. Kidney Int 1986;29:1188–1196. 16. Bichet DG, Arthus M-F, Barjon JN, et al. Human platelet fraction arginine-vasopressin. J Clin Invest 1987;79:881–887. 17. Bichet DG, Razi M, Arthus MF, et al. Epinephrine and dDAVP administration in patients with congenital nephrogenic diabetes insipidus. Evidence for a pre-cyclic AMP V2 receptor defective mechanism. Kidney Int 1989;36:859–866. 18. Bichet DG, Hendy GN, Lonergan M, et al. X-linked nephrogenic diabetes insipidus: From the ship Hopewell to restriction fragment length polymorphism studies. Am J Hum Genet 1992;51:1089–1102. 19. Bichet DG, Kluge R, Howard RL, Schrier RW. Hyponatremic states. In: Seldin DW, Giebisch G, eds. The Kidney: Physiology and Pathophysiology. New York: Raven Press; 1992: 1727–1751. 20. Bichet DG, Arthus M-F, Lonergan M, et al. X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis. J Clin Invest 1993;92:1262–1268. 21. Bichet DG. Nephrogenic and central diabetes insipidus. In: Schrier RW, Gottschalk CW, eds. Diseases of the Kidney. New York: Little, Brown; 1997: 2429–2449. 22. Bichet DG, Fujiwara TM. Nephrogenic diabetes insipidus. In: Scriver CR, Beaudet AL, Sly WS, et al., eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGrawHill; 2001: 4181–4204.

23. Bichet DG. Nephrogenic diabetes insipidus: New developments. Nephrol Self-Assessment Progr 2004;3:187–191. 24. Bichet DG, Fujiwara TM. Reabsorption of sodium chloride—lessons from the chloride channels. N Engl J Med 2004;350:1281–1283. 25. Bichet DG. Editorial: Lithium, cyclic AMP signaling, A-kinase anchoring proteins and aquaporin-2. J Am Soc Nephrol 2006;17:920–922. 26. Birnbaumer M, Seibold A, Gilbert S, et al. Molecular cloning of the receptor for human antidiuretic hormone. Nature 1992;357:333–335. 27. Bonnardeaux A, Bichet DG. Inherited disorders of the renal tubule. In: Brenner BM, ed. Brenner & Rector’s The Kidney. Philadelphia: Saunders; 2004: 1697–1741. 28. Boton R, Gaviria M, Batlle DC. Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy. Am J Kidney Dis 1987;10:329–345. 29. Bourque CW, Oliet SHR, Richard D. Osmoreceptors, osmoreception, and osmoregulation. Front Neuroendocrinol 1994;15:231–274. 30. Bourque CW, Oliet SHR. Osmoreceptors in the central nervous system. Annu Rev Physiol 1997;59:601–619. 31. Boyd SD, Raz S, Ehrlich RM. Diabetes insipidus and nonobstructive dilatation of urinary tract. Urology 1980;16:266–269. 32. Brenner B, Seligsohn U, Hochberg Z. Normal response of factor VIII and von Willebrand factor to 1-deamino- 8D-arginine vasopressin in nephrogenic diabetes insipidus. J Clin Endocrinol Metab 1988;67:191–193. 33. Brewster UC, Hayslett JP. Diabetes insipidus in the third trimester of pregnancy. Obstet Gynecol 2005;105:1173–1176. 34. Burbach JP, Luckman SM, Murphy D, Gainer H. Gene regulation in the magnocellular hypothalamo-neurohypophysial system. Physiol Rev 2001;81:1197–1267. 35. Camerer JW. Eine ergänzung des Weilschen diabetes-insipidus-stammbaumes. Archiv für Rassenund Gesellschaftshygiene Biologie 1935;28:382–385. 36. Chen L, Rose JP, Breslow E, et al. Crystal structure of a bovine neurophysin II dipeptide complex at 2.8 Angström determined from the single-wave length anomalous scattering signal of an incorporated iodine atom. Proc Natl Acad Sci U S A 1991;88:4240–4244. 37. Cheng A, van Hoek AN, Yeager M, et al. Three-dimensional organization of a human water channel. Nature 1997;387:627–630. 38. Chillaron J, Estevez R, Samarzija I, et al. An intracellular trafficking defect in type I cystinuria rBAT mutants M467T and M467K. J Biol Chem 1997;272:9543–9549. 39. Chou C-L, Knepper MA, van Hoek AN, et al. Reduced water permeability and altered ultrastructure in thin descending limb of Henle in aquaporin-1 null mice. J Clin Invest 1999;103:491–496. 40. Chou CL, DiGiovanni SR, Luther A, et al. Oxytocin as an antidiuretic hormone II. Role of V2 vasopressin receptor. Am J Physiol 1995;269(1pt2):F78–F85. 41. Christensen JH, Rittig S. Familial neurohypophyseal diabetes insipidus—an update. Semin Nephrol 2006;26:209–223. 42. Christensen S, Kusano E, Yusufi AN, et al. Pathogenesis of nephrogenic diabetes insipidus due to chronic administration of lithium in rats. J Clin Invest 1985;75:1869–1879. 43. Cogan E, Svoboda M, Abramow M. Mechanisms of lithium-vasopressin interaction in rabbit cortical collecting tubule. Am J Physiol 1987;252:F1080–1087. 44. Cohen FE, Kelly JW. Therapeutic approaches to protein-misfolding diseases. Nature 2003;426:905–909. 45. Couture Y, Arthus M-F, Fujiwara TM, et al. Severe early-onset autosomal recessive familial neurohypophyseal diabetes insipidus secondary to novel AVP mutations. Submitted. 46. Crawford JD, Bode HH. Disorders of the posterior pituitary in children. In: Gardner LI, ed. Endocrine and Genetic Diseases of Childhood and Adolescence. Philadelphia: WB Saunders; 1975:126–158. 47. Czernichow P, Pomarede R, Brauner R, Rappaport R. Neurogenic diabetes insipidus in children. In: Czernichow P, Robinson AG, eds. Frontiers of Hormone Research. Basel, Switzerland: S. Karger; 1985:190–209. 48. Davison JM, Gilmore EA, Durr J, et al. Altered osmotic thresholds for vasopressin secretion and thirst in human pregnancy. Am J Physiol 1984;246:F105–109. 49. Davison JM, Shiells EA, Philips PR, Lindheimer MD. Serial evaluation of vasopressin release and thirst in human pregnancy. Role of human chorionic gonadotrophin in the osmoregulatory changes of gestation. J Clin Invest 1988;81:798–806. 50. De Mota N, Reaux-Le Goazigo A, El Messari S, et al. Apelin, a potent diuretic neuropeptide counteracting vasopressin actions through inhibition of vasopressin neuron activity and vasopressin release. Proc Natl Acad Sci U S A 2004;101:10464–10469. 51. Deen PMT, Verdijk MAJ, Knoers NVAM, et al. Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine. Science 1994;264:92–95. 52. Deen PMT, Weghuis DO, Sinke RJ, et al. Assignment of the human gene for the water channel of renal collecting duct aquaporin 2 (AQP2) to chromosome 12 region q12-⬎q13. Cytogenet Cell Genet 1994;66:260–262. 53. Domenech E, Gomez-Zaera M, Nunes V. Study of the WFS1 gene and mitochondrial DNA in Spanish Wolfram syndrome families. Clin Genet 2004;65:463–469. 54. Durr JA, Hoggard JG, Hunt JM, Schrier RW. Diabetes insipidus in pregnancy associated with abnormally high circulating vasopressinase activity. N Engl J Med 1987;316:1070–1074. 55. Dölle W. Eine weitere ergänzung des Weilschen diabetes-insipidus-stammbaumes. Zeitschrift für Menschliche Vererbungsund Konstitutionslehre 1951;30:372–374. 56. Elliot S, Goldsmith P, Knepper M, et al. Urinary excretion of aquaporin-2 in humans: a potential marker of collecting duct responsiveness to vasopressin. J Am Soc Nephrol 1996;7: 403–409. 57. Fenton RA, Shodeinde A, Knepper MA. UT-A urea transporter promoter, UT-Aalpha, targets principal cells of the renal inner medullary collecting duct. Am J Physiol Renal Physiol 2006;290:F188–195. 58. Fery F, Plat L, van de Borne P, et al. Impaired counterregulation of glucose in a patient with hypothalamic sarcoidosis. N Engl J Med 1999;340:852–856. 59. Fitzsimons JT. Angiotensin, thirst, and sodium appetite. Physiol Rev 1998;78:583–686. 60. Fleming EF, Athirakul K, Oliverio MI, et al. Urinary concentrating function in mice lacking EP3 receptors for prostaglandin E2. Am J Physiol 1998;275:F955–961.

CHAPTER 43

61. Forssman H. On the mode of hereditary transmission in diabetes insipidus. Nordisk Medicine 1942;16:3211–3213. 62. Forssman H. On hereditary diabetes insipidus, with special regard to a sex-linked form. Acta Med Scand 1945;159:1–196. 63. Frokiaer J, Marples D, Knepper MA, Nielsen S. Bilateral ureteral obstruction downregulates expression of vasopressin-sensitive AQP-2 water channel in rat kidney. Am J Physiol 1996; 270:F657–F668. 64. Fujiwara TM, Bichet DG. Molecular biology of hereditary diabetes insipidus. J Am Soc Nephrol 2005;16:2836–2846. 65. Fushimi K, Sasaki S, Yamamoto T, et al. Functional characterization and cell immunolocalization of AQP-CD water channel in kidney collecting duct. Am J Physiol 1994;267:F573–582. 66. Gautier B, Thieblot P, Steg A. Mégauretère, mégavessie et diabète insipide familial. Semin Hop 1981;57:60–61. 67. Gennari FJ. Current concepts. Serum osmolality. Uses and limitations. N Engl J Med 1984;310:102–105. 68. Glover DJ, Lipps HJ, Jans DA. Towards safe, non-viral therapeutic gene expression in humans. Nat Rev Genet 2005;6:299–310. 69. Goldberg H, Clayman P, Skorecki K. Mechanism of Li inhibition of vasopressin-sensitive adenylate cyclase in cultured renal epithelial cells. Am J Physiol 1988;255:F995–1002. 70. Goldman MB, Luchins DJ, Robertson GL. Mechanisms of altered water metabolism in psychotic patients with polydipsia and hyponatremia. N Engl J Med 1988;318:397–403. 71. Greger NG, Kirkland RT, Clayton GW, Kirkland JL. Central diabetes insipidus. 22 years’ experience. Am J Dis Child 1986;140:551–554. 72. Hartter E, Woloszczuk W. Radioimmunological determination of arginine vasopressin and human atrial natriuretic peptide after simultaneous extraction from plasma. J Clin Chem Clin Biochem 1986;24:559–563. 73. Hayama A, Rai T, Sasaki S, Uchida S. Molecular mechanisms of Bartter syndrome caused by mutations in the BSND gene. Histochem Cell Biol 2003;119:485–493. 74. Hein L, Barsh GS, Pratt RE, et al. Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor gene in mice. Nature 1995;377:744–747. 75. Hermosilla R, Oueslati M, Donalies U, et al. Disease-causing V(2) vasopressin receptors are retained in different compartments of the early secretory pathway. Traffic 2004;5: 993–1005. 76. Hiett AK, Barton JR. Diabetes insipidus associated with craniopharyngioma in pregnancy. Obstet Gynecol 1990;76:982–984. 77. Hobbs HH, Russell DW, Brown MS, Goldstein JL. The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annu Rev Genet 1990; 24: 133–170. 78. Howard RL, Bichet DG, Schrier RW. Hypernatremic and polyuric states. In: Seldin DW, Giebisch G, eds. The Kidney: Physiology and Pathophysiology. New York: Raven Press; 1992:753–1778. 79. Huber D, Veinante P, Stoop R. Vasopressin and oxytocin excite distinct neuronal populations in the central amygdala. Science 2005;308:245–248. 80. Imura H, Nakao K, Shimatsu A, et al. Lymphocytic infundibuloneurohypophysitis as a cause of central diabetes insipidus. N Engl J Med 1993;329:683–689. 81. Insel TR, Young LJ. The neurobiology of attachment. Nat Rev Neurosci 2001;2:129–136. 82. Ishihara H, Takeda S, Tamura A, et al. Disruption of the WFS1 gene in mice causes progressive beta-cell loss and impaired stimulus-secretion coupling in insulin secretion. Hum Mol Genet 2004;13:1159–1170. 83. Ito M, Oliverio MI, Mannon PJ, et al. Regulation of blood pressure by the type 1A angiotensin II receptor gene. Proc Natl Acad Sci U S A 1995;92:3521–3525. 84. Ito M, Jameson JL, Ito M. Molecular basis of autosomal dominant neurohypophyseal diabetes insipidus. Cellular toxicity caused by the accumulation of mutant vasopressin precursors within the endoplasmic reticulum. J Clin Invest 1997;99:1897–1905. 85. Ito M, Yu RN, Jameson JL. Mutant vasopressin precursors that cause autosomal dominant neurohypophyseal diabetes insipidus retain dimerization and impair the secretion of wildtype proteins. J Biol Chem 1999;274:9029–9037. 86. Iwasaki Y, Oiso Y, Kondo K, et al. Aggravation of subclinical diabetes insipidus during pregnancy. N Engl J Med 1991;324:522–526. 87. Jans DA, van Oost BA, Ropers HH, Fahrenholz F. Derivatives of somatic cell hybrids which carry the human gene locus for nephrogenic diabetes insipidus (NDI) express functional vasopressin renal V2-type receptors. J Biol Chem 1990;265:15379–15382. 88. Jard S, Elands J, Schmidt A, Barberis C. Vasopressin and oxytocin receptors: an overview. In: Imura H, Shizume K, eds. Progress in Endocrinology. Amsterdam: Elsevier Science; 1988: 1183–1188. 89. Jeck N, Schlingmann KP, Reinalter SC, et al. Salt handling in the distal nephron: lessons learned from inherited human disorders. Am J Physiol Regul Integr Comp Physiol 2005;288: R782–795. 90. Kalogeras KT, Nieman LN, Friedman TC, et al. Inferior petrosal sinus sampling in healthy human subjects reveals a unilateral corticotropin-releasing hormone-induced arginine vasopressin release associated with ipsilateral adrenocorticotropin secretion. J Clin Invest 1996;97: 2045–2050. 91. Kambouris M, Dlouhy SR, Trofatter JA, et al. Localization of the gene for X-linked nephrogenic diabetes insipidus to Xq28. Am J Med Genet 1988;29:239–246. 92. Kamsteeg E-J, Bichet DG, Konings IBM, et al. Reversed polarized delivery of an aquaporin-2 mutant causes dominant nephrogenic diabetes insipidus. J Cell Biol 2003;163: 1099–1109. 93. Kanno K, Sasaki S, Hirata Y, et al. Urinary excretion of aquaporin-2 in patients with diabetes insipidus. N Engl J Med 1995;332:1540–1545. 94. Kennan A, Aherne A, Humphries P. Light in retinitis pigmentosa. Trends Genet 2005;21: 103–110. 95. Knoers N, van der Heyden H, van Oost BA, et al. Three-point linkage analysis using multiple DNA polymorphic markers in families with X-linked nephrogenic diabetes insipidus. Genomics 1989;4:434–437.

•

Polyuria and Diabetes Insipidus

1245

96. Knoers N, Monnens LA. A variant of nephrogenic diabetes insipidus: V2 receptor abnormality restricted to the kidney. Eur J Pediatr 1991;150:370–373. 97. Knoers N, Monnens LA. Nephrogenic diabetes insipidus: clinical symptoms, pathogenesis, genetics and treatment. Pediatr Nephrol 1992;6:476–482. 98. Kunchaparty S, Palcso M, Berkman J, et al. Defective processing and expression of thiazidesensitive Na-Cl cotransporter as a cause of Gitelman’s syndrome. Am J Physiol 1999;277: F643–649. 99. Kuwahara M, Iwai K, Ooeda T, et al. Three families with autosomal dominant nephrogenic diabetes insipidus caused by aquaporin-2 mutations in the C-terminus. Am J Hum Genet 2001;69:738–748. 100. Lacombe UL. De la polydipsie. In: Imprimerie et Fonderie de Rignoux. Paris; 1841:87. 101. Langley JM, Balfe JW, Selander T, et al. Autosomal recessive inheritance of vasopressinresistant diabetes insipidus. Am J Med Genet 1991;38:90–94. 102. LaRochelle FT, Jr., North WG, Stern P. A new extraction of arginine vasopressin from blood: the use of octadecasilyl-silica. Pflugers Arch 1980;387:79–81. 103. Lawless MW, Greene CM, Mulgrew A, et al. Activation of endoplasmic reticulum-specific stress responses associated with the conformational disease Z alpha 1-antitrypsin deficiency. J Immunol 2004;172:5722–5726. 104. Leaf A. Neurogenic diabetes insipidus. Kidney Int 1979;15:572–580. 105. Leibowitz SF. Impact of brain monoamines and neuropeptides on vasopressin release. In: Cowley AWJ, Liard JF, Ausiello DA, eds. Vasopressin. Cellular and Integrative Functions. New York: Raven; 1988:379–388. 106. Li Y, Shaw S, Kamsteeg E-J, et al. Development of lithium-induced nephrogenic diabetes insipidus is dissociated from adenylyl cyclase activity. J Am Soc Nephrol 2006;17:1063–1072. 107. Lloyd DJ, Hall FW, Tarantino LM, Gekakis N. Diabetes insipidus in mice with a mutation in aquaporin-2. PLoS Genet 2005;1:e20. 108. Lomas DA, Evans DL, Finch JT, Carrell RW. The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature 1992;357:605–607. 109. Lopez-Rodriguez C, Antos CL, Shelton JM, et al. Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression. Proc Natl Acad Sci U S A 2004;101: 2392–2397. 110. Ma T, Yang B, Gillespie A, et al. Generation and phenotype of a transgenic knockout mouse lacking the mercurial-insensitive water channel aquaporin-4. J Clin Invest 1997;100: 957–962. 111. Ma T, Yang B, Gillespie A, et al. Severely impaired urinary concentrating ability in transgenic mice lacking aquaporin-1 water channels. J Biol Chem 1998;273:4296–4299. 112. Ma T, Song Y, Yang B, et al. Nephrogenic diabetes insipidus in mice lacking aquaporin-3 water channels. Proc Natl Acad Sci U S A 2000;97:4386–4391. 113. Maas AH, Siggaard-Andersen O, Weisberg HF, Zijlstra WG. Ion-selective electrodes for sodium and potassium: a new problem of what is measured and what should be reported. Clin Chem 1985;31:482–485. 114. Maghnie M, Cosi G, Genovese E, et al. Central diabetes insipidus in children and young adults. N Engl J Med 2000;343:998–1007. 115. Magner PO, Halperin ML. Polyuria—a pathophysiological approach. Med North Am 1987;15:2987–2997. 116. Mankin AS, Liebman SW. Baby, don’t stop! Nat Genet 1999;23:8–10. 117. Marek S, Tekesin I, Hellmeyer L, et al. [Differential diagnosis of a polyhydramnion in hyperprostaglandin e syndrome: a case report]. Z Geburtshilfe Neonatol 2004;208: 232–235. 118. Marples D, Christensen S, Christensen EI, et al. Lithium-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla. J Clin Invest 1995;95:1838– 1845. 119. Marples D, Frokiaer J, Dorup J, et al. Hypokalemia-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla and cortex. J Clin Invest 1996;97:1960– 1968. 120. Marr N, Bichet DG, Lonergan M, et al. Heteroligomerization of an aquaporin-2 mutant with wild-type aquaporin-2 and their misrouting to late endosomes/lysosomes explains dominant nephrogenic diabetes insipidus. Hum Mol Genet 2002;11:779–789. 121. Masera N, Grant DB, Stanhope R, Preece MA. Diabetes insipidus with impaired osmotic regulation in septo-optic dysplasia and agenesis of the corpus callosum. Arch Dis Child 1994;70:51–53. 122. Matsumura Y, Uchida S, Kondo Y, et al. Overt nephrogenic diabetes insipidus in mice lacking the CLC-K1 chloride channel. Nat Genet 1999;21:95–98. 123. McDill BW, Li SZ, Kovach PA, et al. Congenital progressive hydronephrosis (cph) is caused by an S256L mutation in aquaporin-2 that affects its phosphorylation and apical membrane accumulation. Proc Natl Acad Sci U S A 2006;103:6952–6957. 124. McIlraith CH. Notes on some cases of diabetes insipidus with marked family and hereditary tendencies. Lancet 1892;2:767–768. 125. Miller M, Dalakos T, Moses AM, et al. Recognition of partial defects in antidiuretic hormone secretion. Ann Intern Med 1970;73:721–729. 126. Miller WL. Molecular genetics of familial central diabetes insipidus. J Clin Endocrinol Metab 1993;77:592–595. 127. Morello JP, Salahpour A, Laperrière A, et al. Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J Clin Invest 2000; s105:887–895. 128. Moses AM, Blumenthal SA, Streeten DHP. Acid-base and electrolyte disorders associated with endocrine disease: pituitary and thyroid. In: Arieff AI, de Fronzo RA, eds. Fluid, Electrolyte and Acid-Base Disorders. New York: Churchill Livingstone; 1985:851–892. 129. Mouillac B, Chini B, Balestre MN, et al. The binding site of neuropeptide vasopressin V1a receptor. Evidence for a major localization within transmembrane regions. J Biol Chem 1995;270:25771–25777. 130. Nathanson MH, Moyer MS, Burgstahler AD, et al. Mechanisms of subcellular cytosolic Ca2⫹ signaling evoked by stimulation of the vasopressin V1a receptor. J Biol Chem 1992;267: 23282–23289.

1246

SECTION III

•

Regulation and Disorders of Water Homeostasis

131. Nemergut EC, Zuo Z, Jane JA, Jr., Laws ER, Jr. Predictors of diabetes insipidus after transsphenoidal surgery: a review of 881 patients. J Neurosurg 2005;103:448–454. 132. Niaudet P, Dechaux M, Trivin C, et al. Nephrogenic diabetes insipidus: Clinical and pathophysiological aspects. Adv Nephrol Necker Hosp 1984;13:247–260. 133. Nielsen S, DiGiovanni SR, Christensen EI, et al. Cellular and subcellular immunolocalization of vasopressin-regulated water channel in rat kidney. Proc Natl Acad Sci U S A 1993;90:11663–11667. 134. Nielsen S, Chou C-L, Marples D, et al. Vasopressin increases water permeability of kidney collecting duct by inducing translocation of aquaporin-CD water channels to plasma membrane. Proc Natl Acad Sci U S A 1995;92:1013–1017. 135. Nimura F, Labosky P, Kakuchi J, et al. Gene targeting in mice reveals a requirement for angiotensin in the development and maintenance of kidney morphology and growth factor regulation. J Clin Invest 1995;96:2947–2954. 136. Nomura Y, Onigata K, Nagashima T, et al. Detection of skewed X-inactivation in two female carriers of vasopressin type 2 receptor gene mutation. J Clin Endocrinol Metab 1997;82:3434– 3437. 137. Odell WD, Doggett RS. Xanthoma disseminatum, a rare cause of diabetes insipidus. J Clin Endocrinol Metab 1993;76:777–780. 138. Oksche A, Dickson J, Schülein R, et al. Two novel mutations in the vasopressin V2 receptor gene in patients with congenital nephrogenic diabetes insipidus. Biophys Biochem Res Com 1994;205:552–557. 139. Okubo S, Niimura F, Matsusaka T, et al. Angiotensinogen gene null-mutant mice lack homeostatic regulation of glomerular filtration and tubular reabsorption. Kidney Int 1998;53: 617–625. 140. Olson BR, Gumowski J, Rubino D, Oldfield EH. Pathophysiology of hyponatremia after transsphenoidal pituitary surgery. J Neurosurg 1997;87:499–507. 141. Online Mendelian Inheritance in Man, OMIM. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD). Available at: http://www. ncbi.nlm.nih.gov/omim/. 142. Peters M, Jeck N, Reinalter S, et al. Clinical presentation of genetically defined patients with hypokalemic salt-losing tubulopathies. Am J Med 2002;112:183–190. 143. Peters M, Ermert S, Jeck N, et al. Classification and rescue of ROMK mutations underlying hyperprostaglandin E syndrome/antenatal Bartter syndrome. Kidney Int 2003;64: 923–932. 144. Preibisz JJ, Sealey JE, Laragh JH, et al. Plasma and platelet vasopressin in essential hypertension and congestive heart failure. Hypertension 1983;5:I129–138. 145. Preston GM, Smith BL, Zeidel ML, et al. Mutations in aquaporin-1 in phenotypically normal humans without functional CHIP water channels. Science 1994;265:1585–1587. 146. Randle JC, Mazurek M, Kneifel D, et al. Alpha 1-adrenergic receptor activation releases vasopressin and oxytocin from perfused rat hypothalamic explants. Neurosci Lett 1986;65: 219–223. 147. Rao S, Verkman AS. Analysis of organ physiology in transgenic mice. Am J Physiol Cell Physiol 2000;279:C1–C18. 148. Rao VV, Loffler C, Battey J, Hansmann I. The human gene for oxytocin-neurophysin I (OXT) is physically mapped to chromosome 20p13 by in situ hybridization. Cytogenet Cell Genet 1992;61:271–273. 149. Rappaport R. Magnetic resonance imaging in pituitary disease. Growth Genetics & Hormones 1995;11:1–5. 150. Reeves WB, Andreoli TE. Nephrogenic diabetes insipidus. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill; 1995:3045–3071. 151. Richter D. Molecular events in the expression of vasopressin and oxytocin and their cognate receptors. Am J Physiol 1988;255:F207–F219. 152. Rittig R, Robertson GL, Siggaard C, et al. Identification of 13 new mutations in the vasopressin-neurophysin II gene in 17 kindreds with familial autosomal dominant neurohypophyseal diabetes insipidus. Am J Hum Genet 1996;58:107–117. 153. Robertson GL, Klein LA, Roth J, Gorden P. Immunoassay of plasma vasopressin in man. Proc Natl Acad Sci U S A 1970;66:1298–1305. 154. Robertson GL, Mahr EA, Athar S, Sinha T. Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma. J Clin Invest 1973;52:2340–2352. 155. Robertson GL. The physiopathology of ADH secretion. In: Tolis G, Labrie F, Martin JB, Naftolin F, eds. Clinical Neuroendocrinology: A Pathophysiological Approach. New York: Raven Press; 1979:247–260. 156. Robertson GL. Diagnosis of diabetes insipidus. In: Czernichow P, Robinson AG, eds. Frontiers of Hormone Research. Basel: Karger; 1985:176–189. 157. Robertson GL, Oiso Y, Vokes TP, Gaskill MB. Diprenorphine inhibits selectively the vasopressin response to hypovolemic stimuli. Trans Assoc Am Physicians 1985;98:322–333. 158. Robertson GL. Dipsogenic diabetes insipidus: a newly recognized syndrome caused by a selective defect in the osmoregulation of thirst. Trans Assoc Am Physicians 1987;100:241–249. 159. Robertson GL. Differential diagnosis of polyuria. Annu Rev Med 1988;39:425–442. 160. Robertson GL, Berl T. Pathophysiology of water metabolism. In: Brenner BM, Rector FC, eds.The Kidney. Philadelphia: WB Saunders; 1996:873–928. 161. Rojek A, Fuchtbauer EM, Kwon TH, et al. Severe urinary concentrating defect in renal collecting duct-selective AQP2 conditional-knockout mice. Proc Natl Acad Sci U S A 2006;103: 6037–6042. 162. Romisch K. A cure for traffic jams: small molecule chaperones in the endoplasmic reticulum. Traffic 2004;5:815–820. 163. Rose JP, Wu CK, Hsiao CD, et al. Crystal structure of the neurophysin-oxytocin complex. Nat Struct Biol 1996;3:163–169. 164. Russell TA, Ito M, Yu RN, et al. A murine model of autosomal dominant neurohypophyseal diabetes insipidus reveals progressive loss of vasopressin-producing neurons. J Clin Invest 2003;112:1697–1706.

165. Sands JM, Naruse M, Baum M, et al. Apical extracellular calcium/polyvalent cation-sensing receptor regulates vasopressin-elicited water permeability in rat kidney inner medullary collecting duct. J Clin Invest 1997;99:1399–1405. 166. Sands JM, Flores FX, Kato A, et al. Vasopressin-elicited water and urea permeabilities are altered in IMCD in hypercalcemic rats. Am J Physiol 1998;274:F978–985. 167. Sangkuhl K, Schulz A, Rompler H, et al. Aminoglycoside-mediated rescue of a diseasecausing nonsense mutation in the V2 vasopressin receptor gene in vitro and in vivo. Hum Mol Genet 2004;13:893–903. 168. Sasaki S, Fushimi K, Saito H, et al. Cloning, characterization, and chromosomal mapping of human aquaporin of collecting duct. J Clin Invest 1994;93:1250–1256. 169. Schmale H, Richter D. Single base deletion in the vasopressin gene is the cause of diabetes insipidus in Brattleboro rats. Nature 1984;308:705–709. 170. Schoneberg T, Schulz A, Biebermann H, et al. Mutant G-protein-coupled receptors as a cause of human diseases. Pharmacol Ther 2004;104:173–206. 171. Seckl JR, Dunger DB, Bevan JS, et al. Vasopressin antagonist in early postoperative diabetes insipidus. Lancet 1990;355:1353–1356. 172. Seibold A, Brabet P, Rosenthal W, Birnbaumer M. Structure and chromosomal localization of the human antidiuretic hormone receptor gene. Am J Hum Genet 1992;51:1078–1083. 173. Serradeil-Le Gal C, Lacour C, Valette G, et al. Characterization of SR 121463A, a highly potent and selective, orally active vasopressin V2 receptor antagonist. J Clin Invest 1996; 98:2729–2738. 174. Shalev H, Romanovsky I, Knoers NV, et al. Bladder function impairment in aquaporin-2 defective nephrogenic diabetes insipidus. Nephrol Dial Transplant 2004;19:608–613. 175. Sharif Naeini R, Witty MF, Seguela P, Bourque CW. An N-terminal variant of Trpv1 channel is required for osmosensory transduction. Nat Neurosci 2006;9:93–98. 176. Siggaard C, Rittig S, Corydon TJ, et al. Clinical and molecular evidence of abnormal processing and trafficking of the vasopressin preprohormone in a large kindred with familial neurohypophyseal diabetes insipidus due to a signal peptide mutation. J Clin Endocrinol Metab 1999;84:2933–2941. 177. Stern P, Valtin H. Verney was right, but [editorial]. N Engl J Med 1981;305:1581–1582. 178. Streitz JMJ, Streitz JM. Polyuric urinary tract dilatation with renal damage. J Urol 1988;139:784-–785. 179. Sugaya T, Nishimatsu S, Tanimoto K, et al. Angiotensin II type 1a receptor-deficient mice with hypotension and hyperreninemia. J Biol Chem 1995;270:18719–18722. 180. Takahashi N, Chernavvsky DR, Gomez RA, et al. Uncompensated polyuria in a mouse model of Bartter’s syndrome. Proc Natl Acad Sci U S A 2000;97:5434–5439. 181. Takeda K, Inoue H, Tanizawa Y, et al. WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain. Hum Mol Genet 2001;10:477–484. 182. Tamarappoo BK, Verkman AS. Defective aquaporin-2 trafficking in nephrogenic diabetes insipidus and correction by chemical chaperones. J Clin Invest 1998;101:2257–2267. 183. Tesmer JJ, Sunahara RK, Gilman AG, Sprang SR. Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha.GTPgammaS. Science 1997;278:1907–1916. 184. Ulinski T, Grapin C, Forin V, et al. Severe bladder dysfunction in a family with ADH receptor gene mutation responsible for X-linked nephrogenic diabetes insipidus. Nephrol Dial Transplant 2004;19:2928–2929. 185. Ulloa-Aguirre A, Janovick JA, Brothers SP, Conn PM. Pharmacologic rescue of conformationally-defective proteins: implications for the treatment of human disease. Traffic 2004;5: 821–837. 186. van den Ouweland AM, Knoop MT, Knoers VV, et al. Colocalization of the gene for nephrogenic diabetes insipidus (DIR) and the vasopressin type 2 receptor gene (AVPR2) in the Xq28 region. Genomics 1992;13:1350–1352. 187. van Lieburg AF, Verdijk MAJ, Schoute F, et al. Clinical phenotype of nephrogenic diabetes insipidus in females heterozygous for a vasopressin type 2 receptor mutation. Hum Genet 1995;96:70–78. 188. Venkatesh B, Si-Hoe SL, Murphy D, Brenner S. Transgenic rats reveal functional conservation of regulatory controls between the Fugu isotocin and rat oxytocin genes. Proc Natl Acad Sci U S A 1997;94:12462–12466. 189. Verbalis JG, Robinson AG, Moses AM. Postoperative and post-traumatic diabetes insipidus. In: Czernichow P, Robinson AG, eds. Frontiers of Hormone Research. Basel, Switzerland: S. Karger; 1985:247–265. 190. Vokes T, Robertson GL. Physiology of secretion of vasopressin. In: Czernichow P, Robinson AG, eds. Diabetes Insipidus in Man. Basel: S. Karger; 1985: 27–155. 191. Vokes TP, Aycinena PR, Robertson GL. Effect of insulin on osmoregulation of vasopressin. Am J Physiol 1987;252:E538–548. 192. Ward DT, Hammond TG, Harris HW. Modulation of vasopressin-elicited water transport by trafficking of aquaporin-2-containing vesicles. Annu Rev Physiol 1999;61:683–697. 193. Waring AG, Kajdi L, Tappan V. Congenital defect of water metabolism. Am J Dis Child 1945;69:323–325. 194. Watson S, Arkinstall S. The G Protein Linked Receptor Factsbook. London: Academic Press; 1994. 195. Weil A. Ueber die hereditare form des diabetes insipidus. Archives fur Pathologische Anatomie und Physiologie and fur Klinische Medicine (Virchow’s Archives) 1884;95:70–95. 196. Weil A. Ueber die hereditare form des diabetes insipidus. Deutches Archiv fur Klinische Medizin 1908;93:180–290. 197. Welch WJ, Howard M. Commentary: Antagonists to the rescue. J Clin Invest 2000;105: 853–854. 198. Willcutts MD, Felner E, White PC. Autosomal recessive familial neurohypophyseal diabetes insipidus with continued secretion of mutant weakly active vasopressin. Hum Mol Genet 1999;8:1303–1307. 199. Williams PD, Pettibone DJ. Recent advances in the development of oxytocin receptor antagonists. Curr Pharm Design 1996;2:41–58. 200. Williams RM, Henry C. Nephrogenic diabetes insipidus transmitted by females and appearing during infancy in males. Ann Int Med 1947;27:84–95.

CHAPTER 43

201. Wuller S, Wiesner B, Loffler A, et al. Pharmacochaperones post-translationally enhance cell surface expression by increasing conformational stability of wild-type and mutant vasopressin V2 receptors. J Biol Chem 2004;279:47254–47263. 202. Yang B, Gillespie A, Carlson EJ, et al. Neonatal mortality in an aquaporin-2 knock-in mouse model of recessive nephrogenic diabetes insipidus. J Biol Chem 2001;276:2775–2779. 203. Yang B, Zhou D, Verkman AS. Mouse model of inducible nephrogenic diabetes insipidus produced by floxed aquaporin-2 gene deletion. Am J Physiol Renal Physiol 2006;291:F465–572. 204. Ysewijn-Van Brussel KA, De Leenheer AP. Development and evaluation of a radioimmunoassay for Arg8-vasopressin, after extraction with Sep-Pak C18. Clin Chem 1985;31:861–863.

•

Polyuria and Diabetes Insipidus

1247

205. Yun J, Schoneberg T, Liu J, et al. Generation and phenotype of mice harboring a nonsense mutation in the V2 vasopressin receptor gene. J Clin Invest 2000;106:1361–1371. 206. Zerbe RL, Robertson GL. A comparison of plasma vasopressin measurements with a standard indirect test in the differential diagnosis of polyuria. N Engl J Med 1981;305: 1539–1546. 207. Zerbe RL, Robertson GL. Osmoregulation of thirst and vasopressin secretion in human subjects: effect of various solutes. Am J Physiol 1983;244:E607–614. 208. Zerbe RL, Robertson GL. Disorders of ADH. Med Clin North Am 1984;13:1570–1574.

A NH2 49

61

75

65

23

59

78

11 25

71 82 69

37 29

COOH 32

B

FIGURE 43–3.

13

39