Mild Dehydration, Vasopressin and the Kidney: Animal and Human Studies

ORIGINAL COMMUNICATION Mild dehydration, vasopressin and the kidney: animal and human studies

N Bouby1* and S Fernandes1

1INSERM U 367, Paris, France

Water balance depends essentially on fluid intake and urine excretion. Mild dehydration and the consequent hypertonicity of the extracellular fluid induce an increase in vasopressin secretion, thus stimulating urine concentrating processes and the feeling of thirst. The osmotic threshold for the release of vasopressin is lower than that for thirst and also shows appreciable individual variation. Sustained high levels of vasopressin and low hydration induce morphological and functional changes in the kidney. However, they could also be risk factors in several renal disorders, such as chronic renal failure, diabetic nephropathy and salt- sensitive hypertension. European Journal of Clinical Nutrition (2003) 57, Suppl 2, S39–S46. doi:10.1038/sj.ejcn.1601900

Keywords: water intake; dehydration; vasopressin; kidney

Introduction temperature, angiotensin (Berl & Robertson, 2000). Increase Water balance depends essentially on two parameters: thirst in plasma osmolality is also the main stimulus for thirst. that influences input, and urine excretion that determines However, the desire to drink is triggered by an osmotic level output. In humans and most other mammals, the rate at considerably higher than that leading to the secretion of which the kidneys excrete free water is regulated primarily vasopressin (Robertson, 1984). AVP release begins at an by antidiuretic hormone or vasopressin. Vasopressin is the average plasma osmolality of about 280 mosm/kg H2O, first hormone to be secreted during dehydration. Changes in whereas thirst is not perceived until plasma osmolality the plasma level of other hormones are also observed reaches about 290 mosm/kg H2O. Thus, during normal living (increases in atrial natriuretic peptide and catecholamines, conditions, vasopressin is constantly present in the blood, fall in aldosterone), but they occur later and in response to whereas the perception of thirst is intermittent. The severe dehydration. sensitivity and threshold of the osmoregulatory systems Vasopressin is synthesized in specific neurons in the show wide inter-individual variability in both humans and supraoptic and paraventricular nuclei and stored in the rats (Zerbe et al, 1991; Bankir, 2001). These individual neurohypophysis. Under physiological conditions, the most differences are constant over prolonged periods and appear important stimulus of vasopressin secretion is the effective to be determined mainly by genetic factors (Zerbe et al, osmotic pressure of the plasma. Increase in plasma osmol- 1991). Since the osmoregulatory mechanisms are not equally ality is related physiologically to dehydration and a change sensitive in all healthy individuals, one could expect some in water balance, and can be induced experimentally by subjects to tend to be continuously in a state of slight infusing hypertonic solutions. Vasopressin secretion is also dehydration, and to have a high level of vasopressin to influenced by hemodynamic factors (reduction of blood compensate. pressure or blood volume), emetic factors (nausea, drugs Three vasopressin receptors have been identified and such as nicotine or morphine) and factors such as stress, cloned, V2 with cAMP as second messenger, and V1a and V1b with calcium as second messenger. The antidiuretic *Correspondence: N Bouby, INSERM U 367, 17 rue du Fer a` Moulin, 75005 action of vasopressin depends mainly on V2 receptor- Paris, France. E-mail: [email protected] mediated effects in the renal collecting duct. This minire- Guarantor: N Bouby view addresses the functional impact on the kidney of mild Contributors: NB was primarily responsible for the writing of the dehydration and activation of V2 receptor of vasopressin, in paper. SF took part in the acquisition of some experimental data and preparation of the paper. health and disease. Animal and human studies N Bouby and S Fernandes S40 Renal consequences of a high level of vasopressin a in a healthy subject 2.0 In healthy subjects, high vasopressin levels induce morpho- Cortex Medulla logical and functional changes in the kidney resulting in greater urine-concentrating activity. Urine concentration 1.5 depends on the water permeability of the collecting duct and on the presence of a corticomedullary osmotic gradient. 1.0 Vasopressin contributes to the urine-concentrating mechan-

ism by influencing the permeability to water and urea, and AQP2 mRNA sodium transport in the distal part of the tubule. 0.5 At least six types of water channel proteins (aquaporins, AQP) are known to be expressed in the kidney. Among these, AQP2, localized in the luminal membrane of the principal 0 cells of the collecting duct, is the chief target for the short- term regulation of the collecting duct permeability by b vasopressin. AQP2, and also AQP3 and AQP4 (basolateral 7

)

n water channels of the collecting duct), are regulated via the i 6

long-term effects of chronic dehydration that change the g 5

n total abundance of these three channels in collecting duct (

e cells (Figure 1a) (Yamamoto et al, 1995; Ishibashi et al, 1997; t 4

a Murillo-Carretero et al, 1999; Kwon et al, 2001) (the effect on r

2 3

AQP3 is only partially mediated by stimulating vasopressin P

Q 2

V2 receptors). As urinary AQP2 excretion is very low A - r=0.67, p<0.006 compared to the total AQP2 in the kidney (E3%), it may u 1

∆

not reflect intrarenal changes in the protein. Nevertheless, a 0 positive correlation has been found recently between the 0 12345 6 maximum changes in the urinary excretion of AQP2 and the ∆ AVP (pmol/l) maximum changes in plasma vasopressin in healthy subjects Figure 1 Influence of water intake on the expression of aquaporin et al (Pedersen , 2001) (Figure 1b). 2. (a) Relative mRNA levels of AQP2 in the renal cortex and medulla The driving force behind the water flux and urine of rats maintained for 2.5 days on different water intake levels concentration is an osmotic corticomedullary gradient that resulting in urine osmolality values of 906, 3140 and 380 mosm/kg is built-up as a result of the reabsorption of sodium in the H2O in control (open bars), thirsty (solid bars) and highly hydrated (hatched bars) rats, respectively, adapted from Murillo-Carretero et al thick ascending limb and the accumulation of urea in the (1999). (b) Correlation between the maximum changes in plasma inner medulla. An increase in the abundance of the vasopressin (DAVP) and maximum changes in urinary AQP2 (Du- bumetamide-sensitive Na–K–2Cl cotransporter protein in AQP2) rate in healthy subject during water deprivation for 24 h, the thick ascending limb has been observed in the rat kidney reproduced from Pedersen et al (2001). in response to either chronic water restriction or chronic infusion of a vasopressin V2 receptor agonist (Kim et al, 1999). However, this direct effect of vasopressin on the In addition to its effects on water and urea permeability, reabsorption of sodium in the thick ascending limb occurs vasopressin also improves urine concentration by stimulat- only in some rodents. In humans, this nephron segment is ing the reabsorption of sodium from the connecting tubule devoid of vasopressin-sensitive adenylate cyclase activity and the collecting duct, which promotes additional iso- (Morel et al, 1987). Facilitated urea transporters are respon- osmotic water reabsorption. This effect involves the activa- sible for accumulation of urea in the renal inner medulla. tion of the amiloride-sensitive epithelial sodium channel Three major urea transporters have been cloned and located (ENaC). It has been shown recently that vasopressin not only in different structures of the kidney: UT-A1, UT-A2 and UT- has an acute impact on ENaC-dependent sodium transport B1 (Figure 2a). In rats and human beings, UT-A1 is located in (Tomita et al, 1985; Verrey, 1994; Blot-Chabaud et al, 1996; the terminal part of the inner medullary collecting duct and Djelidi et al, 1997) but also has a delayed effect on the accounts for the vasopressin-dependent increase in the urea expression of b and gENaC subunits, in the kidney, by permeability of this segment (Knepper & Star, 1990; activating the V2 receptors (Ecelbarger et al, 2000; Nicco et al, Bagnasco et al, 2001). Like the aquaporins, chronic vaso- 2001) (Figure 3). This effect is accompanied by a significant pressin infusion affects not only UT-A1 but also another urea increase in sodium and water transport (Nicco et al, 2001) transporter, UT-A2, located in the thin descending limb of (Figure 4), suggesting associated changes in functional ENaC Henle’s loop (Bankir & Trinh-Trang-Tan, 2000) (Figure 2b). membrane proteins. Interestingly, an increase in the mRNA This effect on UT-A2 must be indirect because there are no expression of b and gENaC subunits has also been observed vasopressin receptors in the thin descending limb. in the lung of rats with either chronic water restriction or

European Journal of Clinical Nutrition Animal and human studies N Bouby and S Fernandes S41 a a *** 4

2 **

ENaC/ GAPDH 1 A

0 α β γ

b 2.5 ** 2.0 *** *** *

1.5

b 1.0

Urine osmolality (mosm/kg H20) ENaC/ GAPDH 440 918 2800 3300 0.5

0.0 α β γ UT-A2 IS Figure 3 Influence of vasopressin on the mRNA level of the three subunits (a, b, g) of the epithelial sodium channel (ENaC) in the renal cortex. (a) Brattleboro rats chronically treated with a V2 agonist of vasopressin (n¼6, solid bars) or untreated (n¼5, open bars). (b) Sprague–Dawley rats chronically treated with a V2 agonist of UT-A1 vasopressin (n¼6, solid bars), with restricted drinking water (n¼6, UT-A2 hatched bars) or untreated (n¼6, open bars). Mean7SEM, IM *Po0.05, **Po0.002, ***Po0.0005, reproduced from Nicco et al (2001). Figure 2 Influence of vasopressin on urea transporters. (a) Pathway for urea recycling in the kidney in the presence of vasopressin, reproduced from Bankir and Trinh-Trang-Tan (2000). C: cortex; OS: ∆ + ∆ Na flux H20 flux outer stripe of the outer medulla; IS: inner stripe of the outer 5 medulla; IM: inner medulla; DVR: descending vasa recta; AVR: 400 * ascending vasa recta; LH: loop of Henle; CD: collecting duct; UT: *

m 4

urea transporter; AVP: vasopressin. (b) Northern blotting of RNA m

300 m

m extracted from the inner stripe of the outer medulla (IS) and the i

. 3

m inner medulla (IM) of the kidneys of rats with different levels of urine i / 200

concentrating activity, reproduced from Bankir and Trinh-Trang-Tan l l 2

o (2000). n

p 100 1 0 chronic infusion of a vasopressin V2 receptor agonist. The 0 concomitant decrease in extrarenal water losses (water intake Figure 4 Acute effect of vasopressin on transepithelial sodium minus urine flow rate) suggests indirectly that mRNA (right) and water (left) net fluxes in isolated perfused cortical upregulation is followed by an increase in functional collecting duct from Brattleboro rats pretreated with a V2 agonist of vasopressin (n¼4, solid bars) or untreated (n¼5, open bars). channels and sodium transport and, consequently, in the Mean7SEM, *Po0.01, adapted from Nicco et al (2001). reabsorption of water (Nicco et al, 2001). But overall, the most important consequence of urine concentrating activity is the effect on renal hemodynamics. renal plasma flow and glomerular filtration rate. Chronic Several studies have shown that a sustained increase in infusion of vasopressin to Brattleboro rats, which are devoid vasopressin concentration is accompanied by a rise in the of endogenous vasopressin, increased their renal blood flow

European Journal of Clinical Nutrition Animal and human studies N Bouby and S Fernandes S42 a and glomerular filtration rate by 40% (Gellai et al, 1984) 160 (Figure 5a). In rats exhibiting various levels of experimentally induced urine concentrating activity, glomerular filtra- 140 tion was highly and positively correlated with urine osmolality (but only if the kidney was producing hyper- 120 osmotic urine to plasma) (Bouby et al, 1996) (Figure 5b). The increase in the glomerular filtration rate induced by a

% Control 100 protein meal is lower in subjects with high hydration levels than those with low hydration levels (Hadj-Aissa et al, 1992) 80 chronic vasopressin infusion (Figure 5c). Recently, a positive correlation has been observed between the glomerular filtration rate and urine 0 024681012 osmolality with normal fluid intake, but not in the context days of water diuresis (Anastasio et al, 2001) (Figure 5d). The b normal human glomerular filtration rate is approximately 3 150 l/day, and 95–99.5% of the water and 99% of the sodium are reabsorbed. So an increase of only 20% of the glomerular filtration rate corresponds to a large additional work load for 2 the kidney. The mechanism behind the effect of vasopressin on the glomerular filtration rate has not been fully elucidated. It ml/ min 1 seems to be indirect and related to the depression of tubuloglomerular feedback. It is noteworthy that in contrast r = 0.830, p<0.001 during severe dehydration and volume contraction, the kidney perfusion and glomerular filtration rate both de- 0 crease. 0 1000 2000 3000

Urine osmolality (mosm/ kg H2O) c Functional consequences of high levels of 130 vasopressin in disease states * Animal and human studies have demonstrated that under 2 normal conditions, chronic low hydration plus a high level 125 of vasopressin induce an increase in the expression and activity of water and solute transporters in the kidney, 120 leading to an improvement in the efficiency of the urine concentrating mechanism, and an increase in the glomerular ml/ min. 1.73 m 115 filtration rate. Although several findings suggest that high levels of vasopressin could have deleterious effects in some 110 diseases, there has been little investigation of this topic. We Control 1 hr 2hr 3hr investigated the functional consequences of sustained high levels of vasopressin and urine concentrating activity in the d rat in three pathological conditions: chronic renal failure, diabetic nephropathy and salt-sensitive hypertension. 140 r = 0.237

120 Figure 5 Influence of vasopressin on the glomerular filtration rate

n in rats and humans. (a) Effect of the chronic infusion of vasopressin i r = 0.703 7

m on the glomerular filtration rate in Brattleboro rats. Mean SEM of / l 100

m five rats, adapted from Gellai et al (1984). (b) Relationship between glomerular filtration rate (averaged 24 h inulin clearance) and urine 80 osmolality in Sprague–Dawley rats, reproduced from Bouby et al (1996). (c) Glomerular filtration rate during the control period and 3 h after a protein meal in 10 healthy subjects on high (open dots) or 7 60 low hydration (closed dots). Mean SEM, Po0.05, reproduced from 0200 400 600 800 1000 Hadj-Aissa et al (1992) (d) Correlation analysis of glomerular filtration rate and urine osmolality in 12 healthy individuals on low Urine osmolality (mosm/ kg H2O) (open dots) or high (closed dots) hydration regimens (average of two consecutive 45 min measurements), reproduced from Anastasio et al (2001).

European Journal of Clinical Nutrition Animal and human studies N Bouby and S Fernandes S43 Chronic renal failure omy, and in which the urine concentrating activity was Chronic renal failure can result from various primary renal reduced by increasing water intake. In the second experi- diseases, but inevitably leads to deterioration of renal ment, we studied the effect of restoring urine concentrating function. Owing to the reduced number of functional activity by chronic infusion of a V2 agonist in 5/6 nephrons, the final urine concentration is reduced, although nephrectomized Brattleboro rats (which are devoid of the glomerular filtration rate and concentrating activity of endogenous vasopressin). Both these experiments showed the individual nephrons are increased. We assume that that rats with the lowest urine concentrating activity this hyperconcentration work must have a deleterious effect displayed the slowest progression of chronic renal failure as on the remaining nephrons. This hypothesis was supported assessed by the reduction in proteinuria, kidney hypertro- by the fact that several studies have shown that a reduction phy, incidence of glomerulosclerosis and mortality (Bouby in protein intake slows the progression of chronic renal et al, 1990, 1999) (Figure 6). In another study, it has been failure, and we demonstrated that the hyperfiltration shown that Brattleboro rats, unlike normal rats, do not induced by high protein intake in normal rats depends, at present any increase in the single-nephron glomerular least in part, on vasopressin and increased urine concentrat- hyperfiltration rate after 5/6 nephrectomy (Bregman et al, ing activity (Bankir & Kriz, 1995). We devised two experi- 1990). These findings show that ADH plays an essential role ments in which chronic changes in the concentrating in the hyperfiltration and degradation of renal function activity were induced by manipulating water intake and/or observed in chronic renal failure. Reducing this hypercon- vasopressin without changing protein intake. The first centration work load could therefore be expected to enhance experiment was undertaken in Sprague–Dawley rats, in the preservation of the remaining nephrons, at least during which chronic renal failure was induced by 5/6 nephrect- the early stages of CRF.

Sprague Dawley rats Brattleboro rats

URINE OSMOLALITY URINE OSMOLALITY 1200 1200 0 2 0 2 900 900

600 600 O 2 mosm/kg H

300 mosm/kg H 300

0 0

SYSTOLIC BLOOD PRESSURE 180 10 8 160 6 140 mm Hg 4

surviving rats MORTALITY 120 2

0 0

PROTEIN EXCRETION PROTEIN EXCRETION 40 80

30 60 mg/day

mg/day 20 40

10 20

0 0 1 2 3 4 5 6 7 89 1 3 5 7 9 11 13 weeks weeks Figure 6 Influence of urine concentrating activity on the progression of chronic renal failure. Left: Sprague–Dawley rats with 5/6 nephrectomy were given an increased water intake for 10 weeks by mixing a water-rich agar gel with their feed (open dots) and were compared to rats with similar initial renal impairement but normal water intake (closed dots). Mean7SEM, n¼9 rats per group at the beginning of the experiment, three rats in each group died or were killed during weeks 6–7, adapted from Bouby et al (1990). Right: Brattleboro rats with 5/6 nephrectomy were given an i.p. infusion of a V2 agonist of vasopressin for 15 weeks (open triangles) and were compared to rats with similar initial renal impairment, but no agonist infusion (open dots). Mean7SEM, n¼10 rats per group at the beginning of the experiment, adapted from Bouby et al (1999).

European Journal of Clinical Nutrition Animal and human studies N Bouby and S Fernandes S44 Diabetic nephropathy CREATININE CLEARANCE Diabetic nephropathy develops in 30–50% of type-I and 4 about 10% of type-II diabetic patients. This disease is the ** most common cause of the end-stage renal disease in the 3 United States and Europe. The presence of elevated micro- albuminuria, an early marker of diabetic nephropathy, further increases the risk of cardiovascular disease in diabetic 2

patients at least threefold. Thus, it is important to identify ml/ min the factors that influence the appearance and onset of 1 albuminuria. In diabetes mellitus, the urine flow rate is markedly increased and urine osmolality decreased, which suggests that kidney’s concentrating ability is impaired. 0 However, if we calculate the free water reabsorption that takes into account the load of solutes excreted, it seems that ALBUMIN EXCRETION urine concentrating activity is in fact considerably enhanced 3 in diabetes. It was already known that the level of vasopressin increases during diabetes (Bankir et al, 2001), *** and this elevation of vasopressin is probably an adaptation that limits the osmotic diuresis caused by the high load of 2 solutes originating from glucose wasting and hyperphagia. Secondarily this change could contribute to the development of diabetic nephropathy by a mechanism similar to that responsible for the deleterious effect of vasopressin on mg/ day 1 the progression of chronic renal failure. Experimental diabetes was induced by destroying the b cells of the islets of Langherans (injection of streptozotocin), in Long–Evans rats, which do have endogenous vasopressin 0 secretion, and in Brattleboro rats, which are devoid of Cont DM Cont DM endogenous vasopressin. These rats were compared to the Long Evans Brattleboro corresponding healthy control rats. At 4 weeks after inducing of diabetes, the glomerular filtration rate rose significantly in Figure 7 Creatinine clearance and urinary albumin excretion in control (cont) and diabetic (DM) rats with (Long–Evans) or without the Long–Evans rats but not in the Brattleboro rats, even (Brattleboro) endogenous vasopressin, 4 weeks after induction of though they had similar blood glucose values. Urine diabetes. Mean7SEM, n¼7–8 per group, **Po0.01, ***Po0.001, albumin excretion, which reflects the degree of glomerular adapted from Bardoux et al (1999). damage and renal mass, increased much less in rats without vasopressin than those with endogenous vasopressin (Bar- doux et al, 1999) (Figure 7). In another experiment, we could increase the risk of sodium retention as a result of its showed that albuminuria was prevented during experimen- effect on epithelial sodium channel activity. Our hypothesis tal diabetes in Wistar rats when a V2 receptor antagonist was was based on three main arguments: (1) The importance of administered for several weeks (Bardoux et al, 2003). These the epithelial sodium channel in the sodium balance has findings suggest that the action of vasopressin on the kidney been demonstrated by the finding that mutations in the is necessary for the manifestation of diabetic hyperfiltration, genes coding for its subunits lead to permanent activation of and that this hormone plays a crucial role in the onset of the the channel and are responsible for Liddle’s syndrome, renal complications of diabetes. which is characterized by a severe hypertension (Lifton, 1996; Rossier, 1997). (2) High levels of vasopressin or a tendency to concentrate urine are often associated with a Salt-sensitive hypertension tendency to develop salt-sensitive hypertension (Matsuguchi A reduced capacity to excrete sodium is considered to be et al, 1981; Yagil et al, 1996; Zhang et al, 1999). (3) Under involved in the pathogenesis of some forms of hypertension. physiological conditions, the urinary excretion of water and The nature of the defect in renal function responsible for this solutes are independently regulated, but only within given impaired sodium excretion remains unclear. Several factors limits. However, when the urine flow rate is relatively low are likely to be involved in salt-sensitive hypertension. These and vasopressin high, the excretion of solutes and especially include the possible contribution of vasopressin related to its that of sodium decreases with water excretion (Andersen et al, pressor effects, through the activation of V1-vascular 1990; Bankir et al, 1995, 1998; Choukroun et al, 1997). In receptors, and its water-retention effects, via activation of some studies, vasopressin has been reported to have a V2-tubular receptors. However, a high level of vasopressin natriuretic effect, but this was observed only when intense

European Journal of Clinical Nutrition Animal and human studies N Bouby and S Fernandes S45 diuresis was interrupted by the systemic infusion of vaso- by V2 agonism and prevented by V2 antagonism (Fernandes pressin, resulting in a volume expansion (Walter et al, 1996). et al, 2002). These findings provide evidence that chronic During severe dehydration, it is the fall in aldosterone that is stimulation of vasopressin V2 receptor raises basal blood responsible for natriuresis (Merrill et al, 1986). pressure in rats, and exacerbates the development of DOCA- We studied the influence of stimulating ENaC by the V2 salt hypertension, organ damage and mortality. These effects effect of vasopressin in an experimental model of sodium- could be, at least in part, due to the sustained stimulation of dependent hypertension: the deoxycorticosterone acetate- sodium reabsorption by ENaC in the distal part of the salt model. DOCA-salt hypertension was induced in unine- nephron, which promotes sodium retention. phrectomized rats. Three levels of water intake and urine osmolality were obtained by chronically pretreating rats with a V2 agonist or a V2 antagonist or giving no treatment. These Acknowledgements treatments induced no major changes in blood volume, and We thank L Bankir for fruitful scientific discussions, and plasma osmolality and natremia were similar in all the Carole Nicco and Pascale Bardoux, PhD students, who groups. Blood pressure was significantly increased by V2 performed some of the work reported in this paper. agonist pretreatment ( þ 11 mmHg) and this effect was exacerbated after DOCA–salt-induced hypertension ( þ 17 mmHg) (Figure 8). The V2-agonist-treated rats had a References fivefold higher albuminuria, higher mortality rate (50% vs Anastasio P, Cirillo M, Spitali L, Frangiosa A, Pollastro RM & DeSanto 0% and 0%) and cardiac and renal hypertrophy than those in NG (2001): Level of hydration and renal function in healthy the other groups. Histological renal lesions were exacerbated humans. Kidney Int. 60, 748–756. Andersen LJ, Andersen JL, Schu¨tten HJ, Warberg J & Bie P (1990): Antidiuretic effect of subnormal levels of arginine vasopressin in normal humans. Am. J. Physiol. 259, R53–R60. SYSTOLIC BLOOD PRESSURE Bagnasco SM, Peng T, Janech MG, Karakashian A & Sands JM (2001): Cloning and characterization of the human urea transporter UT- 220 A1 and mapping of the human Slc14a2 gene. Am. J. Physiol. Renal * Physiol. 281, F400–F406. 200 Bankir L (2001): Antidiuretic action of vasopressin: quantitative aspects and interaction between V1a and V2 receptor-mediated effects. Cardiovas. Res. 51, 372–390. 180 Bankir L, Bardoux P & Ahloulay M (2001): Vasopressin and diabetes mellitus. Nephron 87, 8–18. 160 Bankir L & Kriz W (1995): Adaptation of the kidney to protein intake and to urine concentrating activity: similar consequences in mm Hg health and CRF. Kidney Int. 47, 7–24. 140 Bankir L, Niesor R & Bouby N (1995): Sodium excretion is impaired by high urinary concentration. FASEB J. 9, A5. 120 Bankir L, Pouzet B, Choukroun G, Bouby N, Schmitt F & Mallie JP (1998): Concentrer l’urine ou excre´ter le sodium: deux exigences parfois contradictoires. Ne´phrologie 19, 203–209. 100 Bankir L & Trinh-Trang-Tan MM (2000): Renal urea transporters. Direct and indirect regulation by vasopressin. Exp. Physiol. 85, ALBUMIN EXCRETION 243S–252S. 100 Bardoux P, Bruneval P, Heudes D, Bouby N & Bankir L (2003): Diabetes-induced albuminuria: role of antidiuretic hormone as revealed by chronic V2 receptor antagonism in the rat. Nephrol. 80 *** Dial. Transplant. 18, 1755–1763. Bardoux P, Martin H, Ahloulay M, Schmitt F, Bouby N, Trinh-Trang- Tan MM & Bankir L (1999): Vasopressin contributes to hyperfil-

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