Clinical Science and Molecular Medicine (1976) 51, 33-40.
Effect of vasopressin on uric acid excretion:
evidence for distal nephron reabsorption of urate in man
A. MEISEL A N D H. D I A M O N D
Departments of Medicine, State University of New York, Downstate Medical Center, Brooklyn, New York, U.S.A.
(Received 2 October 1975)
localized predominantly, if not entirely, to the
proximal tubule (Mudge, Bcrndt & Valtin, 1973).
The distal part of the nephron including the collecting duct has been thought to be almost impermeable
to urate (Mudge et al., 1973; Kramp, Lassiter &
Gottschalk, 1971). Urate excretion in man has
been shown to increase both with increased urine
flow rate (Diamond, Lazarus, Kaplan & Halberstam,
1972; Brockner-Mortenson, 1937) and after extracellular fluid volume expansion (Stele, 1969;
Cannon, Svahn & &Martini, 1970). In a previous
report, the uricosuria associated with increased urine
flow rate in the apparent absence of expansion of
extracellular fluid volume was attributed to diminished urate reabsorption in the collecting duct
(Diamond et al., 1972). In that study, changes in
urine flow rate were induced by alteration in oral
water load. Thus concomitant minor changes in
extracellular fluid volume could not be entirely
excluded.
In the present study, changes in urine flow rate
were induced by administration of vasopressin
to further define the effect of urine flow rate on urate
excretion in man. Vasopressin was administered
under various conditions of water load so as to
distinguish between the effect of volume load and
urine flow rate on urate excretion.
summary
1. When changes in urine flow rate were induced
by vasopressin administration in eight subjects,
urate excretion decreased by a mean of 14% and
was positively correlated with urine flow rate
( r = 0.88, PcO-01).The effect of vasopressin on
urate excretion was not influenced by prior changes
in extracellular fluid volume.
2. Mannitol administration in a dose sufficient
to prevent vasopressin-induced alterations in urine
flow rate blocked the effect of vasopressin on urate
excretion.
3. Alterations in urate excretion produced by
changes in extracellular fluid volume could be
distinguished from the urate-retaining effect of
vasopressin-mediated decrease in urine flow. Urate
retention after vasopressin was entirely attributed to
a decrease in pyrazinamide-suppressible urate
excretion, consistent with either decreased secretion
or enhanced post-secretory reabsorption of urate.
4. Since diminished urine flow rate in the distal
part of the nephron is more likely to lead to enhanced
reabsorptionofurate, these results provide additional
evidence for urate reabsorption in the distal part of
the nephron.
Key words: kidney, nephron, reabsorption, uric
acid, vasopressin.
Introduction
Methods
Tubular transport of urate has been considered to be
Subjects and clearance stiidies
Correspondence: Dr Allen Meisel, Downstate Medical
Center, 450 Clarkson Avenue, Box 42, Brooklyn, New
York 11203, U.S.A.
All studies were carried out after obtaining signed
informed consent based upon a protocol approved
33
34
A. Meisel and H . Diamond
by the Human Research Committee and in accordance with the principles of the Declaration of
Helsinki.
Thirty-five clearance studies were carried out in
nine healthy male volunteer subjects, ranging in
age from 27 to 67 years. All subjects had a blood
urea nitrogen of less than 4.1 mmol/l. All subjects
were admitted to the Clinical Research Center and
maintained on a normal protein, constant purine,
constant food-energy diet. All medications affecting
serum urate concentrations were discontinued at
least 1 week before the studies, and 3 days were
allowed for dietary adjustment. All studies were
conducted in the morning after an overnight fast.
Urine was collected by voiding. Prolonged collection
periods were utilized after vasopressin administration
to ensure that all urine collections were greater than
50 ml.
Glomerular filtration rate was estimated on the
basis of endogenous creatinine clearance. Creatinine
was determined by the Auto-Analyzer method
(Technicon Corp., Tarrytown, N.Y., U.S.A.).
Creatinine excretion has been determined in all
urine collections in studies involving pyrazinamide
administration in this laboratory over the past 5
years. Creatinine excretion and clearance have not
been altered by pyrazinamide administration.
Urate was determined by an enzymatic spectrophotometric technique (Crowley & Alton, 1968).
Sodium was measured by an automated technique
(Mabry, Gevedon, Roeckel & Gochman, 1966).
Studies were performed according to the following
protocols.
Administration of lysine vasopression during constant
mannitol infusion
In three subjects, mannitol(25 g) was administered
as a primary injection intravenously over 5 min,
followed by a constant intravenous infusion of
mannitol (200 g/l) at a rate of 5 ml/min. Two
control clearance intervals of 15-20 min each were
obtained after the start of the mannitol infusion.
Although mannitol infusion would be expected to
cause endogenous vasopressin release, 10 units of
lysine vasopressin were administered intramuscularly.
Three additional clearance intervals of 15-20 min
were obtained. Values for mannitol and postvasopressin periods were calculated as the mean of
all the control and all the post-vasopressin intervals
respectively.
Pyrarinamide studies
In studies of the effect of pyrazinamide on urate
excretion, pyrazinamide (3 g) was administered
after two control clearance intervals. Water was
administered only to replace urinary loss. Lysine
vasopressin (10 units) was administered 90 min
after pyrazinamide at the start of a clearance
interval. The effect of pyrazinamide on control
urate excretion was assessed by similar studies in
which administration of vasopressin was omitted.
For each clearance study, pyrazinamide-suppressible
urate excretion was calculated as the mean urate
excretion for the two control periods minus urate
excretion in the period after administration of
pyrazinamide. The latter value is referred to as
post-pyrazinamide urate excretion.
Lysinr vasopressin without volume expansion
Sufficient distilled water was administered orally
to establish a steady state of urine flow at a rate
of approximately 5 ml/min. Thereafter, water was
administered only to replace urinary losses. Two or
three control clearance periods of approximately
20 min were obtained with a venous blood sample
obtained in the middle of each period. At the
conclusion of these control urine collections, 10
units of lysine vasopressin were administered
intramuscularly. Two additional clearance intervals
of 60-90 min were then obtained. Values for control
and post-vasopressin excretion were calculated as
the mean of all the control and all the vasopressin
clearance intervals respectively.
Lysine vasopressin followed by volume expansion
In six subjects, two initial control clearance
intervals were followed by the administration of
lysine vasopressin. The subjects then drank 5001000 ml of water/h throughout the remainder of the
study. After 2 h, two 45 min clearance periods were
obtained with venous blood samples in the middle of
each clearance interval. Subjects were weighed
immediately after vasopressin administration and
at the conclusion of the study.
Results have been expressed as mean values f SEM.
Statistical comparison was made with either paired
or unpaired t-tests as appropriate. Values less than
P = 0.05 were considered significant.
Effect of vasopressin on uric acid excretioti
Results
The effects of administration of lysine vasopressin
without water loading are summarized in Table 1
and Fig. 1 . Vasopressin administration reduced the
mean urine flow rate from 4.5k1.4 ml/min to
1.9kO.7 ml/min and increased the mean urine
sodium concentration from 2.2 f0.7 mmol/l to
4.2 f 1.3 mmol/l. The mean urate excretion decreased
Control
After
vasopressin
FIG. 1. Effect of administration of vasopressin on (a) urine
flow rate, (b) urine sodium concentration, (c) urate excretion,
and (d) urate clearance/glomerular filtration rate (GFR)
ratio, at constant volume. Mean results for subjects studied
without volume loading are shown by small symbols.
Large symbols indicate mean results for subjects in whom
vasopressin was administered after volume expansion. In all
subjects studied, administration of vasopressin resulted in
diminished urine flow rate, increased urine sodium concentration and diminished urate excretion.
35
by 14%, from 2.98 f0. 22 .umol/min during control
collections to 2.57 k0.23 pmol/min after vasopressin.
Decreased urate excretion was observed in all six
subjects (Fig. 1). There was no change in serum
urate concentration. Urate clearance and the urate
clearance/glomerular filtration rate ratio also decreased. Urate excretion and urine flow rate were
positively correlated (r = 0.88,P< 0.01).
Glomerular filtration rate did not change after
administration of vasopressin. A small increment in
sodium excretion after administration of vasopressin
occurred in the four patients studied, but the increase
was not statistically significant. In order to demonstrate that vasopressin-induced urate retention was
not due to inadvertent volume contraction, in two
subjects (Table 1b) volume expansion was induced
by administration of a net excess of 3.5 1 of water
(excess of intake over urinary output) before the
administration of vasopressin. Volume expansion
was confirmed by a mean weight gain of 3.5 kg and
an increase in sodium excretion. Thereafter, water
was administered only in quantities sufficient to
replace urinary loss. Urine collections were then
carried out as for the subjects who were not volumeexpanded. Administration of vasopressin after
volume expansion resulted in a decrease in urine
flow rate in both subjects and a concomitant decrease
in urate excretion (Table lb).
To determine whether vasopressin had a direct
effect on urate excretion or whether the effect of
vasopressin was secondary to changes in urine
flow rate, vasopressin was administered during a
constant mannitol infusion (Table 2). During
mannitol infusion, administration of vasopressin
did not decrease urine flow rate. Urate excretion
was not changed by administration of vasopressin
during mannitol infusion.
The effect of pyrazinamide on urate excretion was
assessed in five subjects under control conditions
and after vasopressin (Table 3). Urate retention
after vasopressin was entirely attributed to a decrease
in pyrazinamide-suppressible urate excretion, which
decreased from a mean value of 2 5 f0.24 pmol/min
to 2.1 f0-27 pmol/min, consistent with either
decreased urate secretion or enhanced post-secretory
reabsorption of urate. Post-pyrazinamide urate
excretion was unchanged.
Volume expansion is known to be uricosuric in
man (Steele, 1969; Cannon et a]., 1970). In six
subjects, volume expansion was induced by oral
water intake sufficient to produce a mean positive
36
A . Meisel and H . Diamond
TABLE1. Effect of administration of vasopressin on urate excretion
Statistical analysis is by t-test for paired samples: Pc0.01;otherwise, P>O.OS. G F R = glomerular filtration rate.
Urate
excretion
b’iol/min)
Subject
(a) Without volume expansion
3.36
R.G.
Control
Vasopressin
2.77
J.P.
Control
1.95
Vasopressin
1.57
M.P.
Control
3.43
Vasopressin
3.27
D.B.
Control
3.0
Vasopressin
2.6
L.S. Control
2.9
Vasopressin
2.5
M.S.
Control
3.2
Vasopressin
2.7
Mean+ SEM
Control
2.98& 0.22
Vasopressin
2 3 7 k 0.23*
Urate
clearance
Urate
(ml/min) clearance/GFR
Serum
urate
(mmol/l)
Glomerular
filtration
rate (rnl/min)
5.4
3.9
0.48
0.49
143
1.5
0.5
0.4
0.7
5.6
3.5
11.3
8.0
0.35
0.36
0.26
0.30
99
123
1.0
0.7
2.9
3.5
118
140
8.8
4.7
-
102
7.5
5.7
3.8
6.7
0.27
0.27
9.0
0.5
0.5
110
121
102
131
5.1
0.35
0.42
139
126
0.5
3.6
5.9
8.7& 1.3
7.0k 1.1.
7.5* 1.0
5.3k0.8’
0.37k0.04
0.39+0.04
116+6
131k4
4.5+ 1.4
1.9+ 0.7
2.2k0.7
4.2+ 1.3
0.25
7.0
5.6
5.5
4.3
13.4
11.0
11.2
9.5
5.8
5.0
9.3
6.5
Urine
Flow rate sodium concn.
(ml/rnin)
(mrnol/l)
I30
-
1.5
-
3.6
3.4
6.5
3.5
1.8
(b) Affer volume expansion
T.G.
Control
Vasopressin
2.46
2.14
9.8
8.6
5.7
5.5
0.25
171
156
4.8
0.6
0.17
1.09
M.P.
5.1
206
16.2
14.2
13.0
0.25
0.24
145
124
11.4
1.8
2.04
9.25
Control
Vasopressin
3.94
TABLE
2. Effect of vasopressin on urate excretion during infusion of mannitol
Statistical analysis is by t-test for paired samples: P>O.O5. G F R = glomerular filtration rate.
Subject
M.P.
Mannitol
Mannitol plus
vasopressin
D.B.
Mannitol
Mannitol plus
vasopressin
R.S.
Mannitol
Mannitol plus
vasopressin
Mean& SEM Mannitol
Mannitol plus
vasopressin
Urate
excretion
(pmol/min)
Urate
clearance
(ml/min)
3.94
11.5
4.3
12.5
4.6
I5
4.8
1.95
Urate
Serum urate
(pnol/l)
clearance/GFR
Glomerular
filtration rate
(ml/min)
Flow rate
(ml/min)
8.5
0.32
135
11
9.0
0.33
0.30
139
12.5
12.3
122
11
16.5
6.0
13.4
6.8
0.30
0.34
123
88
10
2.23
3.33k0.72
6.5
10.8&2.6
6.3
0.34
I03
9.2& 1.6
0.32+0.01
1 IS+ 14
9.2k 1.8
3.50k0.80
1 1 4 & 2.9
9.6k2.0
0.32&001
121+10
9.5+ 1.9
5.6
6.0
Effect of vasopressin on uric acid excretion
37
TABLE
3. Effect of pyrazinamide (PZA) on vasopressin-mediated urate retenfion
Statistical analysis is by t-test for paired samples: * P< 0.01 ; otherwise, P> 0.05. P values refer to comparison of changes in
respective fractions of urate excretion after vasopressin administration. To convert urate from pmol into pg multiply by 168.
~~
Control urate excretion (pmol/min)
Urate excretion after vasopressin (pnol/min)
Subject
J.P.
M.P.
D.B.
L.S.
C.S.
Mean+ SEM
Control
Post-PZA
PZA-suppressible
Control
Post-PZA
PZA-suppressible
1.95
3.43
3.00
2.93
3.2
2.9+ 0 2
0.3
036
0.48
0.46
0.3
0.38f 004
1.65
3.07
2.52
2.47
2.9
2.5k 024
1.57
3.27
2.6
2.5
2.7
2.53f027
033
0.36
0.42
059
047
0.43+ 005
1.24
2.91
22
1.91
223
2.1+027*
fluid balance of 3.5 1 after administration of vasopressin (Table 4). There was a mean increase of
3.5 kg in body weight and an increase in mean urine
sodium excretion from 2.0 mmol/min to 4.8 mmoll
min. Administration of vasopressin did not prevent
the uricosuric response to volume expansion. Mean
urate excretion increased from a control value of
2.94 pmol/min to 3.72 pmollmin after vasopressin
and volume expansion. Serum urate did not change
and urate clearance increased from 8.5 ml/min to
10.7 mllmin. Urine flow rate was decreased after
vasopressin even in the presence of volume expansion
(control 4.8 ml/min; vasopressin plus volume expansion 1.3 ml/min).
In five of these six subjects, the volume-expansion
study was repeated a second time except that
pyrazinamide (3 g) was administered 90 min before
administration of vasopressin (Table 5). In these
five subjects, volume expansion after vasopressin
was associated with an increase in pyrazinamidesuppressible urate excretion from 253 pmollmin
to 3.4 pmollmin (P<0.02). Post-pyrazinamide urate
excretion increased from 0-36 pmol/min to 0.89
pmollmin (P<0.02).
Discussion
The diminished urate excretion which followed
vasopressin administration in the present study is
consistent with the earlier observation of a significant
association of urate excretion with urine flow rate in
man (Diamond et al., 1972; Brockner-Mortenson,
1937). Changes in filtered load of urate did not
account for the diminished urate excretion after
vasopressin. The small but consistent increase in
glomerular filtration rate observed after administration of vasopressin would increase the filtered load
of urate and might increase excretion.
Contraction of extracellular fluid volume is
associated with urate retention (Steele & Oppenheimer, 1969) and extracellular fluid volume expansion results in enhanced urate excretion (Steele
TABLE
4. Effect of volume expansion after adminisfration of vasopressin on urate excretion in six
subjects
Statistical analysis is by f-test for paired samples: *P<O.O2; **P<001;***Pc005;
otherwise,
P> 0.05. To convert urate from pmol into pug multiply by 168.
Control
Urate excretion (pmol/min)
Urate clearance (ml/min)
Urate clearance/glomerular filtration rate
Glomerular filtration rate (ml/min)
Serum urate (pmol/I)
Flow rate (ml/min)
Sodium excretion (mmol/rnin)
294k 026
8.5+ 1.4
1*4*1.0
113k9.0
038f004
48+ 1.3
2.0+ 0 6
Volume expansion
3.72+0.26*
107k 1*6**
8.5+ 1.3*
126k6.0
038+004
1.3f04***
48+ 2.2
A . Meisel and H . Diamond
38
TABLE
5. Efecr of pyrazinamide ( P Z A ) on vasopressin-mediated volume expansion
Statistical analysis is by t-test for paired samples: * P < 0.02. P values refer to comparison in respective fractions of urate excretion
after vasopressin-mediated volume expansion. To convert urate from pnol into pg multiply by 168.
Urate excretion after vasopressin (,umol/min)
Control urate excretion (pmol/min)
Subject
M.P.
D.B.
L.S.
1,s.
F.T.
Meanf SEM
Control
Post-PZA
PZA-suppressible
Control
Post-PZA
PZA-suppressible
3.29
2.99
2.50
1.83
3.8
2.8820.34
0.36
0.3
0.46
0.25
0.40
2.93
2.69
2.04
3.4
4.2
4.02
3.52
3.64
6.08
1.04
1.25
0.59
0.59
0.96
3.16
2.77
2.93
3.05
5.12
0.36+ 0.04
2.53f0.33
4.29f0.46*
0.89+0.13*
3.40+0.45*
1.58
et al., 1969; Cannon et al., 1970). The alteration in
urate excretion produced by changes in extracellular
fluid volume can be distinguished from the urate
retaining effect of vasopressin-mediated decrease in
urine flow. In the present study, vasopressin-induced
urate retention occurred even when vasopressin
was administered after volume expansion. Thus
urate retention after administration of vasopressin
could not be attributed to volume contraction.
When flow rate was held constant after administration of vasopressin, the expected uricosuric response
to extracellular fluid volume expansion was observed. In the latter studies, there were probably two
opposite effects on urate excretion: the uricosuric
response to extracellular fluid volume expansion and
the anti-uricosuric effect of vasopressin administration.
Vasopressin may inhibit solute reabsorption in
the loop of Henle (Antoniou, Burke, Robinson &
Clapp, 1973), but does not appear to alter solute
transport in the proximal tubule. Alterations in
extracellular fluid volume appear to modulate
solute reabsorption in the proximal renal tubule
(Diamond & Meisel, 1975). Clearance studies and
direct intratubular micro-injections in the rat have
demonstrated that net urate reabsorption is influenced by the state of hydration, and that these
alterations are mediated by changes in the rates of
reabsorption in the proximal tubule (Weinman,
Eknoyan & Suki, 1975). Decrease in urine flow rate
resulted in diminished urate excretion even when
vasopressin was administered after volume expansion. Effects of flow rate on urate transport
appear to be independent of alterations in solute
transport in the proximal renal tubule.
The acute changes demonstrated in the present
study are consistent with clinical and laboratory
observations associated with chronicvolume changes.
Uricosuria has been observed in volumeexpanded
patients with inappropriate antidiuretic hormone
syndrome, and in normal subjects in whom chronic
volume expansion was induced by the administration
of vasopressin and water loading (Mees, van
Assendelft & Nieuwenhuis, 1971). Vasopressinresistant diabetes insipidus results in chronic
volume depletion and urate retention in spite of
high urine flow rates (Gordon, Robertson &
Seegmiller, 1971).
Oral administration of pyrazinamide in man is
associated with a decrease in urate excretion
permitting subdivision of excreted urate into
pyrazinamide-suppressible and post-pyrazinamide
fractions (Steele & Reiselbach, 1967; Gutman,
Yu & Berger, 1969). The decrease in the pyrazinamide-suppressible fraction of total urate excretion
after vasopressin is similar to that observed when
diminished urine flow rate was induced by decreased
water intake (Diamond et a/., 1972). Diminished
pyrazinamide-suppressible urate excretion at low
urine flow rate has been considered to represent
enhanced
post-secretory
urate
reabsorption
(Diamond et al., 1972). Alternatively, diminished
pyrazinamide-suppressible urate excretion might
reflect inhibition of urate secretion by lysine vasopressin. This appears unlikely since similar results
have previously been obtained when urine flow
rate was diminished by decreasing water intake
without the use of vasopressin (Diamond et al.,
1972). Moreover, when volume expansion was
induced after lysine vasopressin, both pyrazinamidesuppressible and post-pyrazinamide urate excretion
increased. An increase in pyrazinamide-suppressible
Efect of vasopressiir on uric acid excretion
urate excretion would not be expected if urate
secretion were inhibited by lysine vasopressin.
Microperfusion and free-flow studies of urate
transport in the rat kidney have demonstrated
bidirectional transport of urate with net secretion in
the proximal tubule and net reabsorption distal to
the proximal tubule (Greger, Lang & Deetjen,
1971; Lang, Greger & Deetjen, 1972). Although
most reabsorption distal to the proximal tubule
probably occurred in the loop of Henle, these results
are consistent with some urate reabsorption in the
distal part of the nephron.
In the Cebus monkey, micropuncture and stopflow studies have localized urate reabsorption
predominantly to the proximal tubule (Roch-Ramel
& Weiner, 1973). However, these studies were
consistent with reabsorption of a small fraction of
filtered urate in the distal part of the nephron,
accounting for less than 13% of net urate reabsorption. Theenhanced uratereabsorption associated with
administration of vasopressin is most likely localized
to the distal nephron tubule or collecting duct.
Alterations in urine flow rate and permeability
resulting from administration of vasopressin are
probably localized to the distal nephron tubule and
collecting duct (Handler & Orloff, 1973). Since
vasopressin accelerates transport of uric acid by the
toad bladder (Levine, Franki & Hays, 1974), it
may accelerate urate reabsorption in the collecting
duct in man. This would also represent enhanced
post-secretory urate reabsorption by vasopressin
and would be associated with a decrease in pyrazinamide-suppressible urate excretion (Diamond et al.,
1972; Diamond & Paolino, 1973). Alternatively,
vasopressin may have a direct effect on postproximal solute transport in the loop of Henle
(Antoniou et a]., 1973). Since reabsorption of other
solutes in the loop of Henle decreases with increases
in flow rate (Greger, Lang & Deetjen, 1974), prior
administration of mannitol might inhibit urate
reabsorption at this site and therefore might block
an anti-uricosuric effect of vasopressin in the loop of
Henle. This hypothesis would not explain the
uricosuric effect induced by altering water intake in
the absence of volume expansion.
Urate retention after administration of vasopressin
occurred only when there was an accompanying
decrease in urine flow rate. Administration of
mannitol in a dose sufficient to prevent vasopressininduced alterations in urine flow rate blocked the
effect of vasopressin on urate excretion. Thus urate
39
retention after vasopressin can be attributed to
diminished distal tubular urine flow rather than to a
direct effect of vasopressin.
The decrease in urate reabsorption induced by
vasopressin-mediated decrease in urine flow rate
represents only approximately 2% of net urate
reabsorption in man. Thus the postulated reabsorptive site for urate in the distal part of the
nephron probably accounts for only a minor portion
of total urate reabsorption. However, the terminal
location of this reabsorptive site in the nephron
may permit a significant modulation of urate
reabsorption. The mean change in excreted urate
associated with changes in urine flow in the present
study was 14%. The postulated reabsorptive site
in the distal part of the nephron may be of physiological significance in reducing high urine urate
concentrations during uricosuria at low rates of
urine flow.
Acknowledgments
We are indebted to Mr David Halberstam and Ms
Pam Unschuld for their skilled technical assistance,
and to the staff of the Clinical Research Center for
their invaluabie aid in these studies. This work is
supported by grant RR-318 from the General
Clinical Research Center Program of the Division
of Research Resources, and by a grant from the
Arthritis Foundation.
References
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K. (1937) Uric acid in blood and
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F.E. (1970) The
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