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Postsecretory reabsorption of urate in man.

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805
POSTSECRETORY REABSORPTION
OF URATE IN MAN
HERBERT S. DIAMOND and ALLEN D. MEISEL
Urinary uric acid is derived from two sources:
uric acid filtered at the glomerulus and incompletely
reabsorbed, and uric acid secreted by the renal tubules
(1). Until recently, tubular reabsorption of uric acid
has been assumed to occur proximal to the urate
secretory site. If this assumption were correct, the
magnitude of the secretory component of urinary uric
acid could be estimated as the decrease in urinary uric
acid that follows administration of pyrazinamide (2-4).
Taken together, several observations have suggested that urate reabsorption occurs at least in part
coextensive with or distal to urate secretion and that
urate secretion greatly exceeds total urate excretion.
Most secreted urate is reabsorbed. Blocking reabsorption results in an increase i n the apparently secreted
fraction of urinary uric acid.
RESULTS
W e have previously reported ( 5 ) that, when
urine flow rate was increased from 2.7 ml/minute to
6.5 ml/minute by oral hydration with water, urate
excretion increased from 290 to 41 0 pglminute (Table
1). This increase was blocked by pyrazinamide. A p
From the Department of Medicine, State University of
New York, Downstate Medical Center, Brooklyn, New York.
Herbert S. Diamond, M.D.: Department of Medicinc,
State University of New York, Downstate Medical Center; Allen
D. Meisel, M.D.: Department of Medicine, State University of
New York, Downstate Medical Center.
Address reprint requests to Dr. Diamond.
Table 1. Comparison of Results of Decreased Urine Flow
(Sludy 1) and Increased Urine Flow (Sludy 2 ) in 12 Subjects*
1’(ml/minute)
CFR (ml/minute)
U,,V (hg/minute)
CUR (ml/minute)
SUR (pg/minute)
Post-PZA U,,V (pglminute)
U,,V/GFR
CURjCFR
Study 1
Study2
Pt
2.7 f 0.6
102f 10
290243
4.0 t_ 0.7
244 f 4 4
36 t 4
2.93 f 0.35
7.09 t 0.56
6.4 f 0.9
1 1 1 f 10
410 -C 52
6.2 f 1.1
339’47
57-C 13
3.79 f 0.40
5.89 -C 0.84
0.001
NS
0.001
0.005
0.01
NS
0.005
0.01
*
I’alues expressed as mean
standard error of mean.
*Abbreviations used: V, urine flow rate; GFR, glomerular filtration rate: UcR\’, mate excretion: CUR, urate clearance; SUR,
PZA supprcssible urate; PZA, pyrazinamide.
t/ test for paired variables.
parent urate secretion, estimated as the decrease in
excretion that followed pyrazinamide administration,
increased from 244 pg/minute at low urine flow to 338
pg/minute a t higher urine flow. Since increasing urine
flow rate is more likely to decrease postsecretory reabsorption of urate than to stimulate urate secretion, this
finding suggested that a portion of secreted urate was
normally reabsorbed.
T o test further the hypothesis that part or all
of renal tubular reabsorption of urate occurs distal to
urate secretion, pyrazinamide suppression tests were
carried out after inhibition of urate reabsorption (6).
Probenecid of sulfinpyrazone was used to block urate
reabsorption.
Uricosuria was established i n 6 subjects by the
Arthritis and Rheumatism, Vol. 18, No. 6 (November-December 1975), Supplement
DIAMOND AND MEISEL
806
Table 2. Effect of Acute Oral Administration of Pyrazinainide, 3 g, on Probenecid Uricosuria
(probenecid, 500 m g , every 6 hr)
Probenecid Alone
Subject
HS
HD
LK
AM
OP
JS
Mean k SEM
*P
+P
Probenecid plus PZA
UCRV
(pglminute)
CUR
(ml/minute)
UCRV
(pg/minute)
CUR
(ml/minute)
212
638
587
622
375
345
463 f 72
2.9
10.8
10.7
20.5
6.7
6.3
9.7 t 2.5
49
137
163
200
162
98
135 k 21*
0.6
2.3
2.4
6.0
2.7
1.5
2.6 -+ 0.8t
< 0.01 (t test for paired samples).
< 0.05 (t test for paired samples).
oral administration of probenecid, 2 g daily. T h e
acute oral administration of pyrazinamide, 3 g, during
probenecid uricosuria decreased urate excretion from
a mean of 463 -+ 72 pg/minute when probenecid alone
was given to 135 21 pg/minute when probenecid
was given with pyrazinamide (Table 2). This tlifference was statistically significant with P < 0.01. Pyrazinamide administration reversed probenecid uricosuria, resulting in urate excretion that was less than
control urate excretion when no drug was administered.
T h e decrement in urate excretion produced by
pyrazinamide was more pronounced when profound
uricosuria was induced by oral administration of a
single 2-g dose of probenecid. Urate excretion was 407
pg/minute on no drug and increased to a peak of 2528
pg/minute after 2 g of probenecid alone (Table 3).
When 3 g of pyrazinamide was administered together
with probenecid, maximal urate excretion was only
574 pglminute, a decrease of 1954 pg/minute.
Similarly urate excretion increased from a mean
of 334 pg/minute when no drug was given to a peak
of 1885 pg/minute following administration of a single
800-mg oral dose of sulfinpyrazone. When 3 g of
pyrazinamide was administered together with sulfinpyrazone, maximum urate excretion was only 475 pg/
minute, a decrease of 1410 pg/minute. T h e decrease in
*
urate excretion attributed to pyrazinamide at the time
of maximal probenecid or sulfinpyrazone effect was 4
times as large as urate excretion when no drug was
taken. If pyrazinamide effect is attributed to inhibition
of renal tubular urate secretion, urate secretion must
be greater than total urinary uric acid on no drug.
T h u s apparent renal tubular urate secretion (measured
as the decrease in urinary uric acid resulting from
pyrazinamide administration) appeared to vary, dependent upon the degree of drug-induced inhibition
of uric acid reabsorption.
When urate secretion was inhibited with a 300mg oral dose of aspirin, the results were similar to
those when urate secretion was inhibited with pyrazinamide. Administration of 300 mg of aspirin with 2 g
of probenecid resulted in a decrease in maximal urate
excretion from 3162 pglminute when receiving probenecid alone to 1152 pg/minute when probenecid
plus aspirin was given. Again the decrement in urate
excretion of 2010 pglminute, which followed inhibition of urate secretion by aspirin, exceeded control
urate excretion by almost fourfold. This result suggested that secretion exceeds total iirate excretion by
at least fourfold.
These studies probably underestimate the magnitude of urate secretion. Probenecid and sulfinpyrazone may not completely block reabsorption of filtered
Table 3. Effect of Acute Administration of Probenecid, 2 g, Alone or in Combination
w i t h Pyrazinamide, 3 g , on Uric Acid Excretion
Probenecid Alone
Subject
LS
IiD
HP
Mean t SEM
Control Uu,V
(pglminute)
350
546
313
407 t 75
Probenecid plus PZA
Peak UuRV
(pg/minute)
Control Uu,V
(pg/minute)
Peak UG,V
(pglminute)
2983
3340
1261
2528 -+ 642
41 1
522
329
421 k 56
69 1
656
374
574 i: 100
807
POSTSECRETORY REABSORPTION OF URATE IN MAN
Table 4. Eflect
of
Infusion of 2 Liters of 37! Saline (10 Subjects}
Control
UVRV(pg/min)
CUR (ml/min)
CFR (ml/min)
Pur (mg/100 mi)+
Saline Infusion
449 f 49
7.3 f 1.5
128 & 11
7.1 f 0.6
834 f 116
15.4 f 3.6
131 f. 7
6.5 -t 0.6
P<
0.005
0.01
NS
0.001
* Pur, plasma urate.
urate. I n addition urate secretion may be partially
inhibited by these drugs.
Uricosuria induced by sulfinpyrazone or highdose aspirin was not additive to maximal probenecid
uricosuria. This fact suggests that these drugs may all
inhibit urate reabsorption at the same site.
T h e results are not explained by drug interactions since similar results are obtained when uricosuria is induced without drugs. Volume expansion is
uricosuric. T h e effect of changes in extracellular volume or urate excretion was studied by the infusion of
hypertonic (3y0)saline, isotonic (0.9%) saline, or hypotonic (0.45) saline (7). I n all studies, there was an
increase in both fractional excretion of sodium and
fractional excretion of urate following both 1-liter and
2-liter volume expansion. Urate excretion increased
significantly and by a similar magnitude following 2liter volume expansion with either hypotonic, isotonic,
or hypertonic saline. T h e magnitude of uricosuria was
correlated with volume load and was not related to
plasma sodium or sodium load. Thus the uricosuria
following saline infusion is attributed to volume expansion. Uricosuria was induced by infusion of 2 liters
of 3y0 saline at a rate of 10 to 12 ml/minute. Urate
excretion increased from 449 pg/minute during the
control period to 834 pg/minute ( P < 0.005) (Table 4).
Urate clearance increased from 7.3 ml/minute to 15.4
ml/minute ( P < 0.01). This increase was not attributed
to an increase in estimated urate filtration since glomerular filtration rate was unchanged and serum uric
acid concentration decreased.
T h e uricosuric effect of saline infusion was not
attributed to enhanced urate secretion since saline infusion was still uricosuric after inhibition of tubular
secretion of urate with pyrazinamide, 3 g (urate excretion increased from 54 5 pg/minute after pyrazinamide alone to 170 f 40 pg/minute after pyrazinamide plus saline infusion).
Hypertonic saline infusion did not appear to
inhibit urate reabsorption at the same site as probenecid. Saline infusion was still uricosuric during maximal probenecid-induced inhibition of urate reabsorption (increase with saline alone, 195 -t 81 pg/minute;
*
Table 5. Pyrazinamide Inhibition of the Uricosuric Response
to Probenecid (2 g ) Orally or Saline Infusion (2 liters)
Control UcRV (pglmin)
Maximum UVRV(pg/min)
Increase in UoRV (pgimin)
Control post-PZA U,,V (pg/min)
Maximum post-PZA UuRV (pglmin)
Post-PZA increase UVRV(pg/min)
PZA-suppressible increase in UuRV
(rglmin)
PZA-suppressible increase in UuRV
(yototal increase)
P%A-resistantincrease in UVRV
(Yo total increase)
Probenecid
(2 g)
Saline
(2 liters)
407 rfi 75
2528 -t 642
2123 f 589
56 t 2.6
574 f 100
518 k 101
468 k 93
794 f 116
326 -+ 56
59 rfi 6.6
221 rfi 58
164 k 52
1605
162
76%
50%
24%
50%
increase when saline is administered during maximal
probenecid-induced uricosuria (2 g) 478 2 394 pg/
minute) (Table 6).
Pyrazinamide was less effective in inhibiting
uricosuria produced by hypertonic saline than that
resulting from probenecid. Oral administration of
pyrazinamide, 3 g, resulted in a 76y0 decrease in the
peak uricosuric response to probenecid, 2 g. In contrast, pyrazinamide administration resulted in only a
50y0 decrease in the peak uricosuric response to hypertonic saline infusion (Table 5).
Probenecid was still uricosuric when administered after urate secretion was inhibited with pyrazinamide. Urate excretion increased from 56 +- 2.6 pg/
minute after pyrazinamide alone to 574 100 pg/
minute when probenecid, 2 g, was administered with
pyrazinamide ( P < 0.05) (Table 5 ) . Postpyrazinamide
uricosuria accounted for only 24% of the uricosuric
response to probenecid. I n contrast, enhanced postpyrazinamide urate excretion accounted for 50% of
the uricosuric response to hypertonic saline infusion.
These results are consistent with the hypothesis that
hypertonic saline infusion and probenecid inhibit
urate reabsorption by different mechanisms. Alternatively, the difference in magnitude of uricosuric response to saline infusion and probenecid might account for the difference in response to pyrazinamide.
*
Table 6. Eflect of Probenecid ( P b ) on Uricosuria Induced
6y Saline Infusion in 5 Subjects
Control (U,RV)
Saline infusion (U,,V)
Increase (UuRV)
Saline
Infusion
Alone
Saline Infusion
plus
Pb (2 g) Peak Effect
364 f 30
559 f 83
195 k 81
1669 f 378
2106 -t 519
478 t 394
DIAMOND AND MEISEL
808
I n another approach to the study of alteration
of urate transport, the authors studied the effect of
changes in urine flow rate induced by vasopressin administration. When volume expansion was avoided by
prohibiting water intake, the administration of lysine
vasopressin resulted in a decrease in urine flow rate
and a 14y0 decrease in urate excretion ( P < 0.01).
There was no change in serum uric acid concentration.
This decrease i n urate excretion paralleled the decrease in urine flow rate. Results were similar when
2-liter volume expansion was induced prior to vasopressin administration. However vasopressin did not
prevent the uricosuric response to volume expansion.
When volume expansion was avoided, the decrease in
total urate excretion following vasopressin administration was attributed to a decrease in pyrazinamide-suppressible urate excretion.
DISCUSSION
T h e most direct interpretation of the results of
these studies is that urate reabsorption occurs, at least
in part, distal to the urate secretory site. Alternate
interpretations based upon drug interaction (8,9)
would not account for the results since results were
similar in studies involving water loading.
T h e results of the probenecid and hypertonic
saline studies suggest that there may be at least two
distinct renal tubular reabsorptive mechanisms for
urate in man. T h e results of the flow rate and vasopressin studies suggest urate reabsorption in the collecting duct.
T h e decrease in urate excretion after lysine
vasopressin in the absence of water loading is probably
due to diminished urine flow (5,lO).
Diminished urate excretion at low urine flow
rates has been attributed to enhanced postsecretory
reabsorption (5). Vasopressin effects on urine flow rate
are probably localized to the distal tubule and collecting ducts with no effect on flow in the proximal tubule. Thus, if the urate retention that follows lysine
vasopressin administration in the absence of water
loading is due to enhanced urate reabsorption at low
flow rates, the reabsorptive site must be localized to
the distal tubule or collecting duct.
Extracellular fluid volume expansion results in
enhanced urate excretion (1 1,lZ). Uricosuria following
lysine vasopressin administration was only observed
when extracellular fluid volume expansion was induced, and thus is attributable to volume expansion.
T h e increase in urate excretion following lysine vaso-
pressin plus volume expansion i n the present study
was similar to that seen when expansion of a comparable degree was induced by saline infusion without
the administration of exogenous vasopressin (7,12).
Diminished net reabsorption of sodium and
other solutes during expansion of extracellular fluid
volume has been localized by micropuncture and clearance studies predominantly to the proximal tubule
(13-15). Enhanced postpyrazinamide urate excretion
has generally been interpreted as indicating diminished urate reabsorption (11,lZ). Such reabsorption
suggests that volume expansion may be associated with
diminished urate reabsorption at a proximal tubular
site.
If urate retention following lysine vasopressin
is attributed to diminished urine flow rate and the
uricosuria that follows lysine vasopressin plus water
loading is attributed to volume expansion, these results provide indirect support for the concept that
urate reabsorptive systems exist in both the proximal
and distal tubules in man.
SUMMARY
These results are consistent with a model for
renal tubular transport of urate in which there is
reabsorption of both filtered and secreted urate. Urate
secretion greatly exceeds total urate excretion, and
most secreted urate is reabsorbed. At least a portion of
mate reabsorption occurs at a site distal to or coextensive with the urate secretory site. There appear to be
at least two distinct reabsorptive mechanisms for urate.
T h e results of the flow rate and vasopressin studies
are consistent with the hypothesis that urate reabsorption occurs in both the distal and the proximal tubule
in man.
T h e distal reabsorptive site appears to be quite
small. It may well be passive since it does not appear
to be inhibited by uricosuric drugs. This reabsorptive
site may account for less than 15y0 of total urate
reabsorption.
Both volume expansion and probenecid may inhibit urate absorption only i n the proximal tubule.
T h u s reabsorption in the proximal tubule could account for more than 90% of total urate reabsorption.
Reabsorption at the postulated collecting duct reabsorptive site appears to be too small in magnitude to
account for all reabsorption of secreted urate. This
could be explained if the reabsorptive site in the
proximal tubule is coextensive with or distal to the
secretory site. Alternatively, there might be two reab-
POSTSECRETORY REABSORPTION OF U R A T E I N MAN
sorptive sites i n the proximal tubule: a presecretory
site accounting for the reabsorption of most filtered
urate, a n d a site either coextensive or distal to the
secretory site accounting for a major component of
reabsorption of secreted urate. Finally iirate reabsorption would also take place in the collecting duct, perhaps a t a passive, flow-dependent site.
REFERENCES
1. Gutman AB, Yu TF: A three component system for
regulation of renal excretion of urate in man. Trans
Assoc Am Physicians 74:353-365, 1961
2. Berliner RW, Hilton JG, Yu TF, et al: The renal
mechanism of urate excretion in man. J Clin Invest 29:
396401, 1950
3. Yu TF, Berger L, Stone DJ. et al: Effect of pyrazinamide and pyrazinoic acid urate clearance and other
discrete renal functions. Proc SOC Exp Biol Med 96:
261-267, 1957
4. Gutman AB, Yu TF, Berger L: Tubular secretion of
urate in man. J Clin Invest 38:1779-1781, 1959
5. Diamond HD, Lazarus R, Kaplan D, et al: Effect of
urine flow rate on uric acid excretion in man. Arthritis
Rheum 15:338-349, 1972
6. Diamond HD, Paolino J: Evidence for a post-secretory
reabsorptive site for uric acid in man. J Clin Invest 52:
1491-1499, 1973
809
7. Diamond HD, Meisel A: Influence of volume expansion,
serum sodium and fractional excretion of sodium on
urate excretion. Pfugers Archiv 356:47-57, 1975
8. Yu T F , Dayton PG, Gutman AB: Mutual suppression
of the uricosuric effects of sulfinpyrazone and salicylate:
a study in interactions between drugs. J Clin Invest 42:
1330-1337, 1963
9. Bluestone R, Kippen I, Klinenberg JR, et al: Effect of
some uricosuric and anti-inflammatory drugs on the
binding of uric acid to human serum albumin in vitro.
J Lab Clin Med 76:85-91, 1970
10. Brochner-Mortenson K: Uric acid in blood and urine.
Acta Med Scand 84:l-269, 1937 (suppl)
11. Steele T H : Evidence for altered renal urate reabsorption during changes in volume of the extracellular
fluid. J Lab Clin Med 74:288-299, 1969
12. Cannon PJ, Svahn DS, DeMartini FE: The influence
of hypertonic saline infusions upon the fractional reabsorption of urate and other ions in normal and hypertensive man. Circulation 41:97-107, 1970
13. Howards SS, Davis BB, Knox FG, et al: Depression of
fractional sodium reabsorption by the proximal tubule
of the dog without sodium diuresis. J Clin Invest 47:
1561-1572, 1968
14. Blythe WB, Gitelman HJ, Welt LG: Effect of expansion
of the extracellular space on the rate of urinary excretion of calcium. Am J Physiol 214:52-57, 1968
15. Dirks JH, Cirksena W, Berliner RW: The effect of
saline infusion on sodium reabsorption by the proximal
tubule of the dog. J Clin Invest 44:1160-1170, 1965
810
From the collection of Gerald Rodnan. M D
The Learned Scotchman or Magistrates Mistake!! Engraving (colored impression) by Thomas Rowlandson from
an original drawing by George M. Woodward. Published by T. Tegg, London, 1812.
T h e Scot: “I own your Worship-I was a little inebriated but your Worship knows ‘Nemo
Mortatium [sic]-Omnibus Hooris Saupit [horis sapit]!! [No man always knows what is
right]’ ”
T h e Magistrate: “What’s that you say fellow about Whores in a Saw Pit!!-a
very improper place to go with such company-I wonder you are not ashamed to mention such a thing and before my Wife too!!-but however as it is your first offence I
will discharge you this time-but never come here with such a story again!l”
Note the slashed left shoe on the gouty magistrate and the ear trumpet. Magistrates were often depicted as victims of the gout in the social satires of the great caricaturists.
“Selecting for its victims subjects of all temperaments and widely divergent conditions,
it [the gout] attacks the comparatively young, the middle-aged, and the old; its fastens
upon the man of robust constitution equally with him of frail habit; it invades the
home of the scholar, and prisons Plutus in his bed. Cruel and relentless, it strikes the
professor at his desk [so true!], the general in his camp, the judge upon his bench. Its
poison comes by heritage, its venom lurks in the wine-cup, its seeds are sown at the
gatherings of good-cheer.”
-George H. Ellwanger,
Meditations on Gout, 1897
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