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Renal excretion of hydrogen in primary gout
Renal Excretion of Hydrogen in Primary Gout By
GERARD
E. PLANTE,
JA~:~UES DWRLVAGE.4hm GUY LEMIEUS
Acidification of the urine and urinary excretion of hydrogen was studied in ten gouty subjects (age 24-56, mean 38) with normal renal function. In three gouty patients on low purine intake, urinary pH and net acid excretion were not different from that found in normal controls. Furthermore, the response to ammonium chloride load was similar in both groups. In contrast, gouty patients on high purine intake showed permanent aciduria with lowered ammonium excretion and a diminished response to ammonium chloride load. In the four gouty subjects given ammonium chloride during high purine intake, mean urinary
uric acid excretion decreased by 300 mg. day while serum urate did not change. This decrement was closely related to the progressive increase in uriThree gouty subjects nary ammonium. given equivalent amount of dilute hydrochloric acid failed to show a similar response. The present study indicates that protein and purine intake may influence urinary acidification in primary gout. The data further suggest a possible relationship between ammonia and uric acid production during high purine intake and ammonium chloride load. (Metabolism 17: No. 4, April, 377-385, 1968)
Table 1 .-Renal
Patient
____
Age
Function Data in Gouty Subjects
Serum Crentinine me.%
Endoge~ous Creatinine CkZXZiIlCf2 ml./min.
15min. P. s. P. Excretion
Specifk Gravitv
, Atter 13-b.
Dehydr.ltmn)
R. T.
43
1.4
120
34%
1026
8.
L.
46
0.9
111
26%
1020
F. D. M. L. R. D.
56 24 35
1.1 1.1 0.7
100 125 130
33% 45% 36%
1022 1025 1026 1025
Ii. G.
36
1.1
106
52%
P.
D.
38
0.8
159
37%
1020
c. P. R. L.
25 37
0.9 1.1
125 88
54% 34%
1025 1017
c.
40
1.2
95
35%
1027
P.
uric acid stone formers.4 Gutman and Yu have reported similar findings in a series of patients with well documented gout many of whom had no history of urinary calculi.5 In contrast, these findings could not be confirmed by Sperling, Frank and DeVries in a group of 15 gouty patients.” Thus the evidence favoring a definite relationship between uric acid stone formation. gout and acidi6cation of the urine remains conflicting and uncertain. Depression of renal function in relation with ageing or the goutv condition per se has been held responsible for the notable differences between the reported work of various groups of investigators.2,“*c The present study was undertaken in a group of young gouty patients with normal renal function and no evidence of urinary calculi. Dietary conditions were carefully controlled and the results compared with those obtained in normal subjects under similar conditions. The data indicate that protein and purine intake influences urinary acidification in gouty subjects. While a low purine diet failed to influence urinary pH, excretion of acid or the response to an acid load, a high purine intake was found to result in permanent aciduria with lowered ammonium excretion and a less efficient response to ammonium chloride load. MATERIALS
AND METHODS
Studies were performed in ten male gouty subjects (age 24-56, mean 38) and nine male healthy medical students (age Z-25. mean 23). The gouty subjects were selected on the hasis of typical clinical history of gouty attacks, unequivocal hyperuricemia and a positive response to colchicine. All drugs except colchicine were discontinued at least four weeks prior to the present study. No patient had a previous history of renal calculi and no clinical or radiological evidence of renal stones could be demonstrated at the time of study. Renal function was evaluated by serial measurements of serum creatinine, endogenous crentinine clearance, 15-minute P.S.P. excretion test and urinary specific gravity measured after a 15hour dehydration period. Urinalysis was normal and urine culture negative in all patients. These tests failed to indicate renal dysfunction in any gouty subject (Table 1). Gouty patients and control subjects were submitted to either a low or high purine diet during fourteen consecutive days. After a control period lasting five (la\-s, every subject received an acid load orally during four days. This was followed hy a five day recovery period. The acid load was given either as ammonimlr chloride 9 Cm./day ( 166 mEq. of hydrogen) or as an equivalent amount of dilute hydrochloric acid taken through a glass straw.
Three fi,mh_ sllbiects (age 43, 46 and ,561 and he nor~nd controls were submitted to the low pxrinc~ dirt. The Jatter pro\%led $56 (inI. of protein. 80 (ZI~I. of lipids. 350 Cm. of curl)ohydratcs, 1800 calories, 158 mEq. sodium. 86 mEcJ. potassillm and 27 rnIl of pho+ phorus per clay. I&~ calculated purine content averaged 25 Inp. per day. Both gollt\ aJ111 control sllbjects received the acid load in thr form of ammonium chloride. controls were subjected to Se\en gouty subjects (age 24-40, mean 29) ancl four normal the high p”rine tlicxt. This diet pro\icJecl 13-1
Of I.ow
bring
the
Plrrine Intake administration
of the
purine
restricted
diet,
mean
$asma
uric
6.9 mg. in the gouty and 3.9 mg. percent in the normal subjects. These values did not change during the administration of ammonium chloride (Table 2). The administration of acid resulted in a similar fall in plasma bicarbonate dropping from 26 to 20 mM/L. Serum sodium or potassium did not change while plasma chloride rose in proportion to the decrement in plasma bicarbonate. I’rinar\- pII measurements of individuallv voided specimens were not si,c_ acid
was
380
I’LAS’N’.
IXJIIIVAGE
.4X1) LEhlllXJX
l.-UriFig. nary pH during inlow purine take in gout? (closed symbols) and control subjects (open symbols )
Table 3.-Urinary
Acid-base Values in Gouty and Control Subjects” Low Pusinr Control (5)
Control
Urine PH
Acid land f Control
-
GOllty (31 ~~
Control (4)
High Purim GOUtY NH,CI _..~
(1)
GWtY HCI (31 __^ ~-.-
6.11
5.94
6.13
5.62
,5.97
4.99
4.79
5.09
4.91
5.00
“”
“7
38
49
35
:39
43
53
66
.x3
38
26
64
53
3X
72
73
126
87
93
10
3
IO
s
0
8
0
2
0
2
44
4x
Y.7
97
73
102
116
177
15:3
147
70
76
9”
71
x7
T. A. mEq./day
NH, m&.,/day
Acid
loud
Control
*
Acid
loxl
Control
HCO,mEq.,‘day
Acid
load
Control Net acid mEq./day
Acid
load
hlasimum NH4 increment mEq./day ‘Values thlinimal
are means for each pH value.
group.
diRerent between the gouty and control subjects (Fig. 1). In the gouty subjects, urinary pH averaged 5.69 with a range of 4.78-6.38 while the control subjects showed a mean value of 5.93 with a range of 5.00-7.02. During the administration of ammonium chloride, the mean 24-hour urinary pH dropped from 5.94 to a minimum value of 4.79 in the gouty and from 6.11
nificantly
.
Fig.
B.--UC
liar! pH during high purine inin goutv take (closed svmbols’b and cont;ol subjects (open svmbols).
.
Born
12nmn
4Prn
Bpl
42 OnI
.om
to 3.9~1 in the control subjects (Table 3 ). Net acid excretion was comparable in both groups during the control period or following the administration of ammonium chloride this value rising from 48 to 116 mEq./day in the gout! and from 43 to 102 mEq./day in the control subjects (Table 3). Furthermore the maximum increment in urinary ammonium observed following ammonium c:hloridc vws similar in both groups averaging 76 mEq./day above control values in the gouty and 70 mEq./dav in the control subjects (Table 3 1. Thus. under these circumstances, the data failed to indicate any significant differcncc in acidification of the urine between gouty and control subjects. Daily rlrinarv excretion of uric acid during the control period averaged 714 mg. iu the goutv and 646 mg. in the control subjects. This difference was not statistically significant (P > 0.05). Th cse valuc~ did not change during the administration of ammonium chloride [ Table 2 ).
The adlninistration of a high purine diet resulted in serum uric acid values which were much higher in the gouty than the control subjects (Table 2). During and following the administration of ammonium chloride, these values did not change in either the gouty or control subjects (Table 2). Acid loading resulted in a greater fall in plasma bicarbonate (6 mM/L.) in the gout? than the control subjects (3 mM/L.). Thus, the goutv subjects developed a greater dcgrce of mc+abolic acidosis during the administration of ammonium chloride. In contrast to the observation made during low purine intake, urinary pH measured on individuallv voided specimens ww ohviouslv lower in the goutv than the cmtrol subjects (Fig. 2). The mean pH \-alue a;eraged 5.51 ( rang< 4.81-6.65) in the gouty patients in contrast to ;I value of 6.00 (range &X&7.43) found in the four control subjects. This difference was found to he statisticall%? significant iP < 0.01). Following thr administration of ammonium chloride, mean 24-hour urinary
382
I’LAN’I’E,
lRJl1I\‘AGk:
ANll
Lk:MIKUX
160
140
Fig. 3.-Urinary ammonium in relation to urinary pH in gout\’ (closed svmbols) and control sul;jects (opkn symbols) on high purine intake.
,20 ‘On l l '
80
60
'*r' .
.
.O 20
:
O
o OO 00 W 0 ,go lf .““O” O8 . l **> ‘8, : L ..a: . a a0 . 0
h
.70
0 0
40 :
40
20
Fig. 4.-Changes (a) in uriliar\. ammonium and uric acid excreiion following ammonium chloride load in gout? subjects on high pllrine intake.
q
.,O
o
A”“w.
b . ;
W/W -100
8o
b
-300
-600
d .
0 .
h
h
0
l
0
* . 0 l
.
0
D
A A b 8
-200
-WC!
0 0
& 0
0 A D h
l
-4w
: 0
LI :
40 r10
t
0
0
0 0
D 0
0 D
B
.
-700
pH dropped from a control value of 5.62 to a minimum value of 4.91 in the gouty subjects while it decreased from 6.13 to 5.09 in the control group (Table 3). Although the observed decrement was greater in the control subjects, the minimum urinary value observed following the acid load was similar in both groups. Net acid excretion value was identical in both groups during the control period, the gouty patients excreting more titratable acid and less ammonium than control subjects (Table 3). Following the administration of ammonium
IIENAL.
EXCXETlON
OF
HYDROGEN
00
30 80
Fig. S.-Inverse relationship between urinary ammonium and uric acid excretion following ammonillrn chloride load in a 36-vear-old illgoutv subject on high p&w tnkt-:
TO 60
1 b
chloride, the gouty subjects failed to excrete as much acid as the control (Table 3). While the increment in urinary titratablr acid excretion was similar in both groups, maximum increment in ammonium excretion remained lower in the gouty patients averaging 71 mEq./day in contrast to a mean valuc~ of 92 mEq./day observed in the control subjects (Table 3). When plotted against urinary pH, urinary ammonium excretion was generally lower in thch gouty than the control subjects for any given pH value (Fig. 3). During the control period urinary uric acid excretion was much higher than that observed during low purine intake. However there was no significant difference between the gouty (1239 mg./day) and the control subjects ( 1283 mg./day) (Table 2). A significant decrease in urinary uric acid excretion W;IS observed in all four gouty subjects during ammonium chloride administration. the mean value decreasing from 1239 to 1047 mg./day. In contrast, the foul control subjects who received an identical load of ammonium chloride showed no obvious change in urinary uric acid excretion (Table 2). During the period which followed ammonium chloride loading, mean urinary uric acid excretion dropped further to 1016 mg./day in the gouty subjects. From Fig. 4 it can 1~ seen that this decrement in uric acid excretion was closely related to thch progressive increment in urinary ammonium. This relationship is clearly illustrated in Fig. 5 which shows the data obtained in a 36-year-old gouty subject given an ammonium chloride load during high purine intake. It should b(a emphasized that the decrement in urinarv uric wid excretion observed in all
four gouty subjects was not accompanied by ;L rise in $as~ii~~ uratc‘ concentration. The three additional gouty pnticnts who were given dilute hvdrochloric acid instead of ammonium chloride showed a maximum increment in urinarv ammonium excretion almost similar to that observed in the control subjects given ammonium chloride (Table 3). Furthermore they failed to show any decrement in urinary uric acid excretion (Table 2 ). DISCXJSSIO~ The present d at a indicate a defect in both urinary acidification and excretion of hydrogen in young gouty patients with normal renal function who are subjected to a high purine intake and challenged with an ammonium chloride load. The defect is characterized by permanent aciduria and diminished urinary ammonium excretion. It is of interest that these differences are not apparent when gouty subjects are submitted to a low purine diet even if they are challenged by an equivalent load of ammonium chloride. Thus, it is quite possible that the conflicting results reported by various investigators may bc related not only to renal dysfunction associated with aging”.“.” but also to the failure to control dietary intake of both purine and protein. Gutman and Yu have proposed an abnormality of glutamine metabolism in primary gout.“’ Following isotope incorporation studies, they postulated that part of the glutamine normally utilized for the renal production of ammonia was recycled and made available to the liver for conversion to uric acid. These studies suggested that less glutamine was delivered to or extracted by the kidneys or that it was not properly utilized by the latter for ammonia production. The present data are not in disagreement with the theory of Gutman md Yu if the defect in glutamine utilization can at times manifest itself either as deficient renal production of ammonia or decreased uric acid production. Thus under conditions of low purine intake, gouty subjects are able to cope with both uric acid and ammonia production even when challenged with an ammonium chloride load. However, when given a high protein high purine diet, gouty individuals cannot adequately meet the demand for both increased uric acid glutaminc could be and ammonia production. Under these circumstances, utilized on a preferential basis for the production of uric acid, renal production of ammonia becoming less efficient. The unequivocal decrement in urinary uric acid excretion observed during ammonium chloride loading and high purine intake in four gouty subjects is best interpreted as representing decreased production of uric acid. The fact that plasma urate concentration did not rise does not support renal retention of uric acid. The inverse relationship between urinary ammonium and uric acid excretion is of great interest since it could suggest a preferential shift in glutamine utilization for renal production of ammonia. This explanation, however, is not supported by the observations made in the three gouty subjects who received hydrochloric acid instead of ammonium chloride. It is oonceivable that the observed difference is related to ammonium ion and not to
ion has been reported to inactivate glutamine acidosis per SC. Ammonium chloride synthetaze in Escherichia coli.“~‘” It is thus possible that ammonium administration to gouty subjects may influence glutamine svnthesis in such a manner as to affect uric acid production. It has been suggested that potassium chloride or ammonium chloride administration could favor the transfer of uric acid from the extracellular to the cellular compartment through increased pH gradient between these phases.‘” That such an effect prevented a rise in plasma urnte in the ammonium chloride The decrement in uric acid escretion is unlikely. loaded hwutv _ subjects observed in the present studv was of such magnitude that a rise in plasma m-ate, howwer modest, would have been espected if renal retention \IXS failurc~ of hydrochloric, a(%1 to rcsponsiblc for this decrement. Furthcrmor~, excretion constitlltes further e\id(wc*c* influence plasma urate and urinarv against such a mechanism. REFERENCES I. llenllc~lll;lrr. 1’. H., Wallach. s., and Dempsey. b:. F.: Aletabolic defect responsible for llric acid stoue formation. J. Cliu. Invest. ‘1I 537, 1962. 2. Barz~l, I’. S.. Sperling, 0.. Frank, hl.. ;~ntl DeVrics, A.: Renal ammonium excretion antI urinary pli in idiopathic uric acid lithiasis. J. 1’rol. 92:1, 1964. 3. ~letc;llfc,-Gibson. A., SlcCnllum. F. 11.. \lorrison. R. 13. I., and Wrong, 0.: I’rinar? csscretion u)f hydrogen ion in patients with Ilric acid calcrlli. Clin. Sci. 38:325, 1965. -1. Rnpoport. .A., Crassweller. P. O., 1 Ius(Ian. II., I’ronr. (:. I.. A.. Zweig, Xl., and Johllson, 11 .I~.: The renal excretion of hydrogcxlr ion in 11r.c acitl stone formrrs. \let:tl,oIixnl 16:176, 1967. 5. (:utman. :I. R., and Yii, T. F.: I!rinaT a111moniunl excretion in primary pout. J. (:lin. Invest. 44: 1474. 1965. 6. Sperhng. 0.. Frank. hi., and DeVries. 4.: I,‘escr~tioll urinairc d’ammoniac au tours d(b 1;~ golttte. 11f.v. Franc. Etud. Clin. Biol.
I I A0 I, 1966. 7. 131~OM”I. I I.: The determination
of uric
acid in h~m~a~i blood. J. Hiol. (:henl. I -iS: 601. 1945. 8. I.ehnrann, J.: Elektromrtrische nlikrollcdnmmug van chlor in volblut ser~n~1 :tntl ham. Acta Paed. 26:258, 1939. 9. Lemieus, G.. and <:ervais. 51.: .icutt chloride deplction alkalosis: effect of anions on its maintenance and correction. ;\~n. J, I’hysiol. 007: 1079, 1964. 10. Cutman, A. B., and Yii, 1‘. I;.. ,111 aI,Imrmality of $lltamine metabolism in primary golIt. Amer. J. Xled., 35:820, 1963. 11. Slecke, D.. LVulff. K., and IIolzcr. II.: I\letnbolit-indluierte inaktiviernng \‘on glutaminsynthetnse :I~IS Escherichia coli itI1 AIreicn systeln. Rioc,hiltl. Hiophy<. ;1c+a. 178: i;SO. 1966. I”. --. .~ntl 1 lolzer, f f .: Reprcassioll 1m(1 inakti\.ierlmg van filllt;lminsynthetnsr iu Ecchcrichia c,oli tlurch 611,t. Hiochinl. Riophys. r\ctn. 13”:3411 1966. 13. Zweifler. A. J., and Thompson, ( :. R.. (:orrt-c+ion of thiazide hypernricemia I~! potassium chloride and ammoniam chlorides. Arthritis Rheom. 8: I 131, 1965.
GERARD
E. PLANTE,
JA~:~UES DWRLVAGE.4hm GUY LEMIEUS
Acidification of the urine and urinary excretion of hydrogen was studied in ten gouty subjects (age 24-56, mean 38) with normal renal function. In three gouty patients on low purine intake, urinary pH and net acid excretion were not different from that found in normal controls. Furthermore, the response to ammonium chloride load was similar in both groups. In contrast, gouty patients on high purine intake showed permanent aciduria with lowered ammonium excretion and a diminished response to ammonium chloride load. In the four gouty subjects given ammonium chloride during high purine intake, mean urinary
uric acid excretion decreased by 300 mg. day while serum urate did not change. This decrement was closely related to the progressive increase in uriThree gouty subjects nary ammonium. given equivalent amount of dilute hydrochloric acid failed to show a similar response. The present study indicates that protein and purine intake may influence urinary acidification in primary gout. The data further suggest a possible relationship between ammonia and uric acid production during high purine intake and ammonium chloride load. (Metabolism 17: No. 4, April, 377-385, 1968)
Table 1 .-Renal
Patient
____
Age
Function Data in Gouty Subjects
Serum Crentinine me.%
Endoge~ous Creatinine CkZXZiIlCf2 ml./min.
15min. P. s. P. Excretion
Specifk Gravitv
, Atter 13-b.
Dehydr.ltmn)
R. T.
43
1.4
120
34%
1026
8.
L.
46
0.9
111
26%
1020
F. D. M. L. R. D.
56 24 35
1.1 1.1 0.7
100 125 130
33% 45% 36%
1022 1025 1026 1025
Ii. G.
36
1.1
106
52%
P.
D.
38
0.8
159
37%
1020
c. P. R. L.
25 37
0.9 1.1
125 88
54% 34%
1025 1017
c.
40
1.2
95
35%
1027
P.
uric acid stone formers.4 Gutman and Yu have reported similar findings in a series of patients with well documented gout many of whom had no history of urinary calculi.5 In contrast, these findings could not be confirmed by Sperling, Frank and DeVries in a group of 15 gouty patients.” Thus the evidence favoring a definite relationship between uric acid stone formation. gout and acidi6cation of the urine remains conflicting and uncertain. Depression of renal function in relation with ageing or the goutv condition per se has been held responsible for the notable differences between the reported work of various groups of investigators.2,“*c The present study was undertaken in a group of young gouty patients with normal renal function and no evidence of urinary calculi. Dietary conditions were carefully controlled and the results compared with those obtained in normal subjects under similar conditions. The data indicate that protein and purine intake influences urinary acidification in gouty subjects. While a low purine diet failed to influence urinary pH, excretion of acid or the response to an acid load, a high purine intake was found to result in permanent aciduria with lowered ammonium excretion and a less efficient response to ammonium chloride load. MATERIALS
AND METHODS
Studies were performed in ten male gouty subjects (age 24-56, mean 38) and nine male healthy medical students (age Z-25. mean 23). The gouty subjects were selected on the hasis of typical clinical history of gouty attacks, unequivocal hyperuricemia and a positive response to colchicine. All drugs except colchicine were discontinued at least four weeks prior to the present study. No patient had a previous history of renal calculi and no clinical or radiological evidence of renal stones could be demonstrated at the time of study. Renal function was evaluated by serial measurements of serum creatinine, endogenous crentinine clearance, 15-minute P.S.P. excretion test and urinary specific gravity measured after a 15hour dehydration period. Urinalysis was normal and urine culture negative in all patients. These tests failed to indicate renal dysfunction in any gouty subject (Table 1). Gouty patients and control subjects were submitted to either a low or high purine diet during fourteen consecutive days. After a control period lasting five (la\-s, every subject received an acid load orally during four days. This was followed hy a five day recovery period. The acid load was given either as ammonimlr chloride 9 Cm./day ( 166 mEq. of hydrogen) or as an equivalent amount of dilute hydrochloric acid taken through a glass straw.
Three fi,mh_ sllbiects (age 43, 46 and ,561 and he nor~nd controls were submitted to the low pxrinc~ dirt. The Jatter pro\%led $56 (inI. of protein. 80 (ZI~I. of lipids. 350 Cm. of curl)ohydratcs, 1800 calories, 158 mEq. sodium. 86 mEcJ. potassillm and 27 rnIl of pho+ phorus per clay. I&~ calculated purine content averaged 25 Inp. per day. Both gollt\ aJ111 control sllbjects received the acid load in thr form of ammonium chloride. controls were subjected to Se\en gouty subjects (age 24-40, mean 29) ancl four normal the high p”rine tlicxt. This diet pro\icJecl 13-1
Of I.ow
bring
the
Plrrine Intake administration
of the
purine
restricted
diet,
mean
$asma
uric
6.9 mg. in the gouty and 3.9 mg. percent in the normal subjects. These values did not change during the administration of ammonium chloride (Table 2). The administration of acid resulted in a similar fall in plasma bicarbonate dropping from 26 to 20 mM/L. Serum sodium or potassium did not change while plasma chloride rose in proportion to the decrement in plasma bicarbonate. I’rinar\- pII measurements of individuallv voided specimens were not si,c_ acid
was
380
I’LAS’N’.
IXJIIIVAGE
.4X1) LEhlllXJX
l.-UriFig. nary pH during inlow purine take in gout? (closed symbols) and control subjects (open symbols )
Table 3.-Urinary
Acid-base Values in Gouty and Control Subjects” Low Pusinr Control (5)
Control
Urine PH
Acid land f Control
-
GOllty (31 ~~
Control (4)
High Purim GOUtY NH,CI _..~
(1)
GWtY HCI (31 __^ ~-.-
6.11
5.94
6.13
5.62
,5.97
4.99
4.79
5.09
4.91
5.00
“”
“7
38
49
35
:39
43
53
66
.x3
38
26
64
53
3X
72
73
126
87
93
10
3
IO
s
0
8
0
2
0
2
44
4x
Y.7
97
73
102
116
177
15:3
147
70
76
9”
71
x7
T. A. mEq./day
NH, m&.,/day
Acid
loud
Control
*
Acid
loxl
Control
HCO,mEq.,‘day
Acid
load
Control Net acid mEq./day
Acid
load
hlasimum NH4 increment mEq./day ‘Values thlinimal
are means for each pH value.
group.
diRerent between the gouty and control subjects (Fig. 1). In the gouty subjects, urinary pH averaged 5.69 with a range of 4.78-6.38 while the control subjects showed a mean value of 5.93 with a range of 5.00-7.02. During the administration of ammonium chloride, the mean 24-hour urinary pH dropped from 5.94 to a minimum value of 4.79 in the gouty and from 6.11
nificantly
.
Fig.
B.--UC
liar! pH during high purine inin goutv take (closed svmbols’b and cont;ol subjects (open svmbols).
.
Born
12nmn
4Prn
Bpl
42 OnI
.om
to 3.9~1 in the control subjects (Table 3 ). Net acid excretion was comparable in both groups during the control period or following the administration of ammonium chloride this value rising from 48 to 116 mEq./day in the gout! and from 43 to 102 mEq./day in the control subjects (Table 3). Furthermore the maximum increment in urinary ammonium observed following ammonium c:hloridc vws similar in both groups averaging 76 mEq./day above control values in the gouty and 70 mEq./dav in the control subjects (Table 3 1. Thus. under these circumstances, the data failed to indicate any significant differcncc in acidification of the urine between gouty and control subjects. Daily rlrinarv excretion of uric acid during the control period averaged 714 mg. iu the goutv and 646 mg. in the control subjects. This difference was not statistically significant (P > 0.05). Th cse valuc~ did not change during the administration of ammonium chloride [ Table 2 ).
The adlninistration of a high purine diet resulted in serum uric acid values which were much higher in the gouty than the control subjects (Table 2). During and following the administration of ammonium chloride, these values did not change in either the gouty or control subjects (Table 2). Acid loading resulted in a greater fall in plasma bicarbonate (6 mM/L.) in the gout? than the control subjects (3 mM/L.). Thus, the goutv subjects developed a greater dcgrce of mc+abolic acidosis during the administration of ammonium chloride. In contrast to the observation made during low purine intake, urinary pH measured on individuallv voided specimens ww ohviouslv lower in the goutv than the cmtrol subjects (Fig. 2). The mean pH \-alue a;eraged 5.51 ( rang< 4.81-6.65) in the gouty patients in contrast to ;I value of 6.00 (range &X&7.43) found in the four control subjects. This difference was found to he statisticall%? significant iP < 0.01). Following thr administration of ammonium chloride, mean 24-hour urinary
382
I’LAN’I’E,
lRJl1I\‘AGk:
ANll
Lk:MIKUX
160
140
Fig. 3.-Urinary ammonium in relation to urinary pH in gout\’ (closed svmbols) and control sul;jects (opkn symbols) on high purine intake.
,20 ‘On l l '
80
60
'*r' .
.
.O 20
:
O
o OO 00 W 0 ,go lf .““O” O8 . l **> ‘8, : L ..a: . a a0 . 0
h
.70
0 0
40 :
40
20
Fig. 4.-Changes (a) in uriliar\. ammonium and uric acid excreiion following ammonium chloride load in gout? subjects on high pllrine intake.
q
.,O
o
A”“w.
b . ;
W/W -100
8o
b
-300
-600
d .
0 .
h
h
0
l
0
* . 0 l
.
0
D
A A b 8
-200
-WC!
0 0
& 0
0 A D h
l
-4w
: 0
LI :
40 r10
t
0
0
0 0
D 0
0 D
B
.
-700
pH dropped from a control value of 5.62 to a minimum value of 4.91 in the gouty subjects while it decreased from 6.13 to 5.09 in the control group (Table 3). Although the observed decrement was greater in the control subjects, the minimum urinary value observed following the acid load was similar in both groups. Net acid excretion value was identical in both groups during the control period, the gouty patients excreting more titratable acid and less ammonium than control subjects (Table 3). Following the administration of ammonium
IIENAL.
EXCXETlON
OF
HYDROGEN
00
30 80
Fig. S.-Inverse relationship between urinary ammonium and uric acid excretion following ammonillrn chloride load in a 36-vear-old illgoutv subject on high p&w tnkt-:
TO 60
1 b
chloride, the gouty subjects failed to excrete as much acid as the control (Table 3). While the increment in urinary titratablr acid excretion was similar in both groups, maximum increment in ammonium excretion remained lower in the gouty patients averaging 71 mEq./day in contrast to a mean valuc~ of 92 mEq./day observed in the control subjects (Table 3). When plotted against urinary pH, urinary ammonium excretion was generally lower in thch gouty than the control subjects for any given pH value (Fig. 3). During the control period urinary uric acid excretion was much higher than that observed during low purine intake. However there was no significant difference between the gouty (1239 mg./day) and the control subjects ( 1283 mg./day) (Table 2). A significant decrease in urinary uric acid excretion W;IS observed in all four gouty subjects during ammonium chloride administration. the mean value decreasing from 1239 to 1047 mg./day. In contrast, the foul control subjects who received an identical load of ammonium chloride showed no obvious change in urinary uric acid excretion (Table 2). During the period which followed ammonium chloride loading, mean urinary uric acid excretion dropped further to 1016 mg./day in the gouty subjects. From Fig. 4 it can 1~ seen that this decrement in uric acid excretion was closely related to thch progressive increment in urinary ammonium. This relationship is clearly illustrated in Fig. 5 which shows the data obtained in a 36-year-old gouty subject given an ammonium chloride load during high purine intake. It should b(a emphasized that the decrement in urinarv uric wid excretion observed in all
four gouty subjects was not accompanied by ;L rise in $as~ii~~ uratc‘ concentration. The three additional gouty pnticnts who were given dilute hvdrochloric acid instead of ammonium chloride showed a maximum increment in urinarv ammonium excretion almost similar to that observed in the control subjects given ammonium chloride (Table 3). Furthermore they failed to show any decrement in urinary uric acid excretion (Table 2 ). DISCXJSSIO~ The present d at a indicate a defect in both urinary acidification and excretion of hydrogen in young gouty patients with normal renal function who are subjected to a high purine intake and challenged with an ammonium chloride load. The defect is characterized by permanent aciduria and diminished urinary ammonium excretion. It is of interest that these differences are not apparent when gouty subjects are submitted to a low purine diet even if they are challenged by an equivalent load of ammonium chloride. Thus, it is quite possible that the conflicting results reported by various investigators may bc related not only to renal dysfunction associated with aging”.“.” but also to the failure to control dietary intake of both purine and protein. Gutman and Yu have proposed an abnormality of glutamine metabolism in primary gout.“’ Following isotope incorporation studies, they postulated that part of the glutamine normally utilized for the renal production of ammonia was recycled and made available to the liver for conversion to uric acid. These studies suggested that less glutamine was delivered to or extracted by the kidneys or that it was not properly utilized by the latter for ammonia production. The present data are not in disagreement with the theory of Gutman md Yu if the defect in glutamine utilization can at times manifest itself either as deficient renal production of ammonia or decreased uric acid production. Thus under conditions of low purine intake, gouty subjects are able to cope with both uric acid and ammonia production even when challenged with an ammonium chloride load. However, when given a high protein high purine diet, gouty individuals cannot adequately meet the demand for both increased uric acid glutaminc could be and ammonia production. Under these circumstances, utilized on a preferential basis for the production of uric acid, renal production of ammonia becoming less efficient. The unequivocal decrement in urinary uric acid excretion observed during ammonium chloride loading and high purine intake in four gouty subjects is best interpreted as representing decreased production of uric acid. The fact that plasma urate concentration did not rise does not support renal retention of uric acid. The inverse relationship between urinary ammonium and uric acid excretion is of great interest since it could suggest a preferential shift in glutamine utilization for renal production of ammonia. This explanation, however, is not supported by the observations made in the three gouty subjects who received hydrochloric acid instead of ammonium chloride. It is oonceivable that the observed difference is related to ammonium ion and not to
ion has been reported to inactivate glutamine acidosis per SC. Ammonium chloride synthetaze in Escherichia coli.“~‘” It is thus possible that ammonium administration to gouty subjects may influence glutamine svnthesis in such a manner as to affect uric acid production. It has been suggested that potassium chloride or ammonium chloride administration could favor the transfer of uric acid from the extracellular to the cellular compartment through increased pH gradient between these phases.‘” That such an effect prevented a rise in plasma urnte in the ammonium chloride The decrement in uric acid escretion is unlikely. loaded hwutv _ subjects observed in the present studv was of such magnitude that a rise in plasma m-ate, howwer modest, would have been espected if renal retention \IXS failurc~ of hydrochloric, a(%1 to rcsponsiblc for this decrement. Furthcrmor~, excretion constitlltes further e\id(wc*c* influence plasma urate and urinarv against such a mechanism. REFERENCES I. llenllc~lll;lrr. 1’. H., Wallach. s., and Dempsey. b:. F.: Aletabolic defect responsible for llric acid stoue formation. J. Cliu. Invest. ‘1I 537, 1962. 2. Barz~l, I’. S.. Sperling, 0.. Frank, hl.. ;~ntl DeVrics, A.: Renal ammonium excretion antI urinary pli in idiopathic uric acid lithiasis. J. 1’rol. 92:1, 1964. 3. ~letc;llfc,-Gibson. A., SlcCnllum. F. 11.. \lorrison. R. 13. I., and Wrong, 0.: I’rinar? csscretion u)f hydrogen ion in patients with Ilric acid calcrlli. Clin. Sci. 38:325, 1965. -1. Rnpoport. .A., Crassweller. P. O., 1 Ius(Ian. II., I’ronr. (:. I.. A.. Zweig, Xl., and Johllson, 11 .I~.: The renal excretion of hydrogcxlr ion in 11r.c acitl stone formrrs. \let:tl,oIixnl 16:176, 1967. 5. (:utman. :I. R., and Yii, T. F.: I!rinaT a111moniunl excretion in primary pout. J. (:lin. Invest. 44: 1474. 1965. 6. Sperhng. 0.. Frank. hi., and DeVries. 4.: I,‘escr~tioll urinairc d’ammoniac au tours d(b 1;~ golttte. 11f.v. Franc. Etud. Clin. Biol.
I I A0 I, 1966. 7. 131~OM”I. I I.: The determination
of uric
acid in h~m~a~i blood. J. Hiol. (:henl. I -iS: 601. 1945. 8. I.ehnrann, J.: Elektromrtrische nlikrollcdnmmug van chlor in volblut ser~n~1 :tntl ham. Acta Paed. 26:258, 1939. 9. Lemieus, G.. and <:ervais. 51.: .icutt chloride deplction alkalosis: effect of anions on its maintenance and correction. ;\~n. J, I’hysiol. 007: 1079, 1964. 10. Cutman, A. B., and Yii, 1‘. I;.. ,111 aI,Imrmality of $lltamine metabolism in primary golIt. Amer. J. Xled., 35:820, 1963. 11. Slecke, D.. LVulff. K., and IIolzcr. II.: I\letnbolit-indluierte inaktiviernng \‘on glutaminsynthetnse :I~IS Escherichia coli itI1 AIreicn systeln. Rioc,hiltl. Hiophy<. ;1c+a. 178: i;SO. 1966. I”. --. .~ntl 1 lolzer, f f .: Reprcassioll 1m(1 inakti\.ierlmg van filllt;lminsynthetnsr iu Ecchcrichia c,oli tlurch 611,t. Hiochinl. Riophys. r\ctn. 13”:3411 1966. 13. Zweifler. A. J., and Thompson, ( :. R.. (:orrt-c+ion of thiazide hypernricemia I~! potassium chloride and ammoniam chlorides. Arthritis Rheom. 8: I 131, 1965.