Holloway, 1964; Goldfinger, Klinenberg, and. Seegmiller, 1965), starvation (Pabico, Canfield, and. Barry, 1965), and von Gierke's disease (Howell,. Ashton, and ...
Ann. rheum. Dis. (1969), 28, 180
AMINO ACID EXCRETION IN PRIMARY HYPERURICAEMIA* BY
D. KAPLAN, H. DIAMOND, S. L. WALLACE,
AND
D. HALBERSTAM
From the Departments of Medicine, State University of New York Downstate Medical Center, and the Jewish Hospital of Brooklyn, Brooklyn, New York
The demonstration that patients with primary hyperuricaemia are also hyperaminoacidaemic (Kaplan, Bernstein, Wallace, and Halberstam, 1965) has suggested the possibility that the presumptive renal tubular defect in the handling of uric acid by many such patients (Nugent and Tyler, 1959; Seegmiller, Grayzel, Howell, and Plato, 1962) may be only one manifestation of a more generalized defect in renal tubular cell transport that involves substances other than uric acid. For glycine, at least, this has been demonstrated; the renal clearance of endogenous glycine was decreased in subjects with primary hyperuricaemia compared with normouricaemic individuals. Furthermore, after either an oral or an intravenous glycine load, hyperuricaemic subjects failed to increase their renal clearance of glycine as much as did the normal subjects (Kaplan, Wallace, and Halberstam, 1966). The present report records observations on 26 normouricaemic individuals and 25 subjects with primary hyperuricaemia and normal glomerular filtration rates in whom serum amino acid levels and renal clearances of twelve amino acids were measured. Responses to oral loads of three amino acids and the effects of RNA feeding on these parameters have also been investigated.
any drugs for at least 3 days before the study, except for three gouty subjects who were maintained on their prophylactic colchicine up to the day of the investigation. No subject had known hepatic or gastrointestinal disease. All had glomerular filtration rates higher than 80 ml./ min. and normal urinary sediments. The hyperuricaemic subjects were ambulatory clinic patients or hospitalized patients who were convalescent from either an attack of gouty arthritis or some other disease. The normouricaemic subjects consisted of either normal hospital personnel or hospitalized patients in the convalescent phase of their disease. All observations were made after an overnight fast. To rule out the possibility that serum levels of amino acids might be related to the type of diet before the study, six patients were studied after an ad lib diet and again after 2 days on a 40 g. protein diet. No differences in serum levels were observed. An estimation of glomerular filtration rates was made on each subject by measurement of either inulin clearances or endogenous creatinine clearance. Uric acid and amino acid clearances were measured simultaneously. Urine and serum samples for amino acid analyses were stored at -70°C. before analysis. Standard techniques were used for the measurement of creatinine (Bonsnes and Taussky, 1945), inulin (Harrison, 1942), uric acid (Praetorius, 1949), and amino acids (Kaplan and others, 1965; Dickinson, Rosenblum, and Hamilton, 1965). Fourteen normouricaemic and fourteen hyperuricaemic individuals were subjected to oral amino acid tolerance tests. After the overnight fast, a 2-hour urine Material and Methods specimen was collected and blood was drawn so that 51 men between the ages of 21 and 67 years were uric acid, creatinine, and amino acid clearances could be studied; 26 were normouricaemic, and 25 had primary determined. At this point, each subject ingested either hyperuricaemia (serum uric acid greater than 7 mg. per 5 g. glycine alone (6 in each group), 5 g. each of glycine, cent.), of whom all but two had a history of gouty arthritis, valine, and arginine (7 in each group), 5 g. each of glycine though none were tophaceous. None of the subjects and arginine (1 normouricaemic subject), or 5 g. each of was acutely ill at the time of the study. None had taken glycine and valine (1 hyperuricaemic subject). Blood was collected at 15, 30, 45, 60, 90, and 120 minutes after the dose of amino acid and another urine specimen was *This work was supported by USPHS grants AM-0'671, TI-AM- collected 2 hours after the amino acid loading. 08106 and a grant from the NY Chapter of the Arthritis Foundation. 180
181
AMINO ACID EXCRETION IN PRIMARY HYPERURICAEMIA Results these 51 subjects is shown in
The mean glomerular filtration rate (GFR) of the hyperuricaemic group was 117 + 24 ml./min., and that of the normal group 130 ± 37 ml./min. (0-2 > P > 0-1). One "hyperuricaemic" subject (No. 36)
The mean age of the patients with hyperuricaemia 42 + 11 years, and that of the normal group 37 + 11 years (0 10 > P > 0 05).
actually had a serum uric acid of 4 * 5 mg. per cent. He was included here because he had a history of gouty arthritis (several episodes of monarticular
Pertinent data Tables I and II.
on
was
TABLE I
DATA ON 26 NORMOURICAEMIC SUBJECTS
Patient No.
Age (yrs)
1 2 3 4 5 6 7 8 9 10 11
36
12 13 14 15
16
17 18 19 20 21 22 23 24 25 26
52 22 35 52 24 29
28 56 45 29 43
50 30 35
34 34 44 47 58 38 45 21 25 27 28
Diagnosis Normal Pneumonia Normal Normal Myocardial infarction Normal Normal Normal Pneumonia Coronary artery disease Normal Normal Coronary artery disease Pneumonia Pneumonia Pneumonia Normal Pneumonia Pneumonia Coronary artery disease Normal Normal Normal Normal Normal Normal
GFR* (mi./min.)
Serum Uric Acid (mg. per cent.)
Total Serumt Amino Acids
Uric Acid/ Creatinine Clearance x 100
125 155 115 182 81 141 82 186 121 154 138 158* 141 104* 108* 122* 121 * 147*
5-3 5-9 5*8 5-4 6-0 6-4 6-2 4-1 2*9 5*4 4-7 4-8 3*7 3*0 6-4 4-1 5*5 4-4 5 1 4-9 5*4 5*6
2-354 2-170 2-552 2-128 2-707 2-743 2-296 2-143 2*442 2-209 2-431 1868 2*098 2*371 2 414 1596 1717 1771 1-553 2-322 2-181 1866
7-5 4-1 3*0 5-7 4-5 4-1 7-1 8-0
161* 112 119* 140* 132* 104 108 116
4*0 5*8
4-4
6-0
(,tM/ml.)
2*025
2-018 2-262 2*412
6*7 3*9 7*1 8-3 61I 9*7 5 9 7*6 6-8 7-3 9-6 5*8 7-2 6-0 11 7 3*6 6-3 71
*Glomerular filtration rate (GFR) is measured either as inulin clearance (*) or 2-hour endogenous creatinine clearance. tTotal serum amino acids include aspartic acid, threonine, serine, glutamic acid, glycine, alanine, valine, isoleucine, leucine, tyrosine, phenylalanine, ornithine, lysine and histidine. TABLE Ii
DATA ON 25 HYPERURICAEMIC SUBJECTS
Patient No.
Age (yrs)
27 28 29 30 31 32 33 34 35 36 37 38 39
45 42 28 23
40
41 42 43 44 45 46 47
48 49 50 51
47
38 54 35
38 48
52 25 35 57 67 56 34 44 43 33 44 53 34 42 44
Diagnosis Gout Gout Gout Hyperuricaemia Gout Gout Gout Gout Gout Gout Gout Gout Gout Gout Gout Gout Gout Gout Gout Gout Gout Gout Gout Gout
Hyperuricaemia
GFR
(ml./min.) 172 99 89 125 102 86 83 112 98 142 110 107 123 97 124 88 119 173 98 141 110 141 135 120 120
Serum Uric Acid (mg. per cent.) 10*9 10*2 7*8 7 -2 9 3
8*2 8 -7
11*1
7 *9 4-5
10*2 81I 8*9
7 -8 9 8 7 *6 8 *6 7-4 7-8 7-2 8*3 8-5
8*2 7 3 9 *0
Total Serum Amino Acids
(1.M/ml.) 2-789
2*945
2 226 2-721 2 538 2-661 2-603
3-284
2-861 2-680 2-232 2- 536 2*688 2- 547
3*009 2*675 3 -239 3 385 1*614 2 375
1972 2 405 2*650 2-258 2*538
Uric Acid/ Creatinine Clearance x 100 3 *8 16 1*0 6-7 0*9 5*8 6-2 2-2 6-7 7*5 8-7 6-4 118 2-3 4-8 7*6 10*8 9 1 8 *4 6- 5 4-6 5 *6 2*6 2-0 9*2
182
ANNALS OF THE RHEUMATIC DISEASES
arthritis responsive to colchicine) and
a history of hyperuricaemia (7 4 mg. per cent.) 2 years earlier. Because of the lower GFR in the hyperuricaemic individuals, urate/creatinine ratios x 100 are reported rather than urate clearances. While the urate/creatinine clearance ratio is lower in the hyperuricaemic group (5 7 + 3-2 compared with 6-6 + 2 0), it is not significantly so (0 3 > P > 0 2). The total serum amino acid levels (where "total" equals the sum of aspartic acid, threonine, serine, glutamic acid, glycine, alanine, valine, isoleucine, leucine, tyrosine, phenylalanine, ornithine, lysine and histidine) show the mean in the hyperuricaemic group (2-617 + 0 397) to be significantly greater than in the control group (2 179 + 0-313) (P < 0-001) in confirmation of a previous report (Kaplan and others, 1965). In addition, the mean value of
each amino acid is greater in the hyperuricaemic
subjects. In order to determine whether the raised serum levels of amino acids could be accounted for on the basis of renal retention, renal clearances for individual amino acids were calculated, as were amino acid/creatinine clearance ratios. Table III records the range of values obtained for three amino acids: glycine, a purine precursor; valine, a neutral amino acid unrelated to purine metabolism; arginine, a basic amino acid. It is clear that the hyperuricaemic subjects have a decreased clearance of both glycine and valine. Arginine clearance is the same for both groups. Glutamic acid, glycine, valine, tyrosine, phenylalanine, and histidine all show significantly reduced clearance by the kidneys of hyperuricaemic individuals (Table IV). If the amino acids are separated
TABLE III
RATIOS OF AMINO ACID/CREATININE CLEARANCE x 100 P determined by Student's "t" test
Glycine Normouricaemic 0 4 04 1-0 12 14 1-5
Hyperuricaemic 0-4 0-7
0-8 0-8 0-8 0-8 0-8
1-5 1 5 1-7 1 8 1.9 2-4 2 5 2-6 2-7 3 0 3-2 5.1
09 0 9 1 2 1 2 1-3
1*4 1*5 1-5
1*8 2-0 2-1
6-8 7-6
Mean
2-9
2 5
1 3
P < 0O01
Valine Normouricaemic Hyperuricaemic 0-02 0-02 003 0-04 0 03 0-04 0-08 0-08 0-10 0-11 0 11
Arginine Normouricaemic 0 00 0-07 0-08 0 09 0 09 0-13 014 0-16
0 04 0 04
0-06 0-06 007 0-08 0-08 0-08 0-08 0-08 009 0 11 0 12 0 12 0-13
0-11 0-11 0 12 0 12 0-13 014 0 16 0.19 0-23 0-23 0-26 0 31 0-13
0-17 0 18 0-21
0 07
Hyperuricaemic 0-06 006 0-06 0 10 0-12 0-13 014 0-15 0-15 0-21 0-22 0-23 0-29
0-12
P < 0O005
0.15 P > 0O05
TABLE IV
RATIO OF AMINO ACID/CREATININE CLEARANCES P determined by Student's "t" test
Amino Acids Acidic
Neutral
Basic
x
100
Subject
Normouricaemic
082 Aspartic Acid. Glutamic Acid. 015 246 Glycine. Alanine. 034 Valine .013 Leucine. 016 092 Tyrosine. 056 Phenylalanine. Histidine. 510 043 Ornithine. 011 Lysine. 012 Arginine.
Hyperuricaemic
1*06 0*08 1*25 0-30 0*07 0*12 0*73 0*46 2-40
0*37 0-16 0*15
Probability P < 0*25 P < 0*02
0*01 0-30 0*01 0*45 0*05 0*05 0*01 P < 0*50 P < 0-15 P < 0*35
P< P< P< P< P< P< P
