Renal function in gout

Renal

Function

in Gout*

II. Effect of Uric Acid L oading on Renal Excretion of Uric Acid TS’AI-FAN Yi_i, M.D., LAWRENCE BERGER, M.D. and ALEXANDER B. GUTMAN, M.D. New York, New York

W

likewise fail to reveal, at least in our hands, discernible differences in the renal regulation of uric acid excretion in these two groups [73]. A second reservation is interpretive, concerning the inference that at comparably high F,,, however achieved and at whatever level, tubular transport of uric acid should be considered defective if U,,V and C,, do not increase proportionately. This does hold if U,,V stands in some direct association with F,,, as prescribed by the concept that limits renal regulation of uric acid excretion in man to filtration and reabsorption but, as will be shown, it does not necessarily obtain, particularly under conditions of uric acid loading, if U,,V in man ordinarily derives almost entirely from tubular secretion, and F,, hence is virtually completely reabsorbed. The data here recorded further reveal instructive similarities and dissimilarities in the results of oral RNA loading compared with intravenous uric acid loading, and both compared with gouty and non-gouty subjects under natural conditions. These comparisons emphasize the like characteristics of tubular transfer of uric acid in normal and gouty man. It seems justifiable to conclude that under conditions of exogenous uric acid loading, as under natural circumstances [ird], the renal regulation of uric acid excretion in gout operates within the framework of that of normal man, subject of course to secondary modifications of aging and disease.

HEN the uric acid level of the blood plasma (Pu,) and glomerular filtrate (F,,) of normal man is artificially raised to gouty levels by the feeding of ribonucleic acid (RNA) [l-5], or by the intravenous injection of uric acid [ 1-341, the urinary excretion of uric acid (U,,V) and the uric acid clearance (C,,) are found, at equivalent F,,, to exceed the U,,V and C,, of gouty subjects on a low purine intake [4,5,7]. This disparity, first clearly pointed out by Nugent and Tyler [4], has been interpreted to signify innate impairment of the capacity of the kidney of gouty subjects to excrete uric acid [4,5,7-72, and others]. The present study impugns, not the stated experimental observations, but the deduction drawn from them, chiefly on two grounds. One since in such comparisons is methodologic, although one variable (F,,) in the non-gouty subject has been brought to the level in the gouty subject, in doing so another variable, apparently even more significant, has been introduced-the normal group is abruptly subjected to large exogenous uric acid loads whereas the gouty group is not, but remains in a relatively steady state regulated essentially by the rate of de nouo uric acid production. The data here recorded indicate that it is this selective loading of non-gouty subjects with uric acid, not the presence or absence of gout, that is responsible for the disparity in U,,V and C,,. It is shown, in fact, that when gouty subjects are challenged with the same RNA load the increases which develop in P,,, U,,V and C,, are no whit less than in non-gouty subjects. Parallel experiments in which uric acid was rapidly infused intravenously into non-gouty and gouty subjects, and the tubular transport mechanisms for uric acid more heavily taxed,

METHODS

Oral Loading with RNA. This experiment followed the protocol of Nugent and Tyler [4] in thirteen nongouty men but was amplified to include twelve gouty men. Of the non-gouty subjects, seven had serum uric

acid

levels not in excess

of our upper

normal

* From the Department of Medicine, The Mount Sinai Hospital, New York, New York. This work was supported in part by a grant-in-aid (A-162) from the National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, U. S. Public Health Service. VOL.

33,

DECEMBER

1962

829

Renal Function limit in males of 6.5 mg. per cent; three had unexplained hyperuricemia of 7.3 to 7.7 mg. per cent, not attributable to manifest gout, renal disease or blood dyscrasia; two had polycythemia vera with hyperuricemia, renal function being apparently intact in one, but impaired in the other; and one had chronic myelocytic leukemia with hyperuricemia and reduced glomerular filtration rate. The gouty subjects, most of whom had glomerular filtration rates within normal limits, represented a hyperuricemia range from 6.8 to 10.9 mg. per cent. In nine of these the urinary excretion of uric acid was within normal limits (normoexcretors). Two of these (A. Ra. and M. C.) had been included in previous glycine-Ni5 studies and were found to have apparently normal incorporation of total uric acid-Nib (but increased incorporation after correction for their expanded uric acid pools) and abnormal distribution of N’s among the four uric acid nitrogens-evidence of a metabolic derangement, not explicable by renal retention. In one (A. Ra.) the uric acid turnover rate had been determined and was found to be increased to 1,270 mg. per day. Three of the gouty subjects were classified as unequivocal “overexcretors” of uric acid, as previously defined [~4], and isotopic methods had confirmed gross overproduction of uric acid. All subjects were ambulatory, without standardization of diet save for purine restriction.* Clearance studies were performed in the morning with all subjects in the postabsorptive state, and with forced hydration throughout to sustain ample urine flow, usually 8 to 10 ml. per minute. For preloading clearances, inulin in physiologic saline solution was infused, first to prime, then in 1 per cent concentration at a constant rate of 3 ml. per minute. After equilibration for fifty or sixty minutes, urine was collected by spontaneous voidings every forty to sixty minutes for three or four periods. Heparinized venous blood samples were obtained at the midpoint of each collection period. Later, after the oral administration of yeast RNA, 4.0 gm./day for four successive days, this procedure was repeated on the fifth day, about three hours after the subject had taken an additional 1.0 gm. dose of RNA. In some instances, clearance measurements were repeated after ingestion of RNA for an additional week and again after another week. To avoid possible precipitation of acute attacks in the gouty subjects given RNA, colchicine prophylaxis was maintained, with success in all cases. None was taking uricosuric drugs. Intravenous Loading with Uric Acid. These studies were made in twenty-seven men, ten non-gouty and seventeen gouty. Of the non-gouty men, seven were * Total urinary excretion of nitrogen in control clearance periods averaged 11.2 f 2.2 mg. per minute; after RNA feeding (yeast RNA nitrogen content, 14 per cent dry weight) the mean urinary excretion of nitrogen was 11 .O f 1.8 mg. per minute.

in Gout-E

et al.

normouricemic and three had hyperuricemia of 7.0 to 7.6 mg. per cent. Of the gouty men, most of whom had glomerular filtration rates within normal limits, five were distinct overexcretors of uric acid. The degree of initial hyperuricemia represented in the men with gout ranged from 6.5 to 10.6 mg. per cent. All subjects were ambulatory and taking a regular diet which was low in purines. Control renal clearance measurements were obtained as already described except that urine was collected by indwelling catheter. After equilibration with inulin for fifty or sixty minutes and three control collection periods, uric acid was infused to a total of 1 .l to 2.5 gm. The injectate was prepared by freshly dissolving uric acid in a warm solution of lithium carbonate (5 uric acid: 1 lithium carbonate), then passed through a Seitz filter and made up to volume in 5 per cent

glucose solution. Ten subjects received the infusion at one constant rate, variously 10 to 28 mg. uric acid per minute, throughout for seventy to 184 minutes. In thirteen subjects, uric acid was infused at two or three increasing rates successively; twenty to thirty minutes were usually allowed for equilibration at each rate, followed by three five- to fifteen-minute collection periods. In four subjects, three gouty and one non-gouty, 1 to 2 gm. uric acid was infused to raise the filtered load to about 13 mg. per minute or more, and after about half of the total amount of uric acid had been infused, 0.5 gm. pyrazinoic acid was given orally to inhibit tubular secretion of uric acid. The uric acid infusion was continued at an unaltered rate and collections maintained for forty-five to seventy minutes or more. Except for mild chills and gastric upsets in four subjects studied, no untoward reactions were noted. One patient who received pyrazinoic acid had transitory flushing of the face. The amount of uric acid in serum and urine was determined spectrophotometrically [75], of inulin by a resorcinol method [%I. There was no interference by glucose, which was usually absent from the urine but occasionally appeared in trace amounts in terminal periods. All analyses were completed on the day of study to avoid losses of uric acid, particularly by precipitation in the urine on standing in the cold. RESULTS

Oral Loading with RNA (Tables I and II). Non-gouty subjects: Plasma and urinary uric acid levels increased in ail thirteen non-gouty subjects given RNA in the prescribed dosage. After four days of RNA administration the mean P,,, in the seven normouricemic subjects rose from 5.4 to 7.3 mg. per cent and the mean U,,V from 0.44 to 0.85 mg. per minute. A corresponding rise was noted in F,,, C,,, C,,/GFR, and in apparent “T”,,r calculated as F,, - U,,V. AMERICAN

JOURNAL

OF

MEDICINE

Renal Function Taking into account the small population samples studied, and the differences in antecedent dietary control, the results are in satisfactory agreement with those recorded by Nugent and Tyler [4] and Seegmiller et al. [5]. Our non-gouty subjects, like those of Nugent and Tyler, include some with control P,, levels in excess of the accepted upper limit of normal. * None gave a history of familial gout or of acute arthritis; to be sure, the possibility of primary gout cannot be excluded, notably in one subject (L. R.) with a history of urate urolithiasis, but in three others (M. H., S. D. and H. G., Table I) hyperuricemia is adequately accounted for by enhanced hemopoiesis. All of these hyperuricemic subjects responded to RNA administration with further increases in P,,, U,,V and derived parameters, in a manner comparable to that of the normouricemic subjects. Included in Table I (but not in the averages of Table II) are two non-gouty subjects with hyperuricemia (H. G. and S. D.) in whom the glomerular filtration rate (GFR) was markedly reduced. Despite low initial and only moderately increased experimental F,,, the control U,,V was not low, and about doubled after RNA administration; the apparent “T”,,/lOO ml. GFR, high normal initially, rose appreciably. Thus, in the face of markedly compromised GFR and hence F,,, tubular transport of uric acid apparently was unimpaired and the tubular response to RNA loading was quite within normal limits. With more advanced renal damage, however, the tubular transport mechanisms for uric acid, of course, may be affected. Gouty subjects: It is apparent from Tables I and II that all twelve gouty subjects given RNA likewise responded with an increase in P,, and U,,V. When the quantitative responses of the gouty subjects are compared to those of the nongouty subjects given the same dose of RNA, no significant differences in increment are discernible either in plasma or urinary uric acid levels; they certainly were not less in the gouty subjects. Thus in the nine gouty normoexcretors of uric acid studied, the mean P,, rose from an initial value of 8.2 to 11.9 mg. per cent, F,, correspondingly from 8.9 to 12.9 mg. per * Note that in two non-gouty subjects (A. R. and A. G., Table I), whose F,, was within the gouty range before taking RNA, U,,V was quite within the range of variation of U,,V in gouty normoexcretors before taking RNA. VOL.

33,

DECEMBER

1962

in Gout--Yii

et al.

831

minute. U,,V doubled, from 0.59 to 1.17 mg. per minute. The mean increment in C,, was 2.7 ml. per minute as compared to 3.4 ml. per minute in normouricemic non-gouty subjects, the increment in C,,/GFR was 0.027 as compared to 0.024, the increment in apparent “T”Ur) calculated as F,, - U,,V, was 3.4 as compared to 2.4 mg. per minute.* Since Nugent and Tyler and Seegmiller et al. did not give RNA to their gouty subjects, direct comparison is not possible. However, when our data in gouty normoexcretors are compared to their data in non-gouty subjects, the correspondence is close. (Table II.) Except for smaller increments in C,, and C,,/GFR, the same can be said for our three gouty overexcretors. Our data also correspond in the disparity in U,,V between the RNA-treated non-gouty subjects and the untreated gouty subjects at equivalent F,,, as emphasized by Nugent and Tyler and Seegmiller et al. Thus (Table II) the mean U,,V in our non-gouty, normouricemic subjects after RNA administration was 0.85 mg. per minute, at P,, 7.3 mg. per cent and F,, 9.3 mg. per minute, whereas the mean U,,V in the gouty normoexcretors before RNA administration was 0.59 mg. per minute, at P,, 8.2 mg. per cent and F,, 8.9 mg. per minute. This disparity is not attributable to gout, however, since it is present also in non-gouty hyperurecemic subjects. In Figure 1, the means for apparent “T”“*, calculated as F,, - U,,V, are shown in relation to the means for F,, in our non-gouty and gouty subjects before and after RNA administration. (The true T,, values, it is suspected, are practically superimposable on the diagonal line representing complete tubular reabsorption of the filtered uric acid, except perhaps at extremely high F,, and rapid flow rates.) The apparent “T”UT increases as F,, increases, * This response in P,, U,,V and C,, of gouty subjects to a high purine intake is hardly unexpected since it is the basis for the traditional restriction of dietary purines and has long served as an objective means for detecting dietary violations in gout. Br@mer-Mortensen [7-31 in particular emphasized the increased U,,V and C., after the ingestion of ordinary meals in both non-gouty and gouty subjects. What the literature does not make clear, however, is that the rate of elimination of a large preformed purine load in gouty subjects is quite within the limits of the normal response. The data of Br@chnerMortensen [3] on this point conflict with ours, in suggesting slower elimination of large nucleic acid loads in most gouty subjects. This critical question otherwise does not seem to have been examined closely.

832

Renal

Function

in Gout-K

TABLE RENAL

CLEARANCES THIRTEEN

BEFORE

NON-GOUTY (VALUES

AND

AFTER

SUBJECTS NOT

ORAL

I LOADING

ARRANGED

CORRECTED

et al.

IN TO

WITH

RNA

ASCENDING

BODY

IN

TWELVE

ORDER

SURFACE

OF

GOUTY

CONTROL

AREA)

Subject, Age (yr.1 and Body Surface Area

Timc*

Pur (mg. %)

U,rV (mg./min.)

Ci, (mI./min.)

Apparent “T”, (mg./min.)

Fur (mg./min.)

C.. ml./min.)

AND

Pur

DLKation of Overt Gout

Remarks

C.JGFR

Tophi

(yr.)

(Ma.1 Non-gouty

>

mouricemic

J. C., 20, 1.64

C L

4.3 5.4

0.64 1.08

125 120

5.35 6.37

4.7 5.3

14.9 20.4

P. K., 48, 2.12

C L

4.8 7.3

0.39 0.88

130 149

6.24 10.88

5.9 10.0

8.1 12.1

0.063 0.081

Osteoarthritis,

W. G., 22, I.68

C L

5.0 6.3

0.31 0.55

128 138

6.40 8.70

6.1 8.2

6.2 8.7

0.050 0.063

Peptic

ulcer

J. W., 26, 1.61

C L

5.0 7.3

0.25 0.60

110 113

5.45 8.25

5.2 7.7

5.1 8.2

0.046 0.073

Peptic

ulcer

J. A., 29, 1.45

C L

5.6 7.8

0.42 0.71

103 100

5.77 7.80

5.4 7.1

7.5 9.1

0.073 0.091

Rheumatoid mild

L. B., 37, 1.89

C LI L?

6.4 8.4 IO.1

0.56 0.97 1.30

116 133 126

7.46 11 17 12.73

69 10.2 11.4

8.8 11.5 12.9

0 075 0.087 0.102

Healthy

M. J., 26, 1.84

C L

6.5 9.0

0.53 I.15

134 134

8.71 12.06

8.2 10.9

8.2 12.8

0.062 0.095

Healthy

Non-g&y

wruricemic

A. R., 27, 1.81

C L, LS

7.3 11.4 10.2

0.48 0.76 0.96

116 96 110

8.50 10.98 Il.22

8.0 10.2 10.3

6.6 6.7 9.4

0.056 0.069 0.086

Healthy

A. G., 60, 2.10

C L

73 10.3

0.53 0.87

112 108

8.20 11.12

7.3 8.5

0 065 0.079

Healthy

L. R., 37, 1.91

C L

7.7 11 0

0.72 1.27

108 115

8.32 12.65

7.6 11.3

0.087 0.100

Urate urolithiasis

S. D., 70, 1.66

C L

9.6 13.5

0.45 1.09

57 59

5.48 7.95

5.0 6.9

0.082 0.137

Polycythemia GFR low

vcra,

M. H., 32, 1.98

C L

10.1 10.5

0.82 1 .08

124 145

12.50 15.23

11.7 14.2

8.1 10.3

0.065 0.071

Polycythemia

vera

H. G., 65, 1..74

C L

10.4 14.2

0.98 1.74

32 36

3.28 5.06

2.3 3.3

9.4 12.3

0.294 0.342

Chronic myelocytic leukemia, GFR low

G. C., 40, 2.10

C L

6.8 10.2

0.57 1.25

125 136

8.44 13.87

7.9 12.6

8.4 12.3

0.067 0.092

J. O., 72, 1.95

C L1 L? LX

6.8 11.0 11.3 10.9

0.52 1.18 1.09 1.01

108 115 110 108

7.34 12.65 12 43 11 77

6.8 11.4 11.3 10.8

7.6 10.7 9.7 9.3

0.071 0.099 0.088 0.086

J. S., 56, 2.02

C L1 LZ La

7.3 10.7 11 .o 10.9

0.45 0.98 0.94 0.95

108 110 112 106

7.88 11.72 12.32 11.55

7.4 10.7 11.4 10.6

6.2 9.2 8.6 8.7

0.057 0.089 0.084 0.082

A. Ra., 52, 1.97

C L

8.4 12.0

0.62 1.16

124 125

10.42 15.00

9.8 13.8

7.4 9.7

0.060 0.093

A. C., 48, 1.76

C L

8.5 12.7

0.62 1.22

115 116

9.72 14.73

9.1 13.5

7.3 9.6

0.064 0.083

D. L., 67, 1.90

C L

8.5 12.8

0.59 1 .Ol

102 98

8 67 12.60

8.1 11 6

6.9 7.9

0.068 0.080

Lobar pneumonia, resolved mild

arthritis,

-

-

-

!_

AMERICAN

JOURNAL

OF

MEDICINE

Renal Function

in Gout--I%

833

et al.

TABLE I (Continued) RENAL CLEARANCES BEFORE THIRTEEN

NON-GOUTY

-

-

AND

AFTER

SUBJECTS

(VALUES

NOT

-

ORAL

LOADING

ARRANGED

CORRECTED

IN TO

WITH

RNA

ASCENDING

BODY

-

IN

ORDER

SURFACE

TWELVE OF

GOUTY

CONTROL

AREA)

-

-

Subject, Age (YF.) and Body Surface Area

:

P”. (Img. %: )

Ci. (ml./min.)

U”,V

(mg./min.)

Apparent “T”, :mg./min.)

F”, mg./min.)

C”, (1nl./min.)

:,r/GFR

Remarks

(yr.)

8.6 12.7 12.8

0.69 1.20 1.20

80 80 80

B. R., 52, 1.95

C L

8.6 11.7

0.62 1.19

126 122

B. L., 62, 1.99

C L1 LZ

9.9 13.0 12.1

0.61 1.30 1.27

97 86 107

-

-

6.2 8.9 9.0

8.0 9.4 9.4

0.101 0.119 0.118

10.84 14.27

7.2 10.2

0.064 0.083

9.55 11 18 12 95

6.2 10.0 11.3

0 064 0.116 0.098

-

-

M. K., 42, 1.92

C L

10.7 13.6

0.87 1.52

115 107

12.31 14.55

11.4

8.1

0.070

13.0

11.2

0.104

c.

c L

10.8 12.2

1.13 1.53

128 150

13.87 18.25

12.7

10.5

0.082

16.7

12.5

0.083

C LI L1

10.9 14.4 14.3

0.90 1.25 1.37

112 112 112

12.20 16.13 16 02

11.3 14 9 14.7

39,

H. Go., 49, 2.14

7rophi

=

C Ll LZ

w., 2.04

tion of ,3vert Gout

==

==

E=

C., 63, 1.97

Dura-

rime *

(Ml.)

M.

AND

Pur

8.3 8.7 9.6

0.074 0.078 0 086

6

0

6

0

24

+

* C = Control. L and LI = After four davs administration of RNA. administration of RNA.

whether spontaneously as in the control points for gouty subjects as compared to normouricemic non-gouty subjects, or after RNA administration in both gouty and non-gouty subjects. The control points lie within the area representing the narrow spontaneous spread in gouty and non-gouty subjects ([Id], Fig. 8); the points after RNA loads lie within or just at the lower border of this area, since the increases in U,,V, even though sizable, are small in relation to the large T,,. Thus a hardly perceptible deflection from the spontaneous apparent “T”Ur was produced by oral loading with RNA, even at the highest F,, achieved in gouty subjects. (This is in contrast to the sharp deflection observed after rapid intravenous loading with uric acid.) There is no indication in this plot that the reabsorptive T, for uric acid is being approached at the highest F,, reached either in gouty subjects before or after RNA administration or in non-gouty subjects after taking RNA. Intravenous Loading with Uric Acid (Tables III, IV and V). Non-gouty subjects: In six non-gouty normouricemic subjects, the mean P,, more than doubled after delivery of 1.6 to 2.0 gm. VOL. 33,

DECEMBER 1962

L2 = After eleven days administration of RNA.

Ln = After eighteen days

uric acid over a period of eighty to 180 minutes, rising from an initial mean of 5.3 to a mean maximum of 12.8 mg. per cent; F,, likewise rose from 7.5 to 17.9 mg. per minute. There was a concomitant almost tenfold increase in U,,V, from a control mean of 0.57 to a mean maximum of 5.08 mg. per minute, an increase of 4.5 mg. per minute. C,, and C,,/GFR increased almost fourfold, from a mean of 10.7 to a mean maximum of 39.3 ml. per minute and from 0.077 to 0.283, respectively. The apparent “T”UT, calculated as F,, - U,,V, rose from a mean control figure of 6.9 to a relatively modest mean maximum of 12.8 mg. per minute. The most striking difference, then, between our results with intravenous uric acid loading and oral RNA loading is the almost tenfold increase as compared to the twofold increase in U,,V. In short, the data in non-gouty, normouricemic man signify that, as expected, with due allowance for considerable individual variation in rates, the larger and more rapid the increase in uric acid load, the larger and more rapid is its renal elimination, The same conclusions apply to non-gouty, hyperuricemic man. Starting at higher mean

834

Renal Function in Gout--I% et al. in apparent “T”,,T was relatively modest, from a mean of 8.3 to a mean maximum of 14.3 mg. per minute. Gouty subjects: In nine gouty normoexcretors given infusions of 1.1 to 2.5 gm. uric acid over a period of seventy to 156 minutes, the mean P,,, 7.7 mg. per cent to start, doubled to a mean maximum of 15.4 mg. per cent. F,, likewise rose from 9.4 to 19.5 mg. per minute. This was accompanied by a mean eightfold increase in U,,V, from 0.66 to a mean maximum of 5.63 mg. per minute, an increase of 4.97 mg. per minute. C,, and C,,/GFR rose more than fourfold, from 8.3 to a mean maximum of 35.9 ml. per minute, and from 0.067 to 0.285, respectively. The apparent “T”UT, calculated as F,, - U,,V, rose from a mean control figure of 8.7 to a mean maximum of only 13.9 mg. per minute. Much the same results were obtained in five gouty overexcretors. Initial mean P,, and F,, levels of 9.1 mg. per cent and 10.9 mg. per minute reached their respective mean maxima at 17.8 mg. per cent and 21.4 mg. per minute. U,,V again increased almost eightfold, from a mean of 0.99 to a mean maximum of 7.25 mg. per minute, a rise of 6.26 mg. per minute, with a manyfold increase in C,, and C,,/GFR. The rise in apparent “T” uTagain was comparatively small, from a mean of 9.9 to a mean maximum of 14.2 mg. per minute. When the responses of U,,V, C,, and allied parameters to intravenous infusion of uric acid are compared in gouty and non-gouty subjects, no consistent differences are discernible. (Table IV.) It would thus appear, at least in our experience, that subjecting the renal excretory

18 -

. After RNA

A Before RNA x Attar RNA

.4

6

8

IO F,,

12 14 M9. /Min.

16

18

20

FIG. 1. The distribution of apparent “T”yl, calculated as F,, - U,,V, in relation to F,, in non-gouty and gouty subjects before and after receiving the same oral load of RNA. The solid diagonal represents complete tubular reabsorption of the filtered uric acid; the broken lines give the range of distribution of apparent r‘T”ur:Fur in non-gouty and gouty subjects on a low purine diet. After RNA administration, the points for the gouty and nongouty subjects fall within or just below the lower broken line. (See text for further explanation). Compare with Figure

2.

P,, and F,,, 7.3 mg. per cent and 9.0 mg. per minute, infusion of comparable quantities of uric acid resulted in somewhat higher mean maximum figures, 15.5 mg. per cent and 20.6 mg. per minute, respectively. Again there was a large increase in U,,V, to a mean maximum of 6.26 mg. per minute, with an accompanying manyfold rise in C,, and C,,/GFR. Again, because of the great increase in U,,V, the rise

TABLE

PUZ(mg. Subjects

UUV

%)

(mg./min.)

Fur (mg./min.)

NO. Cases

Studied

C

L

A

C

L

A

C

normouricemic

Non-gouty . Non-gouty hyperuricemic. . Gouty nornme~cretors. . Gouty O”erCXcretOr8. Nugent, Tyler (41 Non-gouty . Gouty..................... Sccgmiller et al. 151 Non-gouty . Gouty norrnoe~cretor~. . Gouty overexcretors.

L

______

-~~

Presentstudy

II

COMPARISON OF MEAN RESPONSES

7 4 ,”

7 6 7 10 6

5.4 8.1 10.8 8.2

f f f

0.8 7.3 1.210.8 0.911.9 0.113.4

5.6fl.l 9.2 f

1.1

4.6 7.2 9.4

0.3 0.8 1.5

f f f

?I 1.2 +1.9 f 0.4 +2.7 f 0.9 +2.6 rt +3.7

f f f

0.50.44 1.40.64 0.50.59 0.90.97

f 0.140.85 rt 0.141.00 f 0.121.43 0.061.17

7.9f1.3+2.3f1.30.46~0.060.92f0.17+0.46f0.21 ... 0.57 fO.10

. .

8.2

f 1.0 ...

+3.6

f

0.90.38 0.37 . 0.79

. .

f 0.060.94 fO.10 f0.23

* 0.22 zt 0.19 f 0.13 0.09

+0.41 +0.36 +0.46 +0.58

... f 0.27 ...

* 0.12 6.5 f 0.11 9.4 f 0.1312.8 0.08 8.9

. +0.56

.

f 0.20 . . .

f 0.9 9.3 f 1.812.5 zt 0.816.3 It 1.212.9

* 1.9 k 1.7 rt f 1.5 1.6

6.1 9.2

It1.2 f 1.7

8.9f1.5 . .

5.6 6.5 9.2

k 0.9 f 1.4 rt: 1.6

9.7

k 1.9 . .,.

-i AMERICAN

JOURNAL

OF

MEDICINE

Renal Function

in Gout-Yii

mechanisms for uric acid even to heavy loads, much larger and more rapidly delivered than by RNA feeding, fails to disclose any deficiency peculiar to gout. Such comparisons, of course, should be made after injection of uric acid at like loads and rates in both gouty and non-gouty subjects, otherwise the critical factors in any differences observed may be confused. For example, Table v contrasts the results of a slow infusion of uric acid at a sustained rate of 11 mg. per minute over a period of 184 minutes in one non-gouty subject (P. K.), with a rapid infusion at a rate of 28 mg. per minute over a period of eighty-nine minutes in another non-gouty subject (M. E.); in the former, U,,V increased from 0.48 to only 3.96 mg. per minute, in the latter from 0.73 to 11.6 mg. per minute. Similarly, in a gouty subject (G. R.), slow infusion of uric acid at 10 mg. per minute for 120 minutes resulted in a maximum U,,V of only 1.85 mg. per minute whereas in another gouty subject (S. D.) infusion at a rate of 27 mg. per minute for ninety-two minutes caused U,,V to rise to 8.5 mg. per minute. The marked differences in U,,V in these four subjects clearly are due to differences in uric acid loading, not to the presence or absence of gout. Even under quite comparable conditions of uric acid loading, however, substantial differences in U,,V are encountered among both non-gouty and gouty subjects (B. S. and S. W., Table v). In two gouty subjects (J. F. and I. B., Table v) the differences in U,,V observed were well within this range of variation. In order to avoid untoward reactions such as described by Berliner et al. [6], the largest uric acid load delivered was 2.5 gm., and most were 1.5 to 2.0 gm. Under these circumstances, TO

ORAL

LOADING

WITH

FIX (mg./min.)

“T”,,,

*

* In this compilation of gouty subjects we have excluded one (W. N.) who had only one kidney. His GFR consequently was reduced, and the maximal Fur after loading was 12.5 mg. per minute. It shouId be noted that the control U,,,V nevertheless was quite high, and after loading rose to 4.55 mg. per minute.

L

Cur (ml./min.)

1A

CdGFR

A

/p+

C

0.070 0.068 0.068 0.075

f f k k

8.0

f 1.4 ...

+2.4

rt 1.0

8.5 6.2

k 1.2 zk 0.8

11.7

k 1.9 ..,

+3.2

zt 1.4

0.078 0.062

f. 0.014 f0.005

8.8

f 1.7 ... ..,

+3.6

f 1.0 ...

8.4 5.1 8.6

zk 1.5 f 1.3 f 2.9

11.5

f 3.0 ... ...

+3.1

ziz 1.9

0.070 0.059 0.087

zk 0.0160.096 f 0.012 f 0.025

f f

1.1 1.6

1.3

5.2 6.1 8.4

10.9 f 1.3 * 1.5

f f f zk

1962

.

A

L

1.2 0.8 0.9 1.1

5.6 8.6

24

22

the maximal filtered uric acid loads attained varied from 15.6 to 24.3 mg. per minute in the nine non-gouty subjects and from 16.1 to 25.0 mg. per minute in the thirteen gouty subjects;* the corresponding U,,V’s ranged from 3.1 to

rt $: f f

1.2

20

2. The distribution of apparent “T”LV, calculated as F,, - U,,V, in relation to F,, in non-gouty and gouty subjects before and after intravenous uric acid loading. The solid diagonal represents complete tubular reabsorption of the filtered uric acid; the broken lines give the range of distribution of apparent “TIyU,: F,, in non-gouty and gouty subjects on a low purine diet. After uric acid infusion, at levels of F,, > 10 mg. per minute, the points diverge increasingly from the diagonal line (compare with Figure 1). See text for further explanation.

+3.4 $1.4 +2.7 +1.8

f

I8

FIG.

f3.9 f 1.8 k 1.1 f 1.5

+2.8

DECEMBER

14 I6 WqJMln.

11.8 9.3 9.9 10.8

8.5 11.5 11.7 14.9

33,

F “,

i-2.9 f 1.0 fO.l It 1.1

1.1 1.7 1.3 0.6

VOL.

12

8.4 7.9 7.2 9.0

f f rt f

...

IO

1.0 0.6 1.1 1.0

6.1 8.8 8.3 11.8

f

6

f f k f

1.1 0.7 1.1 0.9

..

6

4

+2.4 +2.7 +3.4 +3.1

zt f f f

f4.1

t

1.8 1.8 1.6 1.5

f2.8 +3.1 +4.0 +3.5

.

24

RNA

Apparent (mg./min.)

c/

j

835

et al.

0.0230.094 0.0120.080 0.0120.095 0.0050.088 0.104

f f f f

0.033 0.012 0.013 0.011

+ 0.016 .,. f

.

0.021

.

f0.024 t-O.012 f0.027 +0.013

f f f f

0.012 0.003 0 011 0.015

f0.026

ck 0.013

+0.026

k 0.036

836

Renal Function

in Gout-E

TABLE RENAL

CLEARANCES NINE

BEFORE

NON-GOUTY

AND

SUBJECTS (VALUES

NOT

AFTER

III

INTRAVENOUS

ARRANGED

IN

CORRECTED

URIC

ASCENDING

~0

et al. ACID

LOADING

ORDER

STANDARD

OF

BODY

IN

FOURTEEN

MAXIMAL

SURFACE

GOUTY

FILTERED

AREA)

Uric Acid Infused

Subject, Age Cvr.1. Body Surface Area

AND

LOADS

DUW tion of Overt Gout

Remarks

Cw/GFR

Tophi

cur.1

(Ma.)

-

Non-gouty

c

Normouricemic

Subjects

D. R., 33, 2.02

81

ML

4.6 12.4

0.47 5.58

149 126

6.85 15.60

6.4 10.0

10.2 45.0

0.068 0.357

Healthy

1.7

F. S., 31, 1.82

1.6

148t

C ML

4.9 10.6

0.40 3.26

150 153

7.35 16.20

7.0 12.9

8.2 30.8

0.055 0.201

Rheumatoid arthritis, mild

P. K., 48, 2.12

184

C ML

5.3 12.3

0.48 4.49

152 150

8.05 18.45

7.6 14.0

9.1 36.5

0.060 0.244

Osteoarthritis, mild

2.0

D. G., 23, 1.73

2.0

126t

C ML

4.8 13.4

0.60 4.73

124 139

5.95 18.70

5.4 14.0

12.5 34.0

0.101 0.244

Polycythemia treated

A. S., 25, 2.16

12st

C ML

5.7 11.5

0.83 5.33

164 163

9.35 18.75

8.5 13.4

14.6 46.3

0.089 0.284

Healthy

2.0

B. S., 30, 1.77

115t

C ML

6.5 16.4

0.63 7.11

111 119

7.19 19.50

6.6 12 4

9.7 43.4

0.087 0.365

Healthy

1.9

7.7 11.0

12.3 37.0

0.100 0.313

Healthy

-

-

-

-

-

vers,

Non-g&y

Hyperuricemic Subjeclt

J. P., 28, 1.94

1.6

132t

C ML

7.0 13.6

0.86 5.04

123 118

s. w., 34, 1.92

129t

C ML

7.6 14.1

0.49 3.13

129 152

9.82 21.40

9.3 18.3

6.4 22.2

0.050 0.146

Healthy

2.0

M. E., 47, 1.71

89

C ML

7.2 18.7

0.73 10.60

120 130

8.65 24.30

7.9 13.7

10.1 56.8

0.084 0.437

Healthy

2.5

!

8.60 16.00

I

-

-

-

7.3 12.3

0.65 1.85

127 131

9.28 16.10

8.6 14.3

8.9 15.1

0.070 0.115

13

0

7.8 14.9

0.40 4.00

101 115

7.88 17.20

7.5 13 2

5.1 26.8

0.051 0.234

1

0

C ML

6.6 15.5

0.57 6.34

118 114

7.80 17.68

7.2 11.3

8.6 40.9

0.073 0.360

1

0

C ML

6.9 16.8

0.64 5.34

112 106

7.73 17.80

7.1 12.5

5.4 31.8

0.048 0.300

31

0

134t

8.1 16.1

0.75 6.35

106 118

8.60 19.00

7.9 12.7

9.3 39.4

0.087 0.334

0

82

C ML

8

1.8

L. F., 41, 1.86

8.6 15.9

0.74 6.37

103 123

8.85 19.60

8.1 13.2

8.6 40.0

0.084 0.326

0

123t

C ML

2

2.0

J. S., 50, 1.87

7.0 13.8

0.67 6.00

140 145

9.80 20.00

9.1 14.0

9.6 43.5

0.068 0.300

0

111t

C ML

18

1.1

I. B.. 39, 2.12

10.6 18.7

0.81 7.82

125 140

13.25 23.20

12.4 15.4

7.7 41.9

0.061 0.338

0

85t

C ML

7

2.0

J. F., 55, 2.18

102i

C ML

6.5 14.9

0.72 6.56

172 168

11.20 25.00

10.5 18.4

11.1 44.0

0.065 0.262

23

2.0

G. R., 50, 2.16

1.3

105

J. 0.. 71, 1.95

2.2

11ot

G. S., 60, 2.06

2.0

122t

A. He, 60, 1.80

1.9

P. w., 48, 1.93

C ML

-

-

-

--

-

coutyOuerczcrelors W. N.,S 36, 1.90

1.6

166t

:L

(

1:::

/

“,:“5; )

‘,;

1%

:::

j

if:;

“,:i;: 1

AMERICAN

JOURNAL

1 ~ ’ OF

MEDICINE

Renal

Function TABLE

RENAL

CLEARANCES

BEFORE AND

NINE NON-GOUTY

P

Subject,

Body

Surface Area

_

‘obl

1 he

(’w.) ==

Wt.)

Time :min.)

Idoad’

URIC

Ct.

U”.V ,:mg./min.:

ml./min.

ACID

LOADING

ORDER

STANDARD

BODY

-

I-

P”, (mg. %)

837

et al.

(Continued)

IN ASCENDING

NOT CORRECTED To

T

Uric Acid Infused

III

INTRAVENOUS

SUBJECTS ARRANGED

(VALUES

Age (yr.),

AFTER

in Gout-l%

IN

FOURTEEN

OF MAXIMAL SURFACE

GOUTY

FILTERED

AREA)

DllW

Apparent “T”, I:mg./min.>

FU

) (‘mg./min.)

CU, ml./min.:

t(ion of ,3vert

‘,/GFA

S. F., 60, 1.94

9.4

-

-

== C ML

1?ophi

Gout (Y1.j

-

Ci. A., 35, 1.97

AND

LOADS

17.1

0.91 5.85

127 130

11.90 22.20

11.0 16.4

9.7 34.2

0.076 0.263

C ML

10.3 17.6

1.13 6.03

132 136

13.60 23.70

12.5 17.7

11.0 34.2

0.083 0.252

0

S. D., 36, 1.93

C ML

9.1 19.2

0.87 8.50

121 124

10.98 23.80

10.1 15.3

9.6 44.4

0.079 0.358

0

L. G., 39, 1.97

C ML

8.9 20.5

1.06 11.30

135 121

12.00 24.75

10.9 13.5

11.9 55.0

0.088 0.455

0

-

L

-

6

-

-

-

0

-

* C = control, ML = maximal load. t Increasing rates of infusion. $ Previous left nepbrectomy.

10.6 mg. per minute, and from 1.85 to 11.3 mg. per minute, respectively. The mean maximum F,,/apparent “T”UT was approximately 1.45. Apparent “ T”,, in Gouty and Non-gouty Man After Rapid Intravenous Uric Acid Loads. When the apparent “T”UT, calculated as F,, - U,,V, is plotted against F,, in our non-gouty and gouty subjects before and after the intravenous injection of uric acid (Fig. 2), at levels of F,, > 10 mg. per minute there is a striking divergence from the diagonal line representing complete tubular reabsorption of the filtered uric acid. This divergence conforms to the previous report of Berliner et al. [6] in non-gouty man, and applies indistinguishably to gouty man. The findings in both gouty and non-gouty subjects contrast with the inappreciable displacement of points noted, in gouty and non-gouty subjects alike, after slower and lesser loading by oral administration of RNA. (Fig. 1.)

Apparent Reabsorptive Tm,, in Gouty and Nongouty Subjects. Comparison of our data with those of Berliner et al. [S] after intravenous infusion of uric acid into non-gouty, normouricemic man is complicated by the different loads delivered at different rates, and by the individual variation in members of the small groups studied in both series. However, at F,, of 18 mg. per minute (the mean maximum F,, of our non-gouty, normouricemic subjects), Berliner et al. found U,,V of 1.6, 3.0, 5.3 and 7.0 mg. per minute in the four subjects recorded, all but the first within the range indicated in Table III. The same correspondence in U,,V holds for the range in F,, of 21 to 24 mg. per minute reached in our non-gouty, hyperuricemic subjects. In four of ten non-gouty men Berliner et al. found an apparent reabsorptive Tm,,, at about 13.6, 14.1, 15.0 and 19.5 mg. per minute per 1.73 M2., with a mean of some

TABLE COMPARISON

OF MEAN MAXIMAL

P”r (mg.

---__--__-Non-gouty normouricemic Non-gouty hyperuricemic Gouty normoexcrctor. Gouty overexcretor .

.

33,

.

DECEMBER

_.

6

. .

9

3

5

1962

Fur (mg./min.)

LOADING

Apparent ‘CT”.Z (mg./min.)

WITH

URIC ACID

CW (ml./min.)

CJGFR ______

CML

VOL.

ULUV (mg./min.)

%)

NO. Cases

Subject

IV

RESPONSES TO INTRAVENOUS

A

C

ML

A

C

ML

A

CML

A

C

ML

A

C

ML

A

~_____

5.312.8 +7.50.57 5.08 +4.51 7.5 17.9 +10.46.912.8 +5.910.7 39.3 +28.60.0770.283 7.315.5+8.20.696.26+5.57 9.020.6+11.63.314.3+6.0 9.638.7+29.10.0730.299+0.221 7.715.4 +7.70.66 5.63 f4.97 9.419.5 +lO.l 8.713.9 +5.2 8.3 35.9 +27.60.0670.285 9.1 17.8+8.60.997.25+6.2610.921.4+10.59.914.2+4.310.939.9+29.00.0970.338+0.241

+0.206 +0.218

838

Renal Function in Gout-E TABLE

REPRESENTATIVE

CLEARANCE

INTRAVENOUS

URIC

ACID

Uric Acid

STUDIES LOADS

IN

FOUR

(VALUES

v

NON-GOUTY

NOT

et al. AND

CORRECTED

TO

FOUR

GOUTY

SUBJECTS

Sl ANDARD BODY

-34-

0 o- 21 21- 41 41- 71 71- 91 91-111 Ill-131 131-151 151-184

I?

-3l-

M. E. 47, 1.71

o18345168EO-

_S. W.,

0 0.23 0.45 0.78 ::: 1.4 1.7 2.0

0 18 34 51 68 80 89

0 o- 22 22- 30 30- 35 35- 42 42- 60 60- 68 68- 73 73- 82 82- 99 99-104 104-109 109-115

-___

-35-

B. S., 30, 1.77

--

i.50 0.95 1.4 1.9 2.2 2.5

% 0.85 0.94 1.1 1.5

-_

0 o- 18 18- 23 23- 34 34- 59 59- 70 70- 76 76- 86 86-108 108-114 114-121 121-128

::: 1.9 0

2:: 0.37 0.77 0.95 1.0 1.2 1.6 1.8 1.9 2.0

5.3 5.5 6.8 7.9 8.8 9.6 10.0 11.0 11.7

0.48 0.52 0.69 1.16 1.62 2.00 2.05 3.38 3.96

Z

0.73 1.26 2.71 4.70 8.12

12.4 13.5 16.0 17.4 18.7

0 0.20 0.27 0.32

-29-

34, 1.92

AREA)

Infusion

Non-goufy Subjects P. K., 48, 2.12

RECEIVING

SURFACE

--

~_

152 152 158 147 150 151 150 154 151 ~___ 120 112 100 119 135 132 130 -__~ 111 bration 121 116 128 brarion 111 112 106 bration 113 110 119

::::

6.5

0.63

8.3 9.5 10.6

1.58 2.31 3.26

12.7 13.1 13.9

4.27 4.64 4.22

13.2 14.8 16.4

4.16 5.53 7.11

Eql

Eql

9’

7.61 o.4gEq, ;:i I ::::Eq,

129 lbration :z:

12.3 12.8 13.2

2.58 2.86 2.80

13.8 13.9 14.1

3.43 3.50 3.13

0 0.45 0.90 1.0 1.2

7.3 8.4 9.8 11.4 12.3

0.65 0.75 1.10 1.69 1.85

127 132 133 145 131

z.9 1.3 1.8 2.2 2.5

9.1 11.7 13.8 15.8 17.9 19.2

0.87 2.41 4.40 5.15 7.43 8.50

121 111 111 108 128 124 172 Equilibration 173 175 172 Equihbra;;;

8.05 8.37 10.73 11.60 13.20 14.50 15.00 16.95 17.65

I

I

7.6 7.9 10.0 10.4 11.6 12.5 13.0 13.6 13.7

_-

8.65 9.98 12.40 16.05 21.60 23.00 24.30

7.9 8.7 9.7 11.4 13.5 13.0 12.7

9.1 9.5

%:

10.2 14.7 18.4 20.8

Z:%

20.5 30.7 33.8

::::o’ 0.224

10.2 14.2 21.8

0.085

k% 0.436 0.478

:::3;

Z;:

7.19

6.6

34.8 50.9 57.5 62.0 ~___ 9.7

10.04 11.00 13.55

8.5 8.7 10.3

19.0 24.4 30.8

0.157

14.10 14.80 14.75

9.8 10.2 10.5

33.6 35.4 30.4

0.303 0.314 0.287

14.90 16.30 19.50

10.7 10.8 12.4

31.6 37.4 43.4

0.364

9.82

9.3 10.1 10.6

:;:::

_-

::;::

I 21 .o 22.4 21.2

14.0 14.2 15.0

Eql Aili

0.087

::::: 0.164

I

G. R., 50, 2.16

S. D., 36, 1.93

J. F., 55, 2.18

I. B., 39, 2.12

1: 2;

-35-

0 o- 45 45- 90 go-105 105-120

-3l-

o35506782-

0 35 50 67 82 92

0 o- 20 ZO- 27 27- 32 32- 39 39- 60 60- 65 65- 72 72- 79 79- 89 89- 94 94-102

__

-41-

-3l-

o1429445974-

0 0.18 0.24 ::3: 0.79 0.90

--

0 14 29 44 59 74 85

::: 1.7 1.9 z.3 ::: t:: 2.0

-

6.5

0.72

9.1 9.1 9.1

1.93 2.20 2.29

12.3 12.3 12.3

3.13 3.62 3.96

13.8 14.7

5.46 6.48

10.6 11.6 12.9 14.4 15.0 16.8 18.7

--

0.81 1.05 1.63 2.37 3.16 5.78 7.82

1

Equilibrat;;

__

__

9.28 11.20 13.05 15.50 16.10 10.98 13.00 15.30 17.10 22.90 23.80

__

--

8.6 10.4 11.9 14.8 14.2

8.9 9.1 11.2 14.8 15.1

10.1 10.6 10.9 11.9 15.5 15.3

9.5 20.6 31.9 32.6 41.5 44.3

%Z

I

11.1

0.065

I

20.2 23.2 25.2

!:% 0.147

11.20

10.5

15.70 15.90 15.65

13.8 13.7 13.4

165 167

18.95 20.30 20.60

15.8 16.5 16.6

25.4 31.1 32.2

167

22.40 24.60

2:

I ‘z

_-

125 118 125 124 124 127 124

_-

12.4 12.6 14.5 15.5 15.4 15.6 15.3

13.25 13.68 16.10 17.88 18.60 21.40 23.20

AMERICAN

7.7 9.0 12.6 16.5 21.1 34.3 41.8

0.288

%: 0.357

;:I$ 0.193 0.245 0.254 0.061 “,:% 0.133 ::1:: 0.338

JOURNAL

OF

MEDICINE

Renal Function in Gout-Yii EFFECT

OF PYRAZINOIC

URIC ACID Subject, Age (yr.), Body Surface Area (Mz.)

URIC

ACID ON

INFUSION

ACID

(VALUES

TABLE

VI

EXCRETION

IN

NOT

CORRECTED

Mg./min.

Minutes

uurv

P”r mg. %)

Cumulative Dose (pm.)

0.42 2.24

1.0 1.2 1.5

2.10 1.29 1.22

43

0.74

0.92 1.71

67 77 87

1.1 13 1.5

I. Bo., 50, 1.98, gouty

__

P. Ke., 60, 2.06, gouty

0 8

0 15

2.82 1.31 0.69

12.8 13.5 14.2

SUBJECTS

SURFACE

RECEIVING

AREA)

I

DECEMBER

0.68 0.90

Apparent “T”“, (mg./min.)

F, (mg./min.)

j

I

142 14.50 13.3 Pyrazinoic acid 0.5 gm. orally 137 12.9 141 15.8 133 15.0

_.

I

118 11.20 10.3 121 13.10 11.4 Pvrazinoic acid 0.5 gm. orallv Ii7 16.30 lj.5 114 15.40 14.1 95 13.50 12.8 114 10.25 9.6 110 12.76 11.9 Pyrazinoic acid 0.5 gm. orally

9.0 22.0

0.060 0.155

19.3 10 6 10.0

0.141 0.076 0.075

9.7 15.9

0.082 0.131

22.1 9.7 4.8 ____

0.174 0.085 0.051

7.6 78

0.40

62 102 112

0.53 0.87 0.95

0.069 0.021 0.024

67

0.98

0.070 0 121

83 97 107 127 137

1.2 1.4 1.6 1.9 2.0

14.3 14.8 15.1 15.2 15.3

3.43 3.64 2.47 1.39 1.19

Pyrazinoic acid 0.5 gm. orally 154 22.00 18.6 153 22.65 19.0 157 23.70 21.2 159 24.20 22.6 158 24.20 23.0

24.0 24.6 16.3 9.2 7.8

0.156 0.161 0.104 0.058 0.049

-

15 mg. per minute per 1.73 M2. Our experiments, for the most part carried out at lower uric acid loads, do not indicate that an apparent except in one non-gouty Tmur was reached subject (M. E.) at about 13.2 mg. per minute per 1.73 M2., and in one gouty subject (I. B.) at about 15.5 mg. per minute, or 12.6 mg. per minute per 1.73 M2. (Table v.) The data do not suggest any sharp difference in apparent Tmur for gouty and non-gouty subjects such as reported by Lathem and Rodnan [77], who found a lower apparent Tmur in non-gouty subjects, averaging about 10 mg. per minute per 1.73 M2., and were unable to establish an apparent Tm,,, even at 20 mg. per minute or more, in gouty subjects. Effect of Pyrazinoic Acid on lJ,,V After Intravenous Loading with Uric Acid. Table VI summarizes the effects of interposition of pyrazinoic acid, a potent inhibitor of tubular secretion of uric acid [18,79], during sustained uric acid infusion. Prudence dictated use of a relatively low dosage of pyrazinoic acid (a single orally administered dose of 0.5 gm.) which in normal man rapidly diminishes U,,V, although not as 33,

GOUTY

BODY

48

-

VOL.

AND

STANDARD

Ch (ml./min.)

(mg./min.)

0.75

50 65 79 100

A. C., 51, 1.85, gouty

NON-GOUTY TO

839

Uric Acid Infusion

/

D. W., 39,1.87, non-gouty

P.

et al.

1962

completely as full doses, and more transitorily. In the face of essentially unchanged GFR and mounting F,,, ordinarily associated with a rise in U,,V, a consistent fall in U,,V was noted in both non-gouty and gouty subjects. In one non-gouty subject (D. W.), U,,V declined from 2.24 to 1.22 mg. per minute; in three gouty subjects (I. Bo., P. A. C. and P. Ke), respectively, from 1.71 to 0.69, from 0.90 to 0.44, and from 2.24 to 1.19 mg. per minute. The results indicate the important role of tubular secretion in the renal elimination of uric acid loads. COMMENTS

Our prior [74] and present studies of renal function in primary gout compositely compare the urinary excretion of uric acid in gouty and non-gouty subjects in the following three sets of circumstances: (1) Both Gouty and Non-gouty Subjects Under Steady State Conditions of Low Purine Intake. In 300 male gouty subjects the mean U,,V in twenty-four-hour collections was 497 mg. as compared to 418 mg. in normal adult males. In 67 per cent of these gouty subjects, U,,V was

Renal Function within the broad range of normal variation (normal mean k 2 standard deviations); in 29 per cent U,,V was unequivocally above normal limits; in only 4 per cent was U,,V unequivocally below normal limits, mostly in patients with overt but obviously secondary renal damage. Under the conditions of renal clearance studies, U,,V is substantially higher in both gouty and non-gouty subjects, the mean for 150 gouty subjects being 663 and for normal adult males 493 pg. per minute. In 78 per cent of these gouty subjects U,,V was within 2 standard deviations of the normal mean, in the remaining 22 per cent it was unequivocally in excess of the normal. The mean C,, in the gouty males was 7.5 as compared to 8.7 ml. per minute for non-gouty males, with much overlap. No simple linear relationship between U,,V and F,, could be discerned, U,,V in most gouty subjects remaining within the bounds of the normal mean f 2 standard deviations; and the higher the F,, the more striking this dissociation. However, in about half the subjects with levels of F,, above 12 mg. per minute, those in whom P,, was inordinately high, U,,V exceeded the upper limits of normal variation. (2) Gouty Subjects Under Steady State Conditions of Low Purine Intake; Non-gouty Subjects Receiving Orally Administered RNA or Intravenously Injected Uric Acid. At equivalent F,,, the U,,V and C,, of gouty subjects were found to be quite consistently lower than in non-gouty subjects. These findings are in accord with those of Nugent and Tyler [d] and Seegmiller et al. [5] in relation to RNA administration, and with Zollner’s comparison [7] of the data of Berliner et al. [6] with those of Gutman and Yii [Id]. (3) Both Gouty and Non-gouty Subjects Receiving Orally Administered RNA or Intravenously Injected Uric Acid. The increments in U,,V and C,, in gouty subjects were not found to be less than in non-gouty subjects in any cross comparison made, whether between the normouricemic or hyperuricemic non-gouty subject on the one hand or the gouty normoexcretor or overexcretor of uric acid on the other. In attempting to unravel these seemingly tangled threads, we shall begin with the last set of observations. Since even large and rapidly imposed extraneous loads of uric acid seem to be eliminated by gouty subjects with as much facility as by normal man, there would not appear to be any intrinsic impairment of the renal capacity in gouty subjects to excrete uric

in Gout-Yii

et al.

acid. The disparity in U,,V and C,, when nongouty subjects are given a large load of uric acid, and gouty subjects are not, is attributed to these unequal conditions of the experiment. In conformity with the results of loading experiments with many other compounds in subjects with normal renal function, the larger and more rapid the increase in uric acid load, the larger and more rapid its renal elimination, making due allowance for considerable variation in apparently healthy persons, the effects of aging and disease, differences in rate of urine flow, and the like. One might conceive of several more or less distinct orders in the rate of uric acid loading, at normal GFR, in the experiments herein reported. In normal man, in a steady state on a low purine diet, uric acid “loading” is largely endogenous, determined essentially by the normal rate of de novo uric acid biosynthesis, at a relatively low and regular level of production, to judge from glycine-N15 incorporation into uric acid [20] and other evidence. In the gouty normoexcretor of uric acid, in a steady state on a low purine diet, we presume, for reasons stated elsewhere [27], that the rate of endogenous de novo uric acid biosynthesis is somewhat higher than normal but quite uniform in time, to judge from the small, broad peaks of glycine-N16 incorporation into uric acid [20]. In the flamboyant (primary) gouty overexcretor of uric acid on a low purine diet, the exaggerated, precipitous peak and decline of glycine-Nt5 incorporation into uric acid [20] indicate grossly excessive and more irregular endogenous uric acid production. When, now, these three categories of subjects are given an extraneous uric acid load, renal elimination of the excess uric acid is superimposed upon the natural rate of uric acid excretion. The magnitude of this increment in U,,V depends upon the quantity and rate of the extraneous uric acid load imposed, irrespective of the presence or absence of gout. Thus a single meal of ordinary purine and protein content elicits a small but distinct rise in U,,V and C,, in gouty and non-gouty subjects alike, as Brplchner-Mortensen showed [I-3]. According to our data, this rise is greatly augmented in gouty as well as non-gouty subjects by the addition of substantial doses of RNA, even more by rapid intravenous injection of large amounts of uric acid. In some circumstances, so markedly enhanced is the endogenous production of uric acid by de novo purine bioAMERICAN

JOURNAL

OF

MEDICINE

Renal Function synthesis that it alone seems to be responsible for delivery of uric acid to the kidneys in quantities and at rates equivalent to considerable external loads, with corresponding increases in U,,V. This apparently occurs in gouty overexcretors of uric acid, doubtless also in subjects with various disorders of hemopoiesis associated with hyperuricemia and uricosuria, particularly after certain therapeutic maneuvers. It seems reasonable to suppose that gouty subjects, normoexcretors of uric acid as well as overexcretors, can dispose of their endogenous loads of uric acid with not less than the normal dispatch with which they eliminate larger and more rapidly imposed exogenous uric acid loads. Nevertheless, it is evident that although increased elimination of uric acid via the gut seems to be the rule in gout [22], the majority of gouty subjects are normoexcretors of urinary uric acid. To resolve this dilemma posed by the gouty normoexcretor of uric acid, it has been variously proposed that uric acid is not, in fact, produced in excess, a view increasingly difficult to reconcile, however, with the isotope data accumulating in many such cases; or that there is tubular adaptation to protracted natural hyperuricemia, an adaptation which somehow promptly vanishes when even a small extraneous load of uric acid is introduced; or that there is abnormally augmented tubular reabsorption and/or defective tubular secretion of uric acid. Such a presumptive tubular defect presumably would be associated with overproduction of uric acid, otherwise the U,,V in gout would be consistently lower than normal, and it is not. At the heart of the case for an innate abnormality in renal tubular transfer of uric acid in gout is the assumption that, at equivalent F UT, there should be equivalence of U,,V, whereas this is not found, indeed F,, and U,,V may be strikingly dissociated. It is inferred by many that T,, therefore is abnormal in gout, on the premise that T,, = F,, - U,,V, as defined by the hypothesis that limits regulation of renal excretion of uric acid to glomerular filtration and tubular reabsorption. This deduction does not necessarily follow, however, if one applies the tenets of the filtration-reabsorption-secretion hypothesis of regulation of urinary excretion of uric acid in man, which was suggested in our prior study of renal function in gout [ 141. In this latter view U,,V, except under conditions to be mentioned, derives virtually entirely from VOL.

33,

DECEMBER

1962

in Gout-I%

et al.

841

(active) tubular secretion, and F,, is almost completely (actively) reabsorbed. U,,V therefore is not a fraction of F,,, i.e., U,,V is not any fixed proportion of F,, which normally escapes tubular reabsorption, but is determined independently of F,,, primarily by the factors that control the magnitude of tubular secretion of uric acid, modified as will be discussed. The true T,, is assumed to be roughly equivalent to F,,, as a first approximation, also modified in certain circumstances to be discussed, Thus, according to the filtration-reabsorption-secretion hypothesis in this form, U,,V is not a simple function of F,,; and T,,, while not directly determinate by over-all clearance studies, may be assumed to approximate F,, under ordinary circumstances. The evidence for tubular secretion of uric acid by the mammalian kidney, summarized elsewhere [23], admittedly still is sparse. In man, the direct argument rests chiefly upon the demonstration of U,,V/F,, > 1.0 under appropriate experimental conditions; to be sure, excreted: filtered uric acid ratios only up to 1.23 could be attained, and achievement even of these meager excesses required considerable distortion of the normal processes of uric acid excretion by introducing heavy uric acid loads, with simultaneous suppression of tubular reabsorption of uric acid by uricosuric agents, and vigorous mannitol diuresis [24]. It has been demonstrated further that U,,V is reduced almost to the vanishing point by a 3 gm. dose of pyrazinoic acid (or its amide), a drug which has been shown by stop-flow studies in the dog [I91 to inhibit tubular secretion of uric acid. The indirect argument is based chiefly on the convenience of the assumption of tubular secretion of uric acid in man to explain the paradoxical effects of salicylate [25] and other compounds on uric acid excretion. Should this current filtration-reabsorptionsecretion hypothesis prove to be substantially correct, it will be necessary to modify certain hallowed conventions, long ingrained, in the interpretation of the renal clearance of uric acid. Examination of the recent literature suggests that this transition is already in process, but far from complete, as will be apparent from a consideration of redefined terms. hyFW. The filtration-reabsorption-secretion pothesis accepts the well established premise wholly filtrable at the that P,, is virtually glomerulus [23,26], hence F,, may be equated

Renal Function with P,, X GFR. In this context P,, refers to the median renal arterial P,, of clearance collection periods, although conventionally estimated in blood more conveniently procured from an antecubital vein at the clearance midpoint. This is permissible under natural steady state conditions but equivalence cannot be taken for granted after the customary rather brief period allowed for equilibration following rapid delivery of a large uric acid load intravenously, even at a constant rate. A check on this point in our own experiments indicates, that such discrepancies between however, (antecubital) venous P,, and (brachial) arterial P,, as may occur are small and cannot be held chiefly responsible for the dissociation of U,,V and F,, noted in non-gouty subjects after uric acid loading and in gouty subjects with or without extraneous uric acid loads. In considering the relation of F,, to U,,V, comparatively little attention has been paid to alterations in the GFR component of the F,,; in fact, the influence of this variable has been negated purposely by limiting clearance studies largely to subjects with GFR within the limits of normal variation for the age spans in question. It is apparent, however, from even the three patients mentioned here (H. G. and S. D., Table I; W. N., Table III) that the dissociation of F,, and U,,V may be striking indeed as a result of reduced GFR. c 2(r* Often considered to be a measure solely of the effectiveness of the kidneys ineliminating uric acid, C,, in fact may be affected markedly by extrarenal factors, as shown by the direct influence of uric acid loading on both P,, and U,,V. Derived parameters of C,, lose much of their physiologic meaning in the transition from the filtration-reabsorption hypothesis to the filtration-reabsorption-secretion hypothesis. For which is equivalent to example, C,,/GFR, hitherto that appreciable fraction &V/F,,, of the filtered uric acid which is excreted, has this connotation no longer when U,,V derives virtually entirely from tubular secretion, but becomes simply a mathematical ratio of no particular physiologic significance. Similarly, 1 - C,,/GFR, which is equivalent to T,,/F,,, simply signifies approximate unity when virtually all the filtered uric acid is reabsorbed. T yr and Reabsorfitive Tm,,. Since bidirectional fluxes across the tubules cannot be separately measured by over-all clearance technics, whatever physiologic significance attaches to the

in Gout -Yii

et al.

calculated in apparent “T”Ur, as customarily man by difference, is limited to net terms that under some conditions, such as rapid uric acid loading, may be quite at variance with the absolute, true T,,. According to the filtrationreabsorption-secretion hypothesis, the true T,, ordinarily can be approximated more closely by equating it with F,,. This is not permissible, of course, when tubular reabsorption of uric acid is impaired, whether by disease or design (uricosuric drugs). Nor is the assumption warranted under conditions of inordinately rapid exogenous or endogenous uric acid loading and rapid rates of urine flow; in these latter circumstances an appreciable proportion of the filtered uric acid may well escape reabsorption and thus contribute to the excreted uric acid. Moreover, particularly since the tubular segment in which secretion of uric acid occurs in man has not been identified securely, it is impossible to estimate how much secreted uric acid subsequently is reabsorbed, actively or (in acid urine) passively. In the light of presently available evidence of tubular secretion of uric acid in man, the reabsorptive Tmur as determined in both gouty and non-gouty subjects is apparent only, and should be considered to be the net resultant of concomitant reabsorption and secretion, in indeterminate proportions which vary with the rate and magnitude of uric acid loading, as indicated by a comparison of Figures 1 and 2. Under the usual conditions of spontaneous endogenous loading and normal urine flow, the true tubular reabsorptive capacity for uric acid evidently is considerably greater, in both nongouty and gouty man, than the apparent reabsorptive Tmu, measured under conditions of maximal tubular stress, after rapid loading to unnaturally high levels and at forced diuresis. This is shown clearly in Figure 1, which gives no evidence that the reabsorptive Tmur is being approached, even after administration of RNA to both gouty and non-gouty subjects, at F,, of 15 to 19 mg. per minute. So large indeed does the tubular reabsorptive capacity for uric acid in man appear to be that it seems quite reasonable to assume that T,, approximates F,, at ordinary filtered uric acid loads. Certainly the relatively low affinity of the relevant tubular transport system for uric acid postulated by Berliner et al. [6] to account for the marked splay in uric acid titration curves and urinary excretion of uric acid even at low endogenous AMERICAN

JOURNAL

OF

M&DICINE,

Renal Function loads need no longer be assumed in view of the evidence for tubular secretion of uric acid. Tubular Secretion of Uric Acid and the Secretory The rate and magnitude of tubular Tm,. secretion of uric acid also cannot be measured by over-all clearance technics, hence the present study can offer no comparative figures for gouty and non-gouty subjects in this respect-other means must be found for this critical information. It is shown, however, that pyrazinoic acid, a potent inhibitor of tubular secretion of uric acid, markedly diminishes the increased elimination of uric acid that ensues after imposition of large extraneous loads. This is taken to signify that the renal tubules of gouty subjects as well as normal man are quite capable of secreting uric acid in quantities far larger than they are called upon to dispose of under natural circumstances. Therefore it does not appear that the seemingly sluggish secretory activity of the tubules in the gouty normoexcretor can be attributed to any innate deficiency in the mechanisms of uric acid transfer from the peritubular fluid to the tubular lumen; surely not because the secretory Tm,,, which is as yet undefined in both non-gouty and gouty subjects, is exceeded by the endogenous loads of uric acid usually delivered to the kidneys. While thus indicating that the capacity of the renal tubules in both normal and gouty man for secretion of uric acid is large, the present study throws no light on the precise transfer mechanisms involved, or the factors that regulate them under conditions of natural or artificial uric acid loading.

SUMMARY

Thirteen non-gouty and twelve gouty men to whose regular diet was added 4 gm. of ribonucleic acid (RNA) daily, developed increases in plasma uric acid, urinary excretion of uric acid and derived parameters, without significant differences in the mean increments in non-gouty and gouty subjects. Ten non-gouty and seventeen gouty men were given intravenous injections of 1 .l to 2.5 gm. uric acid to impose even greater demands upon the tubular mechanisms for transfer of uric acid, and again the mean increments in the urinary excretion of uric acid and uric acid clearance in non-gouty and gouty subjects were indistinguishable. Pyrazinoic acid, a potent inhibitor of tubular secretion of uric acid, was found to suppress the urinary eliminaVOL.

33,

DECEMBER

1962

in Gout-E

et al.

843

tion of rapidly infused uric acid in gouty and non-gouty subjects alike. The data indicate that gouty subjects can excrete large extraneous loads of uric acid with as much facility as normal man, and support the view that this obtains also for the usually smaller and more slowly delivered endogenous uric acid loads natural to gout. The results thus argue against any intrinsic defect, peculiar to gout, in the renal mechanisms for excretion of uric acid. Briefly reviewed is the evidence that tubular secretion of uric acid occurs in non-gouty and gouty man, indeed that virtually all the uric acid appearing in the urine ordinarily derives from tubular secretion, hence virtually ail the filtered uric acid ordinarily must be reabsorbed. It is pointed out that in this version of the filtration-reabsorption-secretion hypothesis there need be no simple relationship between the filtered and excreted uric acid, a dissociation found in gout that has been interpreted by others as indicating a primary tubular defect in transfer of uric acid. The implications of the filtration-reabsorption-secretion hypothesis in respect to other aspects of the renal regulation of uric acid are discussed in relation to excretion of uric acid in normal and gouty man under natural and artificial conditions of uric acid loading. The present study, limited to over-all clearances, gives no information as to the precise mechanisms or quantitative aspects of tubular secretion of uric acid in normal or gouty man, nor does it explain just how renal excretion of large and rapidly imposed uric acid loads is regulated. REFERENCES

1. BR~CHNER-MORTENSEN,K. Uric acid in blood and urine. Acta med. scandinau., supp. 84, 1937. 2. BR@HNER-MORTENSEN, K. On variations in the uric acid clearance after administration of purine, with special reference to the threshold problem. Acta med. scandinau., 99: 525, 1939. 3. BR~CHNER-MORTENSEN,K. Diagnosis of gout. Acta &cd. scandinau., 99: 538, 1939.4. NUGENT. C. A. and TYLER. F. H. The renal excretion of uric acid in patients with gout and in nongouty subjects. J. Clin. Invest., 38: 1890, 1959. 5. SEEDMILLER, J. E., GRAYZEL, A. I., HOWELL, R. R. and PLATO, C. The renal excretion of uric acid in gout. J. Clin. Invest., 41: 1094, 1962. 6. BERLINER, R. W., HILTON, J. G., Yij, T. F. and KENNEDY, T. J. The renal mechanism for urate excretion in man. J. Clin. invest., 29: 396.,. 1950. 7. ZGLLNER, N. Moderne Gichtprobleme. Atiologie,

Renal Function Pathogenese. K&n. Ergebn. inn. med. Kinderh., 14: 321, 1960. 8. THANNHAUSER, S. J. The pathogenesis of gout. Metabolrsm, 5: 582, 1956. 9. OGRYZLO, M. A. The renal factor in the etiology of primary gout. Canad. M. A. J., 83: 1326,196O. 10. WYNGAARDEN,J. B. and JONES,0. W. The pathogenesis of gout. M. Clin. North American, 45: 1241, 1961. 11. BISHOP, C. The renal regulation of urate excretion and its relationship to the etiology of gout. AIR 5: 5, 1962. 12. SORENSEN,L. B. The pathogenesis of gout. Arch. Znt. Med., 109: 379, 1962. 13. BERGER, L., Yii, T. F. and GUTMAN, A. B. Renal excretion of urate loads in gouty and nongouty man. Fed. Proc., 21: 434, 1962. 14. GUTMAN,A. B. and Yii, T. F. Renal function in gout. With a commentary on the renal regulation of urate excretion, and the role of the kidney in the pathogenesis of gout. Am. J. Med., 23: 600, 1957. 15. PRAETORIUS,E. An enzymatic method for the determination of uric acid by ultra-violet spectrophotometry. Scandinav. J. Clin. & Lab. Znuest., 1: 222, 1949. 16. SCHREINER,G. E. Determination of inulin by means of resorcinol. Proc. Sot. Exper. Biol. B Med., 74: 117,195o. 17. LATHEM, W. and RODNAN, G. P. The demonstration of an alteration in renal urate transport in gout. Arthritis B Rheumat., 4: 425, 1961. 18. Yii, T. F., BERGER, L., STONE, D. J., WOLF, J. and GUTMAN, A. B. Effect of pyrazinamide and

in Gout-E

19.

20.

21.

22.

23.

24.

25.

26.

et al.

pyrazinoic acid on urate clearance and other discrete renal functions. Proc. Sot. Exfer. Biol. @ Med., 96: 264, 1957. Yii, T. F., BERGER, L. and GUTMAN,A. B. Suppression of tubular secretion of urate by pyrazinamide in the dog. Proc. Sot. Exper. Biol. & Med., 107: 905, 1961. GUTMAN,A. B., Yii, T. F., BLACXC,H., YALOW, R. S. and BERSON,S. A. Incorporation of glycine-l-C”, glycine-2-C” and glycine-N*6 into uric acid in normal and gouty subjects. Am. J. Med., 25: 917, 1958. GUTMAN, A. B. and Yfi, T. F. The case for the metabolic origin of hyperuricemia in primary gout. Am. J. Med., in press. SORENSEN,L. B. The elimination of uric acid in man studied by means of Ci4-labeled uric acid. Uricolysis. Scandinav. J. Clin. & Lab. Invest., supp. 54,196O. GUTMAN, A. B. and Yti, T. F. A three-component system for regulation of renal excretion of uric acid in man. Tr. A. Am. Physicians, 74: 353, 1961. GUTMAN, A. B., Yii, T. F. and BERGER, L. Tubular secretion of urate in man. J. Clin. Invest., 38: 1778, 1959. Yti, T. F. and GUTMAN, A. B. A study of the paradoxical effects of salicylate in low, intermediate and high dosage on the renal mechanisms for excretion of urate in man. J. Clin. Invest., 38: 1298, 1959. Yii, T. F. and GUTMAN, A. B. Ultrafiltrability of plasma urate in man. Proc. Sot. Exper. Biol. & Med., 84: 21, 1953.

AMERICAN

JOURNAL

OF

MEDICINE