Chapter IY

Renal Excretion of Uric Acid in Normal and Gouty Man*

B. GUTMAN,M.D,
By ALEXANDER
Dept. of Medicine, Mount Sinai Hospital

The role of the kidney in the genesis of hyperuricemia in primary gout is

still one of the most difficult and controversial aspects of the gout problem.
The many uncertainties in this connection do not arise so much from dis-
crepancies in the renal data gathered in different laboratories, which are, in
general, quite consistent, but from differences in interpretation. Proper in-
terpretation of the data in gout is all the more difficult because of the com-
plexities of the renal mechanisms for regulation of uric acid excretion in normal
man, presently believed to involve glomerular filtration, “active” tubular re-
absorption, and “active” tubular secretion of uric acid. Moreover, in the many
cases of gout in which overproduction of uric acid has been demonstrated by
the use of isotopes, it is necessary to project the operation of the kidney to
these circumstances, which are not as simple to reproduce faithfully by experi-
ment as might be supposed.
The principal arguments for a primary role of the kidneys in the causation
of hyperuricemia in gout are: 1. The usual isotope procedures for estimating
the rate of uric acid formation do not reveal overproduction in a substantial
proportion of cases of primary gout, implicating the kidneys by exclusion. The
validity of this inference will not be considered here. 2. The urinary excretion
of uric acid usually is not increased, at least not in proportion to the increase
in plasma urate concentration, notably in gouty normoexcretors of uric acid
who constitute some 70 or 75 per cent of the gouty population. Consequently
the uric acid clearance (U,,,V/P,,, ), which is conspicuously low in normal
man, tends to be even lower in gouty man. For example, in one relevant study
C,,, was found to average 8.7 2 2.5 ml./min. in normal men, and 7.5 k 2.4
ml./min. in gouty men.l This is a small difference, with much overlap, never-
theless it is significant because it reflects what has been well established,
namely the divergence in the levels of urinary and plasma uric acid present in
the majority of cases of gout.
We are conditioned, from the experience with urea clearance, creatinine
clearance, etc., to regard any decline in clearance as prima facie evidence of
a deterioration in renal function. We are apt also to ascribe any change in
renal clearance to some intrinsic alteration in the condition of the kidneys,
whereas in fact the clearance may be markedly affected by a variety of whollv
extrarenal factors. It is therefore not surprising that the generally lower C1ir
and C u l / C , m l ~in
, n gout has usually been looked upon as signifying an in-
trinsic renal defect in excretion of uric acid. This is, however, an oversimplified

*Based on studies supported in part by a grant-in-aid, A-162, from the National In-
stitute of Arthritis and Metabolic Diseases, National Institutes of Health, U. S. Public
Health Service.
665

ARTHRITISAND RHEUMATISM,VOL. 8, NO. 5--!?ART 1 ( C k T O B E R ) , 1965

666 GOUT AND PURINE METABOLISM

view of the complex operations of the kidney, which is as much concerned with
conservation, when indicated, as with elimination. Moreover, the interpreta-
tion does not take sufficiently into account the possible effects on the renal
clearance of uric acid of such important extrarenal factors as metabolic over-
production of uric acid.
Strange as it may seem, although uric acid evidently is a useless metabolic
end-product in man, it appears to fall in the category of substances that are
zealously conserved by the kidney. This is reflected in the strikingly low uric
acid clearance of normal man, usually less than 10 ml./min. The reasons for
this low C , , in normal man, and the mechanisms by which it is brought about,
deserve closer scrutiny than they have yet received, all the more in the present
context because the same reasons and mechanisms seem to apply, we believe,
to the operation of the kidney in gout.
The low C,, of normal man surely is not due to any insufficiency in the
quantity of urate filtered at the glomerulus. It is now generally agreed that
the plasma urate is not bound to plasma proteins to any measurable extent,
hence must be freely filtered at the glomerulus. Accepting this premise, it may
be calculated that the filtered urate load presented to the tubules is large,
averaging 6.7 mg./min. in one study.l The quantity of uric acid appearing in
the urine, however, is small, approximately 0.5 mg./min. under the customary
conditions of clearance measurements,l evidently as a result of reabsorption
by the tubules. It was previously thought that the reabsorbate could be very
simply calculated as the difference between the filtered urate load and the
quantity of uric acid excreted in the urine, a calculation that indicates that
90-95 per cent of the filtered urate load normally is reabsorbed by the tubules.
But high as this figure for tubular reabsorption is, it is nevertheless too low an
estimate because, in view of the evidence for tubular secretion of uric acid
in normal man, uric acid probably is added to, as well as abstracted from the
tubular lumen by the tubules, hence any over-all clearance measurement can
yield only net tubular transport data. Indeed, for reasons stated elsewhere:
we think it likely that in normal man under ordinary circumstances, virtually
all of the urate filtered at the glomeruli is reabsorbed by the tubules, conse-
quently the uric acid appearing in the urine derives almost entirely from
tubular secretion-not, as previously supposed, from filtered urate that has
escaped reabsorption by the tubules, in a small but fixed proportion of the
filtered urate load. This would not apply to normal man under certain un-
usual circumstances, such as acute loading of uric acid by infusion or by in-
gestion of uric acid precursors, or after administration of a uricosuric drug; in
these situations, tubular reabsorption of the filtered urate would be expected
to be less complete and more variable than otherwise.
Consistent with this view, i.e., that in normal man under ordinary circum-
stances virtually all of the urate filtered at the glomerulus is reabsorbed, and
conceivably also some that is secreted by the tubules, is the large tubular
reabsorptive capacity (Tm) for urate in normal man, estimated by Berliner
et aL3 to approximate a mean of some 15 mg./min./1.73M.2 Even this high
figure, which is more than twice the rate at which the filtered urate normally
RENAL EXCRETION OF URIC ACID 667

is presented to the tubules, is probably too low, since it does not take into
account the concomitant secretion of urate by the tubules. In fact, so efficient
is tubular reabsorption of the filtered urate, if all our assumptions are correct,
that normally, were it not for tubular secretion of urate, virtually no uric
acid at all would be eliminated by way of the kidneys, but only by way of the
gut, and the renal clearance of uric acid, like that of glucose, would approach
zero. Even with the aid of tubular secretion of urate, which evidently occurs at
a sluggish rate in man, the renal clearance of uric acid is usually less than
10 ml./min., as already mentioned.
This pattern of glomerular filtration and tubular reabsorption is familiar
enough in relation to many other substances, but these are all metabolically
useful, whereas uric acid is not. The explanation for this seemingly eccentric
behavior of the kidney in respect to uric acid in man is not hard to find. In
most mammals the filtered urate is reabsorbed by the tubules for conversion
by uricase, chiefly in the liver, to more readily soluble allantoin, which is
then promptly excreted in the urine; in this way relatively low concentrations
of difficultly soluble uric acid are maintained both in the urine and in the
plasma. As the result of a genetic mutation in man’s more immediate evolu-
tionary forebears, uricase disappeared from the tissues, and with it the main
degradative pathway of uric acid, thus precipitously increasing the body urate
pool. However, even though uricase has been lost in man, renal tubular reab-
sorption of the filtered urate continues. Indeed it could hardly be otherwise
since if all or the greater part of the uric acid formed endogenously (averag-
ing about 750 mg./day in normal man), together with that derived from pre-
formed purines taken with large meals, were permitted to pass freely into the
urine, the mutation leading to loss of uricase might have proved lethal, since
renal excretion of uric acid would increase greatly, and with it the hazard
of clogging the urinary collecting apparatus with uric acid precipitate.
Under these circumstances, it is understandable that the appropriate func-
tion of the kidney, in respect to uric acid in normal man, is not to dump uric
acid as rapidly as it is produced into the urine, but rather to modulate its
elimination. This is accomplished, apparently, by: (1) the large tubular reab-
sorptive capacity for urate; ( 2 ) the slow rate of tubular secretion of uric
acid; and ( 3 ) diversion of urate, reabsorbed by the tubules and recycled, into
the gut, where 1/4 to 113 or more of the total uric acid production is degraded
vicariously by the bacterial flora, which possesses the necessary uricase, al-
lantoinase, etc. The combined clearances of uric acid via the kidney and gut
thus maintain the rate of disposal of uric acid in the urine within ordinarily
safe limits.
In so doing, however, a steady state is re-established at distinctly higher
plasma urate levels, at a mean of about 5.0 mg. per cent in normal men, devoid
of tissue uricase, as compared to about 0.3 mg. per cent in the dog, a mammal
possessing uricase. The net effect on the renal clearance of uric acid is to
lower it, since the renal excretion of uric acid is reduced at the expense (and
in the face) of a higher plasma urate concentration. It would thus appear that,
contrary to the usual renal regulatory pattern, preservation of the composition
668 GOUT AND PURINE METABOLISM

of the urine, in respect to uric acid, seems to take precedence even Over Pres-
ervation of the composition of the internal fluid environment, in respect to Uric
acid.
The relative hyperuricemia of normal man is, of course, not a consequence
of any renal abnormality but reflects the normal response of the human kidney
to an extrarenal alteration which is the metabolic equivalent of increased uric
acid production, namely the loss of the main degradative pathway of uric
acid, tissue uricase. In this respect, gouty man is in double jeopardy. Superim-
posed upon the species-wide loss of uricase and its attendant relative hyper-
uricemia, which sets the stage for gout, there appears to be in most cases of
primary gout another inborn error of metabolism, of as yet uncertain nature,
which adds the onus of overproduction of uric acid to that of the inherent
incapacity to degrade uric acid. There ensues a further increase in the body
pool of urate, with its threat of urate precipitates in susceptible tissues, and a
further increase in the plasma urate and filtered urate load, which threatens
to breach the renal dike that holds back the flood of uric acid from over-
whelming the excretory apparatus.
The kidney seems to meet this additional challenge in much the same way
that it adjusts to the absence of tissue uricase in normal man, although some-
times not as successfully. The modus operandi can be satisfactorily explained,
we believe, by an analysis of the presumptive role of glomerular filtration,
tubular reabsorption and tubular secretion of uric acid under the circumstances
of superimposed metabolic overproduction of uric acid.
The GFR is substantially reduced in some gouty subjects with marked
renal damage, whether the result of renal disorders other than gout and/or
the effects of uric acid calculi or tophaceous deposits in the kidney. In such
instances of glomerular insufficiency there is more or less retention of all
nitrogenous wastes at the level of the glomeruli, including uric acid. These pa-
tients with gout and overt kidney damage suffer a further reduction in uri-
nary excretion of uric acid, further enhancement of their hyperuricemia, and
a consequent further decrease in renal clearance of uric acid, clearly of renal
origin. For the most part, however, the GFR of gouty subjects is within the
range of variation of that of normal man of equal age.l Since the GFR usually
is not unduly reduced, and the plasma urate is higher than normal, and just as
freely ultrafilterable, the filtered urate load usually exceeds the normal. In
one series,l the mean filtered urate load in gouty subjects was found to be 10.1
* 2.8 mg./min., about 50 per cent greater than the normal mean.
Large though such augmented filtered urate loads are, they are nevertheless
smaller than the tubular capacity of the kidney of normal man, and also ap-
parently of gouty man,4,5to reabsorb urate. Clearance data indicate that, con-
fronted with a larger than normal urate load, the tubules can and do reabsorb
more urate, in both normal and gouty man, although probably less completely
when the rate of filtration of urate at the glomerulus becomes inordinately
high. By abstracting more urate from the tubular fluid, and returning it to the
peritubular circulation, the tubules maintain lower urinary and higher plasma
levels of urate than would otherwise obtain, and the urate clearance conse-
quently is lower than it otherwise would be. We do not believe that tubular
RENAL EXCRETION OF URIC ACID 669

reabsorption of larger than normal filtered urate loads, or the resultant fall in
urate clearance under these circumstances, should be construed as signifying
abnormal renal function in respect to uric acid, but rather as the anticipated
response of the normal human kidney to metabolic overproduction of uric
acid.
Tubular secretion of urate evidently does not usually increase, in the pres-
ence of the hyperuricemia of gout, to a degree sufficient to compensate for the
enhanced tubular reabsorption of the augmented filtered urate loads; if it
did, the urinary excretion of uric acid in gout would more frequently be
greater than normal, the plasma urate concentration would be less increased
or not at all, and the uric acid clsarance would not be further depressed. The
expectation that tubular secretion of urate would increase to such an extent
appcars unreasonable, however, because in normal man some 10-20 times
more uric acid is reabsorbed by the tubules (as estimated roughly from the
magnitude of the filtered urate load) than is secreted (as estimated even more
roughly from the excreted uric acid). We therefore do not believe it necessary
to assume a priori that tubular secretion of uric acid ordinarily is impaired in
primary gout. This view cannot be put to the test for the present because
it has not yet been possible to devise means for the direct measurement of
tubular secretion of uric acid in normal or gouty man. It has been shown, how-
ever, that in gout the renal tubules are capable of secreting markedly in-
creased quantities of uric acid when it is rapidly infused, since the administra-
tion of pyrazinamide under these conditions sharply reduces the otherwise
greatly accelerated rate of urinary elimination of uric acid.4
It would thus appear that in gouty, as in normal man, the innately large
tubular reabsorptive capacity and slow secretory rate for urate, and apparent-
ly increased overflow of urate into the gut for vicarious degradation there by
bacteria, all operate in effect to reduce the hazard of urinary tract obstruction
by uric acid precipitate. As a result, the urinary elimination of uric acid is
successfully contained within the broad limits of normal variation in some 70
or 75 per cent of cases of primary gout (gouty nonnoexcretors of uric acid).
In most of the remaining gouty subjects, in whom appropriate isotope studies
invariably indicate a particularly pronounced acceleration in the rate of uric
acid production, the kidneys cannot quite cope with the flood, and the urinary
excretion of uric acid, because of less complete tubular reabsorption and/or
increased tubular secretion of uric acid, is excessive (gouty overexcretors of
uric acid). A similar escape of excess uric acid into the urine, and probably
for much the same reasons, occurs after acute parenteral or oral loading with
uric acid or its precursors; so far as we could determine, to about the same
extent in both normal and gouty man.4
The hazard of excessive urinary excretion of uric acid is indicated by the
accompanying prevalence of uric acid precipitate in the urinary tract. The in-
cidence of uric acid stone in overexcretors of uric acid, whether subjects with
primary or secondary gout, is about 40 per cent in our over-all experience.
The incidence of uric acid stone in gouty normoexcretors of uric acid is stated
by most observers to be 10-20 per cent. Even this latter figure is strikingly
higher than the incidence of uric acid urolithiasis in nongouty men, believed
670 GOUT AND PURINE METABOLISM

to approximate 0.01 per cent, One explanation for this marked discrepancy,
which is not attributable to grossly excessive urinary excretion of uric acid, is
the prevalence of distinctly acid urine in the gouty population. For reasons set
forth elsewhere, a factor contributing to this low urine pH is believed to be
an intrinsic deficiency in renal production of ammonia in the gouty.
To summarize, the kidneys do play an important role in maintaining the
relatively high plasma urate concentration of normal man, and the even higher
plasma urate concentrations of gouty man. In normal man, the role of the
kidneys in respect to uric acid is more comprehensible if looked upon as in-
tended to maintain a relatively slow rate of elimination of uric acid in the
urine, necessitated by the evolutionary loss of tissue uricase. This is ac-
complished, and the hazard of uric acid stone formation minimized, but at the
cost of a considerably higher plasma urate concentration than obtains in other
mammals possessing uricase. In gouty man, assuming metabolic overproduc-
tion of uric acid (admittedly not proved in a substantial minority of cases),
the role of the kidneys is considered to be much the same, and to be accom-
plished in much the same manner as in normal man; we do not believe that it
is necessary to postulate any intrinsic abnormality in the renal tubular trans-
fer of uric acid as a characteristic of primary gout. In the steady state that
ensues, however, while the hazard of uric acid stone formation is more or less
successfully reduced, the plasma urate is maintained at even higher levels.
This initiates a new hazard, that of tophaceous deposits in susceptible tissues,
and the accompanying manifestations of the gouty state.
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1. Gutman, A. B., and Yii, T. F.: Renal and Kennedy, T. J.: The Renal Mech-
Function in Gout. With a Commen- anism for Urate Excretion in Man. J.
tary on the Renal Regulation of Urate Clin. Invest. 29:396, 1950.
Excretion, and the Role of the Kidney 4. Yii, T. F., Berger, L., and Gutman, A.
in the Pathogenesis of Gout. Am. J . B.: Renal Function in Gout. 11. Effect
Med. 233300, 1957. of Uric Acid Loading on Renal Excre-
2. -, and -: A Three-Component System tion of Uric Acid. Am. J. M a d . 33:
for Regulation of Renal Excretion of 829, 1962.
Uric Acid in Man. Trans. Assoc. Am. 5. Lathem, W., and Rodnan, G. P.: Im-
Physicians 74:353, 1961. pairment of Uric Acid Excretion in
3. Berliner, R. W., Hilton, J. G., Yii, T. F., Gout. J. Clin. Invest. 41:1955, 1962.