THE RENAL THEORY OF GOUT
This time-worn hypothesis as to the pathogeny of gout has, perhaps,
provoked more controversy than any other etiological problem in the
sphere of clinical medicine. Nor, unfortunately, despite the endless
laborious research expended upon its solution, the dialectic skill
exercised in attempts at its elucidation, can we claim even to-day that
its complexities have been wholly unravelled. But, perhaps it will be
wiser to postpone decision, pending detailed analysis of the several
grounds upon which the theory of the primary renal origin of gout rests.
Broadly speaking, the arguments adduced tend to concern themselves with
or rather to arise out of certain apparent _abnormalities_ in _uric acid
excretion_, currently held distinctive of gout, certain resemblances also
suggestive of a hidden _nexus_ between _gout_ and _renal_ disorders,
viz.:—
(1) _Anomalies in uric acid excretion in gout._
(2) _Uricæmia, a condition common to gout and nephritis._
(3) _Uratosis, a feature also common to both disorders._
(4) _Occasional co-existence of gout and nephritis._
ANOMALIES IN URIC ACID EXCRETION IN GOUT
As to the variations in _purin_ excretion that occur in _gout_, it must
be admitted that, notwithstanding the magnitude of the researches, no
very striking departures from normal have emerged. Such as have been
elicited occur in relation to (_a_) the acute paroxysm, (_b_) the
excretion of exogenous purin.
_The Acute Paroxysm._—Garrod, it will be recalled, claimed that during
an _acute_ attack of gout the excretion of uric acid was diminished, and
that coincidently therewith the uric acid blood content rose. But these
findings in the _blood_ and _urine_, which constituted the basis of his
hypothesis that gout was due to _renal inadequacy_, have, as previously
noted, been categorically disproved.
Turning to the more modern findings upon which such refutation of
Garrod’s view was achieved, one point emerges that appears to favour
the assumption of _renal block_. It is that, _one or two days prior to
an acute attack_, an appreciable _decline_ in the output of uric acid
occurs.
But this, be it noted, is neither so marked nor so constant as the
subsequent _increase_; in short, at the zenith of an acute attack, _an
augmented output of uric acid_ ensues. At the very time when presumably
the alleged functional renal impediment would be most pronounced, the
impermeability of the organs for uric acid accentuated! Surely such
behaviour seems scarcely compatible with the supposition that there is
even a temporary diminution in the capacity of the kidney to excrete
uric acid. Does it not in truth constitute strong proof of the reverse?
Moreover, the said vagaries that herald the oncoming and that chequer the
course of the paroxysm are not _invariable_, an obvious _caveat_ against
hasty _etiological_ inferences therefrom. Any tendency thereto should
also be curbed by the reflection that, viewing the character of the uric
acid excretion in gout as a whole, the variations therein are not more
extensive than in _healthy_ individuals, and assuredly, _on the mere
basis of the fluctuations in uric acid excretion_, no diagnosis of gout
is possible.
_Retarded Purin Elimination._—The mainstay in argument, however, as
advanced by more modern advocates of the renal theory of gout, is that a
_retarded output of exogenous purin_ is typical of this disorder; but,
here, again, there is no room for dogmatism. Thus Walker Hall reminds
us that “the quantity of purins present in the food does not overstep
the solubility of urates in the blood-stream, for once the material
is metabolised and ready for removal the amount of blood, so far as
solubility goes, places the whole amount of purins within the reach of
the renal cells in less than twenty-five minutes.” We see, therefore, as
far as _rapidity of transport_ to the kidneys is concerned, there is no
delay in presentation of the opportunity for the excretion of exogenous
purin. While the alleged tardiness of output is attributed to defective
action of the _kidneys_, it is at least equally possible that the delay,
as Walker Hall states, “may be due to a defective or idiosyncratic
nuclear metabolism, which results in the formation of isomeric purins or
incomplete purin combination, and which makes greater demands upon the
selective activities of the renal cells;” for it must be recollected that
as yet we are ignorant as to the exact form in which uric acid circulates
in the blood-stream, whether as _sodium mono-urate_ or in _organic_
combination.
Moreover, experimental _injections of uric acid_ into the _tissues_ or
_veins_ show no impairment in the elimination capacity of the kidneys for
uric acid. Thus, Wells cites evidence that “the kidney in gout shows no
lack of ability to excrete uric acid injected into the tissues.”
Again, given _intravenous_ injection of uric acid into a _normal_
man, its excretion occupies several days, and it fails to appear
_quantitatively_ in the urine. But if administered during a course
of _atophan_, then the _whole_ amount injected is excreted within
twenty-four hours. If the same procedure be followed in a _gouty_
individual, precisely the same results are obtained; in other words, both
normal and gouty kidneys react in identical fashion to atophan. Given
an inherent functional defect, _quâ_ uric acid excretion, in the _gouty
kidney_, one would scarcely expect a wholly _normal_ reaction thereto.
Surely some disparity would be disclosed, some aberration in response as
compared with _normal_ renal organs.
Again, while McLester and others claim that atophan exerts “a selective
stimulating influence on uric acid excretion,” it is quite possible that
its _rôle_ may be otherwise explained. May it not influence the actual
_formation_ of uric acid, or, failing this, the _form_ in which it is
presented to the kidneys for excretion? Nicolaier and Dohrn, indeed,
believe that _atophan_ influences in some way purin metabolism within
the _muscles_ and so leads to _increased formation and excretion of uric
acid_. At any rate, whatever be the explanation of the action of atophan,
the fact that _healthy_ and _gouty_ kidneys react _alike_ thereto cannot
be interpreted as proof of defective capacity for uric acid elimination
in gouty subjects, indeed the reverse.
Moreover, in all our attempts to saddle the kidneys with the
responsibility for the delay in exogenous purin excretion, we are for
ever hampered in that we know not whether the alleged renal impairment
is _primary_ or _secondary_ to the gout. That the kidneys are frequently
functionally inefficient in the _later_ stages of gout may be conceded.
But what of the _initial_ phases of the disorder? Some talk very glibly
of subjects who are, they say, “potentially gouty.” But has the rate
of disposal of ingested purins been investigated in persons suffering
from so-called “goutiness,” or, perhaps more pertinently, in those
individuals, not uncommon, who, while exhibiting _auricular tophi_, have
yet experienced no frank attack of gout?
In this connection we may note that McClure has recently emphasised
the fact that the _kidneys_, in the _later_ stages of gout, are often
_functionally_ deficient, and that, accordingly, the faulty elimination
of exogenous uric acid by gouty persons may be simply the result of such
_functional renal depression_; in other words, not due to gout, but to
the _secondary_ or _associated renal deficiency_. Hence, having regard to
the frequency with which renal inefficiency is met with in gout of any
standing, he is inclined to discount the value of studies of _exogenous
uric acid elimination_ as an aid to the diagnosis of gout. Consequently,
he holds that before the diagnostic status of retarded purin
elimination, as a symptom of gout, can be established, an investigation
of the output of uric acid in the different types of _nephritis_ is
essential.
From the foregoing it will be seen that we stand in urgent need of
further studies of _early_ or _oncoming_ gout and of _early nephritis_
before we can with certitude impeach the _kidneys_ as responsible for
the delay in exogenous purin output. Meanwhile, too, we must be careful
not to overlook the further disconcerting fact, previously adverted to,
that the retardation and diminution of exogenous purin output is not
_invariable_ in gout. Nor, for that matter, is it _peculiar_ to gout,
considerations both of which, if confirmed, will still further discount
the _diagnostic_ significance of this phenomenon.
URICÆMIA IN NEPHRITIS
Von Jaksch and Klemperer noted long since that in chronic interstitial
nephritis urates are always present in the _blood_. Now, according to
Folin and Denis, human blood contains 1·5-2·5 mg. of uric acid per 100
c.c.; but if the eliminating powers of the _kidney_ be deficient, the
uric acid content thereof rises, sometimes to as high as from 15-20 mg.
per 100 c.c.
But more interesting still the fact noted by Fine, viz., that even in
_early_ interstitial nephritis the same feature is well marked, _i.e._,
the blood may contain 4-8 mg. of uric acid per 100 c.c. Indeed, according
to this authority, increase in the _uric acid_ content of the blood is
the first signal of impaired renal efficiency. This, be it noted, without
any coincident proportional increase in the blood content of _urea_ or
_creatinine_. The sequence would appear to indicate that the damaged
organ encounters greater difficulty in excreting _uric acid_ than these
other metabolites.
But, _pari passu_ with the advance of the renal disease, retention of
_urea_ is superadded, and still later _creatinine_. So constant, indeed,
the sequence that, by determining the percentage amount of these three
_metabolites in the blood_, the measure of the renal mischief may be
gauged.
But of striking significance is the further point established by Myers
and Fine, viz., that the blood content, in respect of _uric acid_,
_urea_, and _creatinine_, in _early nephritis_, is an almost exact
replica of that met with in typical cases of _gout_. The same is well
illustrated in the following table, in which the blood content, in
respect of these three metabolites, in cases of gout and early and late
nephritis is contrasted. The percentage of the retained metabolites in
relation to the severity of the case is gauged by the blood pressure
findings.
URIC ACID, UREA N, AND CREATININE OF BLOOD IN GOUT AND EARLY AND LATE
NEPHRITIS
===========================+=====+===========+===========+=========
|Uric | Urea N. |Creatinine.|Systolic
Diagnosis. |acid.|Mg. to 100 | | blood
| |c.c. blood.| |pressure.
---------------------------+-----+-----------+-----------+---------
Typical cases of gout. | 9·5 | 13 | 1·1 | 230
| 8·4 | 12 | 2·2 | 164
| 7·2 | 17 | 2·4 | 200
| 6·8 | 14 | 1·7 |
---------------------------+-----+-----------+-----------+---------
Typical early interstitial | 9·5 | 25 | 2·5 | 185
nephritis. | 8·0 | 37 | 2·7 | 150
| 5·0 | 37 | 3·9 | 130
| 7·1 | 16 | 2·0 |
| 6·6 | 24 | 3·3 | 185
| 6·3 | 18 | 2·1 |
| 8·7 | 20 | 3·6 | 100
| 7·0 | 33 | 2·6 | 117
| 6·3 | 31 | 2·1 |
| 6·3 | 23 | 2·4 | 150
---------------------------+-----+-----------+-----------+---------
Chronic diffuse and | 8·0 | 80 | 4·8 | 240
chronic interstitial | 4·9 | 17 | 2·9 | 170
nephritis. | 8·3 | 72 | 3·2 | 238
| 5·3 | 21 | 1·9 | 145
| 9·5 | 44 | 3·5 | 210
| 2·5 | 19 | 1·9 | 120
| 7·7 | 67 | 3·1 |
| 6·7 | 17 | 1·6 | 165
| 8·3 | 39 | 2·9 |
| 6·5 | 24 | 3·0 | 200
---------------------------+-----+-----------+-----------+---------
Typical fatal chronic |22·4 | 236 | 16·7 | 210
interstitial nephritis. |15·0 | 240 | 20·5 | 225
|14·3 | 263 | 22·2 | 220
|13·0 | 90 | 11·1 | 265
| 8·7 | 144 | 11·0 | 225
---------------------------+-----+-----------+-----------+---------
(Myers and Fine: “Arch. Int. Med.,” 1916.)
The salient feature of the table is, however, the fact that in _early
interstitial nephritis_ the retention of _uric acid_ precedes that of
_urea_ or _creatinine_.
Its importance resides in the reflection that it lends support to those
who contend that _renal change_, leading to failure of excretion of uric
acid, _is the primary cause of gout_; in other words, it gives colour to
Magnus Levy’s contention that the phenomena of gout are referable to “a
deficient and restricted secretory power of the kidney.” The existence
of such a selective excretory incapacity, _i.e._, for _uric acid_, does
not, he considers, predicate a genuine nephritis. He maintains that such
disability on the part of the kidney for uric acid excretion may exist
without _morphological_ change; in other words, he thinks it conceivable
that a _single_ function of the kidney can become almost exclusively
insufficient, though later real damage to the organ and a nephritis
frequently follow.
Reflecting on the above theory, it is obvious that, if carried to its
logical conclusion, it would appear to postulate that gout is nothing
more than a form of _renal disorder_, marked simply by _functional
inability to excrete uric acid_. The postulate is no mean one, for,
as Sir Archibald Garrod says, “If the fault is in the kidneys alone,
gout must be removed once and for all from the category of metabolic
disorders, and placed among the sequelæ of renal inadequacy, at least in
so far as the uric acid phenomena of the disease are concerned.”
Furthermore, Levy’s hypothesis involves the assumption that the excreting
functions of the kidney for _uric acid and urea_ are separate and
independent of each other, and to discussion of this we now pass on.
THE RELATIONSHIP, IF ANY, BETWEEN THE AMOUNTS OF URIC ACID AND OF UREA,
AND TOTAL NON-PROTEIN NITROGEN IN HUMAN BLOOD
Taking samples of human blood from (1) _unselected insane_ subjects and
(2) _chronic nephritics_, Folin and Denis determined the amounts therein
of urea, total non-protein nitrogen, and uric acid. The figures obtained
showed that “there is apparently no relationship between the amount of
uric acid and the amount of urea or total non-protein in nitrogen, in
human blood.”
That such a discrepancy should obtain is doubtless of profound though as
yet imperfectly grasped significance. These authorities rightly assume
that, since the kidney is practically the sole avenue for nitrogenous
waste excretion, it follows that the _urea_ and _total non-protein
nitrogen_ of the _blood_ must in the main be inversely proportional to
the general efficiency of the _renal_ organs. Then, obviously, the same
law, too, should, in lack of some other plausible explanation, govern the
excretion of _uric acid_ also. But, as the above generalisation portends,
it is apparently not so.
Fortunately, Folin and Denis prosecuted their study still further,
taking in examples of _gout_ (with and without clinically recognisable
_nephritis_), also instances of _leukæmia_ and _lead poisoning_.
The blood, again, in these disorders betrayed the same peculiarity,
viz., that while containing an excess of uric acid, it did not contain
correspondingly large amounts of urea or other waste nitrogen; in other
words, the findings in the blood in gout were in full accord with the
above generalisation, _i.e._, _the apparent lack of any relationship
between the amount of uric acid and that of urea or total non-protein
nitrogen in the blood_.
Now in _leukæmia_ the cause of the _uricæmia_ is _over-production_ of
uric acid, but in this instance the same is correlated with an increased
_elimination_ of uric acid by the kidneys.
Turning to lead poisoning, the medicinal administration of lead acetate
results in a great _diminution_ of uric acid excretion, a response
consistent with the view that lead inhibits the excretory power of the
kidney for _uric acid_, the change, at first functional, becoming later
organic; for it is held that the _uricæmia_, associated with plumbism,
proves that the action of the lead is not due to inhibition of the
formation of uric acid.
Lastly, as to gout, opinion still wavers as to whether or not the
excretion of uric acid in this disorder is appreciably _lowered_. On
the other hand, it is significant that the reverse is never claimed,
viz., that in gout the uric acid output is _abnormally raised_. Now, as
we saw in _leukæmia_, the _high uric acid blood content_ is accompanied
by a correspondingly _high uric acid output_; but, on the contrary, in
gout, despite the _accumulation of uric acid in the blood_, there is _no
parallel increase in its elimination_.
Reflecting on the above considerations, Folin and Denis claim that
“the mere fact that the uric acid may accumulate in the blood of the
gouty without being accompanied by an increased elimination constitutes
definite proof that the gouty kidney is damaged with reference to its
ability to eliminate uric acid.”
In all deference, we doubt the legitimacy of the inference, if only for
the very excellent reason that, to quote Von Noorden’s words, even to-day
“it remains uncertain whether the retention of urate arises because the
outlet is blocked, or because the uric acid is held fast by chemical
affinities.”
Apart from this, there are several objections to Folin and Denis’
assumption.
URICÆMIA NOT NECESSARILY DUE TO RENAL DEFECT
Thus Pratt, in some examples of his cases of gout, found that there was
no apparent diminution or delay in the output of exogenous purin in
the urine. On the other hand, he observes that “our study of the blood
shows that _a marked increase in retention of uric acid in the blood_
may result from the ingestion of purin bases even when _no evidence of
retention is found on examination of the urine_.” This would appear to
indicate that the uricæmia, sequential to exogenous purin intake, ensues
independently of and apparently despite the absence of any delay or
diminution in uric acid elimination.
Again, Walker Hall, discussing the metabolism of exogenous purins,
reminds us that a gouty subject excretes an excess thereof as completely
as a normal individual, with only this difference, that he takes a longer
time to do so; but even this disability is removed by a simultaneous
intake of atophan. His comment is that “the gouty kidney, therefore, is
not poisoned beyond compensating for and responding to an extra load.”
“Perhaps,” he says, “the situation may be summed up in the observation
that _the uricæmia of the gouty is maintained in spite of a fair renal
elimination_.”
URICÆMIA NOT PECULIAR TO NEPHRITIS
Again, a grave obstacle to the acceptance of Folin and Denis’ inference
is that uricæmia, though incidental to nephritis, is not peculiar thereto.
Thus Roy Upham and Higley noted its presence in 85·6 per cent. of their
cases of _nephritis_; but, on the other hand, they found that no less
than 40 per cent. of another series of clinical cases, not _suffering
from nephritis_, also showed uricæmia.
This would appear to indicate that, while uricæmia is an exceedingly
common symptom of early chronic interstitial nephritis, it is by no means
_specific_ for that disorder; in other words, its diagnostic valency as a
symptom of _nephritis_ is distinctly limited.
_Reverting_ now to _gout_, what evidence is there that the uricæmia
therein is due to defective eliminatory capacity on the part of the
kidney for uric acid? Certainly there is no proof that the kidney, at
any rate in the _initial_ stages of gout, suffers from this particular
functional disability. Indeed, the fact that, at the very acme of an
acute attack, the output of uric acid is not only not diminished, but
actually _increased_, constitutes strong proof of the reverse.
Again, as modern investigations show, the variations in the uric acid
content of the _blood_, _re_ the incidence or intensity of attacks, are
most _erratic_. Far from its being essential that uricæmia be present,
acute attacks may occur with even a _sub-normal_ uric acid blood content;
in short, the variations are so erratic as to seem quite out of keeping
with the assumption that the uricæmia in gout is primarily of _renal_
origin.
If it were so, one would expect no such vagaries in the uric acid content
of the blood. One would rather, given the existence _ab initio_ of a
_renal functional defect_, look for not only a permanent _uricæmia_,
but further, from time to time, augmentations and diminutions thereof,
synchronising with the rise and wane of gouty paroxysms; in other words,
that in gout the clinical course and crises of the disorder would be
linked up with harmonious variations in the degrees of uricæmia.
URICÆMIA DOES NOT NECESSARILY PORTEND GOUT
If it were so, why does not every case of nephritis develop gout?
The researches of Myers and Fine have shown that _uric acid_ is the
nitrogenous metabolite that first _accumulates_ in the _blood_ in _early_
interstitial nephritis. Only in its _later_ stages do urea and other
waste nitrogenous products undergo like retention therein.
Now let us review these findings, _re_ nephritis, in light of another
statement by Folin and Denis, which runs as follows:—
“In pure gout, unaccompanied by any abnormal urea retention in the blood,
the kidney is damaged (so far as we yet know) only with its function of
removing down to the normal level the uric acid of the blood.”
Is it not clear, then, that in the _early_ stages of _nephritis_, viz.,
prior to retention of urea and other waste nitrogen, we have precisely
that isolated functional renal disability, _i.e._, _inability to excrete
uric acid_, that we postulate to be in operation in the _initial_ stages
of _gout_?
Yet, notwithstanding this similitude in the blood content of the two
disorders, cases of nephritis do not necessarily develop gout. Indeed, as
a matter of fact, examples of nephritis, of all grades and intensities,
may run to their full end without manifesting any symptoms even remotely
reminiscent of gout. Even Magnus Levy, ardent advocate as he is of the
primary renal origin of gout, could not but admit that this salient
clinical obstacle barred the way to acceptance of his otherwise plausible
view. However, he fails to proffer any other solution of the problem.
To our mind, albeit, the disparity carries with it the inevitable
postulate that in gout some other factor intrudes, some _tertium quid_,
something vital, something biological, haply an _infection_. For even if
we grant, for the sake of argument, that _renal retention_, if it were
proved, might explain such anomalies in the excretion of uric acid and
other nitrogenous metabolites as occur in gout, yet, nevertheless, no one
could possibly contend that this factor alone could explain the nature of
gout, could adequately account for its dramatic and protean phenomena.
TO WHAT MAY BE ASCRIBED THE DEFICIENT ELIMINATING CAPACITY OF THE KIDNEY
FOR URIC ACID?
Naturally the advocates of the renal theory had to account in some way
for the alleged functional disability of the kidney. Thus, Sir Dyce
Duckworth, recalling the occasional occurrence in hysteria of _anuria_,
held that, judging from the general phenomena of acute gout, “the
influence of the _nervous system_ ... must not be left out of account as
a possible determining factor for renal inadequacy.”
Others, with whom Duckworth disagreed, propounded the view that the
deposition of urates in the renal tissues was essential for the
initiation of a nephritis in the gouty. Duckworth, on the other hand,
held that nephritis could develop in their absence.
Croftan considers the renal changes in gout identical with those of
chronic plumbism. From experiments with hypodermic injections of
_xanthine_ and _hypoxanthine_ over a prolonged period, he concludes that
the presence of minute quantities of purin bases in the circulation is
capable of producing _marked renal changes_. On the other hand, _uric
acid_, injected into the circulation of healthy animals for a period of
over three months, produced _no renal change_ whatever.
As to this possibility, viz., that the _circulating uric acid_ might lead
to _nephritis_ in the _gouty_, some reflections of Folin and Denis are
instructive. Normal blood, according to these observers, contains not
less than from 1-2 or 2-5 mg. per 100 grams, while that of _gouty_ blood
does not, in their experience, exceed 6 mg. Continuing, they observe,
“There is, however, no reason to suppose that a uric acid concentration
of 4-6 mg. per 100 grams of blood is very much more irritating or
stimulating to the kidney than the somewhat more dilute solution
represented by normal blood. Disregarding the insolubility of uric acid,
the elevation of its threshold of elimination from 2-4 or 6 mg. (per 100
grams of blood) is certainly a small one. Kidneys in which the threshold
of elimination for urea has risen by 10-20 mg. (per 100 grams), or even
more, are extraordinarily common.”
While they consider that such _urea_ and _total nitrogen retention may_
possibly bespeak _latent_ or _incipient nephritis_, they recognise
that no appreciable effects on health have as yet been determined in
connection therewith. But more pertinently to our point, they make the
further pregnant observation, “In the case of uric acid it seems to
be purely a matter of insolubility that corresponding or even smaller
degrees of kidney insufficiency with slight uric acid accumulation should
result in all the serious consequences involved in the development of
gout”!
Again, some have attempted to account for the assumed renal incapacity
as being part of the _tissue peculiarity_ of the gouty subject. “Without
doubt,” says Duckworth, “there are peculiarities of tissue in the gouty,
and with this may very possibly be associated peculiarities of tissue
function and metabolism.”
Naturally this suggests the further question, Are there any distinctive
_histological_ changes in the _gouty_ kidney? On this point Walker
Hall has some apposite reflections. Taking Folin’s figures as a
basis, it transpires that in _acute_ and _chronic nephritis_, also in
_arterio-sclerosis_, there is an average content of 2·5 mg. uric acid
per 100 grams of blood. Now, notwithstanding the fact that in these
conditions an appreciable quantity of the renal tissues is, functionally
speaking, temporarily or permanently out of action, nevertheless “the
extraction of uric acid from the blood and its subsequent excretion are
practically normal.” The inference is that a relatively small moiety of
renal tissue suffices for the excretion of the daily quantum of uric acid
in the urine.
Now in contrast thereto, the blood content in _gout_ and _lead poisoning_
is about 4·5 mg. uric acid per 100 grams of blood, or “an increase of
about 50 mg. in the total blood-stream at any one moment (an increase
from the normal 70 up to 120 mg.).” Continuing, Walker Hall observes
that “the gouty kidney _per se_, even when arterio-sclerotic conditions
prevail, does not show anything like the amount of cellular damage which
occurs in acute or chronic diffuse nephritis.” Thence he argues if
_histological_ changes be taken as a criterion of functional efficiency,
then the _gouty_ kidney should be more capable of excreting freely than
the _diffuse nephritic_ organ.
How does this work out in actual daily life? he asks. “0·5 gram, in
a _normal_ adult, represents the _average daily endogenous uric acid
excretion_ in the urine, while that of a _gouty_ subject is about 0·45
gram. Now, assuming that the type and extent of the endogenous metabolism
is identical in each instance, then the balance, _i.e._, 0·05 gram, is
distributed between the uric acid pent up in the tissues and the uratic
deposits, _i.e._, tophi.” Walker Hall tells us it has been stated that
about 0·01 gram suffices to cover the amount deposited as _tophi_ every
twenty-four hours. The residual 0·04 gram runs to swell the amount in the
blood and lymph-streams. “The increase is 0·0114 to 0·0118 gram per litre
of blood; in other words, the actual increase of uric acid circulating
through the kidneys is about 0·00047 per hour,” which, as Walker Hall
contends, “seems to be a very trifling difference, especially as it is
one of amount and not a type.” In other words, it is _quantitative_,
not qualitative. But, trivial as the disparity is, to what may it be
referred? To Walker Hall’s mind, if we are to appreciate the standpoint
of those who maintain that the gouty _uricæmia_ is referable to _renal
inadequacy_, it is necessary to postulate _the presence of a poison
acting upon the renal tubules specifically_.
In the gouty uric acid excretion is maintained at a “_low physiological
level to the very end_,” and it is easier, he thinks, to adopt the above
hypothesis as to its cause than “to conceive of a poison acting upon the
_nuclear_ processes in such a way as to induce a persistently low uniform
level” of purin excretion.
This view, viz., of a _toxin_ acting specifically upon the uric acid
excreting cells of the kidney, seems to be the only reasonable assumption
available. But even this is difficult of adherence when we recall the
fact that the effect of the toxin is so readily neutralised by a few
grains of _atophan_. Always we have to recollect, too, that under
_normal_ conditions, even given a _constant_ diet, the elimination of
uric acid displays _wide variations_. Also the uric acid output in the
subjects of _chronic gout_, when placed on a _fixed_ diet, differs but
little from that of _normal_ individuals on a like dietary. At most the
excretion but tends to fall to, or slightly below, the lower normal
limits of uric acid elimination.
From the foregoing considerations it is but too obvious that those who
render obeisance to the primary renal origin of gout have not only yet to
prove that the functions of the kidney are defective, but also upon them
lies the _onus probandi why_ gouty subjects should exhibit, or acquire,
such a disability.
URATIC DEPOSITS IN NEPHRITIS
Here, again, we light upon another point of contact between gout and
nephritis, for an interesting feature of the latter disorder is that the
retained uric acid, purins, and other excretory products are deposited in
_cartilage_ and _serous membranes_. At these sites they are frequently
detected post mortem, though they fail of _ante-mortem_ recognition.
Impressed by the fact that, at post-mortems, uratic incrustation of the
articular cartilages was frequently observed in persons who had never
suffered from overt gout, Ord and Greenfield sought to ascertain the
frequency with which such uratic deposits were associated with _renal_
disease. Out of ninety-six cases presenting renal lesions, no less than
eighteen exhibited uratic deposits in the joints.
A still more elaborate research in this sphere was undertaken by Norman
Moore. Out of forty-nine cases of chronic interstitial nephritis, uratic
deposits were present in twenty-two instances. Again, out of nine cases
of chronic parenchymatous nephritis, deposits were found in the joints
in two cases. With respect to the first group he observes that “chronic
interstitial nephritis is not invariably accompanied by deposits in
the articular cartilages, though usually accompanied by traces of
degeneration in some of the articular cartilages.”
Levison, too, an ardent supporter of the primary renal origin of gout,
noted that all the subjects dying at the Communal Hospital, Copenhagen,
of granular kidney disease (during a period of fourteen months) exhibited
uratic deposits in one or other of their joints, although they were never
known to have had any definite attack of gout.
Luff, in the following table, shows the results of the examination of the
joints in seventy-seven cases of _granular kidney disease_.
-----------------------------+---------------+----------------
| | Uratic deposits
| No. of cases. | in joint or
| | joints.
-----------------------------+---------------+----------------
Known to have had gout | 10 | 10
Never known to have had gout | 67 | 31
| -- | --
Totals | 77 | 41
-----------------------------+---------------+----------------
Of the ten cases known to have suffered from gout, the renal condition
was in every instance defined as “markedly granular,” or “fairly
granular.” Uratic deposits were invariably present in one or more joints.
Of the sixty-seven examples not known to have had gout, uratic articular
deposits were found in 46 per cent., which approximates, more or less
closely, to Norman Moore’s findings. It is noteworthy that in several of
the instances, lacking uratic deposits in the joints, the kidneys were
described as “slightly granular,” or “faintly granular.”
-------------------------------+---------------+----------------
| | Uratic deposits
| No. of cases. | in joint or
| | joints.
-------------------------------+---------------+----------------
Marked granular kidney disease | 26 | 20
-------------------------------+---------------+----------------
If of the sixty-seven cases there be selected only those described as
“markedly granular,” or “typical granular kidneys,” the incidence of
uratic deposits in the joints, as revealed by the second table, reaches
no less a figure than 77 per cent.
Another authority, discussing the frequency of incidence of uratic
deposits in the joints in cases of chronic interstitial nephritis, states
that, at post-mortem, from 50-80 per cent. show their presence—this,
moreover, in cases _known not to have had gout_.
DIFFERENTIATION OF URATIC DEPOSITS IN GOUT AND NEPHRITIS
Uratic deposits, it is true, occur in both these disorders. But it is
with a difference. In gout the uratic deposit assumes the form of
_tophi_, whereas in nephritis it is not so. In the latter the uratic
deposit is in the nature of a passive deposition—an uratic incrustation
of the articular cartilages.
Again, in gout the deposition is _sudden_ and associated with an acute
paroxysm; while in nephritis it is _gradual_ and unassociated with
inflammatory reaction.
In gout the uratic deposits are overt, manifest as _tophi_; in nephritis,
occult and unrevealed (ante-mortem).
Uratic deposits in the form of tophi occur in gout, in the absence of
clinically recognisable interstitial nephritis. But tophi do not occur in
nephritis if uncomplicated by gout.
In conclusion, the mere fact that uratic deposits affect such widely
disparate forms in these two disorders is to our mind a sure indication
that their mode of origin and formation is equally diverse—the one vital,
biological; the other passive, mechanical.
CLINICAL ASSOCIATIONS OF GOUT AND GRANULAR KIDNEY
It cannot be denied that gout and granular kidney are frequently met
with in close association. But neither can it be disputed that in these
disorders, as in many others, their outward affinities do but hark back
to inward disparities. The occasional overlapping of the two affections,
the trenching of the one upon the clinical or pathological territory of
the other, must not blind us to the essential distinctness of the two
morbid entities. Doubtless to the earlier advocates of the renal theory
their not infrequent _co-existence_ bespoke some hidden _nexus_, and at
least seemed confirmatory of their views as to the pathogeny of gout.
But, even if we allow that the connexion between the two disorders seems
superficially intimate, it cannot be gainsaid that it is neither constant
nor essential. For we have to recollect that—
(1) Some gouty subjects never develop granular kidney.
(2) Some individuals with granular kidney never develop gout.
Also we have to recall that—
(1) Paroxysms of gout often occur for many years before the
symptoms of interstitial nephritis develop.
(2) In persons of gouty stock acute attacks may ensue at an age
at which nephritis is practically unknown.
Apart from the difficulty of reconciling these disparities, we cannot
overlook the fact that both gout and granular kidney are very common
diseases, sufficiently common, as Samuel West pointed out, to be not
infrequently associated accidentally, without any cause or connection.
Again, both affections, be it observed, are prone to develop in the
middle and later decades of life. In light of this, is it not readily
conceivable that both may arise independently, mere coincidences, both
evidences of _pre-senilism_? Hastings Gilford, indeed, classes gout
with syphilis, lead, and alcohol as amongst “the chief promoters of
pre-senility.”
Again, certain toxic agents which predispose to or initiate renal
mischief also favour apparently the incidence of gout, _e.g._, _lead_
and _alcohol_. Samuel West, discussing the relationship of both gout and
lead to granular kidney, maintains that, though each may produce chronic
change in the kidney, neither of them _causes_ granular kidney. But the
presence of granular kidney, he holds, greatly enhances the liability of
the victim to gout on the one hand and plumbism on the other; also, to
both together and in each affection alike markedly increases the gravity
and the risk.
Sir William Roberts, too, has some wholly relevant observations on this
point. Thus all will agree with him that “it is difficult to conceive
that plumbism induces the same constitutional diathesis as that which
obtains in true gout.” He held that gout and plumbism, though they differ
in all other respects, yet have one point in common, a tendency to
uratic deposition. But such precipitation, he contended, was the outcome
of a gouty tendency, reinforced by lead poisoning; or if, on the other
hand, uratic deposits occurred in plumbism, the same had but accentuated
a pre-existing gouty diathesis. In this connexion, too, it should be
recalled that the frequent association of gout and lead poisoning which
exists in London is not seen in the North of England or in North America.
Is it not clear, then, that reflection on the broad clinical affinities
exhibited by gout and granular kidney does but emphasise the essential
distinctness of the two morbid entities? Inferentially, too, it lends no
colour to the assumption that gout is of primary _renal_ origin.
That the victim of gout, despite uricæmia and those unequivocal tokens,
_tophi_, may, notwithstanding repeated arthritic outbreaks, be in the
intervals in sound if not exuberant health, is a clinical truism. His
kidneys, too, may, as far as can be ascertained, be normal; and his
blood pressure not beyond what might be expected at his age. His output
of uric acid may but touch the lower normal limit or a little less, and
his metabolism of purin-rich foods be but a little protracted. Thus he
runs his course, more frequently than not a strenuous one, chequered
by occasional outbreaks which not seldom he regards as salutary rather
than otherwise. Then, sooner or later, in one, two, or even three
decades, that Nemesis of age, _arterio-sclerosis_ overtakes him with its
correlated _chronic nephritic_ change.
Is not this very reminiscent of what Walker Hall reminds us of,
the sequence of events in _lead poisoning_ and _alcoholism_? “These
poisons affect the general metabolism adversely and are connected with
disturbances of purin assimilation and output. At a later stage they
produce arterio-sclerosis and renal insufficiency.” And as he shrewdly
observes, “It is, therefore, of importance to exactly appraise the stage
of the disease when interpreting the results of experiments upon gouty
individuals. When this obtains widened application, many generally
accepted statements will have to be re-written.”
In conclusion, therefore, we see that the weight of clinical evidence
is against the _primary renal_ origin of gout, for not only are renal
changes frequently slight, but they are often entirely lacking in gout.
Confronted with these difficulties, the question inevitably rises as
to whether there does not exist a special morbid entity, gout, which
develops independently of renal abnormalities?