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THE PATHOLOGY OF IR.EMIC INTOXICATIONS.

C. A. HERTEE, M.D.,

Visiting Physician to the City Hospital, Consulting Physician to the Babies'

Hospital, New York.

{Reprinted fro,n Montreal Medtccd Journal May, 1898.)

j o : a

u^O

"/ S-3CS

THE PATHOLOGY OF URililMIC INTOXICATIONS.'

C. A. Herter, M.D.,

Visiting Physician to the City Hospital,

Consulting Physician to tiie Babies' Hospital. New York.

In venturinjT to address you this evening on the suhject of ursemic
intoxications, I am not unmindful of the difficulties that are inseparable
from the problem which I shall undertake to discuss. Indeed it
cannot be denied that one of the attractions of this subject is the
obscurity which surrounds the oft-recurring phenomena which we
call urremic — phenomena that h.vvi' excited the interest and baffled
the insio-ht of Richard Bright, of Traub:.-, of Fi-erichs, and of many
lesser intellects.

Although a study of urseinia th \t has extended over many years does
not make it possible for me to isolate, as definitely as could be wished,
the pathological factors concerned in the production of the symptoms
of unsmia, I believe I can, at least, indicate the direction in which we
should look for an explanation of the nature of these symptoms. It
will be my purpo.se to show that the clinical phenomenn. which we
include under the term urf^mia are dependent on toxa^mic states rather
than upon primarily mechanical causes. In doing this I shall 'iiakc
use of observations which I have accumulated from the study of the
blood in 28 cases of uraemia, which have either been observed by me
in my medical service in the City Hospital, or have been placed at my
disposal by intere.sted colleagues. In addition to this, I shall draw
upon facts which have come to my knowledge from a study of experi-
mental uroemic states. It would be a satisfaction to present these
facts in fnll detail, but as this could hardly be done without exhau.st-
iug your patience, a summary of results must suffice for the present

1 Read before the Montreal Medico-Cbirurgical Society, at McGill University
March 4, 189«.

purpose.' For tlie snke of convenience, the facts to ho surveyed may
1)1' (,n-onpf(l under the followinfjf sulijects : the toxic properties of the
hlood in urpetnic stiites as measured hy intravenous infusion ; the
relation of urremia to the urea of the hk>od, to the extractive sub-
stances, and to the potassium .ialts ; cerebral (edema and urfiemia ;
the internal secretion of the kidney and unemia ; experimental
unemia from double nephrectomy and its relation to human ob-
structive uraemia, and other types of human unemia.

A question of fundamental importance in the patholoory of urfemia is
whether the blood in this condition is more toxic when introduced into
the circulation of animals than is human blood from normal person.s. In
the hope of answering this (juestion, the blood serum from 28 untimic
))atients, who were I)led during life, was introduced intravenously into
rabbits, proper precautions being taken as regax'ds the freshness of
tbi' serum, its temperature, the rate of infusion, the exclusion of air
from the vein, etc. The observations were not confined to rabbits,
but included in some instances dogs and monkeys. Two different
methods of intravenous infusion were employed. In one case the
serum was infused into the femoral vein at a fixed rate until the com-
mencement of fatal symptoms. In the other case, the serum w^as
injected in much smaller amount, either into the femoral vein or into
an ear vein with a view to ascertaining the minimum dose capable of
causing death in the course of 24 or 3C lOurs. A difficulty which at
once confronts the investigator in the use of these methods is the fact
that normal human serum is in itself toxic to rabbHs in a considerable
degree, owing chietfy perhaps to its power of inducing coagulation.
Thus I have found that its re(|uires from 25 — 40 c.c. of normal human
serum to the kilo to initiate fatal symptoms in rabbits when the
inethod of continuous infusion is employed, while it .seems generally
agreed among investigators that the fatal dose of human serum, as
employed by the second method, is from 9 — 12 c c. per kilo. Inas-
much as it is found that there is considerable variation in the
toxicity of the same serum for different rabbits of the same weight,
notwithstanding every precaution in making the infusion, it is clear
that it is necessary to observe much care in concluding that a given
class of serums is more than normall}'^ toxic.''

Of the ursemic serums which were studied with respect to their

' The details of the experimental observations will be elsewhere published.

- Uhlenhuth claims that the serum should be subcutaneously injected into
fjuinea pigs to avoid the error incidental to intravenous infusions. In several
instances where I have employed this method, there seems to be no doubt that the
blood wan more than normally toxic, judging? from the standard of normal toxicity
given by UhleJihuth.

toxicity, 19 were obtained from cases of urminia characterized by the
occurrence of well marked and repeated convulsive seizures/ six of
these being instances of puerperal eclampsia. In the nine remaining?
cases the serum was obtained from patients with chronic nephritis,
characterized by dyspntm and 'ligh tension pulse— none of these
patients having had convulsive seizures. The inferences which we
may make from the study of these serums are as follows : The cases
of nephritis characterized by dyspncea and high tension pulse without
convulsions, taken as a class, do not yield positive indications that
the toxicity of the serum was greater than normal, although in at
least two of the nine cases the toxicity was considerably greater than
any I have observed in health. On the ether hand the least toxic of
these serums possess toxic values that come so near the highest toxic
values observed in normal ^ >rums that we cannot be certain that they
are quite normal. More observations are required before a final judg-
ment can be formed regarding these cases. Taken as a class, the
serums from the convulsive group of uraemias show a degree of
toxicity distinctly greater than any which I have observed for normal
serums, and although there are a few of the 19 cases in which the
results are difficult to interpret, there .seems to l»e no d(jubfc that im
increa.se in the toxic properties of the blood is a characteristic of cases
of convulsive urasmia. This latter statement apparently holds good
also of certain serums from patients with puerperal eclampsia, but
here again more observations are re(|uired. Volhardt has quite
recently denied that there is any increa.se in the toxic properties of
the blood of eclamptic patients, but his results cannot be regarded as
final.

Admitting that the serum in convulsive uraemia is more toxic than
normal .serum, the question at once arises, what is the cause of this
pathological increase ?

It is not possible at present to give a satisfactory answer to this
question, but the following facts bear upon it. In the first place the
toxicity of uraemic serum for animals is greatly reduced l)y exposure
to moderate heat, say 60°C. for a few minutes. This is also true of
the toxic properties of normal human serum. These facts suggest
that the increased toxicity of ursemic blood is dependent on the
presence of an increased amount of a toxic proteid substance which is
normally present in the blood.' We cannot, however, feel certain
that the increased toxicity of the serum does not depend on some

' In one of these cases there were merely coarse twitchings never amouiitinp; to
typical convulsions.

* The toxic properties of urea, extractives, salts, etc., are of course not influenced
by so moderate an elevation of temperature.

unknown foreign substnnco. A fact wliicli strengthens tlie view tliat
a proteid suhstanee is responsible for the toxicity of unemic, as of
normal serum, is that the removal of the proteids hy means of absolute
alcohol almost wholly deprives the serum of toxic pi-operties.

In trying to form an estimate of the significnnee of an increase in
the toxic properties of uranuic as conLrasted with normal serums, it is
important to i-(!Cogni/e that such an inci'ease in toxicity does not con-
stitute proof that the cause (jf this augmented toxicity is the caus(! of
the obtrusive cerebral symptoms of uriemia. It is conceivable that
alterations may occur in tlie blood which possess little pathological
signilicance for the human organism, but which are nevertheloss
capable of rend(>ring the scrum more toxic than normal when intro-
duced into the circulation of rabbits This does not, however, seem a
probable explanation of the phenomenon of augmented serum toxicity,
and is especially at variance with the fact that unv ur.'emic serums
hav, in some instances, exhibited very striking toxic properties when
introduced into dogs and monkeys, which do not possess the peculiar
susc(!ptibility to normal human serum that is observed in the case ol
rabbits. It is much more rational to regard the increase in the toxic
properties of the blood in certain, if not in all, cases of unemia as
evidence of a toxaemia, which is in some way connected with the
symptoms of the uraemic state. It is possible that this toxaemia is
distinctive of uni^mia and always of the same character, l)ut there are
certain dift'erences in the beha\i()ur of different serums which make it
likely that the toxjiemia is not always the same. It is, moreover,
certain that the toxic properties of the blood are augmented in con-
ditions not uraemic in nature, for example, in acute lobar pneumonia,
in scarlet fever, etc.

Urea being by far the largest and most important constituent of the
urine and representing the terminal product of proteid metabolism,
it is not singular that this substance should have been for a long time
regarded as the main factor in the production of unemia. It is thus
of the highest importance to vletermine the actual relation of urea to
uriemic states. The conclusion^ reached by me in reference to this
relation are based upon a considerable number of determinations of
urtsa in the blood of unemic persons, of persons with other pathologi-
cal conditions than unemia, and of entiriily normal persons. Many of
these observations were made upon blood drawn during life, but these
were supplemented by others upon post-mortem blood, after it was
demonstrated both in man and in animals that the urea content of
ante- and post-mortem blood corresponds closely in the case of blood
taken from well preserved bodies. In addition to. making seventy

observation.^ on the urea of human blood, an endeavour was made to
dotenniiio to vvliat extent chemically pure urea possesses toxic proper-
ties. The results of these studies may be brieHy stated as follows :

(a) In a small proportion of typical cases of urnnnia, characterized
by the occurrence of convulsions, the urea content of the blood was
found t(j be well within the normal limits, notwithstanding that in
these same cases the blood serum was distinctly more toxic than
normal. It is plain that in these cases there is no fjrround for lookin<;j
with suspicion upon urea as a factor in pnxlucing symptoms.

(h) In the majority of cases of uraimia, esi)ecially in those cases in
which the .secretion of urhie has for a long time been .scanty, tlie urea
of the blood was distinctly iucreased, this increa.se sometimes reaching
to 5 or 10 or even 20 times the normal urea content. It is, however,
a very .striking fact that many ca.ses oi' chrcmic nephritis were found
to be characterized by a markedly exce.ssive urea cont(Mit, even where
there were no symptoms that would ordinarily be called unomic. Tiiis
is merely a continuation of an old ol)servation by Bright and Christi-
son which has not received the attention which it de.serves. Among
the cases in which the urea was increased in the absence of typical
unemic symptoms were 14 cases of acute lobar pneumonia with fatal
termination. These cases make it clear that renal inadeijuacy is a
feature of many fatal pneumonias. Whether such inadecpiaey is to
be considered unemic in the absence of the usual sym})toms of urjBmia
will be considered later.

(c) Experimental .studies upon dogs and monkeys show that pure
urea is toxic when infused intravenously, but only when very large
quantities are employed, i.e., (juantities e(|ual to many times the daily
urea excretion of the animal. The .sym])toms produced by such in-
fusions are fairly constant in dogs, and consist in initial slower and
stronger heart action, copious diuresis, diarrhd'a, contraction of the
pupils, irregular fibrillary contractions of the nm.scles, and finally
general and severe tonic or clonic spasms and death. If we make the
bold assumption that in human nephritis the su.sceptibility of the
nervous .system to the influence of urea is similar to that observed in
dogs, we would expect convulsive seizures to arise in man when the
urea content of the blood reaches about .o per cent. It was found
however, that in many of the cases of human nephritis, in which con-
vulsions occurred, the percentage of urea was considerably below this
point, while in a few cases in which this percentage was much ex-
ceeded, convulsions were ab.sent.

It is, of course, obvious from the foregoing facts that urea does not
play a necessary part in the causation of the .symptoms of human

convulsive uraemia. This does not, however, prove that the accninu-
lationof the ureain tlieblood in hirge excess is of little importance.
There is good evidence that such an accumulation points to a consider
able degree of degeneration of the; .secreting (•|)ithelium, and the
degeneration which permits the .storage of una, permits the storage
of other constituents of the blood, including sodium chloride, potassium
salts, nitrogenous extractives, and po,ssil.ly a toxic proteid substance.
It is partly on account of this multiplicity of substances retained in
the l)lood at tlie same time with urea that we are unable to fix more
definitely on the part which urea plays as a toxic .substance. It is on
the whole very likely that urea in conjunctiim with the accuiindation
of other substances in the blood, as the result of renal insufficiency,
exerts an influence in the production of uraemic symptoms— es))ecially
ursemic vomiting and diarrho'a. The urea of the blood has been
greatly increased in all the instances of unemic vomituig and
diarrhoea that I have had an opportunity to study.

It is desirable to indicate here that the customary detenninaticn of
urea in the urine in cases of nephritis gives no more indication of the
quantity of urea in the bloo<l than docs a mere record of the volume
and specific gravity of the urine passed by such patients, and that it
is hence an unnecessary procedure. If the kidneys are incompettnt a
large reduction in the urea excreted is indicated sufficiently by the
reduction in the total solids, this being expressed by the volume and
specific gravity. If there is only a moderate daily reduction in the
urea excretion this cannot be discovered by the ordinary methods
used. To determine this it would be necessary to keep a daily record
of the nitrogen taken into the body, of the nitrogen of the urine and
of the faeces, and also of the body weight. It is ea,sy to s(!e how, in the
course of a few months of mild rencl incompetency, the urea of the
blood would increase enormously if the kidney lagged only to the ex-
tent of a few grams of urea daily— too small an amount to miss by
ordinary examinations. It is no exaggeration to state that for prac-
tical purposes the con.'-^Kleration of the volume and specific gravity of
the urine yields all the 'nformation that can be obtained by determin-
ing the urea of the urine. What we really require is an estimai e of
the urea of the blood in our nephritic patients, and this is entirely
practicable, for only a few cubic centimetres of blood are necessary for
this purpose. I have no doubt that this procedure will in time be
frequently employed, as the urea content of the blood is a most
important indication of the competency or incompetency of the

kidneys.

In recent years there has been some disposition to regard the

oxtractivo snltstances as the canso of ura;inic symptoms, Imt the evi-
ilenct' ill support of this view has never been stronj^. The results ot
a personal study t)f this (piestion aiiay be hrieHy referred to. The ex-
traetives of the hlood, that is, the sul (stances which can be extracted
l»y means of ether and alcohol, were determined in more than one
hundred instances, includini; normal human anil (loj^j's blood, blood
fi-om nephritis witli and without unemic symptoms, from septicaemia,
ficute lobar pneumonia, etc. It was found that there is no detinite
relation between uitemia and thetjuantity of extractives in the blood

In /.general the extractives are stmiewhat increased where tlie quan-
tity of urea is increased, but there are cases of unemia where the ex-
tractives are apjiarently normal in amount, and there are cases which
would not usually be classed as anemic where the extractives are
markfidl}' increased. The evidence in<licates that while extractive
substances in excess cannot be regarded as entirely harmless ft^r 1' i
organism, they certainly cannot be looked upon as playing other than
an auxiliary part in the production of urfemic .symptoms. In this
connection it may be stated that Dr. A. J. Wakeman, at my request,
made a series of laborious ob.servations on the blood of uraimie
patients with the use of the Otto-Stas method, for the purpose of
isolating any alkaloidal sub.stances which might exist there. The in-
ji'ction into guinea pigs of the material recovered by the Otto-Stas
method yielded wholly negative results.

The conclusions tliat have been stated regarding the extractives of
the blood ai^e applicable to the potassium salts theory of uraemia, which
was originally advanced by Felz and Ritter, and which constitutes a
most Instructive chapter in the history of theories of ursemia. Numer-
ous observations made by mc confirm the statement of Horbaczewski
that the content of potassium salts in unwmic blood may be quite normal
in amount. This seems to be especially true of the blood of puerperal
clampsia. These salts are, however, distinctly increased in nuiny in-
stances of uraemia, but apparently never enough to make them wholly
responsible for grave nervous symptoms. The potussium theory as
an exclusive cause of uraemia has recently been revived iri France by
(/harriei", l)ut upon wholly insufficient grounds. It may be said at
present that, while the potassium salts cannot be considered to play a
leading part in the production of unemic symptoms, their presence in
excess in the blood must be regarded as a possible factor in precipitat-
ing symptoms of intoxication.

The ammonium carbonate theory of Frerichs, once so popular, has
now only a historical interest and need not be discussed here. An
allied hypothesis has, however, been suggested, namely, that the cause

of unuiuia is the presence in the hUjo-l uf the annuoi.iuiu salt of car-
bamic acid— annnonium carbamate. The recent investigations of Hahn
Pawlow, Massen and Nencki rcnth'r it probable that urea is formed in
the liver by the dehydration of ammonium carbonat<>, and this fact
has led some ph} siologists to snspt.'ct that the high.y toxic ammonium
carbamate mf^y be responsible i\n- uiiemic states, '.riiis view appears to
mo to be at variance with the following facts:

1. In wuterv b^>lu.''>n ammonium carbamate is very unstable and is
i-apidly converted into a.nmonium .carbonate. We know, however,
that ammonium carbcmate does not occur in urannic blood in sufficient
amount to produce .symptoms, and usually cannot be found at all.

2. The toxicity of uremic blood is not le.s.sened by dialysis, as it
wouhl be if the toxicity depended on a difl'u.sible amuKmium salt; nor
does the ditt'usate contain ammonium.

a The uri le of uraiinic patients docs not necessarily contain an in-
creased proportion of N. of ammonia, as it should do if the synthesis
of urea were impaired. On the other hand, in liver diseases in which
there is extensive pav.'nchymatous destruction, the N. of annnonia
may be greatly increased, even in the absence of urtemic symptom.s.

Owing to the instability of ammonium carbamate its isolation from
the blood is impracticable, and inferences as to its occurrence there
depend chiefly on indirect^ evidence. The conclusion seems justified
that such knowledge as we possess does not support the supposition
that ammonium carbamate is concerned with the production of uremic
intoxications.

Before passing to the more constructive consideration of the uroemic
problem, it is proper to make brief reference to two widely diiferent
theories of th>' nature of ura^uia. One of these is the celebrated
hypothesis of Tr»yube that renal disease causes thinning of the blood
plasma, hypertrophy of tin; left ventricle and excessive arterial pres-
sure. Jf the arterial tension is increased beyond a certain point or
the plasma of the blood becomes further thinned, (rdema and anaamia
of the brain are i)ro<luced and urfi)mic symptoms result. There are
fatal objecticms to this theory. These are : 1. That there may be
marked cerebral symptoms without arterial tension. 2. That the
specitic gravity of the serum is often normal in typical uraimia.
.S. That there are uraMiiic patients in whom neither cerebral anoemia
nor cerebral o'dema are found at autopsy. 4. That a marked degree
of anannia of th^ brain and of o'dema is occasionally found in the ab-
sence of all symptoms resembling ura3mia.

It is, however, clear from clinical study that there is often a close
association between certain urannic symptoms, especially convulsions

and dyspiiu'ii tuul high artoriul tension. Nor is there any doubt tluit
vvlien we reduce excessive vascular tension by means of vaso-dihitors,
such as nitro-glycerine, we often relieve the symptoms in the case of
dyspnciea, sometimes in a striking degree. At present it appears prcjb-
able that tlie high arterial tension of uraemia is due to the action of
toxic material in tlie blood. It is not at all inconsistent with this view
that vai-iations in tlie cii'culation of the central nervous system slicndd
influence, in important ways, symptoms wliich, like dyspncea, art; of
central origin.

Although we cannot accept the theory of Traube as advanced by
him, the appearances observed in the central nervous system in persons
dying of ura-mia' (especially the loss of cliioropliyllic substance seen
in nerve cells) indicate that mechanical conditions, such, as local
anasmia, congestion or o'dema, liave been operative in damaging the
nerve elements. It seems probable that these conilitions are not
primary, but depend on toxa^mic states.

Another theory of uraiuiia whicli cannot be passed by, is that of
Brown-Sequard, who holds that the kidney elaborates ;in internal
secretion which is essential to liealth, ami the suppression of which is
lai'gely I'dsponsible for the phenomena of ursemia ; the accumulation
in the blood of to.Kic sulistances which shoidd be excreted by the urine
having little or no influence on the causation of these phenomena .
'i'liis conception of ura3mia rests mainly on the alleged fact that th(>
injection of kidney extract into the circulation of a nephrectomized
dog cau.ses the temporary disappearance of uneuiic phenomena. The
evidence which has been advanced to establish this fact must be
regarded as insufficient. Thus the observation of Brown-Setjuard
that the injection of kidney extract causes an increase in the muscular
power of nephrectomized dogs, rests on a small number of experinx-uts
which appear neither to have yielded decided results nor to have been
subjected to careful control, and Meyer's contention that the injection
of renal extract gives marked relief to the dyspnor^a of double nephrec-
tomy likewise rests on a small number of observations that .seem
distinctly to call for proper controls. Nor can we place much reliance
on the claims of Teissier and Frenkel, in a recent publication, that
the injection of a ^e\v cubic centimeters of renal extract in the human
urrernic sulyect is ciipable of rendering a hypotoxic urine hypertoxic
by stimulating the elimination of to.xines through the urine at tin;
.same time that the symptoms of uraMuia are ameliorated. Consider-

' These cliaiige.s are not by any means (list incfive of ura'inia, but occur in a variety
of condition.s. According to Dr. James Ewing they are best seen where the nerve
elements have been subjected to pressure, as in cerebral hemorrhage.

al)le peivsonal expei'lence makes ine liighly skeptical as to the propriety
of our (1) awing inferences as to the condition of the blood from the
effects of intravenous infusions of urine in animals. A very obvious
and serious gap in the experiments of Teissier and Frenkel is the
absence of observations on the toxic salts ingested with the food and
eliminated with the urine, the toxicity of the urine, both in health
and disease, being largely dependent on its potassium salts. Future
investigations may sliow that the kidney elaborates an internal
secretion, but at pi-esent we are justitied in taking the position that
the observations now i-elating to this question do not help us in ex-
plaining the pathology of uraemia.

Passing now to a consideration of the clinical types of uraemia with
a view to the discu.ssion of their pathology, it is desirable first to
make reference to the phenomena of double nephrectomy in dogs and
their relation to human uraemia of obstructive origin.

The alteration ? in the composition of the blood that are entailed Viy
doultle nephrectomy are of the greatest interest in the study of the
pathology of ui'annia, foi- tlu'V necessarily represent the results of the
mo.st extreme degree; of renal incompetency per se and without com-
plicating factors such as are commonly present in human uraemia.
The following description of the symptoms and pathological altera-
tions incidental to experimental urjiemia, is based on a series of 10
successful cases in dogs, as well as on cases in the pig and rabbit —
an<l also upon a number of instances in which the ureters were tied
upon both sides. It may be stated at the outset that the symptoms
were essentially the same in the case of double nephrectomy as in
ligation of the ureters. These symptoms consist, in a typical case, of
moderate prostration r<j'iIu>Yi::g the operation, of repeated vomiting
sometimes associated with diarriiwa, of slow and deep respiration, of
slow, full and high tension pulse and, not rarely, of fibrillary twitch-
ings. In only one instance did true convulsive seizures occur. Death
is usually preceded by a period of drowsiness or actual coma. In
none of my animals was the operation survived more than four and a
half days, and most of them lived less than three days. In cases
unaccompanied by infection the temperature is generally one or two
degrees below normal for one or two days before death.

A considerable number of observations have been made by me to
determine whether the blixxl of nephrcctomized dogs is more toxic to
rabbits than the blood of normal dogs; or, to put it a little differently,

< The vomiting rufuruble to the removal of the kidneys must be distinguishable
from that which results from peritonitis accompanying accidental infection in these
c ises.

r«

to determine whether the experimental uraemia of double nephrectomy
is comparable with human uruitnia of the convulsive typu as regards
the toxicity' of the blood. There can be little doubt that this is a
most important (juestion in tlie pathology of ursemia, and I regret
that it is not possible for me to make an unqualified statement in
regard to it. Owing to the crudeness of ou'' methods of studying the
toxic properties of the blood, it is not possible to detect moderate
deviations from the normal toxicity. It can, therefore, only be said
that thei-e does not seem to be a marked difi'erence in the toxic
properties of the blood within 4S hours after nephrectomy as com-
pared with the blood of the same animal previous to nephrectomy,
but that the toxicity of the blood seems to be increased in dogs that
live a longer period.

As regards the changes in the chemical composition of the blood,
our information is much more positive. We know, for example, that
the urea of the blood is remarkably increased after double nephrectomy
— often reaching ten times the normal percentage at the end of
three days. The extractives are also distinctly increased. A moder-
ate increase in the total .salts of the blood is pi'obably a regular feature
of the blood of nephrectomized animals. The potassium salts may be
somewhat increased, but on the other hand may not be appreciably
changed. Tho total proteids undergo no alteration in amount. A
very interesting feature of the blood has been the marked increase in
fibrin which was noted in a number of the nephrectomized dogs. This
observation, though one of much interest if confirmed, has not yet
been subjected to the controls which are necessary to establish it as a
fact, for a very definite source of error remains to be eliminated. This
consists in the fact that a part of the increase in fibrin noted after
nephrectomy may be due to the bleeding which was practised several
days before nephrectomy for the purpose of establishing a basis of
comparison before and after operation, for it is known that the fibrin
of the blood is increased l>y bleeding.'

In order to be able to compare the symptoms of double nephrec-
tomy with the obstructive type of human uraemia, the cases of

' Since this paper was read I have succeeded in several instances in performing
double neplirectoraies and ureter ligations without losing more man a few c.c. of
l>lood, through hemorrhage. All these animals have shown a doubling of the normal
fibrin content of the blood after a few days. A dog subjected to laparotomy without
nephrectomy, but with a moderate loss of blood, showed no increase m the llbrin
content of the blood.

These observations seem of especial interest in connection with the altered
toxicity of the blood after nephrectomy, but other sources of error remain to be
eliminated before the increase in fibrin can be positively attributed solely to the sup-
pression of renal functions.

prolonged anui-iii I'roiii oKstructioii access iltlo in literature we're
subjected to analysis. Of the 41 ai)i)arently reliable cases in which
anuria lasted four days, .S.j t)ccurred in males. This sti-iking dilfer-
ence in sexual iii3ideiice is prol)al)ly explained i)y the nature of the
obstruction to the escape of urine. In 14 of the 21 cases in which an
autopsy was made the uret(M- or pelvis of the kidney was obstru(-t(Ml
by a calculus, on one or both sides, tin; obstruction tluis ci'eated bein^''
the cause of the anuria. I have been unable to find the record of i
case in which anuria in a f(;male was due to obstructior. of the ureter
or pelvis by a calculus. Of 30 cases in which there was either absolute
anuria (if we can trust the hi.stories) or in which only an insignificant
(juantity of uriiK! was passed, the condition in 1 1 cases last. 'd nioiv
tiian 4 days and less than 7, in IS cases lasted from 7 to 14 days, and
in 7 cases lasted longer than 14 days.

Although the records are not wholly satisfactory, they serve tu
bring out clearly some important facts ]-egaiding the symptoms of ob-
structive uricmia. It is interesting to note that in seven of our forty-
one cases it is delinitely stated that no uriemic symptoms occuri-eil,
although some of the cases were of con.siderable duration (5, 5, (1, 7,S,
9 and 11 days). Although it is not unlikely that some of the unob-
ti'usive indications of ura-mia were overlooked in these cases, it is fair
to supptjse that there were no well-marked ursemic symptoms. It
seems clear that it is the rule for uriemic symptoms not to begin for
several days after the connnencement of the anuria. In a number of
cases more than a week elapsed before pronounced indications of
ui-semia began. In twelve of the forty-one cases it is noted that
vomiting was present at some period of the anuria. In one case (that
of Russell, lasting twenty <lays) it is said that vomiting was present
from the beginning. iJiarrluBa does not appear to be so frequeyit a
symptom as vomiting. It was noted in only six cases. Headache was
described in only six cases. Insouniia, with restlessness, was observed
in several instances, and may be present from the beginning. Mus-
cular paralysis was not recorded in any of the cases, although a con-
siderable degree of muscular prostration was repeatedly observed, and
is probably a relatively early symptom in most instances. Pronounced
delirium was a rare symptom. General convulsions is another uncom-
mon symptom, having been noted in only five of the forty-one cases.
Twitchings of the nmscles, not sufficiently wide in range to constitute
convulsions, were observed in eleven cases. According to Roberts
this is a highly characteristic symptom of obstructive anuria.
As regards the state of the mental faculties it seems safe to say
that death is usually preceded by drowsiness, if life lasts more than

a week, but that the patient may in most instances be roused at any
time.

In four cases a ui'iiu)us odor of the breatii v/as noticeable and in one
of these the skin also had a urinous odor. In one instance tl e breatli
is described as having an ammoniacal character. In one patient, not
included in the collection, the sui.pression lastetl four days and the
skin of the neek and face was covered by crystals of urea. An im-
portant clinical featui'e of oljstructive unumia is that the temperature
is seldom elevated. In only one case is there a record of any fever,
and in this the rise was slight. It is clearly the rule for the tem-
P^:\*uUre to remain normal throughout or to be a little subnormal dur-
ing the last days of life.

On comparing the symptoms of the.se two sets of ca.sos, the human
obstructive uraemia and the e.xperimental urainiia following doulile
nephrectomy or bilateral ligation of the ureters, .several important
resemblances become apparent. Thus vomiting is an early and fre-
quent symptom, while diarrhu'a, though not rare, is distinctively less
conmion. In both groups of cases marked muscular piostration is
usual fi'om the beginning. Occasionally, however, there is early rest-
lessness. Indications of delirium are absent in the experimental as in
the human cases and paralyses have not been observed. In the ter-
minal stage, fibrillary tremors are common in both the iiuman and the
canine ca.ses, while general convulsions are exceptional. Terminal
coma may occur in either group, but consciousness can usually be
aroused at any time. An important clinical resemblance lies in the
fact that the temperature is either normal throughout or slightly sub-
normal. There are, however, some points of difference. Thus, a
patient with both ureters obstructed may live more than two weeks,
while a dog with both ureters tied or with both kidneys extirpated
lives less than one week. We can hardly attribute this difference in
the duration of life to the shock of operation. It may depend on the
activity of the skin in man. The ammoniacal breath of human
patients de})ends doubtless on the decomposition of urea in the gastro-
enteric tract and the odor of the skin arises from the decomposition of
urea in the sweat. It may happen that a greater accumulation of urea
occurs in the blood in man than in the dog, owing to his longer sur-
vival, and that this occasions the excretion of urea by the gut in ^he
case of man. Notwithstanding these clinical differences, it seems
probable that the pathological conditions which ire responsible for the
symptoms in nephrectomized dogs are esseii.ially those that are
responsible for the symptoms of obstructive uraemia — namely, the
accumulation in the blood of urea, extractives, inorganic salts, and

perhaps of a toxic proteid inntevial the nature of wliicli is at present
unicnown.

Coining now to the consitieration of othei- typ(\s of huiii;ui urfemia,
we lind ourselves upon uncertain (around when we try to lirinj? the
various clinical phenomena into relation with the patlntloifical state or
states which constitute theii" basis. Tliis is i»ecausc tlu' patholoi,fieal
knowledge which we ptjssess is still exceedijinly meagre and prohaltly
inadequate to form the hr.-iis(jf a permanent pathological classiiii.ation
of the ditierent comlnna^'ons of systems which we call unemic. 'i'liire
are, however, certain facts, some of which have already lieen aliuded
to, that seem to me t(j help us in tlu^ intei-pretation of the phenomena
of human urtemia, and to these I wish to direct your attention.

Thei-e is a well recognized group of patit-nts with chronic nephritis
whose leading characteristics clinically are high arterinl tensi(jn,
dyspnoea aiul slight alhunnnurin, ..ml sometimes headache. Although
the kidneys of such patients present consideivdjle variatiuiis in their
cross character, thei-e is in all cases widesi)read degeneration of the
secretiuo' tuhules, hhrous changi^s in the tufts, and a distinct increase
in the ii»tertuhular connective tissue. Cases of this chai-acter are
often heiietited hy venesection (at least temporarily) and it has thus
liecome po.ssible to obtain the blood for study in a luunber of instances.
As already stated, it is not possible to say whether or not the .serum
from such patients is regularly ujore toxic than noi-mal, although it
appears as if this were the case in some instances at least. It is usual
in these cases for the blood to contain an increased percentage of ux-ea,
thus affording a po.sitive indication that the kidney is not wholly com-
petent to perform its excretory functions. Cases of nephritis of this
type may be the distaiit consequences oi infection, but there is no
reason to think that pathogenic bacterial products are present in the
blood at the period when tliese cases run a chronic and entirely afeb-
rile course. The only obvious pathological condition of the blood that
is likely to be connected with the characteristic exacerbations of
dyspncea and the increase in arterial tension, is the retention in the
blood of constituents that should be excreted, perhaps including an un-
known toxic proteid material. In other words (leaving aside the fact
that the water of the plasma may be increased in such cases) the con-
dition of the blood in the cases described is probably analagous to the
condition which was described as characteristic of double nephrectomy,
and which, in all likelihood, is the basis of human obstructive uriumia.
At least this much is certain — in the three different conditions which
we have considered, double nephrectomy, obstructive uraemia and
chronic nephritis, with high tension and ursemic dyspncea — there is an

actual retention of ;.i-oa in the blocd and not improbably an increased
toxicity of the blood duo to a proteid constituent. It is, of course, ob-
vious tJiat there are clinical ditferences between human obstructiv(!
unu. 'a and the dyspnoeic typo which thi,> patlioloj^'ical conception
docii lot explain. We mnst, however, renunnber that in the one case
we have to do with an acute condition arisin<^ .sometimes in persons
whose vascular system is Jiot n'.nrk>.^d!y altored, while in the .second
ca.s<. tlie toxtemia is a chronic state arising hi. a person who, simul-
taneously, and for reasons not understood, has developed curdio-
vasculai- librosis. It is possible that this cardio-vascular fibrosis plays
a mechanical part in the production of dyspntua in the presence of a
urfBinic toxiemia like that referred to.

In the course of the arterio-sclerotic type of chronic nephritis, with
unuinic dy.^^pncea, etc., as well as in other types of nephritis, <;a.stro-
enteric disturliances, espucii'.Uy nausea, vomitin<f, and diarrhcfa of an
intractable character, aie occasionally obsorveil. It will be remembered
that vomitin;^ and diarrho-a are features of experimental urtemia from
nephrectomy and of obstructive unemia.

There can be no doubt that these symptoms are due to a retention
urfemia i.i which urea, extractives, etc., accunudate in the blood in
laro'e. excess and are finally excreted by the oastroenteric uiucou.'^
membrane, causing diarrhci^a, and in wliich vomiting is caused by the
action of these toxic substances upon the medulla. I cainiot under-
take to say whether the known i-etained constituents of the blood
(urea, extractives, salts) are in themselves responsilile for these symp-
toms or whether unknown substances contribute to determine these
symptoms. There are .several facts which are of signiticance in this
connection. One is that the injection of urea into the blood eventu-
ally causes diarrhoeal discharges containing urea. Another fact is that
in every case of uraemia that I have studied in which ur»emic vomit-
inc- or diarrhtiea has been a feature, the blood has contained a marked
excess of urea, etc. Again we tind that vomiting and tliarrhiva are
characteristic syn)ptonis both of obstructive urjemia and of double
nephrectomy. We know that in the former cases crystals of urea
may be found on the skin an<i that in the latter urea may be found in
the intestine. Considering the.se facts together we cannot but feel
justified in belicing that the known retained constituents of the blood
play a part in the production of tlie digestive symptoms of ursemia,
possibly a leading part.

In the course of a small proportion of cases of nephritis, convulsions
constitute an obtrusive occurrence. The convulsive seizures may
form part of the history of almost any type of nephritis — of nephritis

with preponderant parencliynmtous chansje to nephritis with extreme
connective tissue alterations. In a certain ninnher of cases tlio
syiiiptoins previous to the convuisivi; seizures have heen those of the
type ah'eady referre<l to, witli lii^li tension pulse, dyspncta, moderate
alliuininuiia, etc. In other words, this type of urjemia is liable at any
time to become modified hy spastic phenomena. It should be noted
tli.'it in some of these cases, where C(mvulsions are thus superposed,
the temperature remains normal until the seizure, and is then only
sliinhtly elevated — not more than we might expect from violent
musculai" action. How do the.se cases differ patholonjically from the
high tension type of unemia without convulsive seizures ? At the
beginning of this paper reference was made to the fact that the
toxicity of the blood was found to be markedly increased in many of
eighteen cases oi convulsive urannia and at least apparently increased
in all. It was found that the toxic properties of the serum in this
gi'oup of cases were more pronounced than in the non-convulsive
group with high tension. Moreover, it was found that in some of
the.se convulsive cases the urea was not increased beyond the normal
percentage. In a very few instances the urea, the extractives and the
potassium sidts were apparently within normal limits. It is plain that
if the convulsions in these ca.ses are of toxt^mic origin they must
depend upon scmie other substance than urea, and it is not urdikely
that they depend on the presence of the proteid substance to which
the exaggei-ated toxicity of the blood appears to be due. There does
not, however, ajipear to be any significant ditt'erence between the
convulsive and the non-convulsive group of cases, the difference in
the toxicity' of the blood being proViably one of degree rather than of
kind. Again, the clinical facts lend support to the view that the
pathological l)asis of the two sets of cases cannot be very different, for
the spastic phenomena are often .so slight as to ct)nstitute only fibrillary
twitehings that recur infrequently and bring about no noticeable
elinuge in the condition of the j)atient. It may be that the pi'esence
or absence of the.se nervous phenomena is connected with .slight
variations in the degree of toxfiemia or with temporary alterations in
the circulation of the brain.

'I'he evidence thus .'^eems to favour the view that in the group of
cases which has been discussed, the symptoms are dependent lai'gely
upon renal insuff'iciency and upon alterations in the blood that are
secondary to this condition. It is important to realize that although
a kidney may be competent to excrete urea so actively as to prevent
the accumulation of urea in the blood, it does not necessarily follow
that it is competent to excrete, or to transform and excrete other sub-

Htancos which a liealtliy kidney would not permit to remain in the
Mood.'

Ifc may hv tliat furtlicr studies will show that tlu- essential \)>\.t\\n-
In.neal element in the forms of urfemia already considered is the
presence of the i)roteid serum poison to which retcrence has Iteen
made; although in the form of uraunia characterized hy <,'astro-enteric
deranfji'ments, the accumulation of urea, salts, etc., appears to lie a
rr-^nilar and prohahly a diitermininj,^ fact(a-.

An element (piite dilferent from simple renal insufficiency enters
into Jiiany cases of uneniia, namely that of infection.

There is a small hut su-i';:jestive group of patients who, after ex-
posure to cold or wet, develo]) high fever, partial suppression of urine,
alhuminuria and perhaps luematuria, with headache, delirium and
coma. The pecuHarity of the.se cases is that the kidneys have pre-
viously been normal so far as can he determined hy clinical methotls.
There seems little douht that the cen-hral symptoms in such cases
of acute degeneration of the kidney or acute exudative nephritis are
due wholly to the action of toxines and not to the retention of sul)-
stances in the Mood which are normally eliminated hy the kidney.

These unusual hut instructive cases ajjpear to me to n^present the
tvpe of ui-a'mia most widely removed from human obstructive urnMuia
in its pathological basis. As might l)e expected, these cases retain
their purely infective type oidy a short time, for the dnmage to the
kidney soon leads to prou(nniced insufficiency and to the accunuilation
of urea; extractives, etc., in the blood in marked exo<ss. A condition
analogous to that just described can he produced in monkeys by the
subcutaneous injection of pathogenic bacterial filtrates.

In a cimsiderable number of cases of chronic nephritis which have
run an afebrile course there is a sud<len development of fever, partial
suppression with increase in the albumen of the urine and cerel>ral
.' . luptoms such as delirium, coma or convulsions. At autopsy the
kidney may show the lesions of an acute nephritis grafted upon those
of a chronic nephritis. Post-mortem cultures made fiom the blood
and various organs frcMpiently show the presence of pyogenic or other
iKithoo-enic bacteria. In short we have in these cases both clinical
and pathological evidence of the occurrence of an acute infection. It
seems reasonable to suppose that many of the symi)toms which we
call ursemic in these terminal cases arc due to the comljination of this
infection with a pre-existing toxtemia due to chronic renal insuffi-

1 Tlie increase in the fibrin content of tlie blood wliicli I liave found in some
cases of tliis sort is of interest in this connection, though its signillcance is still un-
certain.

ctoncy. But such infections are by no means always terminal states.
It lias heoji shown hy Welch and others that patiei with chronic
nephritis are especially susceptil)le to infection, and it often happens
that a patient with chronic ditluse nephritis develops ^rave cerebral
symptoms at the time of a trivial infection which causes a tonsilitis, rt
sli^'ht bronchitis or an otitis, — symptoms which wo very properlv
look upon as urjemic, but from which tlu-n^ is apparently complete
j'ecovery.

Reference has already been made to the fact that the urea content
of the blood was found to be almost re<^ularly incrt;as"d in persons
dying of acute lobar pneumonia, in other words, that renal insutti-
ciency for urea is > characteristic of fatal pneumonias. This observa-
tion suggests the (juestion whether we are to regi.id a markedly ex-
cessive accumulation of urea in the blood as an indication of uraemia
even in the absence of typical clinical indications of urionua. I
strongly incline to the view tliat we should extend our conception of
the term uramiia to include every case of renal insuHiciency for urea
although well deHncil unemic symptoms lie wanting. It has l)een
made clear that typical unemic symptoms may arise in persons whose
lilood shows no inci'case in urea, but this fact does not deprive the
accumulation of urea, salts, etc., of clinical signiKcance ; it merely
illustrates that the pathrjlcgical basis of what is clinically termed
urseinia i^ not always the same. It seems to me desiraiile that we
should regard any toxsem^a as urremic which can Ite shown to depend
on the incapacity of the kidney to perform the functions of a
healthy kidney, whether these functions consist simply in the elimina-
tion of substances as they exist in the blood furnished by the renal
artery, or whether they shall be shown also to consist in the trans-
formation of certain elements of the blood previous to elimination.

Again it is only rational that we should recognize that the essential
elements of a urfemic intoxication may exist without lieing present in
such a degree as to cause obtrusive and typical uraemic symptoms.
Or, to restate the fact in a ditterent form, )i:e Nhoidd recognize that
there is such n thing tin n latent itra'.niic intoxication. Such a latent
uraemia is probably present in many forms of disease, especially acute
flisease, such as pneumonia, where the kidney is the seat of lesions,
aud in chronic nephritis. In the former condition it constitutes a
complicating state.

The fact that such a toxaemia may be masked by associated condi-
tions or may be in itself unrecognizable clinically does not prove that
it is a state which exerts no influence in determining prognosis.

In conclusion a word must be said about the most obscure type of

nrnpinia — puprporal c'claiDpsin. Ktlurts have heen made to connect this
state with the formation of toxic pnxhicts fonncfl hy thf ehemioil
activities of the livin;,' cells of the emltryo, with the ahsorptioii nf
toxic material ff)i'meil in the inti'stine anil with the accnmulntion of
urea in tin* ItliMid as the result of ne|»hritis or of ))rt sure on the renal
vessels, hut the efficacy of these supposiid aj^encies still remains
unproved.

My personal experience with puerperal eclampsia is limited to the
study of the lilood of six victims of this state.' In at least three of
these cases the in'ea of the hlood was not increased in perrrnta;^!.. |t,
seems hi;^hly prolialtle that the toxicity of the Mood was distinctly in
crea.sed in at least two of these ca.ses. Of the other ca.ses it cannot he
positively stated that the hlood was more toxic to animals than is ever
the case with the hlood of non-eclamptic puerperal women, nor, on the
other liand, can it !>(> stated that the l)l()od was not more toxic than
normal.

At the present time there is a controversy as to the toxicity of the
lilood of eclamptic women, which can V»e definitely settled only hy
ntunerous and very carefully conducted observations. Although there
is thus consideiable uncertainty as to whether an increased toxicity of
the hlood is an essential feature of puerpeial eclampsia there is im-
portant indirect evidence of the existence of such a to-jivmia. This
consists in the presence of ansemic and heinoirhayie airas of necrosis
in the livers of women dying of eclampsia."

Schmorl, who first described these striking lesions, i-egards the
thromboses of the capillaries and small periportal veins with vdiich
they arc associated as dependent on the passage into the blood of
|)Iac*;ntal elements and products of jtlacental degeneration

Flexner has succeeded in producing similar alterations in th" liver
l)y means of experimental intoxications, and there caii Ije little doubt
that we must regard the necrotic changes in the c ms of (^chimptic
women as dependent on a toxa'mia. How this to: .uia a"'«es and
how it is related to the toxaemias of nephritis already ....scus3ed
remains to be discovered.

Although this sketch of the pathology of unwmic condition."-', made
from a somewhat personal standpoint, shows us to be in possession of a
miiagre fund of knowledge respecting the pathological basis of ura3mia,
we may confidently hope for furth.er enlightenment from experimental
pathology. It seems to me that future researches should have refer-

1 The blood from these patients was obtained throut;!! the courtesy of the attend-
ing pliysicians of the Lying-in Hospital of New York.

2 I have never met with these lesions in the livers of persons dying from other
forms of unemia than puerperal eclampsia.

ence especially to the following topics : The toxic properties of the
hlood of uraemic patients, the physiological and chemical changes
induced in the blood by nephrectomy, and the influence of intoxications
of intestinal origin upon the normal organism and upon organisms
which are the seat of nephritis. That the state of bacterial activity
in the intestine is capable of exerting an important influence upon
uraemic conditions is suggested by the observation which I have made
that the albuminuria of a dog with chronic nephritis can be strikingly
increased by feeding with cultures from the stools of entero-cohtis
It is also suggested by the exacerbation of symptoms which we some-
titnes observe clinically in human patients after gross errors in diet.'
This relation deserves further attention, as it is of the utmost practical
importance in chronic uraBuiias.

I had hoped to refer this evening to methods of treatment in
uraemia, but am conscious of having already overstepped the limit of
time imposed by reasonable usage.

' Nephritis and uraetnia may also arise in children as a consequence of intense
enterocolitis,