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in fact oxidised to this acidic form in the body. The chief product of
the oxidation _ol carbon, carbon dioxide, may play a not unimportant
role in the equililjrium of urinary acids and bases, and the existence of
oxidised carbon in the molecules of certain organic compounds in the
1 A. H. Allen, "Chemistry of Uriue," 1895, p. 12.



CHEMICAL REACTION. 575

urine confers upon them a definite acidic cliaracter. The acid oxides of
phosphorus and sulphur, which are the chief end-products of the meta-
bolism of these two elements, are eliminated almost entirely through
the kidneys. Eighty per cent, of the total sulphur ingested, and nearly
all the phosphorus, are eventually found in the urine as sulphuric and
phosphoric acids respectively. That these acids are eliminated as salts,
and not in the free state, depends in the main upon tlie fact that bases/
are continually being ingested in the food in a form availaljle for the
neutralisation of acids. The bases of the food are not all in the state
of stable_neutral salts. Even animal food contains basic phosphates,
together with organic (proteid) combinations of the alkalies and
alkaline earths, and small quantities of alkaline carbonates ; while
vegetable food contains, in addition, salts of the vegetable acids, which
in the body are converted into carbonates by oxidation. By the
ingestion of these unstable ..aunpounds of various bases, the organism
is saved from the necessity of eliminating free mineral acids. When
the supply of available bases is for any reason insufficient, a further
protective mechanism comes into action, metabolism being so modified
that a greater proportion of the nitrogen than usual is eliminated in
the strongly basic form of ammonia. All these factors are normally so
proportioned that, as we have seen, the urine, while containing no free
acid, is acid from acid salts.

Phosphoric acid (H3PO4) as a tribasic acid forms three orders of salts.
Those in which two out of the three hydrogen atoms of the acid molecule
are intact, are known as acid or superphosphates. They are soluble salts, and
react acid to litmus. The second type, in which two hydrogen atoms are
replaced by a base (monohydrogen phosphates), and the third, in which all
the hydrogen is replaced (normal phosphates), are alkaline to litmus. While
all varieties of the phosphates of sodium, potassium, and ammonium are freely
dissolved by water, of the alkaline earth metals only the superphosphates
are at all freely soluble. The monohydrogen and normal phosphates of
calcium, magnesium, and, we may add, of barium, are scarcely taken up by
water.

If to a weak solution of, say, sodium - dihydrogen - phosphate
(]SraH2P04) calcium chloride or barium chloride be added, no pre-
cipitation occurs ; the corresponding salts of these latter metals being
comparatively soluble. On the other hand, from a solution of di-
sodium-monohydrogen-phosphate (]Sra2HP04) nearly all of the phos-
phoric acid is precipitated on the addition of a calcium or barium
salt, in the form of the corresponding monohydrogen phosphate of the
alkaline earth. In any mixed solution of di- and mono-hydrogen
phosphates, the amount of phosphoric acid which is left unprecipitated
by, say, barium chloride, is a measure of the proportion of the di-
hydrogen phosphate originally present. Now, if we apply this test to
urine of average acidity, we find that about 60 per cent, of the total
phosphoric acid remains in solution after the addition of the barium
chloride. We are justified in concluding, therefore, that acid di-
hydrogen phosphates are present in about this proportion ; a fact in itself
sufficient to account for the acid reaction of the fluid towards litmus. The
composition of the barium precipitate from an acid urine proves that the
remaining phosphoric acid is mainly in the form of monohydrogen salts.

If, now, we suppose the excretion to receive an increased quantity



576 THE CHEMISTRY OF THE URINE.

of the acid products of metabolism — what will be the effect on the dis-
tribution of bases ? It has been shown experimentally, that if to a
mixed solution of mono- and di-hydrogen phosphates, a mineral acid
(such as sulphuric acid) be added, in quantity not greater than is
equivalent to the bases present in the monohydrogen form, no free acid
is afterwards found in solution ; but there will be an increase in the
dihydrogen phosphates at the expense of the monohydrogen phosphates
in proportion to the amount of acid added. Not only is this true of
sulphuric acid ; it has been shown that all the weaker acids or acid salts
which are liable to reach the urine from the circulation {e.g. hippuric
acid or acid oxalates) are able, when added to a solution of the mixed
phosphates, to remove base from the monohydrogen form, and so to
produce almost an equivalent increase in the acid phosphates. So long,
therefore, as both these types of phosphate exist side by side (and they
are always found together in acid urine), we can assume that the
acidity of the fluid is due to the acid phosphate, and practically to that
alone. The simultaneous existence of the monohydrogen form will
be seen to be a guarantee of this, as it will have to disappear by inter-
change of bases, before any other urinary constituent can begin to exert
its own proper acidity to any appreciable extent.

When the urine reacts alkaline to litmus, the alkalinity may under
different circumstances be due (1) to excess of basic phosphates, (2) to
carbonates of the fixed alkalies, or (3) to ammonium carbonate.

Determination of the acidity.^ — It is, as we have seen, not difficult
to assign the acidity of the urine to its proper cause ; but when we
endeavour to discover a method by which to estimate the degree, of
acidity, and especially a mode in which to express its value numeric-
ally, we meet with considerable difficulties.

In the case of a fluid the acidity of which is due to a strong acid,
capable of forming stable salts with the alkalies, the ordinary methods
of acidimetry yield a determinate result, and the estimation of acidity
is one of the simplest operations in chemistry. We have but to note
the amount of a standardised solution of alkali which is sufficient
exactly to neutralise the acid present, and the point of neutralisation is
given sharply and exactly by the colour change which occurs in the
presence of one of many available indicators. In urine, owing to the
unstable phosphate equilibrium, and the presence of other salts which
influence the result, the process is much less determinate. To litmus,
as already stated, a dihydrogen phosphate, e.g. 'E^^l^^O^^, is acid, while
Na2HP04 and Na3P04 are alkaline ; but no mixture of these salts can
be found which is, strictly speaking, neutral to litmus paper.

If we start with a urine acid to litmus and gradually add alkali,
we at last reach a point when the fluid shows a paradoxical behaviour.
It makes red litmus paper tend to blue, and blue paper tend to red,
inducing in fact a somewhat violet colour in both. It reacts at once
acid and alkaline. This occurs when the monohydrogen phosphates,
which during the addition of alkali are gradually increased at the
expense of the dihydrogen salts, have come to bear a certain proportion
to the latter.

Many urines exhibit this so-called amphoteric reaction without the

^ I have discussed this subject at wliat may seem disproportionate length, but the pro-
blem involved illustrates well the complexity of chemical conditions in tlie urine ; and
much has been written upon it of late on what I venture to believe are erroneous lines.



DE TERMINA TION OF THE A CIDIT Y. 577

addition of extraneous alkali. The reaction usually betokens that the
monohydrogen salts exist in larger proportion than the dihydrogen, but it
prevails through a considerable range of variations in this proportion ;
its exact limits depending in part upon the delicacy of the litmus paper
used. Throughout the range of the amphoteric reaction a solution of
litmus, actually mixed with the fluid, retains a violet or neutral colour
practically unchanged.

Heintz attempted to explain this amphoteric reaction as follows. The
red colouring matter of litmus acts as a dibasic acid, forming with bases,
either unsaturated salts which are violet, or saturated salts which are blue.
From the saturated salt the dihydrogen phosphates may extract half the base,
leaving the unsaturated violet salt. The monohydrogen phosphates, on the
other hand, may yield to the red acid substance sufficient base to form also
the violet compound. In an amphoteric mixture the affinities are so balanced
that this violet compound can alone exist. When, however, the acid phos-
phate is present in sufficient excess, it removes all the base and leaves the red
free acid ; with a large excess of the more basic phosphate, on the other hand,
the litmus acid obtains its full complement of base and forms its blue salt.

With other indicators we can obtain a colour change at a more
definite point during the process of alkalisation of an acid urine, and to
the use of these we shall shortly return. But it should be made clear
that only in the interaction between a " strong " acid and a " strong "
base is the colour change, with an indicator, synchronous (or approxi-
mately synchronous) with the final replacement of all the acidic hydrogen
atoms by the base. From this special case we have come to attach a
definite value to the expression "degree of acidity," which is not
found when we are dealing with such a substance as phosphoric acid.
The " acidity " is here a quantity varying with the indicator used. The
coloured indicator is itself an unstable compound which, in the play of
acid and basic affinities, suffers a definite change when a certain point
of equilibrium is reached. This point will depend upon the relative
stability of the indicator and of the phosphates with which it is in con-
tact, and may or may not occur simultaneously with the removal of
all replaceable hydrogen from the latter.

The " degree of acidity " of a certain quantity of acid phosphate, in
solution by itself, will be greater than that of an equal quantity mixed
with a proportion of the more basic phosphates ; and this is true, no
matter what the indicator used. During the process of_ neutralisation
by the standard alkali, the proportion of the more basic phosphates is
gradually increased until the tendency of these to affect the indicator
in one direction eventually balances the action of the acid phosphate
in the opposite direction. This "neutral" point will evidently be
reached the sooner, if some basic salt was originally present before
titration was commenced.

Such considerations as these have led to a proposal to estimate the
acidity of urine, not by simple titration, but by actually determining the
proportion between the acid phosphates and the more basic phosphates
present. For this purpose, Lieblein,^ after a careful study of the matter,
has recommended the process of Freund, which is an application of the
barium precipitation method referred to above. The total phosphoric acid

1 ZtscTfir. f.physiol. Cliem., Strassburg, 1895, Bd. xx. S. 52-88. In this paper a criti-
cism of other methods will be found.
VOL. I. — 37



578 THE CHEMISTRY OF THE URINE.

is first determined in the original urine ; that existing as monohydrogen
phospliates is then removed by precipitation with barium chloride, and
that present as acid phosphates is finally determined in the filtrate.^

But how exactly are we to express the urinary acidity in terms of
the results so obtained ?

Some recent writers have denoted the acidity Ijy the figure express-
ing simply the ratio of acid phosphates to total phosphates.^ If the
P2O5 in the former be (say) 54 per cent, of the total PgOg, the relative
acidity of the urine is to be called 54 ; if in another case it is only 27
per cent., the acidity is to be considered as half that in the first case.

Such a procedure seems to be wholly misleading. If of two
specimens of urine one contains twice as much acid phosphate as the
other, but at the same time twice the amount of the monohydrogen salt,
the acidity, expressed in the above manner, will be the same in each case.

Such urines will certainly not hehave as if of equal acidity, nor will
they indicate the same acid production within the body.

We may here ilkistrate what we mean by the expression " behave as if of
equal acidity." One of the most important results of a high grade of acidity
is a tendency for the urine to deposit its uric acid in the free condition. In a
later section, dealing with the urates (q.v.), the mechanism of this separation
will be discussed. We shall find that one essential step in the process con-
sists in the conversion of certain less acid urates (biurates) into more acid
urates (quadriurates).

I^ow it is the acid phosphates which bring this change about, by removing
base from the first form of urate, themselves becoming, of course, converted
pari passu into more basic phosphates. But the latter, as they increase in
quantity, tend to yield back the base to the quadriurates, so that a point is
possible when the whole system will be in equilibrium. The less acid the
urine, the sooner is this point reached. A little consideration will show that
the " degree of acidity," from this point of vieAV (and it is an important aspect),
Avill be a function hotli of the absolute amount of the acid phosphates, and of
the ratio they hear to the total phospihates. But we are hardly in a position
to express the acidity quantitatively in terms of these two factors, because we
do not know precisely at what stage the urates and phosphates are in equi-
librium. It is probable, in fact, that the point of equilibrium is different for
each of the diverse changes which may occur in the urine, as a result of its
acidity, just as it is different for the colour change in diverse indicators. ISo
more striking instance of the relativity of the phenomena involved could be
given than a fact we shall discuss under the head of the pigments. Urinary
hsematoporphyrin is always found in the so-called alkaline form ; and if we
add to any normal urine either neutral or acid hsematoporphyrin, we find
that it immediately assumes the alkaline form. Equilibrium in this case is
only attained when base has been transferred to the pigment from the acid
phosphate. If, then, haematoporphyrin had happened to be our only available
" indicator," we should have said that urine Avas normally an alkahne fluid !

The whole source of the difficulty we have been discussing is found
in the fact that the terms " degree of acidity " or " degree of alkalinity "
are unscientific, though convenient, modes of expression. With increase
of knowledge, they will Idc replaced by expressions denoting the actual

^ For the principles of this determination, see p. 633. An error of some 3 ])er cent, has
to be allowed for, due to a conversion of monohydrogen into dihydrogen phosphate in the
process of precipitation.

- Cf. Hausmann, Ztsclir. f Iclin. Med., Berlin, 1896, Bd. xxx. S. 350.



VABIA TIONS IN A CIDITY. 5 79

chemical energy of the system of mixed salts. The degree of acidity of
the urine (or any analogous fluid) is in fact not an absolute quantity,
but is wholly relative to the means which we employ to measure it.
But by always employing the same means, be it noted, we may obtain
relative results which are strictly comparaljle, and as an outcome of this
somewhat diHicult discussion, it may be suggested that we shall do well
in the present state of our knowledge to continue to employ a simple
titration method, by which we obtain comparable, if only relative,
measurements. But we must employ an indicator which gives a more
definite point of colour change than does litmus, and we must retain
the same indicator for any one series of experiments ; moreover, the
nature of the indicator used must always be stated in stating the
results. Phenolphthalein, and perhaps cochineal, will serve our pur-
pose. If acid urine be gradually neutralised in the presence of the
former of these, which is colourless when acid, a pink tinge is developed
at a certain stage in the process, and we are justified in speaking of a
specimen of urine which requires more alkali to produce this change
as " more acid " than one which requires less.

What has been said in this section will have left a wrong impression if it
be thought that such measurements are of no value. My endeavour has been
to show that we have at present no means of expressing the acidity of the
urine as an absok:te quantity independent of the particular means adopted for
measuring it. But, having chosen a method of estimation, and being careful
always to use the same method, we may accurately follow the variations of
urinary acidity, and obtain results with important bearings.

Variations in acidity. — ^The degree of acidity as determined by
titration is, as we have seen, in the main, a resultant of two opposing
factors ; on the one hand, acid production in metabolism ; on the other,
the ingestion of jinsaturated or unstableHjasic compounds, supplemented
by the production of ammonia within the body. To these, however, a
third factor must be added — the elimination of acids or bases respect-
ively by other than renal channels.

The separation of the acid gastric juice and the consequent libera -
tion of bases_in the blood is associated with increased excretion of the
latter in the urine. On the other hand, the flow of alkaline secretions
— bile, pancreatic juice, etc. — diminishes the urinary bases.

From these considerations, the reasons for the variations in acidity
commonly met with become clear. The acidity increases with increased
proteid metabolism, with exercise, and with the consumption of food,
when this contains a small proportion of bases — in particular, with flesh
food. It diminishes when the food taken contains abundant bases. The
compounds of organic acids with the alkaline metals, which are so
plentiful in vegetable food, become oxidised in the body to carbonates,
and the excretion of bases thence derived tends to alkalise the urine.
From this follows the familiar fact that the urine of herbivorous
animals is alkaline, and that human urine may become alkaline (though
seldom continuously so) when a vegetarian diet is maintained.

The effect of the secretion of gastric juice is to produce what is called |
the alkaline tide. During the period of full gastric digestion the urine
may become less acid, and may even (though this is rare) become alka-
line to litmus. The occurrence of this phenomenon was first noted by
Bence Jones.



58o THE CHEMISTRY OF THE URINE.

It must not be supposed, however, that the post-prandial alkahne
tide is a universal phenomenon. It will be easily seen that the effect
of digestion upon the bases and acids of the blood must be somewhat
complex. The flow of alkaline saliva precedes, and that of bile and pan-
creatic juice rapidly follows, the gastric secretion ; and these, by removing
bases, tend to neutralise the effect of the removal of acid via the
stomach. From this cause, and from the increased proteid metabolism
induced by the food, it not infrequently happens that the urinary acidity
is from the first raised, instead of lowered, after a meal.

According to Quincke, a periodic variation of acidity may occur dur-
ing the day, independently of food ingestion,^ and in my experience this
is a more constant phenomenon.

Gruber found that the urine may become alkaline after a large con-
sumption of sodimn chloride, and Elidel ^ has recently stated that the
pure diuresis produced by such substances is in itself capable of inducing
this result. This may be true, under the somewhat extreme conditions
of experiment, but when the urinary constants are followed under
natural conditions from hour to hour, it is not found that the quantity
of urine passed during a given period has any regular influence on the
total acidity of the same period.^

Pathologically, a tendency to alkalinity is said to be found in most con-
ditions of debility, and especially in some types of ansemia ; probably from
diminished secretion of gastric juice, and from diminished general metabolism.
A process quite distinct from this occurs when, under the influence of
organisms (especially the Micrococcus ureca), the urea and uric acid of the
urine are hydrolised into ammonium carbonate. In cystitis this may occur
in the bladder, and the urine is voided alkaline with ammonia.

The acidity is especially high in scorbutic urine, and is increased to a greater
or less degree in some forms of dyspepsia, in diabetes, leukaemia, and in per-
nicious ansemia.

The ISTiTEOGENOus Compounds.

(a) Total nitrogen. — The urinary nitrogen amounts, on an average,
to 15 grms. in the twenty-four hours. This comprises by far the greater
part of the nitrogenous loss to the body ; less than 1 grm. being eliminated
through the intestinal secretions and all other channels combined.

Pathologically, the amount may be greatly increased ; 20 to 25 grms.
per diem is frequently observed in fever, and in severe forms of diabetes
50 grms. and upwards may be daily eliminated. On the other hand, a
marked diminution of the amount is seen in the condition of contracted
or granular kidney.

Under normal conditions, the urinary nitrogen is distributed in
various compounds in the following proportions : About 86 per cent, of
the whole is found in the form of urea ; about 3 per cent, as ammonia,
3 per cent, as creatinin, 2 per cent, as uric acid and the allied xanthin
bases ; while the remaining 6 per cent, is present, in varying proportions,
in hippuric acid, in indol and skatol, in the urinary nucleo-albumin,
in the pigments, and in minute quantities of other constitutents.

The total nitrogen is estimated by one of the many modifications of
Kjeldahl's process, which is founded on the fact that organic substances,

1 Ztschr.f. klin. Med., Berlin, 1884, Bd. vii. Suppl. 22.

- Arch. f. exjier. Path. u. Pharwakol., Leipzig, 1892, Bd. xxx. S. 41.

^ Of. Hausmann, Ztschr.f. Bin. Med., Berlin, 1896, Bd. xxx. S. 362.



UREA. 581

when heated with concentrated sulphuric acid, become oxidised, and all the
nitrogen (except such as may be originally present in combination with
oxygen) is converted into ammonia. The resulting ammonia is liberated
by the addition of caustic alkali, and distilled into a measured quantity of
standard acid ; its amount being finally determined by titration. Kjeldahl's
method gives admirable results with urine, and may be applied to 5 c.c. of
the fluid.

(b) Urea— CO(NHo)2. — The presence of urea in the urine was first
demonstrated by Eouelle in 1773. It is the chief end-product of nitro-
genous metabohsm in all mammals, in amphibia, and in fishes. In 1828
it was obtained artifically by Wohler, by heating the isomeric substance
ammonium cyanate (NH^.CNO).

The chemical constitution of urea is that of an amide of carbonic
acid (carbamide).

Projjerties. — Urea crystallises in colourless needles or rhombic prisms,
containing no water of crystallisation, and melting at about 130° C. It
is freely soluble in alcohol, and still more so in water ; in pure ether or
chloroform it is insoluble. Urea, like other amides of acids, is neutral
to litmus ; but, owing to the presence of two ammonia residues in its
molecule, it exhibits weak basic properties, and forms loose molecular
compounds, analogous to salts, two of which are of practical im-
portance.

Urea nitrate — CO(NH2)2.N'02.0H. — This compound crystallises out
when excess of pure nitric acid is added to a not too weak solution of
urea ; excess of the acid assists its separation, as it is less soluble in
nitric acid than in water ; crystallisation is accelerated by shaking and
cooling the mixture. The fundamental form of the crystals is a rhombic
table, of which the more acute angles measure 82° ; but, by truncation
of the angles, six-sided tablets are commonly formed, and these are apt
to adhere together and overlap like tiles on a roof (Fig. 49). When
rapidly heated, the crystals deflagrate. At 140° they decompose into
nitrous oxide, carbon dioxide, and ammonium nitrate.

Urea oxalate = GO(^H.^^_^.{GOO'H.\ — is formed in an analogous
manner by mixing solutions of urea and oxalic acid ; like the nitrate,
this salt is less soluble in excess of the acid. Its crystals belong funda-
mentally to the same type as those of the preceding compound, but are
apt to appear as thick short rhombic prisms (Fig. 49).



Online LibraryE. A. (Edward Albert) Sharpey-SchäferText-book of physiology; (Volume v.1) → online text (page 82 of 147)