CHAPTER XLIX

THE URINE AND THE GENITO-URINARY APPARATUS IN THE DIAGNOSIS OF TROPICAL DISEASE

THE URINE

Of the chemical tests employed in the examination of urine that for the presence of sugar is rarely of value, as there is no tropical disease in which the presence or absence of sugar is of diagnostic importance.

The determination not only of the presence of albumin in the urine but, as well, of the variations quantitatively from day to day is, however, most necessary in many of the tropical diseases and

## particularly in yellow fever and blackwater fever.

=Tests for Albumin.=—The simplest and most reliable test for albumin is the heat test with the subsequent addition of a sufficient number of drops of 5% acetic acid to make the boiled urine acid and incidentally to dissolve any phosphates which may have separated out on boiling.

Ulrich’s test is a very simple one and only calls for reagents which are usually at hand. Heat a saturated solution of common salt, containing 2% of glacial acetic acid, and superimpose the urine to be tested upon the hot reagent. A ring shows the presence of albumin.

For Heller’s test, pour a small amount of nitric acid into a narrow test tube and, while holding the tube at an angle of about 45°, superimpose a layer of the urine to be tested, which is delivered drop by drop from a pipette and allowed to flow down the side of the tube.

This test can be converted into a quantitative one which is sufficiently accurate for clinical purposes. It is based on the fact that a specimen of urine containing 0.003% of albumin will give a perceptible ring at the layering of the urine and acid in two minutes. If the ring appears at once or in a few seconds the albumin content is greater. From the qualitative test an idea can be formed as to the amount of albumin which the urine contains, a heavy ring forming immediately showing a considerable albumin content. Probably the highest elimination of albumin is found in chronic parenchymatous nephritis where it may run from 1 to 3%. In an ordinary case of acute nephritis O.5% would be an average content.

Recently I have been using for both qualitative and quantitative albumin tests the following apparatus. This is simply a 5-inch piece of ¼-inch soft glass tubing heated at a point 2 inches from one end, drawn out for about 2 inches and bent to form a U-tube with one end shorter than the other. This form of tube enables one to perform two tests with the same column of nitric acid and is easily cleaned and dried. They may be kept suspended around a glass tumbler’s rim. Taking up a small amount of nitric acid with a capillary bulb pipette it is deposited in the capillary curve of the bent tube. This acid pipette should be kept attached to the acid bottle. With a second pipette the urine is deposited in the short arm of the U-tube and the presence of albumin shows by a distinct ring at the junction of urine and acid in the clear capillary tubing. The long arm will serve for the introduction of a second specimen of urine for the albumin test.

For quantitative test we dilute the filtered urine with one or more parts of normal salt solution according to the intensity of the albumin ring. A very convenient way of making the dilution is with a graduated centrifuge tube. Make a one to ten dilution of the urine, mix and draw up with a bulb pipette and deposit in the short arm of the U-tube. A distinct ring forms in two or three seconds. Pour off one-half of the diluted urine and make up with an equal amount of saline. Deposit this one to twenty dilution in the long arm. The ring forms in about a minute. With further testing it is found that a one to forty dilution shows a perceptible ring in just two minutes. This final and successful dilution multiplied by 0.0033 gives the percentage of albumin in the urine (40 × 0.0033 = 0.13%).

Should it be desired to determine the nature of the proteids present either in urine or in exudates or transudates the following method is applicable. Determine the percentage of total proteid by the method employed above. Then throw down the globulins by the addition of an equal amount of a saturated solution of ammonium sulphate, filter and estimate the proteid content of the filtrate. The difference between that and the total gives the percentage of globulin. The filtrate is now treated with 5% acetic acid until a precipitate of nucleo-proteid ceases to form; the fluid is filtered and the clear filtrate (which should not show any turbidity with a drop of 5% acetic acid) is tested for its proteid content, which represents the serum albumin. When the combined percentage of globulins and serum albumin is subtracted from the total proteid percentage we have the percentage of nucleo-proteid.

=Tests for Blood.=—Very important in tests of the urine are those for blood. With an unaided eye a smoky colored urine, more or less reddish-brown in color, is suggestive in cases of haematuria, while in haemoglobinuria we usually have a more or less porter-colored, turbid fluid which, however, shows a clear haemoglobin-tinged fluid when centrifuged to throw down the haemoglobin casts and granular débris of the disintegrated red cells. Upon shaking such urine we get a pinkish foam instead of the yellowish one of icteric urine.

A strip of white filter-paper when partially dipped into urine shows pinkish-colored waves which are more deeply colored at the summit of the waves while the paper which absorbs bile-containing urine shows the yellowish color and waves less yellow at the summits of the colored waves.

For haematuria we may use either the microscopic method for the recognition of red cells or chemical ones. The red cell is best recognized by the double contour of the 7.5 micron disk. Spores of moulds, which greatly resemble red cells, are smaller, usually not more than 5 microns.

The following technic is of the greatest value not only because it makes the red cells more distinct but because by staining the various epithelial elements it gives us more exact information as to distinction between the segmented nucleus of pus cells and the single one of renal cells. Make a streak of vaseline across a slide one inch from one end. Then deposit a drop of urinary sediment, taken up from the centrifuge tube with a pipette, about ¼ inch from the grease line. Then drop a large drop of Gram’s iodine solution on this sediment and then apply one side of a square cover-glass to the vaseline line and allow it to fall gently on the drop of sediment and stain. There is no current motion, and casts and other urinary elements remain under the cover-glass instead of floating out beyond the margins. It is well to examine the unstained sediment with a ⅔ inch objective before adding the iodine and applying the cover-glass, as one gets a better idea of casts with a low power and unstained than in any other way.

With haemoglobinuria we necessarily turn to chemical or spectroscopic tests which are also applicable to microscopically doubtful cases of haematuria.

For the detection of occult blood, the technique described on page 524 should be observed, and alkaline urines faintly acidified with acetic acid before examination.

=Indicanuria.=—In _sprue_ and _pellagra_ we have a rather marked increase in indican. It is probable that many cases of vague manifestations of neurasthenia with loss of physical and mental energy are connected with auto-intoxication rather than tropical heat or intestinal parasites.

=Urobilinuria.=—In conditions where there is a great destruction of red cells tests for urobilin are important. Plehn considers the presence of urobilin as of importance in the diagnosis of _latent malaria_, which is true, provided other causes for red blood cell destruction are excluded. _Blackwater fever_ cases usually show an intense urobilinuria. Urobilinuria is also a sign of deficient functioning of the liver.

=Bile Pigment Tests.=—In conditions associated with the presence of bile pigments in the urine we may conveniently employ the Gmelin test in the following manner. Filter the urine several times through the filter and then touch the moist inner surface of the paper with a glass rod dipped in commercial nitric acid. A ring-like play of colors, green, blue, violet and red circle out from the spot touched. A green color must be noted for positive diagnosis.

Tests for bile acids seem to have but slight value in differential diagnosis.

A very simple and apparently quite reliable test for deficiencies in liver functioning is that known as Ehrlich’s aldehyde reaction. The reagent is a 2% solution of p. dimethylaminobenzaldehyde in equal parts of water and concentrated hydrochloric acid.

For the test treat 5 cc. urine with 5 to 10 drops of the reagent. Agitate a few minutes and a positive reaction is shown by a fine cherry-red color, thought to be due to urobilinogen.

The urine sample should be perfectly fresh and not long exposed to light.

AMOUNT OF URINE IN 24 HOURS

Normally a man passes about 1200 cc. of urine in twenty-four hours, a woman somewhat less. When the amount is under 750 cc. we have an oliguria. To consider a polyuria as present the patient should pass more than 3000 cc., as this amount may be considered the upper normal limit. In anuria we have a cessation of renal activity.

The disease in which anuria is most characteristic is _cholera_. During the stage of evacuation the urinary secretion becomes less and less along with the progressive failure of circulation and, during the algid stage, we have a suppression of urine.

The anuria seems to run parallel with an acidosis and intravenous injections of bicarbonate of soda solutions tend to prevent anuria. In the stage of reaction the favorable outcome is the reappearance of urine, which increases in amount to become a polyuria. In unfavorable cases the anuria continues.

In _blackwater fever_ anuria may result from the blocking up of the renal tubules by haemoglobin casts.

Blackwater fever also shows an acidosis and alkaline treatment is here indicated. Blackwater urine is irritating so that there is vesical tenesmus with frequent urination.

The degree of renal involvement is of great prognostic value in _yellow fever_, and those cases where the oliguria goes on to suppression are apt to terminate fatally.

In _heat stroke_ there is an oliguria or anuria which may be followed, during convalescence, by a polyuria. Marked irritation of the bladder, associated with suppression of sweating, may be indicative of oncoming heat stroke.

In _dropsical beriberi_ there is an oliguria or, rarely, an anuria which with the rapid disappearance of the general body oedema may become an excessive polyuria.

Rarely one may observe a critical flow of urine in _dengue_ at the time of the fall of the primary febrile accession.

ALBUMINURIA

The disease in which this is of peculiar diagnostic and prognostic value is _yellow fever_. We expect albumin about the second day with a steady increase in amount during succeeding days of the fever. The degree of oliguria or rather anuria is of greater prognostic value than the degree of albuminuria. The albuminuria is of great diagnostic value in differentiating yellow fever from dengue.

_Blackwater fever_ shows a great abundance of albumin with the appearance of the haemoglobinuria and diminishes as the color of the urine clears up.

In _malaria_ albumin was present in 38% of benign tertian infections and 58% of malignant ones at Johns Hopkins Hospital.

The absence of albumin in _beriberic urine_ is important in differential diagnosis from acute nephritis.

HAEMOGLOBINURIA

Paroxysmal haemoglobinuria or haemoglobinuria resulting from potassium chlorate poisoning, severe burns, intravenous injections of foreign sera, or—most commonly—syphilis, may be noted in the tropics.

The vast majority of cases of true tropical haemoglobinuria, however, are due either to blackwater fever or to the administration of the acid salts of quinine to one predisposed to quinine haemoglobinuria. While it must be admitted that haemoglobinuria may result from quinine it is certainly so rare in subtropical countries, where great amounts of quinine are administered in treatment of malaria, as to be unimportant. It is only where the malignant tertian parasite flourishes that we have the question of the importance of quinine in producing haemoglobinuria brought up.

Certain persons have isohaemolysins in their blood which dissolve the red cells of other persons and in paroxysmal haemoglobinuria autohaemolysins may be present which can destroy the patient’s own red cells. This auto-haemolysis seems operative only when a low temperature is followed by a high one. When haemoglobinaemia exists the liver converts it into bile pigment causing bilious stools and jaundice. If one-sixth of the red cells are destroyed haemoglobinuria results.

The dark, porter-colored urine of blackwater is diagnostic even to the patient. The urinary sediment consists of granular débris with occasional haematoidin crystals. Albuminuria runs parallel with the haemoglobinuria. Pain in the loins, probably, from the plugging of the renal tubules by the detritus of red cell destruction, is a feature of blackwater fever. In blackwater fever we have the early appearance, even in a few hours, in a patient who is markedly asthenic and miserable, of jaundice, porter-colored urine and albuminuria.

HAEMATURIA

Among tropical diseases that which immediately suggests haematuria is vesical bilharziasis. The blood in the urine is in the form of red cells; it is a haematuria and not a haemoglobinuria. The passage of blood usually occurs at the end of micturition and it is either in the last few drops of urine or in the sediment obtained after centrifuging that we note the terminal spined eggs of _S. haematobium_ which prove the diagnosis.

Red blood cells in the urine may also be noted in the haematochyluria of filarial disease.

When we have blood in the urine in yellow fever it is a haematuria and comes on about the same time as the black vomit and other haemorrhages resulting from degeneration of the endothelial linings of the blood capillaries, which only takes place about the third or fourth day of the disease.

Haematuria may also be noted in plague at the time when the haemorrhages into the skin occur.

CHYLURIA

Vesical varices from lymphatic obstruction, due to filarial disease, are the most frequent cause of the milky urine of chyluria. The urine usually has a pinkish tinge from blood admixture so that the condition is really a haematochyluria. The thoracic duct may not be the seat of obstruction which has taken place elsewhere when the condition is lymphuria instead of chyluria. Lymph and chyle differ in fat content, the former having from very little to about 3% while the latter has 5% or more of emulsified fat. Chyle has also more than twice as much proteid as does lymph.

In chyluria the morning urine is often clear while that at night is milky. On standing, chylous urine separates into an upper cream-like layer with a pinkish sediment and, between, a pinkish-white fluid in which floats a clot. Filarial embryos may or may not be found.

KIDNEY FUNCTION AND ITS DETERMINATION

The ability of the kidney to excrete substances from the blood stream is frequently affected by disease, especially such as disturbs the kidney, and is usually diminished after the age of 50 years. Disease of the kidney, however, does not necessarily imply an inability to eliminate substances—the functional need not parallel the anatomical lesion. Function may be normal especially when the changes are of focal type.

Impairment of renal function does not affect the excretion of different compounds to the same extent. It is well established that functions for chlorides and for urea are independent of each other. In any urinary examination, then, one should bear in mind the possible effect of an impaired excretory power relative only to the substance under consideration. In this connection, we speak of the _kidney threshhold_ for a substance, i.e., the concentration required in the blood stream before the kidney will excrete it, at least in abnormal amounts. For chlorides, this is quite definite at 562 for blood plasma; for sugar, it is about 160-180 for whole blood. The threshold is not necessarily absolute, but simply indicates that with less sugar, for instance, only the normal traces will be passed. Chloride excretion begins only when their concentration passes the threshold value, and the rate of elimination depends upon their excess. Other compounds, such as urea, for example, may have no definite threshold value. Disease may affect the value, either by raising it and causing abnormal retention, or by lowering it and giving rise to depletion.

We can establish the status of the renal function in any given case, and are then in a position to intelligently prescribe dietetic and other treatment. Chemical analysis of the blood indicates the metabolic products affected and guides us in the adjustment of the diet, etc., to the excretory powers of the kidneys. One must, however, not overlook the nutritive needs of the body.

Many methods are employed for the determination of kidney function, and their relative values are still debatable. Probably those least open to criticism are chemical analysis of the blood, the phenolsulphonephthalein test, and Mosenthal’s method. Ambard, McLean, Van Slyke, and others have devised formulae to this end, based upon chloride, urea, or sugar excretion, which have many warm advocates as well as severe critics. A rough clinical comparison of the two kidneys may be obtained by determining the urea in specimens of urine simultaneously collected by the ureteral catheter.

_Blood Chemistry_, now that its value has been established, is generally given preference and allowed greater weight in case of disagreement with other tests. It measures excretory function for normal metabolic products, and has the additional value of an aid in diagnosis and prognosis and a guide to treatment, especially dietetic. It has the disadvantage of a possibly unfamiliar technique, and does not afford a comparison of the two kidneys.

The substances usually considered are the nitrogenous compounds (nonprotein nitrogen, urea nitrogen, uric acid, etc.), but retention of others (sugar, chlorides, cholesterin, etc.) are also of significance in this connection. Of the nitrogenous constituents, the kidney excretes creatinine most readily, urea next, and uric acid with the most difficulty. As a consequence, an impairment of function results first in the retention of uric acid, then urea, and, finally, creatinine is also retained. Owing to the relatively small amounts of uric acid and creatinine present, the nonprotein nitrogen, which includes the nitrogen in them as well as in other compounds, is not appreciably affected except by the urea increase. This is the basis of an intelligent interpretation of the findings. The urea and nonprotein nitrogen are so markedly affected by diet, especially among nephritics, that judgment must be exercised when they are employed as indices of renal function. This fact was not properly appreciated until recently, and probably accounts for much of the discredit cast upon blood chemistry in this connection. The uric acid, being less exogenous in origin, is perhaps the most delicate and the safest index; the increase appears early, and 3.5 may be considered the high normal value. On the usual restricted hospital diet, over 20 for urea nitrogen should be considered suggestive of impaired kidney function; over 75 speaks decisively for renal involvement and probably uraemia.

_Phenolsulphonephthalein (Phthalein, or Red) Test._—This was developed by Rowntree and Geraghty, and its simplicity makes it very useful, especially to the isolated practitioner with limited laboratory facilities. It estimates only function for a foreign substance, is not considered quite as reliable as chemical analysis of the blood, and, of course, does not give the additional information that the latter supplies. It is, however, of much value, has no contraindications, and does compare the kidneys when combined with ureteral catheterization or use of a separator. Positive results are of more significance than negative, and it is less affected by glomerular than tubular changes. Values of more than 75% for 2 hours may be accompanied by diuresis, and Frank considers such a finding suggestive of renal disturbance with irritation if there is any corroborative evidence.

The technique comprises administration of the dye, determination of the interval before it appears in the urine, and the amount then excreted during definite periods. The dye is employed in solution, and is conveniently purchased already sterilized in ampules, each containing slightly more than 1 cc. of a solution of its monosodium salt of the strength of 6 mg. per cc. The patient drinks 200-400 cc. water, and 6 mg. of the dye are injected intramuscularly (lumbar muscles), or intravenously, 20 minutes later. The bladder is immediately emptied, and the urine discarded. The succeeding portions of urine may be collected by voiding, but it is more accurate to catheterize the bladder or ureters, and catheterization is practically a necessity for determination of the “appearance time.”

The appearance time is the interval of time elapsing between injection of dye and its appearance in the urine. It is determined by allowing the urine to drip from the catheter into a receiver containing a drop of 10% NaOH. The first traces of the dye will cause a pink color.

The time interval chosen for calculating excretion is then computed from the instant of this appearance. There is considerable diversity in practice as regards this time interval, and it would seem that shorter intervals and quicker results are gaining in preference, as well as being considered equal in value to longer periods.

The percentage excretion of the dye is now measured in each sample of urine. To do this, prepare a standard solution, made by diluting 0.5 cc. of the phenolsulphonephthalein solution mentioned above to about 200 cc. with water, adding 5-10% NaOH until no further intensification of the red color is produced (requires a few cc.), diluting to one liter, and mixing. This standard then represents 50% (3 mg.) of the amount of the dye injected. The color of the urine sample is similarly developed with alkali, and the mixture diluted to 1 liter, mixed, and compared with the standard in a colorimeter. The per cent excretion in the specimen equals the reading of the standard solution multiplied by 50 and divided by the reading of the urine mixture, when the colors are matched in the instrument.

For accurate work, it is desirable to balance in the standard the urine color of the unknown, and this is accomplished by including in the standard a volume of urine (dye-free) _proportional_ to that in the unknown. Also, with a low excretion, it is better not to dilute the unknown to 1 liter, but to some lesser volume that will give a tint closer to that of the standard, and then allow for the variation in the calculation.

[Illustration: FIG. 153.—Fibres, starch granules, etc., which may be found in urine sediment. No. 12 gives appearance under microscope of scratches on old used glass slides. No. 15 (_a_), _Tyroglyphus longior_ a mite. No. 15 (_b_), _Trichomonas vaginalis_. No. 16 (_a_), Egg of _Eustrongylus_; (_b_), _Echinococcus hooklets_; (_c_) _Schistosoma_ egg; and (_d_), _Filaria bancrofti_ embryo.]

Dunning has devised a simple, inexpensive colorimetric outfit with permanent standards in ampules for this test. It is satisfactory unless the colors of the standards fade.

After intravenous injection, the normal appearance time is 4-6 minutes, and the normal elimination is 35-40% in 15 minutes, and totals of 50-65% for 30 minutes and 65-80% for 60 minutes; or, for the first 30 minutes, it may be stated as about 1% per minute from each kidney.

After intramuscular injection, the normal appearance time is nearer 10 minutes, and the normal elimination is 30-40% in 30 minutes, and totals of about 50% (40-60) for 60 minutes, and about 80% (60-85) for 2 hours, or 20-25% during the second hour. If the appearance time is not determined, it is customary to allow for it, collecting the first hour’s specimen at 70 minutes after injection of dye and the second hour’s 60 minutes later.

Impairment of kidney function, of course, increases appearance time and lessens excretion, serious cases not unusually excreting less than 1% during two hours.

When the question of the kidney involved arises, the urine must be taken by ureteral catheterization or by a separator.

=Starches and Fibres.=—In examining urinary sediments it is important to be familiar with the various textile fibres and starch grains which are so frequently present, the fibres coming from the clothing and the starch grains from dusting powders. Wool fibre fragments show bark or scale-like imbrications and are round. Cotton fibres are flattened and twisted, while linen ones show a striated flattened fibre with frayed segments as of a cane stalk. Silk shows a glass-like tube with mashed-in ends.

Corn and rice grains are the most common of the starch grains and their nature is immediately disclosed by their blue color when mounted in iodine.

AFFECTIONS OF THE GENITO-URINARY ORGANS

In _blackwater fever_ we have marked pain in the region of the kidneys due to the plugging of the tubules with haemoglobin casts. Vesical tenesmus and pain along the ureters may also be present.

In _malaria_ Thayer states that nephritis occurs in about 2% of malignant tertian cases.

In _bilharziasis_ the kidneys are involved secondarily—the change being brought about by stone in the bladder and cystitis leading to hydronephrosis and pyelonephritis.

Cases of cystitis occurring in dysentery have been reported which showed amoebae in the sediment of the urine. Such cases probably were connected with recto-vesical fistulae caused by amoebic ulceration.

In _cholera_ the kidneys are markedly affected, especially the epithelial lining of the tubules.

_Malta fever_ may rarely be attended by an orchitis.

One of the manifestations of filarial disease is _lymph scrotum_ in which the scrotum is covered with small blebs containing a chylous fluid which may possibly contain microfilariae. It is associated with recurring attacks of lymphangitis. There is also a filarial orchitis and we may have a lymphangitis of the lymphatics of the cord. Again filarial disease may show a chylocele in which the tunica vaginalis contains a fluid similar to that seen in the varices of lymph scrotum. This fluid may also show filarial embryos.

In _endemic funiculitis_ there is a sudden onset with high temperature and pain in spermatic cord and epididymis. The general condition rapidly becomes grave with a hard, tender, cylindrical swelling along the cord and also pain and swelling of epididymis. It is a streptococcus infection usually engrafted on a filarial or bilharzial process and demands immediate surgical measures.

_Kala-azar_ may be accompanied by sloughing of the scrotum at the time manifestations of cancrum oris are noted.

Cases of gangrene of the scrotum have been reported as connected with _malaria_.

Gangrene of the scrotum and penis is not infrequently noted in _Rocky Mountain fever_.

In puzzling febrile cases in the tropics one should always think of a possible _pyelitis_. Then too keep in mind _renal tuberculosis_.

If _leprosy_ comes on before puberty the sexual organs remain in an undeveloped condition. Leprous infiltrations are noted in the testicles and ovaries. In nerve leprosy, which does not usually come on until after puberty, the women may bear healthy children and it is now thought that the view that leprosy markedly tends to produce sterility is lacking in confirmation.

In _ancylostomiasis_ menstruation is markedly interfered with and amenorrhoea is often a prominent symptom. Young men who have been affected before puberty show lack of development of pubic hair along with infantile genital organs. The girls do not show normal breast development.

_Granuloma of the pudenda_ is a disease which is rather frequent in British Guiana.

_Dhobie itch_ is characteristically located in the crotch region.

BACTERIOLOGICAL EXAMINATION OF URINE

About the only tropical disease in which a bacteriological examination of the urine is of particular value is that in connection with _Malta fever_. It is advisable to cleanse the meatus with alcohol and then having discarded the first ounce or so of the urine to receive the remainder in a sterile salt mouth bottle. A drop of this urine can be deposited on a poured agar plate and smeared out over the surface.

As dysentery bacilli and cholera spirilla are practically absent from the blood, urine examination for the causative organisms in these diseases is fruitless.

The culturing of the urine to find paratyphoid or typhoid organisms should be carried out, as well as blood cultures, where we are dealing with puzzling fevers in the tropics. The Teague plating medium described under the chapter on Faeces is a very satisfactory one.

In culturing urine from a case of pyelitis blood agar is a most excellent differentiating medium for streptococci.

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