the total non-protein nitrogen of the blood in ......230 non-protein nitrogen of the blood in...

T H E TOTAL N O N - P R O T E I N NITROGEN OF T H E BLOOD IN N E P H R I T I S AND ALLIED

CONDITIONS.*

BY C L I F F O R D B. FARR, M.D., AND J. H A R O L D A U S T I N , M.D.

(From the John Herr Musser Department of Research Medicine of the Univer- sity of Pennsylvania, Philadelphia.)

In I836 Richard Bright, 1 referring to renal disease, stated: " The chemical qualities of the blood are so far changed that urea is to be detected in that fluid, or, at all events, certain constituents scarcely distinguishable from i t " ; and he expressed the opinion that the occurrence is " a source of disease springing immediately out of the defective action of the kidney." Seventy years later, Friedrich M/iller 2 emphasized the fact that "insufficiency of nitrogenous excretion leads to a definite increase in the retention nitrogen of the blood, particularly in those groups of kidney disease in which experience has shown the danger of uremia." These statements embody all that can be asserted with positiveness at the present moment. The attempt to find an invariable relation between the retained nitrogen of the blood and the degree of uremic intoxica- tion has not been successful. On this account, and because the methods in use until recently required considerable quantities of blood, at least five times as much as the procedures we have employed, the determination of the nitrogen or urea of the blood has not become a routine means of studying the efficiency of the renal function.

Strauss s and others, a decade ago, tried to connote nitrogen retention with definite pathological types of nephritis, but without success. Widal 4 has viewed the subject from a different angle and has defined several distinct types of dis- turbed renal function. He has erred in theory, perhaps, by being too schematic, and in practice by relying on unreliable methods. Thus Rowntree and Fitz 5 state that the hypobromite method for urea in the blood, as employed by Widal, is subject to an error of from io to 60 per cent. Folin, 6 within the last year, by introducing chemical methods which permit of rapid and accurate analyses of both urea and total non-protein nitrogen in minimal quantities of blood, has greatly extended the possibilities of this mode of examination.

* Received for publication, May 3, I913. 1 Bright, R., Guy's Hosp. Rep., i836, i, 338. 2 Mfiller, F:, Verhandl. d. deutsch, path. Gesellsch., I9O5, ix, 64. a Strauss, H., Die chronischen Nierenentz/indungen, Berlin, i9o2. 4 Widal, F., Bull. et m~m. Soc. todd. d. h6p. de Paris, I9II, xxxii, series 3, 627.

Rowntree, L. G., and Fitz, R., Arch. Int. Med., i913, xi, 258. 6 Folin, O., and Denis, W.. Jour. Biol. Chem., IgII-I2, xi, 527.

:28

Clifford B. Farr and J. Harold Austin. 229

The present report deals with the results of .our study of the blood by Folin's methods in a series of fifty-nine hospital patients7 Our main concern has been with nephritis, but we have examined the blood in many other conditions, as opportunity offered.

Throughout the paper we use the term non-protein nitrogen to indicate the nitrogen not precipitable by the methyl alcohol and zinc chloride of Folin's method. The terms retention nitrogen, waste nitrogen, or extractive nitrogen should perhaps be discarded in favor of descriptive appellations, such as non-protein nitrogen, incoagu- lable nitrogen, or simply filtrate nitrogen. This has been suggested by Folin's experiments which indicate that a small fraction of the non-protein nitrogen may be not a waste product, but amino acids available for utilization by the body cells. The unmodified term urea is used to signify the ammonia-urea fraction; that is, the nitrogen determined by the urea method employed. Separate estimations of the ammonia were not made as they seem not to be of clinical value. According to Folin, the older methods exaggerated the quantitative importance of the ammonia fraction. We used the technique described by Folin and his collaborators, and we met with no difficulties of importance.

METHOD.

The principal steps in the analyses will be briefly enumerated, but the minor details, which, however, are essential in practice, will be omitted. The total nitrogen method is a miniature Kjeldahl method, while the urea method is an analogous modification of standard procedures. Accuracy is secured by careful measurements (special pipettes) and by substituting Nesslerization for titration in the final step. Minute amounts of ammonia which it would be impossible to estimate by the usual titrations are thus accurately determined.

,4. Collection of Blood.--(I) Io c.c. of blood are added to about 6o c.c. of pure methyl alcohol in a xoo c.c. volumetric flask, and after being shaken are diluted to volume with the same reagent. (~) After a few hours the coagulated blood is filtered off and the filtrate clarified by the addition of a few drops of zinc chloride solution, and is filtered again. Each Io c.c. of filtrate represents I c.c. of the original blood.

B. Total Nitrogen Determlnation.--(i) Io c.c. of the filtrate are measured into a large Jena test-tube and freed from alcohol by immersion in boiling water. (2) The organic matter is destroyed and the nitrogen converted into ammonium

7 University of Pennsylvania Hospital, service of Dr. Alfred Stengel, and Philadelphia General Hospital, service of Dr. David Riesman.

230 Non-Protein Nitrogen of the Blood in Nephritis.

sulphate by digesting with: potassium sulphate and concentrated sulphuric acid over a microburner. The fumes are carried off by special absorption tubes con- nected with a suction pump. (3) The ammonia is set free by the addition of an excess of sodium hydrate solution and is driven over into dilute hydrochloric acid by a powerful air blast. (4) The acid solution is t rans fe r red to volumetr ic flasks of suitable volume, t reated with a definite quanti ty of dilute Nessler 's solution, and made up to volume. ($) The deep amber color that develops is compared, by the aid of a colorimeter, with that of an ammonium sulphate solution of known strength, similarly treated. F rom the colorimetric readings the amount of ni t rogen is easily calculated.

C. Urea Determination.--The urea method is similar in most respects. The alcohol is removed by the aid of moderate heat (50 ° C.) and an air current. A higher temperature is avoided as it might decompose the urea. Digestion is then carried on by the aid of acetic acid and fused sodium acetate at a temperature of I5o ° C. A condenser is used and the proper heat regulated by the aid of a temperature indicator which is sealed in a glass ampoule and floated on the boiling fluid. The remaining steps are almost identical with those used for the total nitrogen. As we have previously stated, the figures for urea thus obtained include the preformed ammonia.

The results in both cases are stated in terms of mill igrams per Ioo c.c. of blood. In the l i t e ra tu re these values are occasionally stated as grams per liter. Where we have had occasion to refer to such figures we have converted them into mill igrams per Ioo c.c.; i. e., o.25 gin. per liter is equal to 25 mg. per ioo c.c.

In collecting the blood f rom the vein we used an accurately graduated syringe, and in most instances we removed io c.c. (diluted to ioo c.c.) ra ther than the smaller quanti ty originally recommended. This has supplied sufficient filtrate to permit of duplicates both for the ni t rogen and urea estimations and also for retests when required. However, z c.c. would suffice for the ni t rogen estimation in case of necessity.

In order to permit of many examinations at one time we installed an apparatus providing space for eight simultaneous digestions of either ni t rogen or urea. A rocking bar containing the tubes leading to the glass suction pump allowed adjus tment of the fume extract ion tubes without danger of breaking, a convenient modification of the original apparatus. As we also provided an equal number of evaporat ing and blow over units, it was possible for two persons to complete f rom twenty-four to thir ty- two tests in an afternoon, or, in other words, to examine six or eight specimens for both urea and total filtrate ni t rogen with duplicates in each case. The evaporation of the alcohol f rom the specimens consumes the most time, particularly in the case of urea. This can be lessened for the urea if the capillary tubes are made of fairly large caliber. 'It is very important to have good test-tubes of thin Jenag la s s (Schot t ) ; thick tubes, even of the best quality, are of no use and at first caused much delay and the loss of several impor tant specimens. We used large round bulbs s on our blow over tubes instead of the vertical pipette-like ones originally recommended. As a result, we never had the slightest loss of fluid with the s trongest air current. Also we have found it essential to cover the rubber stopper con-

s This was suggested by Mr. Farmer, of Dr. Folin 's laboratory.

Clifford B. F a r r and J. Haro ld Aus t in . 231

nections with water before the air is turned on so as to detect at once any loss by leakage. In Nesslerization we used the Winkler modification and we had no difficulty with cloudiness except rarely af te r too rapid mixing or in too concentrated solutions.

Control experiments were made on a watery solution of urea which theo- retically should have shown 5o mg. of ni t rogen per Ioo c.c., and which gave the following results by the total ni t rogen method: 49.7, 49.5, 5o.o, and 49.7 rag. Wi th the urea method results were far less un i fo rm a n d here slight variat ions in technique were found to be of great moment. Eventual ly sat isfactory analyses by the urea method gave 5o.o and 47.4 mg. Under conditions analogous to those used in blood examinations, i. e., in methyl alcohol solution, the results by the total ni t rogen method were 47.7 and 49,8 mg. In actual blood examinations we found the greatest range of error when it was necessary to Nesslerize in small volumetric flasks (25 or Io c.c.). This we at t r ibuted to the incomplete washing of delivery tubes and receivers necessitated by the nar row margin of fluid available. Taking our duplicate results serially in for ty- four consecutive examinations, we found that the total ni t rogen estimations showed variat ions f rom the average ranging up to 2 rag. per Ioo c.c. of blood, and the urea up to 1.5 rag. The .average difference between duplicates in total ni t rogen estimations was 1.6 mg. per Ioo c.c. of blood, and in the urea estimations L4 mg.

Analyses of the various reagents by means of blanks showed appreciable impurities in the ~otassium sulphate and kerosene; in the quantit ies used they introduce an er ror which when calculated for Ioo.c.c. of blood amounts to about 2 mg.; the quanti ty of these reagents used is the same in every analysis. Finally we have convinced ourselves by experiment that the slight brownish cloud, which occasionally forms in the filtrate on long standing, does not represent an appreciable quanti ty of nitrogen.

Before report ing our own figures we shall present some results obtained with the older methods, as used by other investigators. The principal variat ion in the methods employed has been in the manner of precipitating the albumin. Serum has generally been preferred to blood, and the ni t rogen estimations have almost invariably been made by the Kjeldahl method, variously modified. The methods of precipitation are of several types. Widal 's method, as used by Rowntree and Fitz, ° was as follows: Io c.c. of blood were added to IX5 c.c. of 95 per cent. alcohol, i0o c.c. of the filtrate representing 8 c.c. of blood. This was evaporated to dryness preparatory to making the estimation by the Kjeldahl method. Jackson and Saiki 1° used a similar technique, but washed and ground up the coagulated blood protein with 95 per cent. alcohol, a f te r which filtrate and washings were united. Limbeck and Pick,l~ who seem to have been the first to use the Kjeldahl method for estimating the ni t rogen of the blood, used an alcohol extract ion method. Strauss l~ ran the blood serum into five volumes of boiling distilled water and then added an amount of 2 per cent. acetic acid previously determined to be sufficient to cause a flaky coagulation. The solution

9 Rowntree, L. G., and Fitz, R., loc. cir. l0 Jackson, H. C., and Saiki, T., Arch. Int. Med., I912 , ix, 79. i i Limbeck and Pick, cited by Ascoli, G., Vorlesungen fiber Ur~imie, Jena, ~9o3. m Strauss, H., loc. cir.


T A B L E I .

Author. Diagnosis.

S t r a u s s . . . . . . . . . . . . . . C h r o n i c i n t e r s t i t i a l n e - p h r i t i s . . . . . . . . . . . . .

S t r a u s s . . . . . . . . . . . . . . . C h r o n i c i n t e r s t i t i a l n e - p h r i t i s w i t h u r e m i a . .

S t r a u s s . . . . . . . . . . . . . . C h r o n i c p a r e n c h y m a - t o u s n e p h r i t i s . . . . . . .

S t r a u s s . . . . . . . . . . . . . . C h r o n i c p a r e n c h y m s - t o u s n e p h r i t i s w i t h u r e m i a . . . . . . . . .

S t r a u s s . . . . . . . . . . . . . . T r a n s i t i o n a l f o r m s . . . . . S t r a u s s . . . . . . . . . . . . . . . T r a n s i t i o n a l f o r m s w i t h

u r e m i a . . . . . . . . . . . . S t r a u s s . . . . . . . . . . . . . . J L i v e r d i s e a s e s . . . . . . . . . S t r a u s s . . . . . . . . . . . . . . U n c o m p e n s a t e d h e a r t

d i s e a s e . . . . . . . . . . . . . S t r a u s s . . . . . . . . . . . . . . F e b r i l e d i s e a s e s . . . . . . . S t r a u s s . . . . . . . . . . . . . . . M i s c e l l a n e o u s d i s e a s e s . S t r a u s s . . . . . . . . . . . . . . N o r m a l i n d i v i d u a l s . . . A s c o l i . . . . . . . . . . . . . . . . ] N o n - n e p h r i t i c s . . . . . . .

• ] • .

A s c o h . . . . . . . . . . . . . . . . . N e p h r m c s . . . . . . . . . . O b e r m a y e r a n d P o p p e r U r e m i a . . . . . . . . . . . t . .

O b e r m a y e r a n d P o p p e r [ N e p h r i t i s w i t h o u t u r e m i a . . . . . . . . . . . . . . . . I

O b e r m a y e r a n d P o p p e r l N o r m a l i n d i v i d u a l s . . . .

Mg. of total nitro- No . of gen per xco c.c.

CaSes• Max]- Mini- mum. mum.

28 I I 6 82

I 9 266 68

IO 152 25

5 75 38

I 4 79 ~5 4 29

8 7 ° 31 6 9x 48 6 76 22 5 34 23

24 184 19

3 0 2 1 2 1 4

30 658 33

5 350 56 2 36 35 8 297 39 4 I 1 9 44

7 IO

O b e r m a y e r a n d P o p p e r l P n e u m o n i a . . . . . . . . . . . O b e r m a y e r a n d P o p p e r ] S e p t i c d i s e a s e s . . . . . . . . O b e r m a y e r a n d P o p p e r H e a r t f a i l u r e a n d e m -

p h y s e m a . . . . . . . . . . . O b e r m a y e r a n d P o p p e r C e r e b r a l d i s e a s e . . . . . . . O b e r m a y e r a n d P o p p e r ] I A v e r d i s e a s e s . . . . . . . . . ! 4 H o h l w e g . . . . . . . . . . . . . H e a l t h y k i d n e y s . . . . . . . [ IO H o h h v e g . . . . . . . . . . . . . N e p h r i t i c s . . . . . . . . . . . . 12 H o h l w e g . . . . . . . . . . . . . U r e m i a ( w i t h re -

c o v e r y ) . . . . . . . . . . 4 H o h l w e g . . . . . . . . . . . . . [ U r e m i a ( f a t a l ) . . . . . . . . [ 9 H o h l w e g . . . . . . . . . . . . . F a t a l n e p h r i t i s w i t h o u t ]

u r e m i a . . . . . . . . . . . . . : 7 H o h l w e g . . . . . . . . . . . . . M o r i b u n d c a s e s n o t

I d y i n g of n e p h r i t i s I I I R o w n t r e e a n d F l t z . . . . r N e p h r l t t c s . . . . . . . . . . . ] 5 R o w n t r e e a n d F i t z . . . . P a s s i v e c o n g e s t i o n w i t h I

• a n d w i t h o u t n e p h r i t i s / 8 R o w n t r e e a n d F i t z . . . . N o r m a l i n d i v i d u a l s . . . . ~ 3 M o n a k o w . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

F o s t e r . . . . . . . . . . . . . . . N e p h r i t i c s . . . . . . . . . . . . 16 F o s t e r . . . . . . . . . . . . . . . N o r m a l k i d n e y s . . . . . . . I 5 W i d a l . . . . . . . . . . . . . . . . N e p h r i t i c s . . . . . . . . . . . . i 31

I I

290 8 I

77 60

93

96 340

370

95 280

280 70 98

393 76

24 33 42 41 50

62 I I 7

I 4 4

49 3o

6 0

30 83 43 33

20O

No te s .

t T h i s i n c l u d e s

a t u r e , b u t n o t S t r a u s s ' s .

O n l y f i v e b e l o w I00•

U r e a o n l y w a s d e t e r m i n e d ( h y p o b r o m i t e m e t h o d ) .

l a A g o n a l .


was then filtered, washed with distilled water, tested for albumin, and evaporated to a fixed volume. Folin has recently simplified this process in connect ion with his uric acid method, 14 but he does not bel ieve that the filtrate is ~uniformly free from albumin. Obermayer and Popper 15 acidified 20 c.c. of blood with dilute acetic acid, and boiled, filtered, and washed the so lut ion wi th hot water . T h e filtrate and wash water were united. Hohlweg TM added a special reagent cons is t - ing of acetic acid and monocalcium phosphate, and boiled the so lut ion af ter half saturat ion with sodium chloride.

In table I are given a few figures collected from the literature, indicating the range of non-protein nitrogen found by these methods in the blood in different conditions.

It will be noticed that almost all the results reported range much higher than our own. We thought that this might be due to the use of serum instead of whole blood, as in our work. To determine this point we made parallel observations on two cases taking both whole blood and serum and analyzing each by Folin's method, with the following results :

N o . o f case. Whole b l o o d . S e r u m .

69 34.8 41.3 75 3o.o 3o.o

These results, therefore, do not explain the higher results obtained by those who have wo.rked with serum. Folin attributes the discrepancy to the faulty methods of precipitation generally employed. The figures that follow (table II) are from Folin's recent article, 17 and, as they are based on the same method, are therefore more strictly comparable with our own.

T A B L E II . =: j

M g . o f total nitrogen M g . o f u r e a nitrogen I N o o f t p e r xoo c . c . t p e r zoo c . c .

D i a g n o s i s . c a s e s . . . . ~ - -

M a x i m u m . M i n i m u m . M a x i m u m . M i n i m u m .

Normal individuals . . . . . . . . . . [ 16 [ 26 l 22 [ 13 [ IX Syphilitics . . . . . . . . . . . . . . . . . . 63 45 22 26 13 Insane . . . . . . . . . . . . . . . . . . . . . . l" 21 62 ] 24 ] 46 I 13 Nephritics . . . . . . . . . . . . . . . . . . b i z / 96 / 38 i 68 I 19

14 Folin, O., and Denis, W., Your. Biol. Chem., 1912-13, xiil, 469. 1~ Obermayer, F., and Popper, H., Ztschr. f. klin. Med., 1911, lxxii, 332. x6 Hohlweg, H., Deutsch. Arch. f. klin. Med., 1911, civ, 216. 1~ Folin, O., and Denis, W., Your. Biol. Chem., 1913, xiv, 29.


Folin states that renal lesions were not by any means excluded in all cases. The urea, on the average, constituted from 50 to 56 per cent. of the total non-protein nitrogen; in the most marked cases of nitrogen retention it went up to 7 ° per cent.

In table I I I are summarized the essential features of the fifty- nine individuals that we have studied. They fall readily into four divisions: ( I ) those showing no disturbance of renal function; (2) those with marked cardiovascular disease of some type, a certain number .of which show urinary changes as the result of renal congestion; (3) those showing nephritis; and (4) those in which certain features lead one to suspect nephritis, but in which the e~cist- ence of nephritis is not certain.

All the cases of group I were free from definite evidences of renal disturbance. Four showed an occasional trace of albumin in the urine (table I I I ) . Examination of the non-protein n'itrogen column (table I I I ) shows that all the figures lie between 15 and 43. The ammonia-urea fraction, if we except one case of acute leukemia, constitutes less than 7 ° per cent. of the total non-protein

nitrogen. Group 2 (table I I I ) falls naturally into three subdivisions:

(a) individuals with cardiac disease, either myocardial, valvular, or pericardial; (b) those with aneurysm. ( 2 ) ; (c) those in which arteriosclerosis was the most conspicuous feature, associated, however, with myocardial weakness. Most of the individuals of group 2 showed albuminuria and casts, as a rule small in quantity. Of the four cases in which phthalein elimination was estimated two showed a moderately reduced output. The blood pressure was within normal limits or low (divisions a and b ) ; above normal (division c). Examination both of the non-protein nitrogen and of the ammonia-urea percentage shows that the figures lie within the same range as those of group I. The series is too small for

final conclusions, but it suggests that nitrogen retention does not, as a rule, accompany disturbances of renal function associated with chronic passive congestion, and that we may have here a method of distinguishing more serious renal involvement from mere congestion.

<

Clifford B. Parr and J. Harold Austin. 235

o o o o o o o g g g g g g g 0 0 0 0 0 O0 0 0 0 0 0 O0 0 0 0 0 0 0 0

"SlPa 64464 ~6 G 6 ~ 4 ~ po°lqP~ o o o ~ o o ~ ~o o o ~ o

u ! q ° [ ~ ° m a H ~ o O~ o ~- o ~ ~ I-) ,o o r~- r.,- o~ oo o ~ , o ~ 0 o o 0 o~ Jr.,,. o

oyiD~d S ~) o o 0 0 o o o 0 o o . . . . . .

"S~s~ © 0 0 0 0 0 0 0 0 0 0 0 0 0

• u ! tanq lV o + o o o o o + o o o o + +

0 Z

p o o l ~

• sJq ~ m

- o l ~ ] u l~a.] lq - ~ ~ ~ ~ ~ ..~ ~ ~ ~ ~ ~ e~ o l

• o .ooo~=d ~ - o r - . c ~ ~ o o ~ c ~ T . ~ , ~ - ~ ~-

- o~ !u l ~oL ~ c~ c~ e~ ~ ~ , o ~ -~ ' - • ~ ~ o 0

"~.0~v ~ ~-~,~°'~"~ ~ ' ~ = ~ ' ~

, = . . . . . . . . . "~ : : : : ~ 0 "~

: ~ d . . ~ : ~ : : :--~ : : : : ' ~ . = • = . ~ . . ~ • • . ~ . . . . = , , c :~ ~ ~.=..~ . ~ ...... ~

I ~.. = ~ ~ . .~ ./.., . . . . ~ ~ I ~ ~ = ~ . - - , ~ • ~ ~ ~ , ~ • , ~ . .

c~ ~l ~ ~ r~ 0 • 0~ ~ ' o ~ ~ o 0 - ~ , ~ ~ ~ ,, • o ~ l

i • ~s 'eo JO

"ol~I l ~ P ~ S

o o o o o o o o o o o o o o o

o o ~

+ + + + o

;+ ;+o

0 oO

oJ

0 ¢~ "

= ~ = = = -

~ "~ = ' ~ I o

i o , oo 0~ ~ ~ ~ I

236 No,t-Protein Nitrogen of the Blood in Nephritis.

H 'SlI~3

p o o l q P ~ H

-~a~3 a~d I a ! q o I ~ o m a H I

oo "X:KTA~a~ ~ b ~ d s •

" u ! t u n q l v o "1-

- ; ) . lnss~ad "--~ pOOl~ oo t~

~ . - ~ .~d r,~ U!~l .~q~qd

' : luo3

• 0 ' 3 ooz a o d

- o a l ! u ~aaTl I I

e~

-oal}u | r ~ o L ~ r~

• ~ a xu !~ V NN

m m

< < ' ~ 3 jO

• o n l~!.t~S

ooi 0 0 o o

o o °

o ~ o o

o + -I-

;÷÷ ÷I

ca "d "d

I

o re) r',- ro i

o~' ~

• ~ .~ ~ • ' ~ .

~ . ~ o

i + + +! + _ +

Z

7'

d

os re) 6, d

"rL

- ~ 0 , ~ 0

o o

i ¢,o o ~

+

r

.= az

0 OI

Clifford B. Farr and J, Harold Austin. 2 3 7

o I

o g g g o g g g O0 0 0 0 0 0 0 0

.Sli~ ~ . . . . . . . P ° ° l q P + ~ I oo ° 0 o ° 0 ° 0 o oo oo

"*ua~ aod I

0

oy!0ad S o q q q q q o q q q

+ + + + + + + + + + + + + + o ~

+ + + +

. u tmnqI v + T + + + + 0 • w + + + +

+ m ~ m '

_o _.~

• o o

poota & 7 7 7 ~ ~ ? 7 T tt~ o it~ t~ o0 o to l l~

-~,~ ~, ~ ~ ~ ~ ~ "~u~o a~cI ~ ~ , - ~ m~l'~q~q~. ~ O~ e~O m'~

tt~ ~0 ~D ¢o 0 ~ o o0 t'~ 00 . , . . . . . . $ ~ • . .

o "0"300I ~ d • ~ m u! ua~ ~ ,2. ~ ~ o. . oo ~. ~.

• ~ m u! ua~ ~ e~

-x°s I ~ ~ ~ ~ m ~ ~ mm

t . i . . i

• - : .~ . ~ ~, : ~ - • 0 0

"i ~ ~ '~ ~ " r" i~ "~ ~ .~ ~ . ~ o . o

_ : ~ ~ ~,

. ~ • . ~ ~.~ .~ ~ " ~ ~ • ~ ~ .~,.~ ,~ ~ "~ .~ . . ~ . ~ . , ~ ' ~

-= • .= "e.~ ~ .~

~o

g 'm ~ 0

g g q q g g

e~ eo

q q q

+ + + +

+ + + + + + +

0

I I I

r - ,o o

o

e ~ m ~

~ c , i m

: ~ : • •

• o ,

: ' ~ • ~ ' ~

• ~" o g ' s

• ~,-~ ~ "~, '~

~ ~ 0 ~ • ~-~ ~ .~ .~

0

'u::l

0 z

• o ~ l ~ , , + s . . . . . ~ ~' ~ 2 ~ ,~ ~- ~ ~ ~ ~ '~ ~ -


.¢

g g g o o o

"Sllaa " c; P°°lq P~}[ 'Og ',0¢~ g

~ t',l e o

~!qol*omaH ~ ,~

a~ia~ds q q q

-~s~o + o +

"u!mnqlv + + +

t e~ t

~ ..='= V,

~.~ ~

poolff o o

U!al~q~qcI ~

"llI~O • -

"O'O OOZ a~d o o

-o.nm. s a ~ f l ~ ~ ~w

-a-a oox a~d ~ ~ 0 • ~ m u i u a ~ " ' "

-o~:. l~o~c ~ '~

I:l ~ I:I t= ,~

•

0 - ~ (.)

ro

I

%

g g g g gg g q o o o oo o

0 0 0 0 0 ©

+ + ++ + ++ +

+ ,++,+ + ++ + -~- -T"

trio

d d ~ m et

• , , " l = i

d " : : •

• , ~ ~ o

r~ 0 . . . . .

~'~ o = ~ : -e

o.- ~>~i o

f


Group 3 falls into five divisions: (a.) chronic nephritis with marked albuminuria and cylindruria, marked edema, and little if any increase i n blood pressure; (b) chronic nephritis associated with marked arteriosclerosis and elevated blood pressure,--all cases over fifty years of age ; (c) chronic nephritis in younger individuals, not conspicuously sclerotic, with high blood pressure as a rule, with anemia, and with the frequent appearance of a few red blood cells in the urine; (d) acute nephritis; (e) amyloid kidney. In both cases of the first subgroup, a, cardiac complications existed which render the findings somewhat difficult of interpretation; possibly they should be classified in group 2. In both individuals the non- protein nitrogen and the ammonia-urea percentage lay within the limits established for groups I and 2. -Case 35 is of interest because of the constant presence in the urine of enormous numbers of epithelial and fatty casts and even of free fat droplets. Both cases averaged about seven grams of albumin per liter by Esbach's method. All the cases of subgroup 3, b, except one, showed albumin and casts in the urine, although at times only scantily. The specific gravity was low as a rule. In the majority, retinal changes existed. Anemia was not a conspicuous feature of the group except in two cases. The blood pressure was above normal. The phthaleirr~ elimination, in the few cases in which it was determined, was low.. Inspection of the non-protein nitrogen figures shows them to be: 4o or above; the ammonia-urea percentages, except in case 4, lie; e i thera t the extreme upper level of the range found in group I, or- distinctly above it. In this group, therefore, we find for the first time constant evidence of nitrogen retention. It is of interest to~ note that the case showing next to the highest figures for non-protein nitrogen and the highest ammonia-urea percentages, as well as an extremely low phthalein elimination, showed no elevation o f blood pressure, no eyeground changes, and no evidences of nephritis~ in the urine. The further course of this individual is being followed with special interest.

The cases of subgroup 3, c, all belong to that type of nephritis ir~ which pallor is a characteristic feature and which usually shows also. puffiness beneath the eyes. The urine showed more or less albumin. and, with the possible exception of case 49, casts. In the two cases


not showing blood pressures well above normal, there was definite cardiac decompensation. .With improvement in the general condition a marked rise of blood pressure occurred. The three cases on which phthalein elimination was estimated showed an extremely low output. All the cases showed a non-protein nitrogen above 4o and an ammonia-urea percentage above 7o. That there is a fixed relation between the degree of nitrogen retention and the prognosis can not be claimed, since case 31 with the highest degree of retention, under active treatment, improved rapidly. The uremic condition and the delirium tremens cleared up and later ~n examination of the blood showed a non-protein nitrogen of .only 36. Subgroup 3, d, containing a single case, shows marked nitrogen retention.

Group 4 contains eight cases in which nephritis may be suspected. In all the urine showed albumin and casts. In case 56 the findings, as well as the low phthalein elimination, were possibly due to cardiac decompensation which complicated the condition at the time the observations were made. In case 16 the diagnosis of uremia was based entirely on the data presented in the table. The patient died within an hour or two after admission, and no. clinical history was obtained; an autopsy was not permitted. In the other cases some of the findings suggested a very early stage of nephritis. In none of the eight cases is there evidence of nitrogen retention.

From the foregoing results it appears that there is a definite tendency toward nitrogen retention in most cases of nephritis. This is apparently least marked in the so called chronic parenchy- matous nephritis in which the disturbance is one of fluid retention rather than of poor urea elimination. In the cases in which nitrogen retention is evident the higher percentage ,of the ammonia- urea fraction indicates that it is principally the excretion of this fraction that is impaired. The rapid fluctuations t'hat we have ob- served in two cases from which blood was repeatedly taken indicate that rapid variations in the concentration of the non-protein nitrogen of the blood may occur.

Mere passive congestion of the kidneys produces apparently albuminuria and even ,casts and causes some impairment in the elimination of phenolsulphonephthalein without producing a retention of non-protein nitrogen.


We have in this method an additional aid, and, we believe, a valuable one for ascertaining the state of activity of the kidneys. On the other hand, we are not warranted in inferring any constant relation between the existence or imminence of uremia and the degree of nitrogen retention. The existence of uremia without an increase in the non-protein nitrogen is, we believe, unlikely.

CONCLUSIONS.

I. In a series of non-nephritic individuals the total non-protein nitrogen of the blood, determined by Folin's method, was found to 'lie between 15 and 43 milligrams per IOO cubic centimeters. From 5o to 6o per cent. of this was in the ammonia-urea fraction.

2. In cardiovascular disease with renal congestion, but without other renal lesion, there was no evidence of increase of non-protein nitrogen in the blood, nor of alteration of the ammonia-urea percentage.

3. In chronic nephritis with marked albuminuria and edema there was very little, if any, increase or alteration.

4- In chronic nephritis with hypertension the non-protein nitrogen was definitely increased, ranging from 4o to I8O milligrams per Ioo cubic centimeters of blood. The percentage of the ammonia- urea fraction was usually higher than in non-nephritic cases.

5- Cases showing high non-protein nitrogen values were subject to rapid fluctuations in these values in ,the course of a few days. As a rule, clinical improvement was associated with a fall of the non-protein nitrogen figures to nearer the normal range.

6. Uremia was almost always accompanied by an increase of non-protein nitrogen in the blood, but no constant relation could be established between the degree of increase and the tendency to uremia.

7- Our cases have not yet been followed for a long enough period to admit of conclusions as to the possible relation between the degree of non-protein nitrogen retention and ultimate prognosis.

8. We believe this method to be a valuable aid in the clinical study of n@hritis and that it can be readily carried .out in any well equipped clinical laboratory.

the total non-protein nitrogen of the blood in ......230 non-protein nitrogen of the blood in...

Documents