THE NON-PROTEIN NITROGENOUS COMPOUNDS OF THE BLOOD IN NEPHRITIS, WITH SPECIAL REF-

ERENCE TO CREATININE AND URIC ACID.

BY VICTOR C. MYERS AND MORRIS S. FINE.

(From the Laboratory of Pathological Chemistry, New York Post-Graduate

Medical School and Hospital, New York.)

(Received for publication, January 31, 1915.)

Since the introduction of simple methods for the determination of the total non-protein and urea nitrogen of the blood by Folin and Denis, a considerable literature has accumulated on the sub- ject. Nephritis has been the pathological condition to receive special investigation, since it is in certain types of this disease that a retention occurs. Aside from the observations reported by Folin and Denis, however, practically no data have been presented in this connection dealing with the accumulation of creatinine and uric acid in the blood. Their data represent iso- lated observations on a number of cases. In the present paper consideration has been given especially to this phase of the ques- tion, but the study was made as intensive as conditions would permit on a few selected cases.

The non-protein and urea nitrogen of the blood has been found to fall within normal limits in many cases of nephritis. In those cases tending toward uremia, however, the values are increased and may reach figures of 350 mgm. per 100 cc. for the non-protein nitrogen, and 300 mgm. for the urea nitrogen.’ The series of observations recently reported by Tileston and Com- fort for both the non-protein and urea nitrogen and those by

1 0. Folin and W. Denis: this Journal, xiv, p. 29, 1913; xvii, p. 487, 1914. C. B. Farr and J. H. Austin: Jour. Exper. Med., xviii, p. 228, 1913. J. H. Agnew: Arch. Int. Med., xiii, p. 4%, 1914. F. C. McLean and L. Selling: this Journal, xix, p. 31, 1914. C. Frothingham, Jr., and W. G. Smillie: Arch. Int. Med., xiv, p. 541, 1914. W. Tileston and C. W. Comfort, Jr.: ibid., p. 620. C. B. Farr and E. B. Krumbhaar: Jour. Am. Med. Assn.,

lxiii, p. 2214, 1914. 391

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392 Non-Protein Nitrogenous Compounds of Blood

Frothingham and Smillie for the non-protein nitrogen are especi- ally illuminat’ing on this subject.

As might be expected, cases of uremia are accompanied by an accumulation not only of urea, but also of uric acid and creatinine, as is well illustrated by the recent studies of Folin and Denis. We3 had already taken up this phase of the problem previous to the appearance of the paper by Folin and Denis; and at about the same time Neubauer,4 in studying the impaired ability of the nephritic kidney to eliminate creatinine, reported a marked re- tention of creatinine in the blood in a case of uremia. A few observations on the creatinine content of dog’s blood under dif- ferent experimental conditions have been reported by Shaffer.5

Methods employed.

The total solids were determined by collecting 0.3 to 0.6 of a gram of blood on a block of pressed filter paper and suspended by a wire hook from the stopper of a specially constructed weigh- ing bottle. The Kjeldahl method was employed for the total nitrogen, while for the non-protein nitrogen, uric acid, creatinine, and creatine the technique was, with slight modifications, that described by Folin and Denis. In the urea estimations the con- centrated urease’j described by Van Slyke and Cullen was employed on either the fresh blood or residue of the same alcoholic filtrate employed for the non-protein nitrogen. The ammonia thus obtained was aerated and subsequently determined colorimetri- tally as in the non-protein nitrogen estimation. The chlorides were determined by titration after removal of the protein (by coagulation in t.he presence of r;c acetic acid and subsequent treatment of the filtrate with a few drops of colloidal iron to remove the last t’race of protein). A detailed description of

2 Folin and Denis: this Journal, xvii, p. 487, 1914.

3 V. C. Myers and M. S. Fine: Proc. Sot. Exper. Biol. and Med., xi, p. 132, 1914.

4 0. Neubauer: Mtinchen. med. Wchnschr., Ixi, p. 857, 1914.

5 P. A. Shaffer: this Journal, xviii, p. 535, 1914. ,6 D. D. Van Slyke and G. E. Cullen: ihid., xix, p. 211, 1914. We are

indebted to Dr. I. F. Harris of the Arlington Chemical Company for our

supply of urease.

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V. C. Myers and M. S. Fine 393

the technique we have employed in blood analysis may be .found elsewhere.’

Twenty-five cases8 are included in the present series, the first nine of which are of the retention type of nephritis. In two of these nine cases edema was present. The first three of these cases tabulated are of special interest since they are pronounced illustrations of different types of retention. The few cases other t,han nephritis are tabulated for comparison.

Case 1, suffering from mercuric chloride poisoning, showed a very pronounced retention of all the non-protein nitrogenous constituents, the figures for non-protein nitrogen, urea, uric acid, and creatinine being decidedly higher than in any case reported by previous workers. No urine was passed for the first five days and no appreciable amount for the first ten days. After decapsulation of the kidneys on the sixth day the renal activity appeared to improve, and at one time it had sufficiently recovered to cause a reduction in the concentration of the creatinine from 33.3 to 14.8 mgm. per 100 cc.; but with the decline of the patient, the kidneys became less active and the creatinine again increased. The quite favorable output of total nitrogen was insufficient at any time, however, to reduce materially the non-protein and urea nitrogen of the blood, despite the favorable influence on the uric acid and creatinine. Although the highest concentration of uric acid and creatinine, as well as very high figures for non-prot’ein and urea nitrogen, were found on November 20, uremic symptoms were not observed until a week later. This would seem to lend support to the current view that uremia is not a result wholly of the retention of these nitrogenous waste products.g

Case 2 is interesting as illustrative of t,he condition of the blood and urine in a very severe case of interstitial nephritis with uremia but no edema. In this case there was a gradual decrease in the

i Papers in The Post-Graduate, 191415, and collected as The Chemical

Composition of the Blood in Health and Disease. b Practically all the cases here reported were patients in the medical

wards of this Hospital. We are indebted to the Director of the Depart-

ment, Dr. Quintard, to Drs. Chace, Kast, and Halsey for many courtesies extended in connection with these studies; to the resident physician, Dr. W. G. Lough, and to Dr. F. D. Gorham for aid in following the cases and

arranging the case histories. 9 See F. W. Peabody: Arch. Znt. Med., xiv, p. 236, 1914.

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396 Non-Protein Nitrogenous Compounds of Blood

activity of the kidney with a corresponding retention in the blood. As will be noted, the figure for the uric acid just previous to death, 27 mgm., is very high, even exceeding those reported for Case 1.

Case 3 was found at autopsy to be typically of the interstitial type, although,, as distinguished from Case 2, there was a marked accumulation of fluid during the last two weeks of life which en- abled us to secure large samples of pleural, ascitic, and subcutane- ous fluids for analysis. Uremic symptoms did not show, however, until just preceding death, and it should further be noted that there was not a very marked accumulation of waste products until shortly before the fatal termination. Although the urea and uric acid reached a fairly high level, the figure of 5.3 for the creatinine is not high when compared with the other cases.

Marshall and DavislO have pointed out that urea is quite uni- formly distributed throughout the body. This is certainly true here with regard to t,he body fluid’s, as shown in the tabulated data on this case. A similar state of equable distribution throughout the body fluids and tissues was observed for creatinine. The same may be said in general for uric acid, if we except the spinal fluid, the difference here recorded being of interest in view of t,he position of relative isolation held by this fluid.”

DISCUSSION.

The points of special interest in the tabulated data below bear brief discussion. Very high concentrations of uric acid and creatinine may be encountered in nephritis with retention of nitrogen. Uric acid has been found as high as 27.0 mgm., and creatinine as high as 33.3 mgm. per 100 cc. of blood.

That the retention of the well known end-products of protein metabolism are not in themselves the cause of uremic symptoms would appear evident from the case of mercury bichloride poison- ing, in which uremic symptoms did not appear until more than a week after maximum concentrations of these substances in general had been attained. The possibility that a decomposition prod- uct of creatinine, such as methylguanidine, might play a part

I0 E. K. Marshall, Jr., and D. M. Davis: this Journul, xviii, p. 53, 1914.

I1 See papers by H. Cushing, L. H. Weed, and P. Wegefarth: Jour. Med. Research, xxxi, pp. 1-176, 1914.

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Mq M.

Into

rstit

ial

Jan.

6 ’

neph

ritis,

Jan.

7

urem

ia Ja

n. 22

Fe

b. 18

7,

IX.

8,

T.D.

I 57

Jan.

22

Inter

stitia

l an

d ,Ja

n. 27

Ja

n.30

Feb.

G

Mar

. !)

I I 34

6.

8 8.

9 6.

0 ~

8.4

9.1

~ 11

.0

M

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9.

W.G

.

Mny

14

Ju

ly 8

July

9 Ju

ly 10

Ju

ly 13

Ju

ly 24

Ju

ly 30

1.4

: 8.9

2.9

5.4

’

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0.0

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0 7.

0 3.

7 0.0

5.1

I

I

~ 14

.5 I

2.21

i 00

32

2.5

14

.4 1.9

9 ~

100

71

/ 13

.4 .1.

73’1

3.9

119;

83

4.7

12.1

1.35

i 12

3 1

86

6.6

13.0

1.70

1 13

.1 1.0

4 !

127

; 94

13

1 j

109

j 5.6

j

I 5.1

tis

of

mixe

d Ex

tensiv

e ed

ema.

Phtha

lein

outpu

t: 3

to

8 pe

r ce

nt.

Urine

: lar

ge

amou

nt of

alb

umin,

m

nny

hyalin

e an

d gr

anula

r ca

sts.

few

pus

cells

nnde

rythr

ooyte

s.

Edem

a of

an

kles.

Phtha

lein

outpu

t: 47

pe

r ce

nt.

Urine

: m

oder

ate

amou

nt of

alb

umin,

m

oder

ate

num

ber

of

casts

. 10

gm

. Na

Cl 3

hrs.

prece

ding

2d

teat

. l’h

thalei

n ou

tput:

34pe

r ce

nt.

Urine

: tra

ce

of

album

in,

occa

siona

l hy

aline

casts

. Blo

od

trans

fusion

, M

ar.

27.

10 g

m.

NaCl

on

Apr.

1, I

( hr

s. pre

cedip

g te

st.

Exten

sive

edem

a. Blo

od

press

ure

varie

d fro

m

190

(dias

tolic.

13

0) to

15

0 (d

iastol

ic,

100)

. Ph

thalei

n ou

tput:

33

per

cent.

Ur

ine:

mod

erate

am

ount

of

album

in,

man

y hy

aline

and

gran

ular

casts

. Di

ed.

Mark

ed

edem

a of

ex

trem

ities.

Phtha

lein

outpu

t: 3

per

cent.

Ur

ine:

mod

wate

amou

nt of

alb

umin,

m

any

hya-

line

and

gran

ular

oasta

. fe

w pu

s ce

lls.

Died

. Sl

ight

edem

a of

fe

et

and

ankle

s. Av

erag

e blo

od

pres

sure

: sy

stolic

, 18

0; dia

stolic

, 95

. Ph

thalei

n ou

tput:

16 p

er ce

nt.

Urine

: fe

w hy

aline

casts

, tra

ce

of

album

in.

No

edem

a. Av

erag

e blo

od

pres

sure

: sy

stolic

, 11

0; dia

stolic

, 70

. Ph

thalei

n ou

tput:

10 t

o 22

pe

r ce

nt.

Urine

: tra

ce

of

album

in.

occa

siona

l hy

aline

and

gran

ular

casts

. Sl

ight.

edem

a of

fe

et

and

ankle

s. Sy

stolic

pr

wmre

, 24

0; dia

stolic

. 10

0. Ph

thalei

n ou

tput:

56

per

cent.

Ur

ine:

trace

of

alb

umin,

oc

casio

nal

hylilin

e ca

sts.

4.8

I 3.6

4.2

4.1

2.1

10,

L.R.

~ 45

I

M

Dec.2

8 Ja

n. 11

5.5

40

6.

0

1.8

’

0.72

’ 0.7

5 1

2.57

0.72

2.50

0.61

2.57

2.47

0.59

2.46

j 0.6

2

40

36

30

20

4.0

29

27

38

1.73

0.69

~ 48

~

25

11,

W.M

oL

12,

L.B.

%

“2

13,

KS.

15.9

19.2

17.9

17.6

17.5

18.1

17.5

13.9

4.5

4.6

4.6

3.4

3.0

2.0

2.8

2.9

I d

Mav

12

r/

_.

. .

vB&

Ma;

14

G”r

o”U

d*

r an

d M

ay

23

tubul

*r ne

- .

June

3

P’--‘l

: Ju

ne

8 ~U

L1(.1

8 Ju

ne

0

1.7

1.3

1.6

1.8

3.3

1.5

3.1

Nov.

23

17.3

2.36

39

17

4.1

Dec.

15

21.4

2.98

34

10

4.2

Dec.

28

18.8

2.94

33

/ 2.2

15,

F.S.

16.

L.B.

I 67

/

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17,

L.S.

p 18

, H.

K.

8

19,

A.K.

20,

I.W.

21,

J.B.

22

, B.

23,

G.A

.

24,

F.

25

.GE

- 55

26

52

16

22

43

25,

T.B.

57

- EX

3bro

nic

inte

r- st

itial

ne-

phrit

is,

1 ao

rtic

insu

ffi-

cienc

y ,

Acut

e pa

ren-

ch

ymat

oua

and

tubu

lar

1

neph

ritis

1

Chro

nic

inte

r- st

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- rit

is I

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tis

Syph

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GtX

lgIW

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Arth

ritis

.

Diab

etes

’

GO

UL

DATE

(1

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15)

Jan.

6

17.5

! 2

.43

30

Sept

. 10

19

.7

: 3.04

33

Sept

. 17

20

.7

: 3.24

67

Jan.

6

Dec.

8

May

22

Ju

ne

3 Ju

ne

25

June

27

May

22

20.6

21.1

20

.1

17.1

2.88

3.10

2.82

0.

55

0.64

27

30

27

46

14.8

2.

11

2.18

3.20

0.51

0.51

0.64

22

May

25

15

.6

Dec.

23

20

.7

( De

c.

30

i*

37

36

42

9m.

Per

100

DC.

15

2E

14

1:

3(

1:

21

1:

1:

2.6

0.9

0.9 2.9

1.6

1.4

l.E

1.c

0.C 1.5

l.f

1.4

l.!

REMI

LFatS

3.9

5.9

7.3

8.6

9.c

9.9 7.c

7.s

10.2

9.:

9.4

Syst

olic

pres

sure

, 17

0;

diasto

lic,

60.

Urine

: tm

ce

of

album

in,

occa

siona

l hy

aline

an

d gr

anula

r ca

sts.

Edem

a of

bo

th

ankle

s. Sy

stol

ic pr

essu

re,

140;

dia

stolic

, 80

. Ph

thale

ilein

outp

ut:

32

per

cent

. Ur

ine:

large

am

ount

of

alb

umin,

m

any

hyali

ne

and

gran

ular

cast

s.

[ Sy

stol

ic pr

essu

re,

182;

dia

stolic

, lO

& I

Phth

ayin

outp

ut:

39

yer

cent

.. Ur

me.

tra

ce

of

album

m,

occa

smnd

gr

mula

r ca

sts.

(

Syst

olic

pres

mre

, 13

0;

diasto

lic,

75.

\ Ur

ine:

trace

of

alb

umin,

m

any

pus

cells

.

:

May

22

. Bl

ood

suga

r: 0.

26

per

cent

. M

ay

25.

Bloo

d su

gar:

0.27

pe

r .c

ent.

Uric

acid

in m

usole

tis

sue

obta

ined

at

auto

psy:

0.

7 m

gm.

per

100

co.

of

blood

.

Phth

slein

outp

ut:

35

per

cent

.

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V. C. Myers and M. S. Fine 401

in the development of uremic symptoms needs to be considered, although there are as yet no definite data to support this view.12

In six cases of gout examined in this laboratory, uric acid in 100 cc. of blood ranged from 3.8 to 5.8 mgm. The far higher values for uric acid in the above cases of uremia, in which gouty symptoms were absent, are of interest in view of the controversy existing with regard to the relation between the retention of uric acid in gout and the clinical symptoms.13

TABLE I.

Summary of data on uric acid, creatinine, and creatine in the blood.

6 7 8 9

10 11 12 14 15 17

-_c -

Hg poisoning, uremia ......................... .‘, Chronic interstitial nephritis, uremia .......... Chronic interstitial nephritis, uremia, edema. Chronic interstitial nephritis, uremia ........... Chronic interstitial and parenchymatous nephri

tis, uremia ................................... Nephritis of mixed type, uremia ................ Interstitial nephritis, uremia ................... Interstitial and vascular nephritis, uremia ...... Acute nephritis of mixed type, uremia, edema. ... Interstitial and vascular nephritis ............... Chronic interstitial nephritis, edema ............. Chronic vascular and tubular nephritis. ......... Chronic interstitial nephritis. ................... Chronic parenchymatous nephritis. ............. Chronic interstitial nephritis, aortic insufficiency

i- Per 100 cc.

mgm. mgn. 15.0 33.3 27 .O 20.0 15.4 5.3 11.4 16.6

14.0 14.7 13.4 7.4 8.0 4.8 9.1 11 .o 5.5 7.0 5.5 4.6 4.0 2.1 4.5 1.8 4.1 3.3 4.2 1.5 6.3 2.1

-

,

-

Wm. 19.4 31.4 21.3

15.2 13.1

Another point which appears to possess some little significance is the increase in the creatine content of the blood in those cases showing a very marked rise in the uric acid. There was not a

12 In this connection the papers by N. E. Ditman and W. H. Welker: New York Med. Jour., lxxxix, pp. 1000, 1046, 1091, 1134, 1909, are worthy of note. Also W. M. Kraus: Arch. Int. Med., xi, p. 613, 1913.

18 See M. S. Fine and A. F. Chace: Jour. Pharm. and Exper. Therap., vi, p. 219, 1914; Jour. Am. &fed. Assn., Ixiii, p. 945, 1914.

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402 Non-Protein Nitrogenous Compounds of Blood

complete retention of uric acid, but even if no uric acid were eliminated during the last days of life, the amount of retention, if anything, exceeded the probable endogenous formation (Cases 2 and 3). From the data presented on Cases 3 and 25, we may assume that uric acid is quite evenly distkbuted throughout the fluids and tissues. Since the increased creatine is suggestive of increased tissue destruction,14 it is possible that this in part ex- plains the very high uric acid.

The distribution of these products in the spinal fluid is worthy of note; whereas urea and creatinine approach the concentrations found in the other fluids in uremia, the creatine and uric acid are very low or practically absent.

The comparison between the retention figures for uric acid and creatinine is of interest. In some cases the creatinine is decidedly higher than the uric acid, while in others the reverse is true (Table I). In the majority of the cases a high creatinine is found to accompany a very high urea, while in those cases in which the creatinine is low the urea is generally low. There appears to exist some parallelism, then, between the accumu- lation of urea and creatinine, and, as pointed out above, also be- tween the uric acid and creatine, although it has not been possible to correlate these parallelisms with any specific types of nephritis.

I4 Myers and Fine: this Journal, xv, p. 283, 1913.

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Victor C. Myers and Morris S. FineURIC ACID

REFERENCE TO CREATININE AND NEPHRITIS, WITH SPECIAL

COMPOUNDS OF THE BLOOD IN THE NON-PROTEIN NITROGENOUS

1915, 20:391-402.J. Biol. Chem. 

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