Endogenous creatinine clearance as a measure of renal function in normal and toxemic pregnancies

ENDOGENOUS CREATININE CLEARANCE AS A MEASURE OF RENAL FUNCTION IN NORMAL AND TOXEMIC PREGNANCIEW TOIWMY N. (From

&h7aNS,

the Departmed

fil.I).,

of Obstetrics

F.A.(‘.S.,

and

/In-N

Gynecology,

ARBOR,

IkjlCH.

University

of

XiclGgalt)

INCE proteinuria was recognized as a common occurrence in tosemias 01 s pregnancy, extensive research has been directed toward finding some renal function test which would shed light on thcr eGology of pre-cclampsia and eclampsia, and permit, earlier detection and a more satisfactory mcnns of evaluating the sevcrit.y. progression. and prognosis of the discase. Many tests commonly nscd in assessing impairment of renal function havcl proved to be of littlc Talue in the management oi’ the toxemia patient hecausc they eit,her do not demonstrate abnormality until late in the clispase or are inL-\s statrd by Chesley,’ “Nfb consistent wit,h the clinical r~videncc~ ol’ its severit)-. rcnal function test has been developed which is (Jf iIn>S value in assessing the severity and progression of preeclampsia. ” Simultaneous urea ant1 uric: ii&l clearances have proved to be of som(’ value in the dift’ercntial diagnosis of thr t.osemias of pregnancy although such tests are not entirely specific.” Also, conventional renal function tests may he of value in a.ssessinp the more sevcrr degrees of residual renal damage but oftfln do not reflect the effects of fntnrc> pregnaucies. Most measures of kidney. function involve clearance studies in which varyiltg

prOportionS

CJf

the

t,I?st

s~~hstaluxs

~m)vC

t,O bC

I%Ptiall~

CxCIY~ted

01’

partial!)

reabsorbed by the tubules. The first accurate measure of glomerular filtration followed introduction by Smith and his associates” of the use of inulin, a substance which is completc~ly ant1 frcc~ly filterable at t,he glomcrul~~s md is not reabsorbed by the tubl&s. 1Tnfortlull~ltt~l\-, the innlin clearance is largely confinctl to experimental nsc and is of practically no value to the clinician sincct suc~li a test inrolvcs hospital izat,ion, c*ontinuous int,ravPnuus infusion, iimitatioll ot’ the testing to a relatively short period of time nndcr unphysiologic ~~ntlitions. and many other technical difficulties. Attempts were made to measure glomerular filtrat,ion using exogenous creat,inine” but subscqucntly it- was tlcmonstratcd that som(~ of the ingcstcci creat,inine was sccrctcd by thus tul)ulcs and. therefore, was an inaccurate reflection of glomerular filtration.“, 6, ’ Too, C’amara and associates8 clearly demonstrat.ed the effect of preformed creatininc in mrat on the creatinine clearance. By doing simultaneous c~?oyle~31~s creatininc and inulin clearances, howcvcr, Brad alIt Sirota,Y MiIl(Lr and ‘U’inklcr.” and SI rinitx anti TurkLind’” obsc~rvrct t,hat the inulin cleararirc./crea.tiriinc clearance ratio il.vPr~lged 1.O in normal people. Suc,h c~ido~enons creatinine is neitlict studies indicate that t’or I)i?l?tiCill 1~11 t’l)osCs vwsity

*Supported b.y of Michigan.

a

grant

from

tht:

Horace

H. 123

Ravkham

School

of

Graduate

Studlie%

Uni-

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CREATININE

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reabsorbed nor excreted by the renal tubule cells and that the endogenous creatinine clearance is a good clinical method for the estimation of the glomerular filtration rate. Although there is some excretion of endogenous creatinine by the tubules in patients with severe renal disease, as pointed out by Camara and his co-workers, this potential error is offset for the most part by the use of the Bonsnes and Taussky13 method of measuring serum creatinine since this method determines total chromogen. The higher proportion of noncreatinine chromogen in patients with severe renal disease introduces a second error, but the direction of the two errors is such that they tend to offset each other. This results in only slightly higher values with endogenous creatinine clearances as compared with simultaneous inulin clearances in patients with severe renal disease.* Brod and &rota, observed a difference of at least 10 per cent when the filtration rate was reduced to one-third of normal but such a discrepancy only in the presence of severe renal disease does not detract from the clinical usefulness of the endogenous creatinine clearance test. The hourly urea clearance test has been in use since 192811 and has proved to be of clinical value in assessing renal function in toxemias of pregnancy. It does not meet several desirable requirements, however. As performed in the average hospital, the urea clearance test is often subject to gross errors, usually due to inaccurate hourly collections of urine. As indicated by Camara, a few minutes’ error in one 60 minute collec,tion combined with retention of a few milliliters of urine in the bladder often produces an error greater than 10 per cent. The same inaccuracies in the 24 hour endogenous creatinine clearance test produce an error of less than 1 per cent.8 In addition, the urea clearance This test gives no precise does not measure a single phase of renal function. information about the glomerular filtration rate because of wide variation in tubular reabsorption and excretion of urea. However, reduction of the urea clearance commonly observed in pre-eclampsia and eclampsia is probably due more to a decrease in glomerular filtration than to change in tubular funct,ion. Study

&-oups

In view of the preceding observations, this study was undertaken to assess the clinical value of the 24 hour endogenous creatinine clearance test in obstetrics. The patients studied were divided into three groups : (1) control series of normal pregnant patients, (2) those pregnant patients with hypertension, diabetes mellitus, chronic renal disease, molar pregnancies, or a history of previous pre-eclampsia or eclampsia, and (3) those not in Group 2 who developed preeclampsia-eclampsia. Methods Each patient on whom part of the study was carried out on an outpatient basis was carefully inst,ructed in the collect,ion of a 24 hour urine specimen. For two days before and during the urine collection, the patient.s were on a meatfree d&t. The urine specimens were collectSed through an indwelling catheter from those patients who were hospitalized with toxemias of pregnancy. In the latter group, in several instances the initial specimen was obtained without a preceding meat-free diet. Because there is practically no fluctuation in the

blootl serum crcatinine during a 21 hour period Following such clicxtitry }~1’(‘1)~ a ration, a single specimen of 10 C.C. of blood was obtained from each pat ichrll (Illring or shortly following the 24 hour collection of urine. Quantitative prot,ein and crratinine d(~t~~l.minat,iolIs wcr(’ tlonc on thca sillti(’ urine and blood specimens. Thcl total serum proteins wc>re determined by ntilizing the modified Wcichselbaum biurct reagent,. Quantitative, 21 hour urinar>, pra0tc4tl excrc?ions were determined bycMension of thci stantlartl hinwl method.‘” Bonsnes and Taussky’~‘~ modification of t,lie k‘olin methocl was utitixcl(1 iti blood serum and urinary creatininc deteL’nlillatior]s. The 21 hour clearal~ca:~ was talculatcd by dividing the 24 hour urinary excretion of crclatinine in milligrams bv t,he concentration in the serum rspressed in milligrams per liter. The* clearances were t,hen corrected and rcduccd to per cxent in o~lc~r to st,andardize the results. After the dietary preparation ut,ilized in this seric+ oJI patients, the average-sized patient (surface arca 1.73 scluare mett>rs) hiIs an avcaragtbnormal value of 3.37 liters per 24 hours. Ideal body surface area ill square meters in each patient was dett)rmined 1)~ USP of the table for height ant1 weight without. clothing from the Life lCxt,enslon Inst,itute ot’ New IVark Cit?and the Du Bois Body Surface (~Ihart. One-half pound for cbaehweek ot’ preyuwnqv was added to the ideal nonpregnant weight. iI11

1.73

Ideal

body C’omh3l

surf:~w

,I avt wl

clcaralrr~~ 137

~lramncr

Y 100 =

= p’r

~wrrectcd

clearance

i>cYlt of normxl

C’amara and his collaboraiors found the normal range in nonpregnant womt!!11 to be 85 to 115 per cent, utilizing the actual body surface area..*

Results in Group 1 In those patients with normal pregnancies, a wide variation was observed in the endogenous creatinine clearance (Fig. 1). In 32 normal pregnant women, 107 determinations were carried out during a period ranging from the sevcnt,h week of pregnancy to eight weeks post partum. Over 80 per cent of the antepartum determinations were above the normal nonpregnancy range. All antclpartum tests were above 100 per cent. As the patients approached term thercl was a greater concentration of point,s in and near the normal nonprcgnanq range. The elevation of glomerular filtration during pregnancy with a decrease near term suggested by these data is consistent with the observations of Bonsnes and Lange usmg the inulin clearance. From these endogenous creatinine clearances, a normal pregnancy range of from 100 to 180 per cent was established. After one week post partum, all clearances in the control series had dropped t,o the normal nonpregnancy range. There was no consistency in the individual curves during pregnancy in t,ho c*ontrol series except for the decreast: observed during the two weeks befoI*ca delivery. This is illustrated in Fig. 2 bvI the creatinine clearances in 7 patic%ts representative of Group 1. As was t,he case with the entire control group, thtx was wide individual fluctuation with increases as much as 60 per cent above the* normal nonpregnancy range.

Results in Group 2 A total 0T 12X ant.epari IIIII antI 32 post1)art.r1m(~realininc~c~learanc~cs w(‘ro determined in !) patients with c~ssrl~i i;r t hypc~rtrnsioii, 3 wit,h tliabet,es met1itns. L! with chronic renal disease, !I wit II a hisiory or’ prcviorls T)I,c-(lcJlaInl)si;i 01’ eclampsia, and one wit,h a molar pregnancy.

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6 had clearances which were (‘on01 t,he 9 patients with hypertensior:, sistently normal and in none of these did signs of superimposed toxemia develop. Two oi’ the hypertensive patients had a single clearance just below normal near term. The last patient in this group was a 35-year-old Negro nullipara who had a diagnosis of malignant hypertension established six months prior to conception. Four months before conception, she developed left cerebral artery

seventh flltration

Fig.

Fig.

l.-Endogenous week of pregnancy during pregnancy

2..-Endogenous at or

near

creatinine term

creatinine clearances to eight weeks post with return to normal,

but

clearances otherwise

in 32 normal Dregnant patients pa&urn, demonstrating increased nonpregnancy levels post pa&urn.

in 7 normal no consistency

pregnant in the

patients antepartum

demonstrating ~U~VRS.

from glomerular

the

a drop

This patient’s blood pressure, endogenous thrombosis with residual hemiparesis. creatinine clearances, and urinary protein determinations are presented in Fig. 3. The first clearance was done at about the seventh month of pregnancy and was only 69 per cent with a urinary protein excretion of 0.6 Gm. in 24 hours and a blood pressure of 200/130 mm. Hg. One week later and two days before her delivery by cesarean section, the blood pressure rose to 240/150 mm. Hg, with the c-rcatinine clearance further depressed to 33 per cent with an increase in

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weeks after fetal death and about two weeks before delivery, the creatinine clearance had risen to 89 per cent, which falls into the normal nonpregnancy range. During the third week post partum, the creatinine clearance remained normal

Fig. 4.-A of creatinine pressure. and

5

26-year-old clearance return of

pregnant in advance creatinine

diabetic patient with chronic nephritis. Note depression of increased proteinuria, minimal fluctuation of blood clearance to normal nonpregnancy range after fetal death.

----____

BO-

5

14

16

1.3

20

22

WEEKS Fig. 25-year-old appearance

5.-Blood pressure, pregnant diabetic of pre-eclampsia

24

26 -.

1 28 .~__I._ 30

321-_

I34

..~

OF AMENORRHEA

and creatinine clearances, Creatinine clearance patient. with persistence of depression

-Id__12

WEEKS urinary was post

protein depressed pat-turn.

4

6

8

POSTPARTUM excretions 14 weeks

of a before

There was no apieceand the proteinuria had decreased to 2.5 Cm. in Z-1 hours. The third patient in tltis ciablc change in the blood pressure Ilost partum. group was a 25-year-old para 0, gravida ii, wit.h severe diab&es, who had IXWI known to have diabetes mellitus since the age of I4 years. years, she had had persistent albuminuria ant1 microscopic hcmaturia and pyuria. at. the time of her initial exatnination, during the thirteenth we& of this I~tpimncy, the endogenous creatininc clearance was 11’1 per cent with a llrinnr\, protein excretion of’ 1.5 (im. l)er 2-l hours ant1 il blood prcssnr’e of 130,/‘7-1 111111. 11~ (Fig. 5). By the srvcllt.ecath wvvk. ttw clcamnce had dropped to !IS J”‘l’ Hy t11ct t\vcwi\~cent with an increase in proteinuria to X.L’ (;ni. IWr 2-l hours. second week, the clearance had dropped fnrther to 7X per writ with the pNbtt~IJ1 .b'O1'

the

]JilSt

t\\elb

2

Fig. of pregnancy iincc post ilepression

6-A

2O-yea1'-olcl patient who ~leveloped eclanrpsia with disappearance of proteinuria, hypertension. partum. During the next pregnancy, she developed of creatinine clearance prior to fetal death.

during the and depressed pre-eclampsia

twenty-fifth creatinine with

4

5vrt.k clearmarkwl

excretion essentially unchanged and a normal blood pressure. 1)uring the thirt),first week and approxima.tely 14 weeks after the first laboratory evidence of de pression of glomerular filtration, the patient, developed marked edema, hypertension, and an increase in the 24 hour protein to 5.3 Gm. Bv the time H cesarean section was done during the thirty-sixth week, the creatinine clea,rancc* had dropped to 60 per cent. After a further drop to 52 per cent during the first day post partum, the creatinine clearance rose to 65 per cent on the sixth postpartum day but remained depressed and was only 61 per cent almost eight weeks post partum. The urinary protein level remained at 2 Gm. per 24 hours. The postpartum clearances suggest residual renal damage as a consequence of the events during this pregnancy. The blood pressure returned to normal post partum. The infant survived. Two patients with a history of renal disease presented no laboratory or clinical evidence of impaired renal function at the time of their initial examinations during pregnancy. Both had uncomplicated pregnancies with normal bloo~l pressure, creatinine clearances, and urinary protein excretion. Of the 9 patients in Group 2 with a history of previous pre-eelampsia 01 eclampsia, 8 had normal clinical and laboratory findings throughout. The rc-

22:~:”

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CLEARANCE

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TEST

maining puticnt in this group was a SO-year-oltl, para 0, gravida ii, who had had a spontaneous abortion at, about six weeks of pregnancy one year previously. Shah was first, examinrd (luring the t,wentT-fourth week of pregnancy after cclaml)sia had become established. According to the referring physician, he1 blood pressure was normal during early pregnancy and she had developed no complications until four days previously when a blood pressure of 180/110 mm. LPATIENT:L*.-PREECLAMPSIA

a. PATIENT: V.S.-ECLAMPSIA

I

I I

I

I

ti

I CWAREAN

SECTION ; I

I

66 4 2 BEFORE DELIVERY

2466 POSTPARTUM

I 6 BEFORE DELIVERY

POSTPARTUM

I 6

I 4

I 2

BEFOREOELIVERY

1

I 2

1 4

I I 66

POSTPARTUM

DAYS

Fig. 7.-I, A X-year-old para 0, gravida 1, who developed pre-eclampsia during the thirty-sixth week of pregnancy with marked depression of creatinine clearance and slight proteinuria. Values returned to normal post partum. II, A 3%year-old para 0, gravida i, who developed pre-eclampsia during the thirty-sixth week of pregnancy with depressed creatinine clearance, slight proteinuria, and normal flndings post pa&urn. III, A 33-year-old nullipara who developed eclampsia during the thirtieth week with marked proteinuria and depression of creatinine clearance. Xormal levels had not been re-established by the eighth postpartum day.

Hg and a 4 plus albuminuria were detected on a routine antepartum examination. Within twenty-four hours the patient developed convulsions and about forty-eight hours before her admission to the University of Michigan Hospital the fetal heart tones became imperceptible. At the time of her initial examination here the patient was comatose with a blood pressure of 180/120 mm. Hg, with a creatinine clearance of 45 per cent, and a urinary protein excretion of 10 Cm. per 24 hours (Fig. 6). Her blood pressure rose to a peak of 198/150 mm. Hg and the clearance dropped to 39 per cent during the day before delivery of a stillborn infant. During the first two weeks post partum, the blood

~~l’t’ssnrc clroppt’tl lo l-cO/‘.IOO 111111. llg, wit11 t*iw itr t,licb t*rt~al.inint~ t~lt~aI’ittlt*~~ to 72 per t’rnt. Ky right weeks post, partnm, ihc patient 11atl hetwttlc llolwmttL11~ sivcb with normal t*i*t1atinintl clearant>tl and cluantitative ui*ina.ry protein cst*l*t’t iou. This pal itant was tlcst examined about. thrtae and a half months Iatcr during the first month of 11cr next pregnancy when she was still normotrnsivc wit,11 a normal crcatininc clearanctl. Again, she developed no difficulty until tbc twenty-fifth week of pregnancy when she tlevclopcd signs of pre-cclampsi;l with hypertension, a depression of the tdreatinine clearance to X4 per cent ant1 0.5 (in-r. of urinary protein per 21 hours. During the ensuing week, thr clearan~ dropped to 55 per cent, with the proteinrlria increasing to 1 (:m. per 2-l hout*s. -it this point, fetal death occurred. (fnr week later and one week before tl~hlivery of a stillborn infant, the clraranre had risen to 72 per cent with disapl)ral*illlCC of the protrinuria. Post partum the creatinine clearance ros(? lo the iionpregnancy normal range and t.he patient- became normotensive. Since tllcn. howtver, the patient, has demonstrated a labile, mild hypertension. ib

it

Results in Group 3 In this group 36 antepartum and 3-1 postpartum creatinine clearances mtl quantitative urinary protein determinations were carried out on 10 patients with pre-eclampsia and 3 with rclampsia. All of these laboratory data. WCI’(’ obtained after the appearance of clinical evidence of toxemia. None of thcst, patients presented evidence of abnormalitp previously. In retrospect, 6 primiparas had onI?- mild evidence of pre-cclampsia wit,11 minimal edema, albuminuria, and hypertension of short duration. All 6 had normal endogenous creatinine clearances ante partum and post partum. 0111) 8 of the 7 had 24 hour urinary protein excretions in excess of 0.5 Gm. Ontl with ’ ’ mild ” pre-eclampsia, howevt>r, chscrtlted as much as 6.1 (:m. protein iu 2-c llours. By comparison, the -l remaining pre-eclamptic patients presented evidentac 01’ severe toxemia with more marked hypertension and severe depression of tlita creatinine clearance. In all 4 there was a poor correlation between the degree of proteinuria and other clvidence of bhe sevcritg of t,he toxemia. The findings in the first of these paCents are presented in Fig. 7 (1-F. S.). This patient was a 21-year-old para 0, beravida i, who was normotensivc and without apparent complication until the thirt,y-sixth week of gestation when hypertension and slight albuminuria were detected. One week later and five days befort, delivery her blood pressure was 140/100 mm. Hg with a creatinine clearanct> of 82 per cent and a 24 hour urinary protein of 0.3 (+m. Two days later, thtb clearance had dropped to 62 per cent with a rise to 72 per cent during the nest 24 hours. After the appearance of hypertension, the blood pressure ante partum fluctuated between 140/100 and 180/124 mm. Hg. The quant,ity of urinaq protein was essentially unchanged. Post partum the blood pressure returned to normal with a rise in t,hc creatinine clearance to 122 and 118 per cent ant1 disappearance of the slight albuminnria. This labor was medically induced and t,he infant survived. The second patient with severe pre-eclampsia was a 3% year-old para 0, gravida i (Fig. 7, II-1~. A.) who appeared normal until th(b thirty-sixth week of pregnancy when she developed edema, albuminuria, and hypertension. During the 24 hours following detection of these signs of prerclampsia, the blood pressure averaged 165,000 mm. Hg and the creatininc clearance was decreased to 54 per cent with a proteinuria of 0.75 Gm. per 24 hours. One da? later and one day before medical induction of labor and delivery, the creatlnine clearance remained essentially unchanged with only a slight increase in the degree of proteinuria. Although this patient developed an intrapartum partial abruptio placentae, the infant survived. By the seventh post-

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partum day the creatinine clearance had risen to a normal 98 per cent with a normal blood pressure and the disappearance of the edema and albuminuria. Another pre-eclamptic patient presented clinical and laboratory findings comparable to those of the two patients just discussed. The last in this group had pre-eclampsia associated with a molar pregnancy. This case will be discussed later (fig. 8). One of the 3 cases of eelampsia has been presented in detail (Fig. 6). The data from a second patient with eclampsia are presented in Fig. 7 (III-V. S.). This patient was a 33-year-old para 0, gravida i, who developed recent excessive weight gain, edema, albuminuria, and hypertension. These signs of toxemia progressively increased in severity and three weeks later she developed convulsions. One day later she was first examined at the University of Michigan Haspita1 when the blood pressure was 170/110 mm. Hg, with a creatinine clearance of only 62 per cent and a 24 hour urinary protein excretion of 8 Gm. The :.PATIENT: NH-MOLE+

1 I.PATIENT:CR-MOLE+PREECLAMPSIA

PROTElNURlPi I

I ABORTION

HYSTEROTOMY . . . . . 1. . . . . . . . . . . . . . . I

8 6 4 2 BEFORE DELIVERY

2 4 6 s POSTPARTUM

BEFORE DELIVERY

POSTPARTUM

DAYS Fig. S.--f, A 26-year-old marked depression of creatinine 111, with a molar pregnancy, pressure.

pat’a ii, clearance, proteinuria,

gravida iii, with a molar pregnancy, pre-eclampsia, and proteinuria. II, A Z5-year-old para ii, gravida normal creatinine clearances, and normal blood

patient remained comatose during the ensuing seven days and the convulsions were controlled with sedation. The creatinine clearance was further depressed to 56 per cent with an increase in proteinuria to 10 Gm. per 24 hours. After repeated attempts to induce labor had failed, cesarean section was carried out with the delivery of a 3 pound infant who dred on the fourth day. When this patient was last examined on the eighth postpartum da?, the creatinine clearance had risen to 74 per cent with a decrease in the protelnuria to 2.5 Gm. per 24 hours and blood pressure of 150/92 mm. Hg. A longer period of observation, which was not possible in this patient, would be essential to assess the degree of residual hypertension and renal damage. The last eclamptic patient was a 16year-old primagravida who appeared norma. until albuminuria was detected

132

.lm. J. Obst. & Gyrw July, 19.5;

.EV‘ZSS

Molar

Pregnancies There were two 111olar Itt’(‘liiattci~s~~otic’ in ( :roul) 2 ad another in (1roup 3 ( Fig. 8). The first, patient was a %-.~~~ar-old,~tara ii. gravida iii. LSeginnin~ during the seventh week of pregnancy. tlaily \itgiEtl bleeding occurred for two months. At about 3I,$ months ot’ gestation, cdctna, albutninuria, ancl hypcrtensiolt developed with subsequent fluctuation of thcl blood pressure between 150/90 and lt35/110 mm. Hg. Two weeks later, the initial crcntinine clearance was only 67 per crrtt With a 24 hOlt1’ uthli*~ IjrOtcill ~hxVJ’ehIl Of 2. 3 (;rn. One day later, an abdominal hysterotomy was rarricd out witlt c~vautatjon of ihe ~nole from a uterus compatible in siz(b with that ot’ il six-tttctttttt Itregttancy. IJuriItg the first l\n-o clays post parturn, the blood [‘r~‘sslLI’(‘1’~1tto rrot~tnal wit,li i~ri increase in t ltc> Tltc creatinine clcarancc to 8X pcbr cdcnt,aIt,1 cliswppcar*snccof’ the proteinuria. second patient i Fig. S, I/---N. H. i was it 2.L?-ca~*-old pitra ii, gravida iii, who developed vaginal blecdjng during the: t hi rcl tnontlt 01’pregnant)-. This rccurretl at, frequent intervals and one month later alhuminuria appeared. On isolat,ed occasions, the blood pressure rose as high as l-&O,‘90mm. Hg. At t,he end of tht, fifth month of pregnancy? th(t cI’catiItinc1 clc~tt~artcc was 13X ~VI* cent with a 24 hour urinary prolcin cscrc+.iori 01’1.7 ( lm. After it Pitocin inductjon, a molar abortion was contpletcd by uterine ct~rt~i~ago. I’ost pwrtum the patient remajnctll normotensivc with JJO~Jttiil Pt’Vitt iniiicl c~lr:tt’ittl(‘c9 and (lisappearanrc of tllti ltt*oteinuria. Blood Serum Creatinine Using the 1ht~sltW tttlcl ‘I‘;tLtsSky lllct IlOcI, ( ‘illtlill’it I’oLlIld tllc~ range of bicJO(I serum creatinine in normal llOtl~~l’~‘~llilIlt~ womw to ltr 0.77 to O.!tX mg. prr ceni with a,n average of 0.86 ntg. p(‘r’ c7lttt. I tt out’ c*orttt*olseries of normal pregnant women, the scrnm creatinirto was Iws, wit It a I’tttIgcLof 0.18 to 0.86 mg. per cent wit,h an arithmetical 1llCiltt of 0.6-I tttq. per vr~tlt. This tx~duction c~ontributes to the higher clcarancc values clttrirtg prcgttattq- aIt(l is a reflection of the hypervoh~inia of pregnancy and associalet1 iitc~u~ascwl glottlcrutar filtration. After 011,’ week post partum all ot’ 1 ltc WJ~LIIII vtwt inin(t \-atiirs in the wntrot set& wew within Vaniara ‘s tlOI’JJli1 I ratJ$(‘. lit contrast to t Ii11Clcwrances. a sin& blood serum crcatinine dt~trrminatiort wits of pt’il(*tiValI~ no vatuc in thr early detccstjort of impaired renal i’ttnction. \1’ith serial t~~~t~rntinatjonsin the samupatient there was generally aIt jttcIa(:ascin 111~blood SCTIIIIJ creatininc by the time the creatjnjnr clc~rancc was dcpxssctl in tllc pI’~~senc~c I) I’ progrcxsivc renal disease. 1)uring at1 c~;lr*l~ stage 01 tY’tlilI itIrpaitxt:~trt, tlO\v(‘\.~‘t~.111~tttootl serum ercatjninc~ often rcniajned within IltC ;tWt~pt(Xl IlOl~Itlill I’iItl~L’c’ iltlll \VilS c~l~~VaiFt1 otll?- iii cytttlp;tijs(ttt \I-itlt nrevious de1c~InIitiat~ionsin tltcx sittnc paticsttt.

Cord Blood and Amniotic

Fluid Creatinine

In 25 normal patients, sp&mcns of blootl were obtained from the mothcht* and the umbilical cord immediately after deliver\-. The creatinine content of maternal and cord blood was practically the same with an average difference ot only 0.02 mg. per cent. These data suggest that tllcrc~ is no placental barrier in so far as creatinine is conct~rned. The maternal blood serum values in this groqt were higher on the average than those observed before term and all were within the normal nonpregnancy range. The rise in the blootl creatinine is further reflected by the lower clearances at this stagx>.

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In 22 normal patients, the creatinine content of amniotic fluid obtained when the membranes were ruptured artificially immediately before delivery ranged from 1.27 to 3.29 mg. per cent with an average of 2.38 mg. per cent. In 10 of these patients, specimens were obtained simultaneously from the maternal and cord blood and amniotic fluid. The creatinine content of the amniotic fluid was 2 to 3.5 times greater than in the maternal or cord blood with an average of 3 times as much. The creatininc content of amniotic fluid is probably related to fetal excretion.

Total Serum Proteins Serum protein determinations in the three groups of patients were consistent with previous observations.‘* In the normal pregnant patients, the average serum protein concentration was 6.2 Gm. per cent. This average would probably have been somewhat higher had more determinations been made prior to the last trimester of pregnancy when these values were generally lower. There was an even greater reduction in serum proteins in the toxemic patients, with an average of only 5.36 Gm. per cent. There was no clear correlation between the degree of reduction of serum proteins and the clinical status of the toxemia.

Summary A method of measuring glomerular filt,ration during pregnancy by use of the 24 hour endogenous creatinine clearance test is described. This method is compared with other measures of renal function during pregnancy. Antepartum and postpartum quantitjative creatinine and protein determinations in both blood and urine were carried out in three groups of patients: (1) control series of normal pregnant women, (2) paCents with diseases or medical histories predisposing them to the development of toxemia, and (3) those In an patients not included in Group 2 who developed pre-eclampsia-eclampsia. additional series of normal women, the creatinine content of maternal and cord blood and amniotic fluid were determined from specimens obtained at, the time of delivery. An increase in the endogenous creatinine clearance from early pregnancy with a decrease at or near term was observed in normal patients. A normal range during pregnancy was established. Uecreases in the creatinine clearances paralleled the clinical evidence of severity of the toxemias of pregnancy. Little or no decrease was observed in those patients with slight evidence of pre-eclampsia, suggesting that depression of the However, further experience with glomerular filtration is not an early change. more frequent clearances will be essential to establish whether or not the creatinine clearance may serve as an early index of the development of pre-eclampsiaeclampsia. The creatinine clearance indicated depressed renal function earlier than did the blood serum creatinine alone. All three of the pregnant diabetic patients studied start,ed out with normal clearances which subsequently were depressed well in advance of clinical evidence If these observations arc repeated in a larger of superimposed pre-eclampsia. group, such testing would be of real prognostic value in the management of the pregnant diabetic.

T wish to acknowledge my indebtedness to Drs. Henry I<. Schoch and Augusta .\. 1’:111lar:c for their invaluable advice during thcx conrlwt of this study, and to Mrs. Beth Fltwings. w11~ p~~rformed all of the laboratory proce~lurc~s hrarcin report&.

References J. 2. 3. 4. 6. 6. 7. s. 9. IO. 11. 1“. 1:. t-1.

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