SERIAL STUDIES OF RENALFUNCTION DURINGPREGNANCYANDTHE PUERPERIUMIN NORMALWOMEN1"2

By ETHANA. H. SIMS AND KERMIT E. KRANTZ3

(From the Departments of Medicine, Biochemistry, and Obstetrics and Gynecology, College ofMedicine, University of Vermont, Burlington, Vt.)

(Submitted for publication May 19, 1958; accepted August 12, 1958)

Until recently there has been uncertainty as towhether kidney function in normal pregnancy dif-fers significantly from that in the nonpregnantstate. The earlier studies reviewed by Smith (1),Chesley (2) and Bucht (3) were for the most partlimited to the immediate pre- and postpartum pe-riod when deviations from the nonpregnant stateare less marked. On the other hand, the studiesof Nice (4) demonstrated a marked increase ofurea clearance in mid-pregnancy while those ofBonsnes and Lange (5) and Bucht (3) showedsignificant increases in both renal plasma flow andin glomerular filtration rate during mid-preg-nancy which persisted to approximately the thirty-eighth week.

At the time the present study was begun, noserial studies of renal function during normalpregnancy and in the postpartum period had beenreported and it was the purpose of this study tomake such observations. Serial studies eliminatethe element of apprehension encountered in singlestudies which, as emphasized by Miles and De-Wardener (6), may distort the results. Our find-ings confirm the increased renal function in preg-nancy, and define the resultant lowering of the nor-mal range of values for plasma urea and plasmacreatinine during pregnancy. Previous observa-tions are extended to include the puerperium andindicate that there is a decline of renal plasma flowto subnormal values during this period.

METHODS

Experimental and control subjects. The 12 pregnantsubjects of this study ranged from 19 to 35 years of age,

1 This work was supported by a grant (RG-3745)from the National Institutes of Health, United StatesPublic Health Service.

2 Presented in part at a meeting of the American Fed-eration for Clinical Research, December, 1955.

3 Markle Scholar in Medical Science. Present address:Dept. of Obstetrics and Gynecology, School of Medicine,University of Arkansas, Fayetteville, Ark.

averaging 27 years. One subject (K) was studied dur-ing a second pregnancy. Their parity was from one tofive children, with an average of two children. No pa-tient exhibited any suggestion of toxemia during the studyor during any previous pregnancy, nor was there anyevidence of hypertension or urologic disease. One pa-tient (E) was delivered by cesarean section at 38 weeksbecause of a placenta previa, and another (H) spontane-ously delivered twins at 34 weeks. A group of nine non-pregnant women were control subjects. One of the con-trol subjects (N) subsequently became pregnant. Theaverage age was 25.7 years, with a range of 21 through33 years and an average parity of 1.1.

Procedure. Renal clearances of para-aminohippurate(PAH) and of inulin were determined by the constantinfusion technique of Goldring and Chasis (7). Whencreatinine clearances were measured, meat was eliminatedfrom the diet, as recommended by Camara, Arn, Keimerand Newburgh (8). During the period of study, the pa-tients were in a semi-supine position. For comparison,studies were also made on seven subj ects in both supineand left lateral positions. A minimum of three collectionperiods of 15 to 30 minutes in length, depending on theurine flow, were employed. Each period was terminatedby irrigation of the bladder with 100 to 200 ml. of physi-ological saline solution and 50 to 100 ml. of air, both ofwhich were totally recovered before the next period wasbegun. In a subsequent series of clearance studies duringpregnancy (9), the patients were asked to stand at theend of the collection period. In only one instance wasmore than a few additional ml. of urine obtained. Theseobservations in conjunction with those of Chesley andco-workers (10), who found that during pregnancy nobetter results could be obtained by direct irrigation ofthe renal pelves, suggest that recovery of bladder urineis complete. The plasma concentrations of inulin andPAH were graphed for the period of each clearancestudy. The value at the midpoint of each collection pe-riod was interpolated from the graph for calculation ofclearance. No allowance was made for time of delay,since the plasma concentrations of inulin and of PAHwere maintained relatively constant. Concentrations ofinulin ranged between 20 and 30 mg. per 100 ml. and ofPAH between 1 and 2 mg. per 100 ml. The procedureswere made essentially atraumatic by the use of indwellingneedles, using Metacaine® as local anesthetic. In orderto avoid conjugation of dextrose with PAH (11) andconsequent lower apparent clearance rates, saline ratherthan dextrose was used in the preparation of the intra-

1764

RENAL FUNCTION IN NORMALPREGNANCY

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FIG. 1. GRAPHIC PORTRAYALOF CLEARANCEDATA FROMTABLE IThe horizontal dashed lines represent the mean values for the group of normal nonpregnant subjects. The

shaded areas represent two standard deviations from the mean. The paired vertical lines represent the actualtimes of delivery. Values are graphed for a subsequent pregnancy in one patient (K).

venous solutions. Inulin of uniform molecular weight,which was shown to contain negligible amounts of freefructose, was employed throughout the study.4

Blood pressure and pulse rate, except as noted, were

taken at the beginning of each collection period. Bodytemperature was recorded at the beginning and end of theprocedure.

Patients were shown to be free of infection by smears

and cultures of urine taken at the beginning of each study.Heparin was used as an anticoagulant. Blood sampleswere centrifuged within an hour of drawing and analyzedthe same day for PAH, or frozen and stored at - 200 C.until analyzed at a later time.

Analytical procedures. All determinations were car-

ried out in duplicate.Inulin was determined by the method of Roe as modi-

fied by Schreiner (12) and three standard solutions were

run with each set of analyses. Plasma proteins were pre-

cipitated by the Somogyi method using zinc sulfate andsodium hydroxide (13). Correction was made for theinulinoid blank of plasma, but in samples of urine fromthe fasting subjects, a negligible blank value was found.Nine analyses at random of frozen aliquots of a knownpreparation of urine containing 200 mg. per 100 ml. of

4 Inulin from the Warner-Chilcott Company was pro-vided *without charge for the initial studies of theseries. PAH was obtained from the Sharp and DohmeCompany.

inulin had a mean and standard deviation of 202 7.2 mg.

Para-aminohippurate was determined by the method ofBrun (14) employing 3 ml. aliquots of the protein-freefiltrate used for inulin determinations. Recoveries ofPAHadded to urine and plasma were found to be within5 per cent. The Metacaine® used for local anesthesia didnot interfere with this determination.

Creatinine was determined by the method of Borsook,as modified by Hare (15). When analyzing plasma, inorder to obtain satisfactory ranges of optical densityusing the Coleman model 6 spectrophotometer, 6 insteadof 2 ml. of protein-free filtrate was employed in theprocedure.

Urea was determined by a modification of the methodof Gentzkow (16), adding iodine after nesslerization toavoid turbidity (17). Analyses of a series of controlaliquots of plasma containing 14.6 mg. per 100 ml. gave

a standard deviation of + 0.37 mg.

Calculations. All values for clearances were correctedto a standard body surface area of 1.73 M.'. The effectiverenal plasma flow (ERPF) has been taken as the actualclearance of PAH uncorrected for the extraction ratio.The filtration fraction was calculated from the ratioC1N/CPAH.

RESULTS

In Table I the significant data on the subjectsincluding the individual clearance values are re-

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ETHAN A. H. SIMS AND KERMIT E. KRANTZ

TABLE I

Renal clearance studies in 12 patients during pregnancy and the puerperium

Subject Time ofAge dear-Parity ance

weeksE. M.

343

"dC"*

A. M.28

2

R. S.190

G. H.27

1

N. W.32

4

D. B.32

2

D. B.33

3-

M. M.31

2

"A"

P. F.23

1

d"Fp

1324313437496294

17232833385056

122

182637506597

81218324045

242933394555

18232933363850

1015

Bodysurface Hema-

area tocrit

M.2 %1.651.71 401.74 401.77 401.79 381.67 451.63 451.62 48

1.70 341.73 351.74 351.76 331.76 361.69 431.69 371.67 39

1.511.60 371.63 371.55 401.53 391.55 40

1.62 471.64 401.67 401.73 401.75 401.63 51

1.76 371.77 351.78 351.78 321.54 431.61 42

1.78 371.81 401.84 351.85 361.87 341.89 341.68 43

1.77 351.81 40

19 1.5322 1.54 3326 1.56 3333 1.60 3537 1.62 3555 1.50 4669 1.47 4599 1.47 45

32 1.65 3537 1.67 4038 1.67 3951 1.58 4261 1.56 42

BROOd

Bloodpressure Pulse

mm. Hg

115/58 62110/57 58121/58 59114/57 61129/66 44120/62 51105/59 64

98/50107/50 7699/73 76

105/57 78105/54 78115/66 64106/69 6299/57 67

115/65 8098/60 84

117/80 76104/68 60119/74 52106/72 55

108/62 77111/62 8098/68 80

110/60 80119/67 70109/65 65

94/5890/60 7590/60 7586/60

101/67 6089/57 54

97/59 62

102/64 71102/68 67108/72 72102/70 60

102/62 60100/58 74

100/80 75100/70 75100/60 8098/60 6698/75 72

102/70 68103/70 64

110/60 76

111/60 6097/53 68

Clearanceof para-amino- Clearance Plasma Plasma

hippurate Clearance of creati- creati- urea(PAH) of inulin nine nine nitrogen

m1/min. ml./min. ml./min. mg./100 ml. mg./100 ml.772759676790732316456726

756887829875796433480600

673868479373399492

843952739847671640

676902950

535650

678708568663445523564

757860

15416415915317992

124107

155188172196158

9712689

13915913788

10482

119185169146143105

14617917616592

103

189181148176160163107

159178

200199169181192113

134

153181178186175

0.400.460.450.400.400.64

0.56

0.470.500.480.440.50

126 0.67

167 0.42205 0.38114 0.5384 0.6452

103 0.67

170 0.45165 0.46152 0.47124 0.52

87 0.58

106 0.51144 0.52172 0.51142 0.54

136 0.67

183 0.450.41

158 0.43181 0.40116 0.46165 0.41116 0.56

158 0.43195 0.41

131 150 0.63768 128 169 0.50716 125 148 0.51609 119 130 0.62467 107 94 0.66443 89 115 0.71449 94528 108 76 0.72

565 125 149 0.46583 135 164 0.48480 137 139 0.54498 76 94 0.59369 95 88 0.67

10.16.7

7.514.311.5

8.0

11.78.19.58.4

16.114.515.4

8.77.98.5

11.08.9

14.3

10.810.3

8.99.1

10.915.1

12.511.8

9.79.7

13.416.6

8.07.46.98.67.37.9

10.8

8.510.5

8.79.57.69.99.6

10.010.8

8.58.58.0

13.415.6

* The letters in quotation marks are those used in the graph of Figure 1.

1766

RENAL FUNCTION IN NORMALPREGNANCY

TABLE I-Continued

Clearanceof para-

Subject Time of Body amino- Clearance Plasma PlasmaAge clear- surface Hema- Blood hippurate Clearance of creati- creati- ureaParity ance area tocrit pressure Pulse (PAH) of inulin nine nine nitrogen

weeks M.' o mm. Hg ml./min. mi./min. ml./min. mg./100 ml. mg./100 ml.I. B. 15 1.65 631 145 187 0.42 10.3

27 19 1.66 37 100/50 75 809 137 198 0.37 11.30 28 1.69 39 112/55 80 790 130 168 0.41 8.0

32 1.70 39 107/58 81 560 119 138 0.35 8.4"E" 49 1.61 44 100/60 60 433 110 100 0.67 12.9

100 1.60 40 109/63 64 400 101 94 0.61 10.2

G. S. 25 1.58 39 105/58 80 686 143 160 0.53 8.331 29 1.58 40 98/58 76 848 162 173 0.43 8.9

2 34 1.61 37 97/58 76 681 160 152 0.46 6.738 1.65 39 98/60 68 558 165 132 0.59 6.1

"Gyp 44 1.53 47 115/68 56 444 97 99 0.64 12.6

A. Ma. 27 1.89 667 139 150 0.58 10.920 31 1.92 624 158 247 0.44 8.2

1 43 1.80 407 92 122 0.67 16.0"H" 71 1.78 47 100/60 507 100 82 0.71 17.2

G. L. 11 1.37 38 92/50 75 856 147 185 0.43 7.927 19 1.40 39 742 159 134 0.562 7.0

3 27 1.44 35 98/48 78 780 144 117 0.550 7.031 1.44 32 93/53 78 534 124 132 0.500 7.4

"L" 38 1.47 35 110/72 75 598 116 125 0.500 7.653 1.35 40 83/53 80 476 76 79 0.775 11.066 1.33 44 95/61 80 591 84 107 0.800 11.3

corded. Figure 1 graphically portrays the clear-ance data from Table I. Several interesting ob-servations regarding the individual serial studiescan be made: 1) Though the pregnant subjectsdeviate from the nonpregnant normal range, all in-dividuals do not deviate in a similar manner; and2) regardless of when the initial studies were doneduring pregnancy, there is a tendency for the ini-tial values to be relatively but not significantly de-pressed. This was particularly true in the indi-vidual subjects who were poorly relaxed duringtheir initial study. Since serial studies on thesesubjects were to be compared with single observa-tions on nonpregnant control subjects, repeat stud-ies on the controls were done to determine whetherthere might be a significant difference when thesubject became accustomed to the procedure. Themean values with their standard deviations andthe standard deviations of the differences of themeans in clearance of inulin and PAH and thedifference in the standard deviation of the means

between the two sets as shown in Table II were

not significant. For statistical purposes the valuesfrom both sets were averaged to afford data as

nearly comparable as possible to that recordedfrom the experimental subjects.

A difficulty in making comparison with nonpreg-

nant normals might be the possible relationship ofthe menstrual cycle to the measurements. How-ever, no correlation could be found between theresults obtained in 18 clearance studies in the ninenormal subjects and the stage of the menstrualcycle.

In Figure 2 is shown graphically the mean val-ues at various stages of pregnancy and the puer-perium for the clearances of inulin and of PAH, aswell as the filtration fractions with their relation tothe normal, nonpregnant means. In order to haveadequate points for statistical analysis, the points

TABLE II

Comparison of initial and repeated renal clearance studiesin nine normal nonpregnant subjects

Clearance of para-Clearance of inulin aminohippurate

Mean Mean(mi./min.) S.D.* S.E.t (ml./min.) S.D.* S.E.t

Initialstudy 100 11.8 576 99.4

Repeatstudy 108 10.5 3.9 623 57.8 27.4

Average 103.4 9.75 600 70

* Standard deviation.t Standard error, based on comparison of paired obser-

vations.

1767

ETHAN A. H. SIMS AND KERMIT E. KRANTZ

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FIG. 2. DIAGRAM SHOWINGTHE MEANAND Two STANDARDDEVIATIONS OF

SERIAL CLEARANCEVALUESIN NORMALPREGNANCYIN RELATION TO NONPREGNANTCONTROLS

Numbers above the bars represent the number of observations averaged at eachstage of pregnancy. See text for details of construction.

within periods of 11 and 8 weeks were employedthrough the twenty-eighth week of gestation and of4 weeks from the twenty-eighth through the for-tieth week. During the postpartum period, in-tervals of 8 weeks were employed during the first18 weeks and of 18 weeks from the eighteenththrough the thirty-sixth week. Since the datawere not accumulated at the same time intervalsfor each patient, the mean of the time intervals forall studies falling within designated periods are

plotted as the ordinate. This treatment of the dataavoids employing values from straight lines con-

necting widely separated points. In this and sub-sequent graphs the heavy horizontal line representsthe mean of our series of observations on normalsubjects with the stippled area demonstrating therange of two standard deviations above and belowthe mean.

Effective renal plasma flow

The effective renal plasma flow (ERPF) was

found to be significantly elevated (p < 0.01) to

770 ml. per minute by the fifteenth week of preg-

nancy and remained elevated through the twenty-fourth week. However, during the weeks im-mediately ante partum the ERPF progressivelyreturned to normal range. During the postpartumperiod, the values were observed to be significantlybelow normal for a variable number of weeks andas long as 25 weeks in five subjects. In all exceptthree subjects (E, F and H) in whom late follow-up studies could not be obtained, it was found thatthe values eventually returned to the normal range.

In this small series no correlation could be foundbetween the depression of renal plasma flow andthe presence or absence of lactation. If renalblood flow is calculated from the renal plasma flowin the usual manner from the hematocrit, a sig-nificant increase over the nonpregnant state is stillfound during the periods from the fifteenththrough the thirty-sixth weeks of pregnancy, butnot thereafter. Thus the increased plasma flowapparently represents a true increase in total bloodflow and not merely a reflection of the hemodilu-

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RENAL FUNCTION IN NORMALPREGNANCY

tion of the latter months of pregnancy. Accord-ingly the postpartum depression of plasma flowis reflected in a similarly significant depression ofrenal blood flow.

One patient, designated as N in Figure 1, hadpreviously served as a normal control and waslater studied in the ninth week of pregnancy.The renal plasma flow was increased from 557 to805 ml. per minute, but the glomerular filtrationrate (GFR) was essentially unchanged (105 and113 ml. per minute) giving a decrease in filtrationfraction from 0.19 to 0.14.

Glomerular filtration rate

In contrast to the renal plasma flow, the glo-merular filtration rate, as indicated by the inulinclearance, remained significantly elevated (p <0.01) from the fifteenth to thirty-eighth week ofpregnancy and fell to the range of normal as earlyas measured in the postpartum period. Onceagain, individual subjects (A, D, H and L) devi-ated from this pattern.

Filtration fraction

The filtration fraction (GFR/ERPF) was sig-nificantly elevated throughout the entire courseof pregnancy and did not return to normal rangeuntil the postpartum period. Because the in-creased glomerular filtration rate was maintainedin spite of the return to normal of the plasma flow,the filtration fraction became more markedly ele-vated as term was approached. Patients whoinitially had low values for plasma flow, neverthe-less consistently developed an increase in filtrationfraction.

Endogenous creatinine clearance and serum cre-atinine concentration

Figure 3 shows the variations in endogenouscreatinine clearance. The changes for the mostpart closely parallel those of the inulin clearance.However, there is wide individual variation in theratio of creatinine to inulin clearance. As notedoriginally by Bucht (3), the ratio drops towardunity as term is approached, though in this seriesthe change was not statistically significant. Dur-ing the latter part of pregnancy there is less devi-ation in the values of this ratio. As a result a morereliable approximation of the true filtration rate

is obtained. Consistent with the increase in filtra-tion rate, the plasma creatinine concentrations dur-ing pregnancy (Figure 4) are sharply reducedfrom 0.67 + 0.14 to 0.46 ± 0.13 mg. per 100 ml.(p < 0.01). There is very little overlap with therange found in nonpregnant women. Since themethod employed in which creatinine is adsorbedon Lloyd's reagent is more specific, these valuesfor plasma creatinine are lower than if they hadbeen determined by the more commonly used un-modified Folin method.

Plasma urea nitrogen concentrations

In the control subjects the usual wide range ofnormal concentrations of plasma urea nitrogen wasfound: a mean of 13.1 with a standard deviationof + 3.0. In the pregnant subjects, as shown inFigure 5, from the fifteenth week to term the meanwas 8.7 mg. with a standard deviation of + 1.5 mg.These returned to the nonpregnant range early inthe postpartum period.

Effect of parity and age

Parity ranged from zero to five previous preg-nancies. Age ranged from 19 through 35. In

ENDOGENOUSCREATININECLEARANCE

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FIG. 3. ENDOGENOUSCREATININE CLEARANCE (HAREMETHOD) DURING PREGNANCYAND THE PUERPERIUMFor method of construction of the graph, see Figure 2.

1769

1770 ETHAN A. H. SIMS AND KERMIT E. KRANTZ

0.9 ANTEPARTUM POST PARTUM

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FIG. 4. PLASMACREATININE (HARE METHOD) DURING PREGNANCYAND THE PUER-PERIUM IN RELATION TO NONPREGNANTSTATE

For details of construction, see Figure 2.

WEEKS

FIG. 5. PLASMAUREA NITROGEN DURING PREGNANCYAND THEPUERPERIUM

For the method of construction of the graph, see Figure 2.

RENAL FUNCTION IN NORMALPREGNANCY

this series no correlation of these factors withrenal function during pregnancy was apparent.

Posture

The effect of posture on renal function in thelate stages of pregnancy was studied. Duplicateclearance determinations were carried out on sub-jects alternately in the supine and in the left lat-eral position. Two sets of duplicate collection pe-riods of 20 to 30 minutes were performed in oneposition and compared with one set in the otherposition. No significant differences were evident.The weighted average of the glomerular filtrationrates in the supine position in seven subjects was147 ml. per minute, while that in the left lateralposition was 139 ml. per minute. In order toinvestigate the possibility that endogenous clear-ances during the daytime might be lower due toerect posture, endogenous creatinine clearancemeasurements were made during day and nightperiods. In six patients so studied there were nosignificant differences between the two periods; inseven the night clearances were higher; and ineight they were lower. Similar comparisons weremade in four institutionalized patients at intervalsof two weeks throughout pregnancy. Again, noconsistent pattern was noted.

DISCUSSION

The data from the above serial studies essen-tially confirm the finding of Bucht (3) that thereis an increase in renal clearance of inulin and ofpara-aminohippurate during pregnancy. Theyalso confirm his finding that in late pregnancy anelevated filtration rate is maintained in the faceof a declining renal plasma flow, producing anelevated filtration fraction. Our findings are simi-lar to those of Bonsnes and Lange, who in theirpreliminary report (5) noted a rise of glomerularfiltration in mid-pregnancy, and PAH clearanceswhich followed the inulin clearances in directionbut not in magnitude. The mean filtration rateand plasma flow found in the present study during-the middle trimester is somewhat lower than thoseof Sohar, Scadron and Levitt (190 ml. and 800 ml.per minute, respectively) (18), but again agreein indicating an elevation of filtration fraction asterm is approached. By extending the serialmeasurements throughout the puerperium until

the values returned to the normal range it is dem-onstrated that for an extended period after de-livery renal plasma flow may be significantly de-pressed.

No attempt has been made to calculate total re-nal resistances since in pregnancy both the meanarterial pressure and the renal venous pressure areuncertain. Likewise fractional renal resistanceshave not been estimated, since the evidence pro-vided by Pappenheirner and Kinter (19) hasraised considerable doubt as to the mechanism ofproduction and localization of such resistances.

In this study the conventional correction ofclearance values to a body surface area of 1.73 M.2has been made, which tends to minimize the in-crease in these values in relation to lean bodymass, since as pregnancy advances there is a dis-proportionate gain in total body water (20).

There are a number of consequences of the in-crease in filtration rate during pregnancy. Thegenerally accepted normal ranges of plasma con-centration of urea and of creatinine, which arecleared predominantly by glomerular filtration,must be revised downward for pregnant subjects.Likewise any substance which is cleared pre-dominantly by filtration and which is normallyreabsorbed by the renal tubules will be excreted inincreased quantities during pregnancy, unless thereis a concomitant increase in the capacity of therenal tubules to reabsorb that substance. Page,Glendening, Dignam and Harper (21), in thecourse of studies on the mechanism of histidinuriain pregnancy, noted the increase in glomerularfiltration rate during pregnancy and found that thisincrease in the quantity filtered accounted forabout half of the excess histidine excreted. Stud-ies in this laboratory indicate that a similar mecha-nism accounts for certain instances of benign gly-cosuria of pregnancy (9).

Simultaneous endogenous creatinine clearancesparallel the increase in inulin clearance duringpregnancy. Active tubular secretion of creatinineis suggested by a ratio of creatinine to inulin clear-ance greater than unity. Like Bucht (3) we havenoted that the ratio approaches unity as pregnancynears term, though in our series the observationwas not of statistical significance.

The increase in renal function during pregnancyraises the question as to whether true anatomicalhypertrophy of the kidney may develop. Available

1771

ETHAN A. H. SIMS AND KERMIT E. KRANTZ

evidence suggests that this is not so. In guineapigs the kidneys increase in weight only duringthe puerperium (22). We have found (23) inour laboratory that there is no absolute increasein weight of the kidneys during pregnancy in therat, but that there is an actual decrease in theweight of the kidney per unit of rat weight. Wehave also found that there is no change in thenumber of active glomeruli, when these are dem-onstrated by the technique of Moses and Schlegel(24) employing the fluorescent dye, thioflavin-S.

Coincident with the increase in renal functionduring pregnancy, there is an increase both in totalbody water (20) and in plasma volume. Thelatter, as shown by Berlin, Goetsch, Hyde andParsons (25), reaches 125 per cent of normal bythe sixteenth week and increases to 155 per centof normal by the thirty-sixth week. By the timethat plasma volume reaches its peak, however,renal plasma flow has already declined well to-ward the nonpregnant range. Hence it seemsunlikely that the increase in renal plasma flow ismerely a passive reflection of some correlate ofhypervolemia. There is a closer correlation be-tween renal plasma flow and resting cardiac outputduring the course of pregnancy. This has recentlybeen shown by Bader, Bader, Rose and Braun-wald (26) to be elevated to 4.1 L. per minutefrom the fourteenth to the twenty-fourth weeks,and to decline toward the nonpregnant normalafter the twenty-fifth week. While a major por-tion of the increment in cardiac output in mid-preg-nancy is accounted for by the demands of theplacenta (27), approximately 300 ml. per minuteof the increment can be accounted for by the in-crease in renal blood flow.

A number of observations suggest that the in-crease in renal function in pregnancy is mediatedby endocrine factors. The secretion of a numberof hormones of both adrenal and placental originis markedly increased during gestation. Certainhormones, notably thyroid, adrenal cortical, andsomatotropic, have the capacity to cause an in-crease in renal function and therefore may ac-tively contribute to the increased renal function ofpregnancy, and their partial withdrawal during thepostpartum period may in part explain the regres-sion of renal function during the puerperium.Thyroid hormone produces renal hypertrophy inrats (28) and an increase in filtration rate and

TmDin normal dogs (29). The concentration ofprecipitable iodine rises early in pregnancy (30),but in contrast to the effect of this agent in ani-mals there is apparently no histological hyper-trophy of the kidney, and TmPAH(and hence pre-sumably TmD) is not increased (18). In addition,in subsequent studies in this laboratory no differ-ence was found in the concentration of protein-bound iodine between a group of six pregnantpatients with low filtration rates as opposed tosix comparable patients with high filtration rates.Thus the contribution of the thyroid remains to bedefined. Relative to the adrenal steroids, Garrod,Davies and Cahill (31) have shown in the dogthat desoxycorticosterone increased GFR onlywhen causing excessive retention of sodium andwater; on the other hand, cortisone exerts an im-mediate increase in the filtration rate. The excre-tion of aldosterone has been found by chemicaldetermination to be increased to 10 times normalvalues during late pregnancy (32) and to returnto the nonpregnant rate of excretion immediatelypostpartum. Ingbar and co-workers (33) foundin man that inulin clearance was increased byadrenocorticotropic hormone (ACTH) and bycortisone. The excretion of glucocorticoids is in-creased during pregnancy (34) and the serumconcentration of 17-hydroxycorticoids increasesearly in pregnancy, reaching nearly seven timesthe normal nonpregnant value (35), so it is reason-able to assume that cortical steroids may contributesignificantly. Finally, striking augmentation ofrenal function has been produced experimentallyby anterior pituitary hormone. In the dog, White,Heinbecker and Rolf (36) have demonstrateddoubling of the clearance of PAH and of inulinafter 9 to 12 days of administration of growthhormone. In man, Heller, Smith and Lubin (37)described in five male patients with acromegalyaugmented clearance of PAHand a proportionallygreater increase in filtration rate, similar to thatseen in the latter months of pregnancy. However,in contrast to the findings in pregnancy there is ab-normally high tubular excretory capacity for PAHas well. There are no data to indicate whetherthere is increased secretion of somatotropin inhuman pregnancy. However, Contopoulos andSimpson (38) recently demonstrated that there isa threefold increase in growth-promoting activityof plasma from pregnant rats at the sixteenth to

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twentieth days of gestation as measured by bio-as-say on hypophysectomized rats. This increasedactivity was not decreased by hypophysectomy ofthe mother at the twelfth day of pregnancy, whichsuggests a fetal or placental origin of the growth-promoting factor.

Thus it appears likely on the basis of the indirectevidence cited above, although not proven, thataugmented endocrine secretions, notably somato-tropin, adrenal cortical and possibly thyroid, ac-count for the increase in renal function in preg-nancy.

SUMMARY

Serial renal function studies by standard tech-niques have been carried out on 9 control subjectsand 12 pregnant subjects from the fifteenth throughthe fortieth weeks of pregnancy and at intervalsduring the puerperium, with the following results:

1. The estimated renal plasma flow and renalblood flow were approximately 25 per cent higherthan control values throughout early and mid-pregnancy, declined to control values during thelast trimester, and then decreased to values sig-nificantly below the control values for manymonths during the puerperium.

2. The glomerular filtration rate was increasedapproximately 50 per cent throughout pregnancy,returning to the range of nonpregnant subjectsearly in the puerperium.

3. The filtration fraction was significantly ele-vated throughout pregnancy, rising to approxi-mately 40 per cent above control values as termwas approached, and remaining inconstantly ele-vated during the puerperium.

4. As a result of the increase in filtration rate theconcentrations of urea and creatinine in the plasmawere reduced to approximately one-half and two-thirds, respectively, of the concentrations in non-pregnant subjects.

The possible mechanisms producing thesechanges are discussed.

ACKNOWLEDGMENTS

The authors wish to express their appreciation forthe valuable help of Dr. William VanB. Robertson inthe handling of the statistical data and review of themanuscript, and also for the encouragement and valu-able suggestions of Dr. Homer Smith. We wish toacknowledge the technical assistance of Miss Nancy

Crane, Mrs. Grace Hill, Mrs. Patricia Peattie and Mrs.Margaret Tjaden, and the provision of space and ancil-lary services for this study by the Mary Fletcher Hos-pital.

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