1 Department of Obstetrics and Gynecology, University of Newcastle upon Tyne, Newcastle upon Tyne, NE1 4LP United Kingdom; and 2 Departments of Medicine, Obstetrics and Gynecology, and Clinical Pharmacology, University of Chicago, Chicago, Illinois 60637
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Human pregnancy is associated with
substantial increments in glomerular filtration rate (GFR) and renal
plasma flow (RPF). We have previously demonstrated that permselectivity
to neutral dextrans is altered in pregnancy, theoretical analysis of
the dextran sieving curves suggesting that elevated GFR is due to increased RPF and decreased glomerular oncotic pressure
(GC) with no evidence of increased transglomerular
hydrostatic pressure difference (
P). These conclusions have been
challenged, with claims that the rise in GFR is primarily a result of a
decrement in
GC. With refined laboratory and infusion
protocols, we have reexplored the determinants of ultrafiltration in a
serial study of 11 healthy women in late pregnancy (LP) and 4 mo
postpartum (PP), both in the baseline state and after increasing GFR
and RPF by infusion of amino acids. Results were analyzed using two computer modeling programs. Increased GFR in LP (38%, P < 0.05) was due to a combination of elevated RPF (22%) and a decrement in
GC and associated with an increased ultrafiltration
coefficient, without evidence of increased
P, and additional amino
acid-provoked GFR increments (P < 0.05) produced
similar findings. In addition, refined methodology permitted collection
of sufficient data on excreted large-radii dextrans (>60 Å) to
better define the nondiscriminatory "shunt" pathway
(
0) and the standard deviation of pore size
(S) about the mean radius of the distribution. Thus it was
possible to demonstrate that the physiological increase in total
protein excretion in LP is associated with a prominent shunt and an
upward shift in breadth of distribution of pore sizes. This ability to quantify
0 and S will now permit better
evaluation of the pathophysiological changes in the glomerulus
associated with pregnancy in women with renal disease and in gravidas
developing preeclampsia.
renal hemodynamics; dextran clearance; pregnancy
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
HUMAN PREGNANCY IS
ASSOCIATED with striking increments in renal hemodynamics, often
exceeding 50%, yet both glomerular filtration rate (GFR) and renal
plasma flow (RPF) increase further when gravidas are loaded with
protein or amino acids (2, 29). Such observations raise
the question as to whether such increases are potentially harmful to
the kidney (5, 19, 22), especially in women with
underlying kidney disorders who conceive, many of whom will also
manifest gestational increments in GFR and RPF (8, 18). Our approach to these questions has been to adapt techniques used in
nonpregnant populations whereby fractional clearances of neutral dextrans (Cdextran/Cinulin = D) and other input data are analyzed in mathematical
models that predict the ultrafiltration coefficient (Kf) and glomerular size-selective function and
allow assumptions to be made about transglomerular hydrostatic pressure
difference (
P) (10, 12, 28).
In a previous serial study during pregnancy, we demonstrated that
permselectivity to neutral dextrans was altered and theoretical analysis of the sieving curves suggested that, especially in the third
trimester, hyperfiltration was due to a combination of increases in RPF
and decreased glomerular oncotic pressure (GC)
(28). Glomerular size selectivity appeared to be altered,
but there was no evidence of increased
P, data reassuring to those
concerned that hyperfiltration might be detrimental to the kidney.
Our previous study, however, had problems. There were too little data
on excreted large-radii dextrans (>60 Å) to accurately quantify
the nondiscriminatory "shunt" pathway (0) or the
standard deviation of pore size (S) about the mean pore
radius (U) that in the "isoporous + shunt" and
"log-normal" models, respectively, are especially important for
understanding the pathophysiology of the glomerular filtration barrier
in patients with a variety of renal diseases (10, 12,
13). Moreover, Lafayette et al. (21) have
evaluated women in the immediate puerperium, postcesarean section, and
concluded that hyperfiltration in healthy pregnant women is
predominantly, if not uniquely, due to a 27% depression of
GC, in essence challenging our conclusion.
This study was therefore designed to reexplore the determinants of
ultrafiltration in late pregnancy both in the baseline state when GFR
is elevated and after increasing renal hemodynamics further by infusing
amino acids. In addition, we refined our methodology in a manner
permitting better quantification of both o and S in
normal pregnant women. The results confirm that the gestational increase in GFR is due to a combination of increased RPF and decreased oncotic pressure, and again modeling produced no evidence that either
the basal or amino acid-provoked GFR increments were associated with
increases in
P.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Subjects. Eleven normotensive healthy Caucasian women with no evidence or family history of renal or cardiovascular disease were studied during late pregnancy (LP: 36-38 wk gestation) and again 4 mo postpartum (PP), when none were breast feeding or ingesting oral contraceptives. All gave informed consent in writing to protocols approved by the Joint Ethics Committee of the Universities of Newcastle upon Tyne and Northumbria and the Newcastle upon Tyne and North Tyneside Health Authority.
Protocols. There were no limitations on diet and/or activity before investigation, but on the morning of each study subjects were requested to ingest a light carbohydrate breakfast and to avoid tea or coffee. A 24-h urine collection to measure total protein excretion (TPE) and urinary albumin excretion (UAE) was completed on the very morning of the study. On arrival the subjects were seated comfortably, basal blood samples were collected, and then a priming infusion containing 48 ml of dextran (10% dextran-40 in 0.9% saline; Baxter Healthcare, Thetford, UK), 10 ml of inulin (25% Inutest; Fresenius Kabi, Linz, Austria) and 2 ml of p-aminohippurate (PAH; 20% PAH; Merck, Sharp & Dohme, Hoddesdon, UK) was administered over 10 min followed by a sustaining infusion (which contained 264 ml of dextran, 75 ml inulin, and 36 ml of PAH) set at 60 ml/h. Sixty minutes later the volunteer voided, and three 20-min urine collections combined with midperiod blood sampling were obtained (clearance periods 1, 2, and 3). After these "control" collection periods, an amino acid infusion (Vamin 9; Kabi Pharmacia, Milton Keynes, UK) was administered at 4 ml/min as described previously (29), with a further 60 min of equilibration elapsing, and then clearance periods 4, 5, and 6 were measured (as described for the control collections). To minimize errors due to incomplete bladder emptying, an adequate diuresis was ensured by ad libitum oral tap water intake. Blood pressure was measured at 30-min intervals.
GFR and RPF were calculated as the mean of three inulin and PAH clearances, respectively (1, 2, and 3 then 4, 5, and 6). The renal PAH extraction rate in healthy pregnancy was assumed to be 0.85 (1, 6). The clearances of neutral dextrans (Analysis of renal hemodynamics.
Afferent glomerular oncotic pressure (A) was derived
from total serum protein concentrations (C) in grams per 100 ml using Eq. 1 (17)
![]() |
(1) |
![]() |
(2) |
![]() |
(3) |
Precis of theoretical analyses of transglomerular capillary water
and dextran flux and calculation of determinants of ultrafiltration.
Two theoretical models of glomerular function were assessed for
analysis of alterations in renal hemodynamics and transcapillary dextran flux in pregnancy (10, 13, 24-27). Each
represents the glomerular capillary wall as a heteroporous membrane
characterized by two pore parameters. The isoporous + shunt model
assumes that the capillary wall is perforated by a series of
restrictive pores of identical radius (r0) and
has a parallel shunt pathway (0) that fails to restrict
the passage of large molecules (10, 11). The shunt
contribution (
0) represents the fraction of the filtrate passing through the shunt. The log-normal model represents the capillary wall as being perforated by a single continuous population of
pores with a log-normal distribution of radii, characterized by the
mean pore radius (U) and the standard deviation of pore sizes (S) about the mean distribution of pore sizes
(10-12). Both models take into account the effect of
GFR determinants on convective and diffusive transmembrane transport of
varying sized neutral dextrans and require input values for GFR, RPF,
A, and
P.
Statistical analysis.
Each woman acted as her own nonpregnant control. Differences in
D curves were assessed by first splitting each curve
into four bands (30-39, 40-49, 50-59, and 60-65
Å), and differences among band areas were assessed across test
occasions. The significance of changes in GFR, RPF,
A,
and
D band area (i.e., between test occasions) were
estimated using an analysis of variance for repeated measurements, and
the significance of differences between each stage of the study was
estimated using a paired t-test. Wilcoxon's matched pair
testing was used to assess differences in TPE and UAE. All P
values are two-tailed, and results are considered significant for
P < 0.05.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Seven of the 11 women were nulliparas. All had uneventful pregnancies. Maternal age was 27.1 ± 1.6 (SE) yr, while weight during and after gestation was 76.2 ± 2.2 and 68.1 ± 2.7 kg, respectively.
Renal function.
Serum creatinine (SCr), renal hemodynamics, estimated
A and
E, TPE, UAE, and mean arterial
pressure (MAP) are summarized in Table 1.
Compared with PP values, both GFR and RPF were significantly greater in
LP (38 and 22%, respectively; P < 0.05), associated with a corresponding decrease in SCr, illustrating normal
pregnancy-induced hyperfiltration. In LP,
A was
decreased (
17.1% vs. PP) as was the calculated value for
E.
|
|
Renal handling of neutral dextrans.
Fractional clearances of smaller dextrans (30-49 Å)
were significantly decreased in LP (P < 0.05). The
decrease in the clearance of larger dextrans was not significant. Amino
acid infusion further reduced clearance of all-radii dextrans,
attaining significance only for radii 40-49 Å in LP
(P < 0.05) but for radii 40-59 Å in PP
(P < 0.05) (Table 2).
|
Urinary protein and albumin excretion. TPE was greater in LP (195 ± 40 mg/24 h) than PP (95 ± 11 mg/24 h) (P < 0.05), but there were no differences in UAE between LP and PP. Ongoing studies in our laboratory demonstrate that UAE continues to decrease throughout the puerperium, not attaining nonpregnant levels (<5 mg/24 h) until well after 5 m PP (Davison JM, unpublished observations).
Theoretical analysis of membrane parameters.
The isoporous + shunt and log-normal models (10) were
used to predict membrane parameters for the mean dextran sieving
curves (Table 2). If P was held constant, then the minimum value of Kf was increased in LP compared with PP, with
values similar to those obtained in our earlier investigation (Table
3). Such a gestational change would
correspond with increased filtration surface area or membrane
permeability. Amino acid infusion produced a nonsignificant decrease in
Kf in LP and a nonsignificant increment in
Kf when PP. Both models predicted a decreased
pore size (r0 and U) in LP compared
with PP (in line with the dextran sieving curves), attaining
significance only for U (P < 0.05), with
amino acid infusion having the effect of further decreasing pore size both LP and PP (P < 0.05 PP). The isoporous + shunt model predicted the presence of a (
0) in LP still
present PP and the log-normal model predicted widening of the standard
deviation of pore sizes (S) in LP compared with PP. With
amino acid infusion, values for both
0 and S
further increased but attained significance only for S when
PP (P < 0.05). As judged by a sum of chi-square, both models predicted
D accurately at each stage of the
study.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
These data confirm those previously described by us, that the
increment in GFR in late pregnancy (38%) is due to a combination of
elevated RPF (22%) as well as a significant contribution from a
decrement in A with an increment in
Kf. By modeling we again suggest that
hyperfiltration in LP is not associated with increments in
P. The
results extend our previous observations (28) by demonstrating that the increased proteinuria of normal pregnancy is
associated the presence of a nondiscriminatory shunt pathway (
0) in the isoporous + shunt model and a wider
standard deviation of pore sizes (S) about the mean in the
log-normal model.
We also infused amino acids during and after pregnancy. Here too
increments in GFR were primarily RPF driven, with
Kf relatively unchanged. Thus even in an already
hyperfiltrating gravida one need not invoke an increase in P to
explain further increments in GFR.
In a recent study by Lafayette et al. (21), GFR and RPF in
nonpregnant women were compared with those from healthy gravidas, the
latter studied immediately after a cesarean delivery while still
receiving epidural anesthesia. The authors were aware of the various
preoperative and postoperative confounding factors but still concluded
that the increased GFR observed immediately after cesarean section
(extrapolated to late gestation) was due to decreased
GC, because, while GFR was still markedly elevated, RPF
values were no different from the nonpregnant controls. The authors
further performed theoretical analyses of pressures and flows and
suggested that third-trimester hyperfiltration was mainly, if not
uniquely, attributable to decreased
GC. Interestingly, our modeled Kf values approximated those of
Lafayette et al., but their investigation did not include neutral
dextran sieving studies, increasing the uncertainty of the many
assumptions made regarding factors influencing glomerular
ultrafiltration. Moreover, in another publication (20)
these authors cite data contrasting with those they utilize here.
In the present studies, we took into account a recent critique and an accompanying editorial on methodological considerations from several publications on glomerular permselectivity to neutral dextrans (15, 26). Our infusion regimen avoids even modest volume expansion, and our Gpc laboratory methodology permits the application of membrane modeling for glomerular permselectivity function over a wide range (30-65 Å) of neutral dextran fractions.
Of interest, basal GFR and RPF values had attained the nonpregnant
range at the time of our tests at 4 mo PP, as had other barrier
parameters except for 0. As previously noted by us
(9) and by others (16), TPE has virtually
halved when 4-mo PP values are compared with LP measurements, but UAE
was similar at the two time points. However, as mentioned earlier, in
contrast to others (16 and reviewed in 2, 8) our accruing unpublished
data indicate that UAE determinations at 4 mo PP may be too early, as
there is a slow decline during the puerperium, reaching truly nonpregnant levels (<5 mg/24 h) only well after PP week 20.
In the present study, the log-normal model detected changes in S distribution that correlated with differences in TPE between LP and PP,
while no change in
0 was apparent. Again, however, our ongoing unpublished serial studies indicate that decrements in
0 (compared to LP values) are not detectable until
6 mo PP, at a time when UAE is approaching truly nonpregnant levels.
Also of interest is that the excretion of albumin, which is anionic,
cannot be accounted for by its size selectivity alone (36 Å),
indicating that although 0 and S as
theoretical concepts correlate overall with proteinuria one must also
take into account other factors such as membrane charge, the
configuration and charge of the protein molecule, and alteration in
tubular function and not just porosity (7, 23, 26).
Indeed, although quantification of
0 and S in
the nonpregnant population correlates with glomerular structural
changes, thus endorsing the membrane modeling approach as representing
glomerular function, it has been emphasized that changes in sieving
behavior toward dextrans are not simply and directly related to the
rate at which proteins are excreted (12, 24, 26).
In conclusion, this study, using improved methodology, suggests that
the increased GFR in LP is due to a combination of elevated RPF and
decreased GC. Within the limitations of analysis of
dextran sieving data, there appears to be no increase in
P. Raising
GFR further by amino acid infusion produces similar findings. The data
further indicate that the physiological increase in proteinuria in
pregnancy is associated with the presence of a shunt pathway (
0) in the isoporous + shunt model and a wider
standard deviation of mean pore size (S) in the log-normal
model. These methodological improvements now permit us to focus on the
effects of pregnancy in women with parenchymal renal disease and/or preeclampsia.
![]() |
ACKNOWLEDGEMENTS |
---|
We gratefully acknowledge Elizabeth A. Shiells and Maureen Kirkley for superb analytical work.
![]() |
FOOTNOTES |
---|
The studies were supported by WellBeing, The Northern Counties Kidney Research Fund, and The Northern and Yorkshire Regional Health Authority and Action Research.
Address for reprint requests and other correspondence: J. M. Davison, Dept. of Obstetrics and Gynecology, 4th Floor, Leazes Wing, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, United Kingdom (E-mail: j.m.davison{at}ncl.ac.uk).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 10 July 2000; accepted in final form 23 August 2001.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Battilana, C,
Zhang H,
Olshen RA,
Wexler L,
and
Myers BD.
PAH extraction and estimation of plasma flow in diseased human kidneys.
Am J Physiol Renal Fluid Electrolyte Physiol
261:
F726-F733,
1991
2.
Baylis, C,
and
Davison JM.
The urinary system.
In: Clinical Physiology in Obstetrics (3rd ed.), edited by Chamberlain G,
and Broughton-Pipkin F.. Oxford, UK: Blackwell Scientific, 1988, p. 263-307.
3.
Baylis, C,
and
Reckelhoff JF.
Renal hemodynamics in normal and hypertensive pregnancy: lessons from micropuncture.
Am J Kidney Dis
17:
98-104,
1991[ISI][Medline].
4.
Blouch, K,
Deen WM,
Fauvel JP,
Bialek J,
Derby G,
and
Myers BD.
Molecular configuration and glomerular size selectivity in healthy and nephrotic humans.
Am J Physiol Renal Physiol
273:
F430-F437,
1997
5.
Brenner, BM,
Meyer TW,
and
Hostetter T.
Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in ageing, renal ablation and intrinsic renal disease.
N Engl J Med
307:
652-659,
1982[ISI][Medline].
6.
Bucht, H.
Studies on renal function in man with special reference to glomerular filtration and renal plasma flow in pregnancy.
Scand J Clin Lab Invest
3:
1-64,
1951[ISI].
7.
Comper, WD,
and
Glasgow EF.
Charge selectivity in kidney ultrafiltration.
Kidney Int
47:
1242-1251,
1995[ISI][Medline].
8.
Conrad, KP,
and
Lindheimer MD.
Renal and cardiovascular changes in normal pregnancy and preeclampsia.
In: Chesley's Hypertensive Disorders in Pregnancy (2nd ed.), edited by Lindheimer MD,
Cunningham FG,
and Roberts JM.. Stamford, CT: Appleton and Lanje, 1999, p. 263-326.
9.
Davison, JM.
The effect of pregnancy on kidney function in renal allograft recipients.
Kidney Int
27:
74-79,
1985[ISI][Medline].
10.
Deen, WM,
Bridges CR,
Brenner BM,
and
Myers BD.
Heteroporous model of glomerular size selectivity: application to normal and nephrotic humans.
Am J Physiol Renal Fluid Electrolyte Physiol
249:
F374-F389,
1985[ISI][Medline].
11.
Deen, WM,
Roberts CR,
and
Brenner BM.
A model of glomerular ultrafiltration in the rat.
Am J Physiol
223:
1178-1183,
1972[ISI][Medline].
12.
Drummond, MC,
Kristal B,
Myers BD,
and
Deen WM.
Structural basis for reduced glomerular filtration capacity in nephrotic humans.
J Clin Invest
94:
1187-1195,
1994[ISI][Medline].
13.
Edwards, A,
Daniels BS,
and
Deen WM.
Ultrastructural model for size selectivity in glomerular filtration.
Am J Physiol Renal Physiol
276:
F892-F902,
1999
14.
Guasch, A,
Deen WM,
and
Myers BD.
Charge selectivity of the glomerular filtration barrier in healthy and nephrotic humans.
J Clin Invest
92:
2274-2282,
1993[ISI][Medline].
15.
Hemmelder, MH,
de Jong PE,
and
de Zeeuw D.
A comparison of analytic procedures for measurement of fractional dextran clearances.
J Lab Clin Med
132:
390-403,
1998[ISI][Medline].
16.
Higby, K,
Suiter CR,
Phelps JY,
Siler-Khodr T,
and
Langer O.
Normal values of urinary albumin and total protein excretion during pregnancy.
Am J Obstet Gynecol
171:
984-989,
1994[ISI][Medline].
17.
Klaur, S,
Schreiner G,
and
Ichikawa I.
The progression of renal damage.
N Engl J Med
318:
1657-1666,
1988[Abstract].
18.
Landis, EM,
and
Pappenheimer JR.
Exchange of substances through capillary walls.
In: Handbook of Physiology. Circulation. Washington, DC: Am Physiol Soc, 1963, vol. II, sect. 2, chapt. 29, p. 961-1034.
19.
Lindheimer, MD,
Grünfeld JP,
and
Davison JM.
Renal disease.
In: Medical Disorders During Pregnancy (3rd ed.), edited by Barron WM,
and Lindheimer MD.. St. Louis, MO: Mosby, 2000, chapt. 2, p. 39-70.
20.
Lafayette, RA,
Duzin M,
Sibley R,
Denby G,
Malik T,
Huie P,
Polheimus C,
Deen WM,
and
Myers BD.
Nature of glomerular dysfunction in preeclampsia.
Kidney Int
54:
1240-1249,
1998[ISI][Medline].
21.
Lafayette, RA,
Malik T,
Druzin M,
Derby G,
and
Myers BD.
The dynamics of glomerular filtration after cesarean section.
J Am Soc Nephrol
10:
1561-1565,
1999
22.
Meyer, TW,
and
Rennke HG.
Progressive glomerular injury after limited renal infarction in the rat.
Am J Physiol Renal Fluid Electrolyte Physiol
254:
F856-F862,
1988
23.
Myers, BD,
and
Guasch A.
Mechanisms of massive proteinuria.
J Nephrol
7:
254-260,
1994.
24.
Myers, BD,
Nelson RG,
Williams GW,
Bennett PH,
Hardy SA,
Berg RL,
Loon N,
Knowler WC,
and
Mitch WE.
Glomerular function in Pima Indians with noninsulin dependent diabetes mellitus of recent onset.
J Clin Invest
88:
524-530,
1991[ISI][Medline].
25.
Remuzzi, A,
and
Deen WM.
Theoretical effects of network structure on glomerular filtration of macromolecules.
Am J Physiol Renal Fluid Electrolyte Physiol
257:
F152-F158,
1989
26.
Remuzzi, A,
and
Remuzzi G.
Assessment of glomerular size-selective function with fractional clearance of neutral dextran.
J Lab Clin Med
132:
360-362,
1998[ISI][Medline].
27.
Remuzzi, G,
and
Bertani T.
Is Glomerulosclerosis a consequence of altered glomerular permeability to macromolecules?
Kidney Int
38:
384-394,
1990[ISI][Medline].
28.
Roberts, M,
Lindheimer MD,
and
Davison JM.
Altered glomerular permselectivity to neutral dextrans and heteroporous membrane modeling in human pregnancy.
Am J Physiol Renal Fluid Electrolyte Physiol
270:
F338-F343,
1996
29.
Sturgiss, SN,
Wilkinson R,
and
Davison JM.
Renal reserve during human pregnancy.
Am J Physiol Renal Fluid Electrolyte Physiol
270:
F16-F20,
1996.