BRIEF REVIEW www.jasn.

org

Pregnancy and the Kidney

Sharon E. Maynard* and Ravi Thadhani†
*Department of Medicine, Division of Renal Diseases and Hypertension, George Washington University School of
Medicine and Health Sciences, Washington, DC; and †Department of Medicine, Renal Unit, Massachusetts General
Hospital, Harvard Medical School, Boston, Massachusetts

ABSTRACT
Nephrologists are frequently called on to diagnose and treat renal disorders in Weight-based formulas, such as Cock-
pregnant women. In this review, we update recent literature pertinent to preg- roft-Gault, might overestimate GFR be-
nancy and renal disease. We initially begin by describing the application of com- cause the increased body weight of preg-
mon clinical estimators of GFR and proteinuria in pregnancy and then summarize nancy does not typically reflect increased
recent studies regarding pregnancy in women with chronic kidney disease and the muscle mass or creatinine production.
latest information on the use of common renal medications in pregnancy. In the In 2007, the accuracy of the MDRD
final section, we describe advances in our understanding of the pathophysiology of formula in pregnant women was for-
preeclampsia and the potential clinical implications of these discoveries for screen- mally evaluated for the first time in two
ing, prevention, and treatment of preeclampsia. prospective studies.2,3 Smith et al.2 com-
pared the performance of the modified
J Am Soc Nephrol 20: 14 –22, 2009. doi: 10.1681/ASN.2008050493
MDRD formula (based on age, serum
creatinine, and gender) with inulin clear-
ance in three groups of women: healthy
In recognizing renal disease, measure- although normal in a nonpregnant indi- pregnant volunteers, women with pre-
ment of kidney function and proteinuria vidual, reflects renal impairment in a eclampsia, and pregnant women with
are the early standard bearers of subclin- pregnant woman. The Modification of CKD before pregnancy. Among healthy
ical pathology. With the dramatic hor- Diet in Renal Disease (MDRD) formula, pregnant women, creatinine clearance by
monal and hemodynamic changes of which estimates GFR using a combina- 24-h urine collection closely approxi-
pregnancy, renal function is altered and tion of serum markers and clinical pa- mated GFR by inulin clearance; however,
these changes must be considered when rameters, has become a standard clinical the MDRD underestimated GFR by ⬎40
assessing renal function in pregnancy method to estimate renal function in pa- ml/min, a degree of bias that is somewhat
and in the choice of medications pro- tients with chronic kidney disease higher than observed in nonpregnant
vided through parturition. Renal func- (CKD). The use of this formula has not kidney transplant donors with normal
tion and filtration are also affected in been well studied in the pregnant popu- renal function (29 ml/min).4 Among
preeclampsia, and recent advances have lation, and guidelines on application of pregnant women with preeclampsia or
greatly expanded our understanding of the MDRD formula specifically exclude CKD, the MDRD formula performed
the pathophysiologic mechanisms of this interpretation in pregnant women. Cre- slightly better, underestimating GFR by
pregnancy-specific renal syndrome. atinine-based formulas developed in 23.3 and 27.3 ml/min, respectively; how-
nonpregnant populations are likely to be ever, the average GFR of all three groups
inaccurate when applied to pregnant
ASSESSMENT OF GFR AND women. For example, the fall in serum Published online ahead of print. Publication date
PROTEINURIA DURING creatinine during pregnancy reflects not available at www.jasn.org.

PREGNANCY
Estimating GFR in Pregnancy
The physiologic increase in GFR during
pregnancy normally results in a decrease
in concentration of serum creatinine,
which falls by an average of 0.4 mg/dl to a
pregnancy range of 0.4 to 0.8 mg/dl.1
Hence, a serum creatinine of 1.0 mg/dl,
only the pregnancy-induced increase in
real GFR but also hemodilution resulting
from the 30 to 50% plasma volume ex-
pansion by parturition. Perhaps more
important, the MDRD formula system-
atically underestimates GFR as GFR rises
above 60 ml/min per m2. This inherent
inaccuracy is likely to be more pro-
nounced at the high GFR of pregnancy.
Correspondence: Dr. Sharon E. Maynard, George
Washington University Medical Faculty Associates,
2150 Pennsylvania Avenue NW, Washington, DC
20037. Phone: 202-741-2283; Fax: 202-741-2285;
E-mail: sharonmaynard@gmail.com; or Dr. Ravi
Thadhani, Bullfinch 127, Massachusetts General
Hospital, Boston, MA 02114. Phone: 617-724-1207;
Fax: 617-726-2340; E-mail: thadhani.r@mgh.harvard.
edu
Copyright 䊚 2009 by the American Society of
Nephrology

14 ISSN : 1046-6673/2001-14 J Am Soc Nephrol 20: 14–22, 2009


was ⬎60 ml/min, a GFR range for which
the MDRD formula is also biased in the
nonpregnant population. Hence, the
bias the authors reported likely repre-
sents the inaccuracy of the MDRD equa-
tion when applied to any patient with
near-normal renal function, regardless
of whether pregnant.
Alper et al.3 studied GFR estimation
in a cohort of 209 women with pre-
eclampsia. They compared creatinine
clearance by 24-h urine collection, the
Cockroft-Gault formula, and two ver-
sions of the MDRD formula. Not sur-
prising, they found the Cockroft-Gault
formula overestimated GFR by approxi-
mately 40 ml/min, whereas the MDRD
formulas underestimated GFR (by 19.68
ml/min for the full MDRD and 12.6 ml/
min for the modified MDRD). As in the
study by Smith et al.2, the mean GFR in
their study participants was well over 60
ml/min, a GFR range for which the
MDRD formula is known to be inaccu-
rate. There are no published data on the
accuracy of the MDRD formula in preg-
nant women with GFR ⬍60 ml/min.
Given these issues, 24-h urine collection
for creatinine clearance remains the gold
standard for GFR estimation in preg-
nancy.
Estimating Proteinuria during
Pregnancy
The urine protein-to-creatinine ratio
(P:C ratio) has become the preferred
method for the quantification of pro-
teinuria in the nonpregnant population,
because of high accuracy, reproducibil-
ity, and convenience when compared
with timed urine collection.5 The quan-
tification of proteinuria in pregnancy is
indicated in at least two clinical situa-
tions. The first is monitoring of protein-
uria in pregnant women with preexisting
proteinuric kidney disease. In this situa-
tion, the assumptions behind use of the
P:C ratio in nonpregnant patients (in ef-
fect, steady state with regard to creatinine
production and excretion) would be ex-
pected roughly to hold, and the ratio can
and should be used to follow changes in
proteinuria during pregnancy.
The second important indication for
the quantification of proteinuria in preg-
J Am Soc Nephrol 20: 14 –22, 2009
nancy is for the diagnosis of preeclamp-
sia. Preeclampsia is defined by the Amer-
ican College of Obstetrics and
Gynecology6 as the new onset of hyper-
tension (BP ⬎140/90) and proteinuria
(ⱖ300 mg protein in a 24-h urine collec-
tion) after 20 wk of gestation. Routine
obstetric care includes dipstick protein
testing of a random voided urine sample
at each prenatal visit, a screening method
that has been shown to have a high rate of
false-positive and false-negative results
when compared with 24-h urine protein
measurement.7 Twenty-four-hour urine
collection, although the gold standard
for proteinuria quantification, has sev-
eral limitations. It is cumbersome for the
patient, it often is inaccurate because of
undercollection, and result availability is
delayed for at least 24 h while the collec-
tion is being completed.
The use of the P:C ratio to estimate
24-h protein excretion for the diagnosis
of preeclampsia has been controversial.
Several studies have compared P:C ratio
with 24-h urine collection in this setting,
with discordant conclusions. These stud-
ies vary in the study population and the
threshold used to define an abnormal ra-
tio. Nevertheless, a meta-analysis involv-
ing 974 pregnant women from 10 studies
showed a pooled sensitivity of 90% and
specificity of 78% using P:C ratio cutoffs
between 0.19 and 0.25, as compared with
the gold standard of 24-h urine protein
excretion (⬎300 mg/d).8 Most misclassi-
fications tended to occur in women with
borderline proteinuria (250 to 400 mg/
d).9 Hence, it is reasonable to use the
urine P:C ratio for the diagnosis of pre-
eclampsia, with 24-h collection under-
taken when the result is equivocal.
PREGNANCY IN THE SETTING OF
CKD
The literature on pregnancy in women
with CKD is dominated by single-center,
retrospective, and often uncontrolled
studies with heterogeneous definitions
of kidney disease and of adverse renal
and pregnancy outcomes. Fortunately,
there is good evidence to suggest that
women with only mild renal impair-
www.jasn.org BRIEF REVIEW
ment, normal BP, and little or no pro-
teinuria have good maternal and fetal
outcomes, with little risk for accelerated
progression toward ESRD or preterm de-
livery.10,11 Although few data are avail-
able regarding pregnancy outcomes in
specific renal diseases, current consensus
suggests the degree of renal insufficiency,
rather than the underlying renal diagno-
sis, is the primary determinant of out-
come.
Moderate to severe CKD results in an
increased risk for pregnancy complica-
tions and neonatal morbidity: More than
70% of women who become pregnant
with a serum creatinine ⬎2.5 mg/dl will
experience preterm delivery, and ⬎40%
develop preeclampsia.12,13 Pregnancy
also may result in deterioration in renal
function in some women, although cau-
sality has been difficult to establish. In a
landmark 1996 study by Jones and Hay-
slett,13 women who initiated pregnancy
with a serum creatinine ⬎2.0 mg/dl had
a high (33%) likelihood of an accelerated
decline in renal function during or im-
mediately after pregnancy. A recent
study by Imbasciati et al.14 is the only
study thus far to compare prospectively
the rate of GFR loss before and after
pregnancy in a cohort of women with
stages 3 through 5 CKD. They found the
rate of decline in GFR was not signifi-
cantly different after delivery compared
with before conception in the entire co-
hort of women with serum creatinine
⬎1.5 mg/dl; however, an accelerated rate
of GFR loss after delivery was observed in
the subgroup of women with both esti-
mated GFR ⬍40 ml/min per 1.73 m2 and
proteinuria ⬎1 g/d before pregnancy.
This group should be considered espe-
cially high risk for both renal loss and
pregnancy complications, and preg-
nancy should probably be avoided.
Pregnancy after Kidney
Transplantation
Fertility rates increase dramatically after
transplantation in women with end-
stage kidney disease; therefore, preg-
nancy is common among young female
transplant recipients. Most evidence sug-
gests that pregnancy after transplanta-
tion does not increase risk for loss of graft
Pregnancy for the Nephrologist 15
 BRIEF REVIEW www.jasn.org
function,15 so long as renal function is
good (creatinine ⬍1.5 mg/dl) and the
patient is on a stable immunosuppressive
regimen. In this situation, rejection rates
are similar to the general transplant pop-
ulation, and there does not seem to be an
increased risk for birth defects.16
Neonatal outcomes in pregnancies
among renal transplantation patients are
generally good. Most adverse neonatal
outcomes are related to a higher rate of
preterm birth (50 to 54%), small for ges-
tational age (33 to 45%), and neonatal
mortality (1 to 3%) as compared with the
general population (12.3, 5, and 0.68%,
respectively).17,18 The highest risk for
preterm birth and small for gestational
age are seen in the setting of maternal
hypertension and impaired baseline re-
nal graft function (creatinine ⬎1.5 mg/
dl).17 Long-term developmental out-
comes of surviving infants seem to be
good.19
MEDICATION USE IN
PREGNANCY
Inhibitors of the Renin-Angiotensin-
Aldosterone System
Widely known teratogenic effects of an-
giotensin-converting enzyme inhibitors
(ACEi) include fetal hypotension, an-
uria-oligohydramnios, growth restric-
tion, pulmonary hypoplasia, renal tubu-
lar dysplasia, neonatal renal failure, and
hypocalvaria. These effects occur with
second- and third-trimester exposure to
ACEi and carry a neonatal mortality rate
as high as 25%.17 Surviving infants have
an increased risk for impaired renal
function and hypertension in childhood
and early adulthood.20 A similar pattern
of fetal anomalies has been reported with
second- and third-trimester exposure to
angiotensin II receptor antagonists.21,22
First-trimester exposure to ACEi was pre-
viously considered innocuous, and contin-
uation of ACEi early in the first trimester
was considered safe by many practitioners;
however, the first large epidemiologic
study of first-trimester exposure to ACEi
reported a higher rate of major congenital
abnormalities (primarily cardiovascular
and central nervous system malforma-
16 Journal of the American Society of Nephrology
tions) compared with unexposed pregnan-
cies (7.1 versus 2.6%).23 Thus, it is now rec-
ommended that ACEi and angiotensin
receptor blockers be discontinued before
conception and that patients be educated
regarding the use of appropriate birth con-
trol while taking these agents. In addition,
women with inadvertent first-trimester ex-
posure to ACEi or angiotensin receptor
blockers should be evaluated by detailed fe-
tal ultrasound and echocardiography in
midgestation to screen for congenital ab-
normalities. There are few to no data on
the safety of aldosterone antagonists or re-
nin inhibitors in pregnancy. Given the es-
tablished teratogenicity of ACEi and the
key role of the renin-angiotensin-aldoste-
rone system in fetal development, the use
of these drugs in pregnancy is generally
contraindicated.
Immunosuppressive Medications
Calcineurin inhibitors, steroids, and aza-
thioprine are the mainstays of safe immu-
nosuppressive therapy in pregnant trans-
plant recipients. Mycophenolate mofetil
(MMF) has long been avoided in preg-
nancy on the basis of animal studies sug-
gesting developmental toxicity, malforma-
tions, and intrauterine death at therapeutic
dosages. Evidence has continued to build
confirming potentially teratogenic effects
of MMF in human pregnancy, such as fetal
bone marrow suppression and structural
malformations including hypoplastic
nails, shortened fingers, microtia (ear mal-
formations), and cleft lip/palate. Current
guidelines suggest that women who take
MMF and are contemplating pregnancy
should discontinue the medication at least
6 wk before conception. Although there
are few human data on the safety of siro-
limus in pregnancy, animal studies sug-
gest teratogenicity, so it, too, should be
avoided.24
RECENT ADVANCES IN
PREECLAMPSIA
Since 2003, evidence has accumulated
supporting the central role of placental
antiangiogenic factors, including soluble
fms-like tyrosine kinase-1 (sFlt1), in the
pathogenesis of preeclampsia (Figure 1).
sFlt1 is a circulating antagonist to both
vascular endothelial growth factor
(VEGF) and placental growth factor
(PlGF) and is overexpressed in the pla-
centa of women with preeclampsia. The
original rat model of sFlt1-induced pre-
eclampsia25 has been reproduced by oth-
ers.26 Animal models of preeclampsia
based on induction of uteroplacental
ischemia in both rats and primates are
characterized by increased circulating
and placental sFlt1.27,28 In women with
preeclampsia, uterine vein sFlt1 concen-
tration exceeds antecubital vein sFlt1,
confirming a fetoplacental source of ex-
cess circulating sFlt1.29 There are now
more than a dozen studies confirming
that circulating levels of sFlt1 and one of
its targets, the proangiogenic PlGF, are
altered several weeks before the onset of
clinical signs and symptoms of preeclamp-
sia—in the case of PlGF, as early as the first
trimester. There is evidence from mouse
models that VEGF is important in main-
taining glomerular endothelial cell health
and healing, and its absence induces pro-
teinuria and thrombotic microangiopathy
resembling pathologic glomerular changes
of preeclampsia.30 These diverse findings
support the theory that altered placental
expression of angiogenic factors, induced
or exacerbated by placental ischemia, is a
major contributor to endothelial dysfunc-
tion in preeclampsia.
sFlt1 is probably only one of several
circulating factors that contribute to en-
dothelial dysfunction. Soluble endoglin
(sEng), a proteolytic cleavage product of
the TGF-␤ receptor endoglin, seems to
act synergistically with sFlt1; when ad-
ministered together in pregnant rats,
sFlt1 and sEng produce a syndrome re-
sembling HELLP (hemolysis, elevated
liver enzymes, and low platelets), a severe
preeclampsia variant.31,32 Subsequent hu-
man studies confirm that sEng increases in
the circulation before onset of preeclamp-
sia, in a gestational pattern similar to sFlt1,
with levels rising precipitously just before
onset of clinical symptoms.33–35
Angiogenic Factors in High-Risk
Groups
Angiogenic factors provide insight into
the pathophysiology of several estab-
J Am Soc Nephrol 20: 14 –22, 2009
 www.jasn.org BRIEF REVIEW

for the development of preeclampsia.

Whether other vascular risk factors,
such as chronic hypertension and dia-
betes, have a similar pattern remains to
be seen.
The molecular pathways affecting
sFlt1 and sEng expression and how these
might relate to other theories of the
pathogenesis of preeclampsia are just
emerging. Heme oxygenase (HO), an an-
ti-inflammatory enzyme with antioxi-
dant properties, attenuates VEGF-in-
duced sFlt1 expression.47 Diminished
HO activity has been observed in women
with preeclampsia48,49 and mediates in-
creased placental sFlt1 and sEng ex-
pression. This observation suggests a
Figure 1. Summary of a current view of pathogenesis for preeclampsia. Placental
dysfunction, triggered by poorly understood mechanisms—including genetic, immuno- potential therapeutic use of statins in
logic, and environmental—plays an early and primary role in the development of pre- preeclampsia, because these agents up-
eclampsia. The damaged placenta in turn secretes the antiangiogenic factors, sFlt1 and regulate HO-1 and decrease VEGF-
sEng, into the maternal circulation. These factors lead to impaired VEGF/PlGF and TGF-␤ induced sFlt1 release from placental
signaling, resulting in systemic endothelial cell dysfunction mediated by a variety of villous explants47; however, adverse fetal
factors, as shown. Endothelial dysfunction, in turn, results in the systemic manifestations effects will first need to be excluded in
of preeclampsia. HO, heme oxygenase; AT1AA, angiotensin type 1 agonistic autoanti- clinical trials, a critical standard for any
bodies; COMT/2ME, catechol-O-methyl-transferase and 2 methoxyestradiol; sFlt1, solu- novel preeclampsia therapy.
ble fms-like tyrosine kinase-1; sEng, soluble endoglin; ET-1, endothelin 1; ROS, reactive A potential role for agonistic autoan-
oxygen species; NO, nitric oxide; IUGR, intrauterine growth retardation; HELLP, hemoly-
tibodies to the angiotensin AT1 receptor
sis, elevated liver enzymes, low platelets.
(AT1-AA) in the pathogenesis of pre-
eclampsia has developed in recent years.
lished preeclampsia risk factors. For ex- genic effects of nicotine.44 Nevertheless, Elevations in circulating levels of AT1-AA
ample, preeclampsia is strongly associ- no one recommends smoking during in women with preeclampsia were first de-
ated with both first pregnancies and pregnancy. scribed in 199950 and posited to mediate
multiple-gestation pregnancies. Higher Several preeclampsia risk factors—in- the enhanced vascular reactivity to angio-
serum sFlt1 levels are observed in both of cluding chronic hypertension, diabetes, tensin II and possibly the endothelial dys-
these groups, as compared with second and obesity—are related to underlying function that are characteristic of pre-
pregnancies and singleton gestations, maternal endothelial dysfunction. These eclampsia. Although subsequent work
respectively.36,37 Similarly, pregnant women may be more susceptible to the has shown these autoantibodies are not
women whose fetuses are affected by tri- adverse endothelial effects of antiangio- specific for preeclampsia, there remains
somy 13 (a condition associated with in- genic factors. If so, then preeclampsia significant experimental evidence to sug-
creased preeclampsia risk) have higher would be expected to develop at a lower gest they may play an important patho-
circulating sFlt1 levels as compared with threshold of circulating sFlt1 in women genic role. AT1-AA are linked to oxida-
control subjects,38 possibly as a result of with these maternal endothelial risk fac- tive stress and decreased trophoblast
the extra copy of the sFlt1 gene, which tors compared with previously healthy invasion,51 and circulating levels increase
resides on chromosome 13. Smoking is women. Indeed, sFlt1 levels are lower in a transgenic mouse model of pre-
associated with both a reduced risk for in obese women with established pre- eclampsia.52 AT1 receptor autoantibod-
preeclampsia39,40 and lower circulating eclampsia as compared with normal- ies stimulate trophoblast sFlt1 produc-
sFlt1 levels in both pregnant33,41 and weight women with preeclampsia.45 tion in vitro and therefore may mediate
nonpregnant42 individuals, as compared Similarly, women with preeclampsia in excess sFlt1 production by the placenta
with nonsmokers. Cigarette smoke ex- association with relatively low levels of in preeclampsia53; however, AT1-AA
tract reduces sFlt1 production by placen- circulating sFlt1 were found to have have not been temporally correlated to
tal cells in vitro.43 The molecular mecha- higher BP at booking (13 to 20 wk ges- the clinical phenotype of preeclampsia in
nism by which smoking downregulates tation) compared with women with large clinical studies.
sFlt1 (thereby lowering preeclampsia high-sFlt1 preeclampsia,46 suggesting Recently, deficiency of placental enzyme
risk) is unknown, but this response is not subclinical endothelial dysfunction catechol-O-methyl-transferase (COMT)
surprising given the known proangio- may result in a lower sFlt1 threshold and 2-methoxyestradiol (2-ME) was also

J Am Soc Nephrol 20: 14 –22, 2009 Pregnancy for the Nephrologist 17

 BRIEF REVIEW www.jasn.org
associated with preeclampsia.54 Mice de-
ficient in COMT develop preeclampsia-
like signs and symptoms that are rescued
by exogenous therapy with 2-ME, possibly
through inhibition of hypoxia-inducible
factor 1-␣ and downstream targets such
as sFlt1. The investigators also demon-
strated that human placenta obtained
from patients with preeclampsia are de-
ficient in COMT, which is accompanied
by low circulating levels of 2-ME. More
work is needed to understand the precise
role of COMT during normal and abnor-
mal pregnancies.
Screening for Preeclampsia
The ability to detect preeclampsia before
the onset of hypertension, proteinuria,
and other overt manifestations of disease
will probably be the first application of
angiogenic factors in the clinical man-
agement of preeclampsia. To date, more
than a dozen independent studies have
verified significant changes in PlGF,
sFlt1, or sEng before the onset of pre-
eclampsia.33,35,55– 69 Changes in PlGF are
seen by the first trimester,67– 69 whereas
reproducible alterations in sFlt1 and
sEng are observed in the mid to late sec-
ond trimester onward. PlGF is excreted
in the urine at lower levels in preeclamp-
sia, and measurement of urinary PlGF
may have a role in preeclampsia screen-
ing70 or diagnosis.71–73 Combining these
three biomarkers into a single angiogenic
index33,55,65 or with uterine artery Dopp-
ler74 –77 may be more predictive than any
single marker.
It remains to be seen whether angio-
genic biomarkers will be sensitive and spe-
cific enough for widespread clinical use.
For example, alterations in angiogenic fac-
tors are associated with normotensive
pregnancies complicated by intrauterine
growth restriction (IUGR).58,78 – 81 Angio-
genic factor changes in IUGR are less pro-
nounced than those seen in preeclampsia
and (with the exception of sEng33) have not
been observed in second- and early third-
trimester samples,33,58,63,82 so this overlap
may not be relevant for an early pre-
eclampsia screening test. An interna-
tional, prospective cohort study of an-
giogenic biomarkers for preeclampsia
screening, sponsored by the World
18 Journal of the American Society of Nephrology
Health Organization and with a recruit-
ment goal of 10,000 women, is ongoing
(http://www.crep.com.ar/plgf/) and will
help clarify many of these controversies.
In addition to screening and diagnosis
before the onset of clinical symptoms,
angiogenic factors may prove useful in
distinguishing preeclampsia from other
hypertensive disorders of pregnancy,
such as gestational hypertension and
chronic hypertension.83,84
Placental protein-13 (PP-13) has also
emerged as an early biomarker for pre-
eclampsia and other disorders related to
inadequate placentation. PP-13 is a pla-
centa-specific protein that is involved in
normal implantation and placental vas-
cular development. First-trimester cir-
culating maternal serum levels of PP-13
are significantly lower in women who go
on to develop preeclampsia, IUGR, and
preterm birth. Some early studies sug-
gested excellent prediction of preeclampsia
by first-trimester serum PP-13,85 although
other work suggested PP-13 is a robust
biomarker only for early-onset disease
and is less useful for preeclampsia occur-
ring closer to term.86 Combining first-
trimester PP-13 serum screening with
uterine artery Doppler may further improve
prediction.87 Mutations in LGALS13, the
gene encoding PP-13, have been detected
in cases of preeclampsia.88 This polymor-
phism may result in production of a
shorter splice variant of PP-13 that is not
detected by conventional assays, contrib-
uting to low circulating levels and de-
creased local activity of PP-13 in some
cases of preeclampsia.
A screening tool for preeclampsia will
have the greatest impact on clinical out-
comes when effective prevention or
treatment becomes available. To date, no
effective prevention is available for pre-
eclampsia, and management is support-
ive, with delivery of the neonate the only
definitive treatment. Nevertheless, early
diagnosis of preeclampsia with angio-
genic biomarkers is likely to improve
clinical outcomes using interventions
currently at hand. For example, intensive
monitoring of screen-positive patients
will allow for timely intervention with
antihypertensive medications, bed rest,
magnesium for seizure prophylaxis, ste-
roids for fetal lung maturity, and expedi-
ent delivery (when appropriate). The ef-
fect of screening on clinical outcomes
using these methods will need to be
proved. The greatest potential impact of
screening and early diagnosis will de-
pend on new treatment or prevention
strategies for preeclampsia, based on al-
tering the placental production or endo-
thelial effects of angiogenic factors. In-
terventions that allow delivery to be
safely postponed as little as 1 wk have the
potential to improve neonatal outcomes
significantly in preeclampsia.89 Such
treatments are further on the horizon but
hold the greatest hope for the transfor-
mation of our care of women with pre-
eclampsia.
PREVENTION AND TREATMENT
OF PREECLAMPSIA
Several medications and new therapies
may play a role in the management of
preeclampsia.
Aspirin
The theoretical benefits of aspirin are
based on prominent alterations in pros-
tacyclin-thromboxane balance in pre-
eclampsia. Aspirin for the prevention of
preeclampsia has been extensively stud-
ied. Dozens of trials have produced
mixed results, culminating in three large
randomized, controlled trials, with a cu-
mulative enrollment of 12,000 high-risk
women in the mid-1990s.90 –92 All three
studies found a small, nonsignificant
trend toward a lower incidence of pre-
eclampsia in the aspirin-treated groups.
A comprehensive meta-analysis pub-
lished in 2004, subsequently reinforced
by a second meta-analysis in 2007, com-
bined randomized, controlled trial data
on ⬎32,000 women of varying risk status
from 31 trials. Both meta-analyses sug-
gested a small but significant overall ben-
efit, with a relative risk for preeclampsia
of 0.81 to 0.90 for aspirin-treated pa-
tients.93,94 A small reduction in the risk
for early preterm birth was also observed
in both analyses. Low-dosage aspirin
seems to be safe: Early concerns of an in-
creased risk for postpartum hemorrhage
J Am Soc Nephrol 20: 14 –22, 2009

have clearly been assuaged. Given the
small but significant protective effect, as-
pirin prophylaxis should be considered
as primary prevention for preeclampsia,
especially for women who are at high
baseline risk and for whom the absolute
risk reduction will be greatest.
Antioxidants
Nutritional supplements, including anti-
oxidants, calcium, and folic acid, all have
been proposed as offering protection from
preeclampsia. Unfortunately, none have
proved effective in randomized, controlled
trials. The use of antioxidants has garnered
particular enthusiasm in the past several
years, fueled in part by research suggesting
a major role for oxidative stress in the
pathogenesis of preeclampsia; however,
three large randomized, controlled trials of
vitamin C and E supplementation, with
sample sizes ranging from 700 to 2400
women, showed no benefit in high-risk95,96
or in healthy, nulliparous women.97 A
larger trial sponsored by the National Insti-
tutes of Health Maternal-Fetal Medicine
Units Network, with anticipated enroll-
ment of 10,000 low-risk women, is ongo-
ing; however, the current data do not sup-
port the routine use of antioxidants for the
prevention of preeclampsia.
Calcium and Folic Acid
Calcium supplementation is not effective
in women with normal or high baseline
calcium intake but may be beneficial in
populations with low (⬍600 mg/d) di-
etary calcium intake.98,99 Folic acid has
been suggested to be protective by obser-
vational data,100 but no randomized,
controlled trials are yet available to sup-
port this claim.
Angiogenic Therapies
Endothelial damage in preeclampsia is
mediated, at least in part, by disruptions
in balance between proangiogenic
(VEGF, PlGF, and TGF-␤) and antian-
giogenic (sFlt1 and sEng) circulating fac-
tors. Given this, interventions that seek
to reestablish angiogenic balance hold
promise for the prevention or treatment
of preeclampsia. In a rat model of sFlt1-
induced preeclampsia, recombinant
VEGF-121 ameliorated hypertension and
J Am Soc Nephrol 20: 14 –22, 2009
renal damage.101 Other strategies that may
be explored include the use of placental
growth factor; mAbs to sFlt1 or sEng;
small-molecule inhibitors of sFlt1 or sEng
action; or agents that enhance endogenous
VEGF, PlGF, or TGF-␤ production.
L-Arginine
Another potential treatment strategy for
preeclampsia capitalizes on the role of
nitric oxide (NO) in the pathogenesis of
disease. The endothelial protective effect
of VEGF and PlGF in normal pregnancy
is mediated by NO, and impaired NO
synthesis may contribute to endothelial
dysfunction in preeclampsia. Women
with preeclampsia have high circulating
levels of asymmetric dimethylarginine,
an endogenous inhibitor of NO syn-
thase, even before the clinical onset of
disease.102,103 Hence, NO donors or pre-
cursors, such as L-arginine, might be ef-
fective for the prevention or treatment of
preeclampsia. Although clinical studies
thus far have been too small to show a
conclusive benefit,104 pilot data sug-
gested L-arginine may prolong preg-
nancy and reduce BP in women with ges-
tational hypertension.105 Larger studies
are needed to determine whether L-argi-
nine or other interventions aimed at re-
storing endothelial NO activity are safe
and effective for preeclampsia.
There remain significant challenges to
the development of new treatments for
preeclampsia, and it is unclear whether
these novel therapies will prove to be safe
and effective. Nevertheless, it is exciting
to witness advances in our understand-
ing of the pathophysiology of pre-
eclampsia that have the potential finally
to lead to treatment options for this chal-
lenging disease.
ACKNOWLEDGMENTS
S.E.M. is supported by the Charles E.
Culpeper Scholarship in Medical Sciences.
R.T. is supported by grant DK67397 from the
National Institutes of Health.
DISCLOSURES
S.E.M. is a co-inventor on a patent filed on behalf
of Beth Israel Deaconess Medical Center for the use
www.jasn.org BRIEF REVIEW
of angiogenesis-related proteins for the diagnosis
and treatment of preeclampsia. R.T. is a co-inven-
tor on patents filed on behalf of the Massachusetts
General Hospital and licensed to multiple diagnostic
companies for the use of proteins including angiogen-
esis-related proteins for the diagnosis of preeclamp-
sia. R.T. also serves as a consultant to the following
diagnostic companies pursuing preeclampsia tests:
Abbott Diagnostics, Beckman Coulter, Roche Diag-
nostics, and Ortho Clinical Diagnostics.
REFERENCES
1. Fischer MJ: Chronic kidney disease and
pregnancy: Maternal and fetal outcomes.
Adv Chronic Kidney Dis 14: 132–145, 2007
2. Smith MC, Moran P, Ward MK, Davison
JM: Assessment of glomerular filtration
rate during pregnancy using the MDRD for-
mula. BJOG 115: 109 –112, 2008
3. Alper AB, Yi Y, Webber LS, Pridjian G, Mu-
muney AA, Saade G, Morgan J, Nuwayhid
B, Belfort M, Puschett J: Estimation of glo-
merular filtration rate in preeclamptic pa-
tients. Am J Perinatol 24: 569 –574, 2007
4. Rule AD, Larson TS, Bergstralh EJ, Slezak
JM, Jacobsen SJ, Cosio FG: Using serum
creatinine to estimate glomerular filtration
rate: Accuracy in good health and in
chronic kidney disease. Ann Intern Med
141: 929 –937, 2004
5. Eknoyan G, Hostetter T, Bakris GL, Hebert
L, Levey AS, Parving HH, Steffes MW, Toto
R: Proteinuria and other markers of chronic
kidney disease: A position statement of the
National Kidney Foundation (NKF) and the
National Institute of Diabetes and Diges-
tive and Kidney Diseases (NIDDK). Am J
Kidney Dis 42: 617– 622, 2003
6. ACOG practice bulletin: Diagnosis and
management of preeclampsia and eclamp-
sia. Number 33, January 2002. American
College of Obstetricians and Gynecologists.
Int J Gynaecol Obstet 77: 67–75, 2002
7. Waugh JJ, Clark TJ, Divakaran TG, Khan
KS, Kilby MD: Accuracy of urinalysis dip-
stick techniques in predicting significant
proteinuria in pregnancy. Obstet Gynecol
103: 769 –777, 2004
8. Price CP, Newall RG, Boyd JC: Use of pro-
tein:creatinine ratio measurements on ran-
dom urine samples for prediction of signif-
icant proteinuria: A systematic review. Clin
Chem 51: 1577–1586, 2005
9. Rodriguez-Thompson D, Lieberman ES:
Use of a random urinary protein-to-creati-
nine ratio for the diagnosis of significant
proteinuria during pregnancy. Am J Obstet
Gynecol 185: 808 – 811, 2001
10. Jungers P, Houillier P, Forget D, Labrunie
M, Skhiri H, Giatras I, Descamps-Latscha B:
Influence of pregnancy on the course of
primary chronic glomerulonephritis. Lancet
346: 1122–1124, 1995
Pregnancy for the Nephrologist 19
 BRIEF REVIEW www.jasn.org
11. Hou S: Pregnancy in chronic renal insuffi-
ciency and end-stage renal disease. Am J
Kidney Dis 33: 235–252, 1999
12. Sanders CL, Lucas MJ: Renal disease in
pregnancy. Obstet Gynecol Clin North Am
28: 593– 600, vii, 2001
13. Jones DC, Hayslett JP: Outcome of preg-
nancy in women with moderate or severe 26.
renal insufficiency. N Engl J Med 335: 226 –
232, 1996
14. Imbasciati E, Gregorini G, Cabiddu G,
Gammaro L, Ambroso G, Del Giudice A,
Ravani P: Pregnancy in CKD stages 3 to 5:
Fetal and maternal outcomes. Am J Kidney
Dis 49: 753–762, 2007
15. Kashanizadeh N, Nemati E, Sharifi-Bonab 27.
M, Moghani-Lankarani M, Ghazizadeh S,
Einollahi B, Lessan-Pezeshki M, Khedmat
H: Impact of pregnancy on the outcome of
kidney transplantation. Transplant Proc 39:
1136 –1138, 2007
16. Framarino dei Malatesta M, Rossi M, Rocca 28.
B, Iappelli M, Poli L, Piccioni MG, Gentile T,
Landucci L, Berloco P: Fertility following
solid organ transplantation. Transplanta-
tion Proceedings 39: 2001–2004, 2007
17. Blowey DL, Warady BA: Outcome of in-
fants born to women with chronic kidney 29.
disease. Adv Chronic Kidney Dis 14: 199 –
205, 2007
18. Armenti VT, Radomski JS, Moritz MJ,
Gaughan WJ, Hecker WP, Lavelanet A, Mc-
Grory CH, Coscia L: Report from the Na-
tional Transplantation Pregnancy Registry:
Outcomes of pregnancy after transplanta- 30.
tion. In: Clinical Transplants 2004, edited
by Cecka JM, Terasaki PI, Los Angeles,
UCLA Immunogenetics Center, 2004, pp
103–114
19. Willis FR, Findlay CA, Gorrie MJ, Watson
MA, Wilkinson AG, Beattie TJ: Children of
renal transplant recipient mothers. J Paedi- 31.
atr Child Health 36: 230 –235, 2000
20. Laube GF, Kemper MJ, Schubiger G, Neu-
haus TJ: Angiotensin-converting enzyme
inhibitor fetopathy: Long-term outcome.
Arch Intern Med Fetal Neonatal Ed 92:
F402–F403, 2007 32.
21. Quan A: Fetopathy associated with expo-
sure to angiotensin converting enzyme in-
hibitors and angiotensin receptor antago-
nists. Early Hum Dev 82: 23–28, 2006
22. Alwan S, Polifka JE, Friedman JM: Angio-
tensin II receptor antagonist treatment dur-
ing pregnancy. Birth Defects Res A Clin
Mol Teratol 73: 123–130, 2005 33.
23. Cooper WO, Hernandez-Diaz S, Arbogast
PG, Dudley JA, Dyer S, Gideon PS, Hall K,
Ray WA: Major congenital malformations
after first-trimester exposure to ACE inhib-
itors. N Engl J Med 354: 2443–2451, 2006
24. Danesi R, Del Tacca M: Teratogenesis and 34.
immunosuppressive treatment. Transplant
Proc 36: 705–707, 2004
25. Maynard SE, Min JY, Merchan J, Lim KH, Li
J, Mondal S, Libermann TA, Morgan JP, 35.
20 Journal of the American Society of Nephrology
Sellke FW, Stillman IE, Epstein FH,
Sukhatme VP, Karumanchi SA: Excess pla-
cental soluble fms-like tyrosine kinase 1
(sFlt1) may contribute to endothelial dys-
function, hypertension, and proteinuria in
preeclampsia. J Clin Invest 111: 649 – 658,
2003
Lu F, Longo M, Tamayo E, Maner W, Al-
Hendy A, Anderson GD, Hankins GDV,
Saade GR: The effect of over-expression of
sFlt-1 on blood pressure and the occur-
rence of other manifestations of pre-
eclampsia in unrestrained conscious preg-
nant mice. Am J Obstet Gynecol 196:
396.e1–396.e7, discussion 396.e7, 2007
Gilbert JS, Babcock SA, Granger JP: Hy-
pertension produced by reduced uterine
perfusion in pregnant rats is associated
with increased soluble fms-like tyrosine ki-
nase-1 expression. Hypertension 50: 1142–
1147, 2007
Makris A, Thornton C, Thompson J, Thom-
son S, Martin R, Ogle R, Waugh R, McKen-
zie P, Kirwan P, Hennessy A: Uteroplacental
ischemia results in proteinuric hypertension
and elevated sFLT-1. Kidney Int 71: 977–
984, 2007
Bujold E, Romero R, Chaiworapongsa T,
Kim YM, Kim GJ, Kim MR, Espinoza J, Gon-
çalves LF, Edwin S, Mazor M: Evidence sup-
porting that the excess of the sVEGFR-1
concentration in maternal plasma in pre-
eclampsia has a uterine origin. J Matern
Fetal Neonatal Med 18: 9 –16, 2005
Eremina V, Jefferson JA, Kowalewska J,
Hochster H, Haas M, Weisstuch J, Richard-
son C, Kopp JB, Kabir MG, Backx PH, Ger-
ber HP, Ferrara N, Barisoni L, Alpers CE,
Quaggin SE: VEGF inhibition and renal
thrombotic microangiopathy. N Engl
J Med 358: 1129 –1136, 2008
Gu Y, Lewis DF, Wang Y: Placental produc-
tions and expressions of soluble endoglin,
soluble fms-like tyrosine kinase receptor-1,
and placental growth factor in normal and
preeclamptic pregnancies. J Clin Endocri-
nol Metab 93: 260 –266, 2007
Venkatesha S, Toporsian M, Lam C, Hanai
J, Mammoto T, Kim YM, Bdolah Y, Lim KH,
Yuan HT, Libermann TA, Stillman IE, Rob-
erts D, D’Amore PA, Epstein FH, Sellke FW,
Romero R, Sukhatme VP, Letarte M, Karu-
manchi SA: Soluble endoglin contributes
to the pathogenesis of preeclampsia. Nat
Med 12: 642– 649, 2006
Levine RJ, Lam C, Qian C, Yu KF, Maynard
SE, Sachs B, Sibai B, Epstein FH, Romero R,
Thadhani R, Karumanchi SA: Soluble en-
doglin and other circulating antiangiogenic
factors in preeclampsia. N Engl J Med 355:
992–1005, 2006
Robinson CJ, Johnson DD: Soluble endo-
glin as a second-trimester marker for pre-
eclampsia. Am J Obstet Gynecol 197: 174
e171– e175, 2007
Rana S, Karumanchi SA, Levine RJ, Ven-
katesha S, Rauh-Hain JA, Tamez H,
Thadhani R: Sequential changes in antian-
giogenic factors in early pregnancy and risk
of developing preeclampsia. Hypertension
50: 137–172, 2007
36. Wolf M, Shah A, Lam C, Martinez A, Smir-
nakis KV, Epstein FH, Taylor RN, Ecker JL,
Karumanchi SA, Thadhani R: Circulating
levels of the antiangiogenic marker sFLT-1
are increased in first versus second preg-
nancies. Am J Obstet Gynecol 193: 16 –22,
2005
37. Maynard SE, Moore Simas TA, Solitro MJ,
Rajan A, Crawford S, Soderland P, Meyer
BA: Circulating angiogenic factors in sin-
gleton vs multiple-gestation pregnancies.
Am J Obstet Gynecol 198: 200.e201–
200.e207, 2008
38. Bdolah Y, Palomaki GE, Yaron Y, Bdolah-
Abram T, Goldman M, Levine RJ, Sachs BP,
Haddow JE, Karumanchi SA: Circulating
angiogenic proteins in trisomy 13. Am J
Obstet Gynecol 194: 239 –245, 2006
39. Conde-Agudelo A, Althabe F, Belizan JM,
Kafury-Goeta AC: Cigarette smoking dur-
ing pregnancy and risk of preeclampsia: A
systematic review. Am J Obstet Gynecol
181: 1026 –1035, 1999
40. Hammoud AO, Bujold E, Sorokin Y, Schild
C, Krapp M, Baumann P: Smoking in preg-
nancy revisited: Findings from a large pop-
ulation-based study. Am J Obstet Gynecol
192: 1856 –1862, discussion 1862–1853,
2005
41. Lain KY, Wilson JW, Crombleholme WR,
Ness RB, Roberts JM: Smoking during
pregnancy is associated with alterations in
markers of endothelial function. Am J Ob-
stet Gynecol 189: 1196 –1201, 2003
42. Schmidt-Lucke C, Belgore F, Reinhold D,
Ansorge S, Klein HU, Schmidt-Lucke JA,
Lip GY: Soluble vascular endothelial
growth factor, soluble VEGF receptor Flt-1
and endothelial function in healthy smok-
ers. Int J Cardiol 100: 207–212, 2005
43. Mehendale R, Hibbard J, Fazleabas A,
Leach R: Placental angiogenesis markers
sFlt-1 and PlGF: Response to cigarette
smoke. Am J Obstet Gynecol 197:
363.e361–363.e365, 2007
44. Cooke JP, Bitterman H: Nicotine and angio-
genesis: A new paradigm for tobacco-re-
lated diseases. Ann Med 36: 33–40, 2004
45. Suwaki N, Masuyama H, Nakatsukasa H,
Masumoto A, Sumida Y, Takamoto N,
Hiramatrsu Y: Hypoadiponectinemia and
circulating angiogenic factors in over-
weight patients complicated with pre-
eclampsia. Am J Obstet Gynecol 195:
1687–1692, 2006
46. Levine RJ, Qian C, Maynard SE, Yu KF,
Epstein FH, Karumanchi SA: Serum sFlt1
concentration during preeclampsia and
mid trimester blood pressure in healthy
nulliparous women. Am J Obstet Gynecol
194: 1034 –1041, 2006
J Am Soc Nephrol 20: 14 –22, 2009

47. Cudmore M, Ahmad S, Al-Ani B, Fujisawa
T, Coxall H, Chudasama K, Devey LR, Wig-
more SJ, Abbas A, Hewett PW, Ahmed A:
Negative regulation of soluble Flt-1 and
soluble endoglin release by heme oxygen-
ase-1. Circulation 115: 1789 –1797, 2007
48. Zenclussen AC, Lim E, Knoeller S, Knackst-
edt M, Hertwig K, Hagen E, Klapp BF, Arck
PC: Heme oxygenases in pregnancy II:
HO-2 is downregulated in human patho-
logic pregnancies. Am J Reprod Immunol
50: 66 –76, 2003
49. Barber A, Robson SC, Myatt L, Bulmer JN,
Lyall F: Heme oxygenase expression in hu-
man placenta and placental bed: reduced
expression of placenta endothelial HO-2 in
preeclampsia and fetal growth restriction.
FASEB J 15: 1158 –1168, 2001
50. Wallukat G, Homuth V, Fischer T, Lind-
schau C, Horstkamp B, Jupner A, Baur E,
Nissen E, Vetter K, Neichel D, Duden-
hausen JW, Haller H, Luft FC: Patients with
preeclampsia develop agonistic autoanti-
bodies against the angiotensin AT1 recep-
tor. J Clin Invest 103: 945–952, 1999
51. Xia Y, Wen H, Bobst S, Day MC, Kellems
RE: Maternal autoantibodies from pre-
eclamptic patients activate angiotensin re-
ceptors on human trophoblast cells. J Soc
Gynecol Investig 10: 82–93, 2003
52. Dragun D, Muller DN, Brasen JH, Fritsche
L, Nieminen-Kelha M, Dechend R,
Kintscher U, Rudolph B, Hoebeke J, Eckert
D, Mazak I, Plehm R, Schonemann C, Un-
ger T, Budde K, Neumayer HH, Luft FC,
Wallukat G: Angiotensin II type 1-receptor
activating antibodies in renal-allograft re-
jection. N Engl J Med 352: 558 –569, 2005
53. Zhou CC, Ahmad S, Mi T, Abbasi S, Xia L,
Day MC, Ramin SM, Ahmed A, Kellems RE,
Xia Y: Autoantibody from women with pre-
eclampsia induces soluble Fms-like ty-
rosine kinase-1 production via angiotensin
type 1 receptor and calcineurin/nuclear
factor of activated T-cells signaling. Hyper-
tension 51: 1010 –1019, 2008
54. Kanasaki K, Palmsten K, Sugimoto H, Ah-
mad S, Hamano Y, Xie L, Parry S, Augustin
HG, Gattone VH, Folkman J, Strauss JF,
Kalluri R: Deficiency in catechol-O-methyl-
transferase and 2-methoxyoestradiol is as-
sociated with pre-eclampsia. Nature 453:
1117–1121, 2008
55. Moore Simas TA, Crawford SL, Solitro MJ,
Frost SC, Meyer BA, Maynard SE: Angio-
genic factors for the prediction of pre-
eclampsia in high-risk women. Am J Obstet
Gynecol 197: 244.e1–244.e8, 2007
56. Su YN, Lee CN, Cheng WF, Shau WY,
Chow SN, Hsieh FJ: Decreased maternal
serum placenta growth factor in early sec-
ond trimester and preeclampsia. Obstet
Gynecol 97: 898 –904, 2001
57. Tjoa ML, van Vugt JM, Mulders MA, Schut-
gens RB, Oudejans CB, van Wijk IJ: Plasma
placenta growth factor levels in midtrimes-
J Am Soc Nephrol 20: 14 –22, 2009
ter pregnancies. Obstet Gynecol 98: 600 –
607, 2001
58. Taylor RN, Grimwood J, Taylor RS, McMas-
ter MT, Fisher SJ, North RA: Longitudinal
serum concentrations of placental growth
factor: Evidence for abnormal placental an-
giogenesis in pathologic pregnancies.
Am J Obstet Gynecol 188: 177–182, 2003
59. Polliotti BM, Fry AG, Saller DN, Mooney
RA, Cox C, Miller RK: Second-trimester ma-
ternal serum placental growth factor and
vascular endothelial growth factor for pre-
dicting severe, early-onset preeclampsia.
Obstet Gynecol 101: 1266 –1274, 2003
60. Levine RJ, Maynard SE, Qian C, Lim KH,
England LJ, Yu KF, Schisterman EF,
Thadhani R, Sachs BP, Epstein FH, Sibai
BM, Sukhatme VP, Karumanchi SA: Circu-
lating angiogenic factors and the risk of
preeclampsia. N Engl J Med 350: 672– 683,
2004
61. Hertig A, Berkane N, Lefevre G, Toumi K,
Marti HP, Capeau J, Uzan S, Rondeau E:
Maternal serum sFlt1 concentration is an
early and reliable predictive marker of pre-
eclampsia. Clin Chem 50: 1702–1703, 2004
62. Krauss T, Pauer HU, Augustin HG: Prospec-
tive analysis of placenta growth factor
(PlGF) concentrations in the plasma of
women with normal pregnancy and preg-
nancies complicated by preeclampsia. Hy-
pertens Pregnancy 23: 101–111, 2004
63. Bersinger NA, Odegard RA: Second- and
third-trimester serum levels of placental
proteins in preeclampsia and small-for-ges-
tational age pregnancies. Acta Obstet Gy-
necol Scand 83: 37– 45, 2004
64. Park CW, Park JS, Shim SS, Jun JK, Yoon
BH, Romero R: An elevated maternal
plasma, but not amniotic fluid, soluble fms-
like tyrosine kinase-1 (sFlt-1) at the time of
mid-trimester genetic amniocentesis is a
risk factor for preeclampsia. Am J Obstet
Gynecol 193: 984 –989, 2005
65. Kim SY, Ryu HM, Yang JH, Kim MY, Han JY,
Kim JO, Chung JH, Park SY, Lee MH, Kim
do J: Increased sFlt-1 to PlGF ratio in women
who subsequently develop preeclampsia. J
Korean Med Sci 22: 873–877, 2007
66. Vatten LJ, Eskild A, Nilsen TI, Jeansson S,
Jenum PA, Staff AC: Changes in circulating
level of angiogenic factors from the first to
second trimester as predictors of pre-
eclampsia. Am J Obstet Gynecol 196:
239.e1–239.e6, 2007
67. Tidwell SC, Ho HN, Chiu WH, Torry RJ,
Torry DS: Low maternal serum levels of
placenta growth factor as an antecedent of
clinical preeclampsia. Am J Obstet Gy-
necol 184: 1267–1272, 2001
68. Thadhani R, Mutter WP, Wolf M, Levine RJ,
Taylor RN, Sukhatme VP, Ecker J, Karu-
manchi SA: First trimester placental growth
factor and soluble fms-like tyrosine kinase 1
and risk for preeclampsia. J Clin Endocrinol
Metab 89: 770 –775, 2004
www.jasn.org BRIEF REVIEW
69. Smith GC, Crossley JA, Aitken DA, Jenkins
N, Lyall F, Cameron AD, Connor JM, Dob-
bie R: Circulating angiogenic factors in
early pregnancy and the risk of preeclamp-
sia, intrauterine growth restriction, sponta-
neous preterm birth, and stillbirth. Obstet
Gynecol 109: 1316 –1324, 2007
70. Levine RJ, Thadhani R, Qian C, Lam C, Lim
KH, Yu KF, Blink AL, Sachs BP, Epstein FH,
Sibai BM, Sukhatme VP, Karumanchi SA:
Urinary placental growth factor and risk of
preeclampsia. JAMA 293: 77– 85, 2005
71. Buhimschi CS, Magloire L, Funai E, Norwitz
ER, Kuczynski E, Martin R, Richman S,
Guller S, Lockwood CJ, Buhimschi IA: Frac-
tional excretion of angiogenic factors in
women with severe preeclampsia. Obstet
Gynecol 107: 1103–1113, 2006
72. Buhimschi CS, Norwitz ER, Funai E, Rich-
man S, Guller S, Lockwood CJ, Buhimschi
IA: Urinary angiogenic factors cluster hy-
pertensive disorders and identify women
with severe preeclampsia. Am J Obstet Gy-
necol 192: 734 –741, 2005
73. Aggarwal PK, Jain V, Sakhuja V, Karuman-
chi SA, Jha V: Low urinary placental growth
factor is a marker of pre-eclampsia. Kidney
Int 69: 621– 624, 2006
74. Espinoza J, Romero R, Nien JK, Gomez R,
Kusanovic JP, Goncalves LF, Medina L, Ed-
win S, Hassan S, Carstens M, Gonzalez R:
Identification of patients at risk for early
onset and/or severe preeclampsia with the
use of uterine artery Doppler velocimetry
and placental growth factor. Am J Obstet
Gynecol 196: 326.e1–326.e13, 2007
75. Stepan H, Unversucht A, Wessel N, Faber
R: Predictive value of maternal angiogenic
factors in second trimester pregnancies
with abnormal uterine perfusion. Hyperten-
sion 49: 818 – 824, 2007
76. Muller PR, James AH, Murtha AP, Yonish B,
Jamison MG, Dekker G: Circulating angio-
genic factors and abnormal uterine artery
Doppler velocimetry in the second trimes-
ter. Hypertens Pregnancy 25: 183–192,
2006
77. Crispi F, Llurba E, Dominguez C, Martin-
Gallan P, Cabero L, Gratacos E: Predictive
value of angiogenic factors and uterine ar-
tery Doppler for early- versus late-onset
pre-eclampsia and intrauterine growth re-
striction. Ultrasound Obstet Gynecol 31:
303–309, 2007
78. Shibata E, Rajakumar A, Powers RW, Larkin
RW, Gilmour C, Bodnar LM, Cromble-
holme WR, Ness RB, Roberts JM, Hubel
CA: Soluble fms-like tyrosine kinase 1 is
increased in preeclampsia but not in nor-
motensive pregnancies with small-for-ges-
tational-age neonates: Relationship to cir-
culating placental growth factor. J Clin
Endocrinol Metab 90: 4895– 4903, 2005
79. Stepan H, Kramer T, Faber R: Maternal
plasma concentrations of soluble endoglin
in pregnancies with intrauterine growth re-
Pregnancy for the Nephrologist 21
 BRIEF REVIEW www.jasn.org
striction. J Clin Endocrinol Metab 92:
2831–2834, 2007
80. Wallner W, Sengenberger R, Strick R, Stris-
sel PL, Meurer B, Beckmann MW, Schlem-
bach D: Angiogenic growth factors in ma- 89.
ternal and fetal serum in pregnancies
complicated by intrauterine growth restric-
tion. Clin Sci (Lond) 112: 51–57, 2007
81. Yinon Y, Nevo O, Xu J, Many A, Rolfo A,
Todros T, Post M, Caniggia I: Severe intra-
uterine growth restriction pregnancies 90.
have increased placental endoglin levels.
Am J Pathol 172: 77– 85, 2008
82. Wathen KA, Tuutti E, Stenman UH, Alf-
than H, Halmesmaki E, Finne P, Ylikorkala
O, Vuorela P: Maternal serum-soluble 91.
vascular endothelial growth factor recep-
tor-1 in early pregnancy ending in pre-
eclampsia or intrauterine growth retarda-
tion. J Clin Endocrinol Metab 91: 180 –
184, 2006
83. Salahuddin S, Lee Y, Vadnais M, Sachs BP,
Karumanchi SA, Lim KH: Diagnostic utility
of soluble fms-like tyrosine kinase 1 and
soluble endoglin in hypertensive diseases 92.
of pregnancy. Am J Obstet Gynecol 197:
28.e1–28.e6, 2007
84. Masuyama H, Suwaki N, Nakatsukasa H,
Masumoto A, Tateishi Y, Hiramatrsu Y: Cir-
culating angiogenic factors in preeclamp-
sia, gestational proteinuria, and pre- 93.
eclampsia superimposed on chronic
glomerulonephritis. Am J Obstet Gynecol
194: 551–556, 2006
85. Chafetz I, Kuhnreich I, Sammar M, Tal Y,
Gibor Y, Meiri H, Cuckle H, Wolf M: First- 94.
trimester placental protein 13 screening for
preeclampsia and intrauterine growth re-
striction. Am J Obstet Gynecol 197: 35.e1–
35.e7, 2007
86. Romero R, Espinoza J, Edwin S, Chefetz I, 95.
Sammar M, Meiri H, Tal Y, Kuhnreich I,
Cuckle H: Assessment of first trimester ma-
ternal serum PP13 in early vs. term sever
preeclampsia. Am J Obstet Gynecol
195[Suppl 1]: S133, 2006 96.
87. Nicolaides KH, Bindra R, Turan OM, Chefetz
I, Sammar M, Meiri H, Tal J, Cuckle HS: A
novel approach to first-trimester screening
for early pre-eclampsia combining serum
PP-13 and Doppler ultrasound. Ultrasound
Obstet Gynecol 27: 13–17, 2006
88. Sammar M, Stalk M, Gebhardt S, Pick-Go- 97.
lan E, Meiri H, Huppertz B, Hillerman R:
22 Journal of the American Society of Nephrology
RNA splicing and DNA polymorphism
leading to two shorter sub-forms of
placenta protein 13 in preeclampsia. Am J
Obstet Gynecol 195[Suppl 1]: S141, 2006
Habli M, Levine RJ, Qian C, Sibai B: Neonatal
outcomes in pregnancies with preeclampsia
or gestational hypertension and in normo-
tensive pregnancies that delivered at 35, 36,
or 37 weeks of gestation. Am J Obstet Gy-
necol 197: 406.e1–406.e7, 2007
Low-dose aspirin in prevention and treat-
ment of intrauterine growth retardation
and pregnancy-induced hypertension. Ital-
ian study of aspirin in pregnancy. Lancet
341: 396 – 400, 1993
Caritis S, Sibai B, Hauth J, Lindheimer MD,
Klebanoff M, Thom E, VanDorsten P,
Landon M, Paul R, Miodovnik M, Meis P,
Thurnau G: Low-dose aspirin to prevent
preeclampsia in women at high risk. Na-
tional Institute of Child Health and Human
Development Network of Maternal-Fetal
Medicine Units. N Engl J Med 338: 701–
705, 1998
CLASP: A randomised trial of low-dose
aspirin for the prevention and treatment
of pre-eclampsia among 9364 pregnant
women. CLASP (Collaborative Low-dose
Aspirin Study in Pregnancy) Collaborative
Group. Lancet 343: 619 – 629, 1994
Askie LM, Duley L, Henderson-Smart DJ,
Stewart LA: Antiplatelet agents for preven-
tion of pre-eclampsia: a meta-analysis of
individual patient data. Lancet 369: 1791–
1798, 2007
Duley L, Henderson-Smart DJ, Knight M,
King JF: Antiplatelet agents for preventing
pre-eclampsia and its complications. Co-
chrane Database Syst Rev (2): CD004659,
2007
Poston L, Briley AL, Seed PT, Kelly FJ,
Shennan AH: Vitamin C and vitamin E in
pregnant women at risk for pre-eclampsia
(VIP trial): Randomised placebo-controlled
trial. Lancet 367: 1145–1154, 2006
Spinnato JA II, Freire S, Pinto e Silva JL,
Cunha Rudge MV, Martins-Costa S, Koch
MA, Goco N, Santos CdB, Cecatti JG,
Costa R, Ramos JG, Moss N, Sibai BM:
Antioxidant therapy to prevent preeclamp-
sia: A randomized controlled trial. Obstet
Gynecol 110: 1311–1318, 2007
Rumbold AR, Crowther CA, Haslam RR,
Dekker GA, Robinson JS: Vitamins C and E
and the risks of preeclampsia and perinatal
complications. N Engl J Med 354: 1796 –
1806, 2006
98. Hofmeyr GJ, Atallah AN, Duley L: Calcium
supplementation during pregnancy for
preventing hypertensive disorders and re-
lated problems. Cochrane Database Syst
Rev 3: CD001059, 2006
99. Villar J, Abdel-Aleem H, Merialdi M, Mathai
M, Ali MM, Zavaleta N, Purwar M, Hofmeyr
J, Nguyen TN, Campodonico L, Landoulsi
S, Carroli G, Lindheimer M: World Health
Organization randomized trial of calcium
supplementation among low calcium in-
take pregnant women. Am J Obstet Gy-
necol 194: 639 – 649, 2006
100. Wen SW, Chen X-K, Rodger M, Rennicks
White R, Yang Q, Smith GN, Sigal RJ, Per-
kins SL, Walker MC: Folic acid supplemen-
tation in early second trimester and the risk
of preeclampsia. Am J Obstet Gynecol
198: 45.e41– 45.e47, 2008
101. Li Z, Zhang Y, Ying Ma J, Kapoun AM,
Shao Q, Kerr I, Lam A, O’Young G, San-
najust F, Stathis P, Schreiner G, Karuman-
chi SA, Protter AA, Pollitt NS: Recombi-
nant vascular endothelial growth factor
121 attenuates hypertension and improves
kidney damage in a rat model of pre-
eclampsia. Hypertension 50: 686 – 692,
2007
102. Savvidou MD, Hingorani AD, Tsikas D,
Frolich JC, Vallance P, Nicolaides KH: En-
dothelial dysfunction and raised plasma
concentrations of asymmetric dimethyl-
arginine in pregnant women who subse-
quently develop pre-eclampsia. Lancet
361: 1511–1517, 2003
103. Speer PD, Powers RW, Frank MP, Harger
G, Markovic N, Roberts JM: Elevated asym-
metric dimethylarginine concentrations
precede clinical preeclampsia, but not
pregnancies with small-for-gestational-age
infants. Am J Obstet Gynecol 198: 112.e1–
112.e7, 2008
104. Meher S, Duley L: Nitric oxide for pre-
venting pre-eclampsia and its complica-
tions. Cochrane Database Syst Rev (2):
CD006490, 2007
105. Facchinetti F, Saade GR, Neri I, Pizzi C,
Longo M, Volpe A: L-arginine supplemen-
tation in patients with gestational hyper-
tension: A pilot study. Hypertens Preg-
nancy 26: 121–130, 2007
J Am Soc Nephrol 20: 14 –22, 2009