Pathophysiology of the Clinical Manifestations of Preeclampsia

In-Depth Review
Pathophysiology of the Clinical Manifestations of
Preeclampsia
Michelle Hladunewich,* S. Ananth Karumanchi,† and Richard Lafayette‡
*Division of Nephrology, University of Toronto, Toronto, Ontario, Canada; †Division of Nephrology, Beth Israel
Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; and ‡Division of Nephrology, Stanford
University, Stanford, California
Clin J Am Soc Nephrol 2: 543-549, 2007. doi: 10.2215/CJN.03761106
F iveto7%ofallpregnanciesarecomplicatedbypre- satilityindex(PI)revealincreaseduterinevascularresistance
eclampsia. Proteinuria and hypertension dominate the
well before the clinical signs and symptoms arise (4,5). More-
clinical picture, because the chief target organ is the
over, mechanical constriction of the uterine arteries produces
kidney (glomerular endotheliosis). The pathogenesis of pre-
hypertension, proteinuria, and, in some species, glomerular
eclampsia is complex; numerous genetic, immunologic, and
endotheliosis, supporting an causative role for placental isch-
environmental factors interact. It has been suggested that pre-
emia in the pathogenesis of preeclampsia (6).
eclampsia is a two-stage disease (1). The first stage is asymp-
Mammalian placentation requires extensive angiogenesis to
tomatic, characterized by abnormal placental development dur-
establish a suitable network for the supply of oxygen and
ing the first trimester resulting in placental insufficiency and
nutrients in the fetus. A variety of pro- and antiangiogenic
the release of excessive amounts of placental materials into the
factors are elaborated by developing placentas. It is believed
maternal circulation. This in turn leads to the second, symp-
that placental angiogenesis is defective in preeclampsia, as
tomatic stage, wherein the pregnant woman develops charac-
evidenced by failure of the cytotrophoblasts to convert from a
teristic hypertension, renal impairment, and proteinuria and is
more epithelial to endothelial phenotype, based on cell surface
at risk for the HELLP syndrome (hemolysis, elevated liver
marker studies (6,7). Normally, invasive cytotrophoblasts
function enzymes and low platelets), eclampsia, and other end-
downregulate the expression of adhesion molecules that are
organ damage. This review focuses on the pathophysiology of
characteristic of their epithelial cell origin and adopt a cell-
stages 1 and 2 and then considers the potential that changes in
soluble angiogenic factors may underlie much of the disease
surface adhesion phenotype that is typical of endothelial cells,
process.
a process that is referred to as pseudovasculogenesis (7,8). In
preeclampsia, cytotrophoblast cells fail to undergo this switch-
Placentation Abnormalities (Stage I)
ing of cell-surface integrins and adhesion molecules (5). This
On the basis of the observation that the only definitive cure
abnormal cytotrophoblast differentiation is an early defect that
for preeclampsia is delivery of the placenta and that women
may eventually lead to placental ischemia. Others have dem-
who experience a molar pregnancy, in which a placenta devel-
onstrated that hypoxia-inducible factor-1 is upregulated in pre-
ops without a fetus, frequently develop severe preeclampsia, it
eclampsia and suggest that it and its target genes may play a
is reasonable to assume that the placenta plays a central role in
central role in the abnormal differentiation phenotype of pre-
the pathogenesis of the disease. Pathologic examination of pla-
eclampsia (9,10). Whether this lack of conversion of cytotropho-
centas from preeclamptic pregnancies generally reveals placen-
blasts to an endothelial phenotype in women with preeclamp-
tal infarcts and sclerotic narrowing of arteries and arterioles,
sia is a primary or secondary event remains uncertain (11).
with characteristic diminished endovascular invasion by cy-
totrophoblasts and inadequate remodeling of the uterine spiral
arterioles (2). Although gross pathologic changes are not al-
The Maternal Syndrome (Stage II)
ways seen in the placentas of women with preeclampsia, pla-
The abnormal placentation that results from failure of tro-
cental profiles including abnormal uterine artery Doppler and
phoblast remodeling of uterine spiral arterioles is thought to
placental morphology have been used to identify a subset from
lead to the release of secreted factors that enter the mother’s
a cohort of high-risk women who go on to develop the syn-
circulation, culminating in the clinical signs and symptoms of
drome (3). Uterine artery Doppler studies that assess the pul-
preeclampsia. All of the clinical manifestations of preeclampsia
can be attributed to glomerular endotheliosis, increased vascu-
lar permeability, and a systemic inflammatory response that
Published online ahead of print. Publication date available at www.cjasn.org.
results in end-organ damage and/or hypoperfusion. These
Address correspondence to: Dr Richard A. Lafayette, Stanford University, Divi-
clinical manifestations typically occur after the 20th week of
sion of Nephrology, 300 Pasteur Drive, Stanford, CA 94305. Phone: 650-723-6247;
Fax: 650-723-7917; E-mail: czar@stanford.edu.
pregnancy.
Copyright © 2007 by the American Society of Nephrology
ISSN: 1555-9041/203–0543

---

544
Clinical Journal of the American Society of Nephrology
Clin J Am Soc Nephrol 2: 543-549, 2007
Hypertension
all components of the RAS are upregulated, but resistance to
Accommodation to normal pregnancy includes a decrease in
the pressor effects of angiotensin II (AngII) allows for normal to
both systolic and diastolic BP as a result of a decrease in
low BP (18,19). Similarly, reduced sensitivity of the renal circu-
systemic vascular resistance primarily secondary to vasodila-
lation has been demonstrated in pregnant rats as AngII infusion
tion. Relaxin, which is released from the ovaries under the
failed to decrease GFR, renal plasma flow (RPF), and urine flow
influence of human chorionic gonadotrophin, upregulates ni-
(28). One explanation may be increased plasma levels and
tric oxide synthase (NOS) (12), the enzyme that generates NO
urinary excretion rates of Ang(1-7), a potent counterregulator of
from arginine, via the endothelial endothelin B receptor (13). In
AngII, documented in human pregnancy (29,30). Ang(1-7) was
preeclampsia, derangement of endothelial-derived vasoactive
demonstrated to be significantly decreased in women with
factors is thought to result in the predominance of substances
preeclampsia compared with normal pregnant control subjects
that are vasoconstrictors (endothelin, thromboxane A2) over
(29).
vasodilators (NO, prostacyclin). Hypertension, defined as re-
It is interesting that evidence supports decreased levels of
peat BP measurements
140/90 mmHg, results from abnormal
renin, AngI, and AngII in women with preeclampsia compared
vasoconstriction.
with normal pregnancy (31). Despite this, enhanced vascular
Normal pregnancy in the rat is accompanied by increased
sensitivity to components of the RAS is seen in women with
production of NO and its second messenger, cyclic guanosine
preeclampsia. Enhanced vascular sensitivity to an angiotensin
3 5 monophosphate (14) with a parallel increase in renal ex-
infusion can identify women who are at increased risk for the
pression of constitutive NOS (12,15). In the pregnant rat, an
development of preeclampsia (32,33).
infusion of NG-nitro-l-arginine methyl ester (L-NAME), an
Recent studies have identified an autoantibody of the IgG
exogenous inhibitor of NOS, has been shown to replicate some
subclass in the plasma of women with preeclampsia that is
of the hemodynamic features of preeclampsia (16). l-Arginine
capable of stimulating the AT1 receptor (34). When serum from
supplementation reversed these adverse effects of L-NAME on
preeclamptic women was added to cultured neonatal rat car-
pregnancy, attenuating hypertension, significantly decreasing
diac myocytes, the chronotropic effect could be blocked by
proteinuria, and reducing the proportion of injured glomeruli
losartan, confirming the effect was mediated via the AT1 re-
(17). However, in humans, evidence to support a role of NO
ceptor (35). Furthermore, the autoantibody might stimulate
deficiency in the pathogenesis of the hypertension in pre-
heterodimerization between the AT1 receptor and the B2 recep-
eclampsia has been conflicting. Although elevated circulating
tor for bradykinin (36). This may play an important role in the
levels of asymmetric dimethyl arginine, an endogenous inhib-
enhanced vascular sensitivity to angiotensin. It might also in-
itor of NOS, has been a consistent finding in pregnancies that
duce the production of reactive oxygen species, which block
are complicated by preeclampsia, plasma concentrations are
cytotrophoblast invasion in vitro and may relate to shallow
typically very low with a narrow distribution among healthy
trophoblastic implantation, thus accounting for several of the
adults, making quantification extremely challenging and the
clinical features of preeclampsia (37). This autoimmune activity
clinical significance of the finding uncertain (18 –20). Further-
wanes after delivery (34). More recently, these antibodies also
more, l-arginine supplementation has not conferred significant
were found in patients with acute vascular rejection (38), sug-
benefit in women with pregnancies that are complicated by
gesting that they may play a role in other forms of endothelial
preeclampsia (21,22).
injury as well.
Another hypothesis considered the possibility that an early
gestational exaggeration of the normal accommodation to preg-
Decreased GFR
nancy can be used to identify and may be pathogenic in pre-
Healthy pregnant women exhibit marked glomerular hyper-
eclampsia (23). A longitudinal study that used Doppler echo-
filtration, peaking above normal, nongravid levels by 40 to 60%
cardiography in 400 primigravidas throughout pregnancy
(39,40). This hyperfiltration seems to result primarily from de-
noted a significantly increased cardiac output without any
pression of the plasma oncotic pressure ( GC) in the glomerular
difference in peripheral vascular resistance in the 24 women
capillaries. The reduction of GC in pregnancy is attributable to
who eventually developed preeclampsia compared with
two phenomena. The first is a hypervolemia-induced hemodi-
healthy control subjects (24). This increased cardiac output was
lution that lowers the protein concentration of plasma that
followed by a marked reduction in the cardiac output and
enters the glomerular microcirculation. The second is an ele-
increased peripheral vascular resistance with the onset of the
vated rate of RPF. Hyperperfusion of glomeruli blunts the
clinical syndrome. This notion of a crossover in the hemody-
extent to which the oncotic pressure can increase along the
namic profile in women who develop preeclampsia resulted in
glomerular capillaries during filtrate formation. In preeclamp-
a handful of studies that used
blockers in a preventive man-
sia, variable degrees of renal insufficiency are associated with a
ner (25–27). These studies were typically small and/or uncon-
characteristic glomerular lesion, “glomerular endotheliosis.”
trolled. Furthermore, reduced fetal growth was noted in the
Precise physiologic measurements in conjunction with imme-
women who received the
blockers, possibly because of an
diate postpartum biopsies were used to examine the determi-
overaggressive decrease in the cardiac output (26,27).
nants of the GFR in women with preeclampsia as compared
More recently, attention has again turned to the renin-angio-
with healthy gravid control subjects (41). The GFR was signif-
tensin system (RAS) to provide a pathophysiologic understand-
icantly depressed to 91 ml/min per 1.73 m2 in women with
ing for the hypertension of preeclampsia. In normal pregnancy,
preeclampsia compared with a value of 149 ml/min per 1.73 m2

---

Clin J Am Soc Nephrol 2: 543-549, 2007
Pathophysiology of the Clinical Manifestations of Preeclampsia
545
in the control subjects. Of interest, no significant differences
earlier or milder form of the same pathology (44). Subendothe-
were found in either RPF or
lial fibrinoid deposits and mesangial cell interposition were
GC. The morphometric analysis
revealed significant ultrastructural differences, including swell-
found only in women with preeclampsia. Unfortunately, the
ing of the endothelial cells, subendothelial fibrinoid deposition,
authors never published any images or acquired confirmation
and mesangial cell interposition (Figure 1). Scanning electron
from a second blinded pathologist to ensure interobserver re-
microscopy was used to characterize the endothelial fenestral
liability. In a second article that examined the same patient
dimensions, allowing the authors to conclude that a reduction
population, the authors found a linear trend between glomer-
in the density and the size of the endothelial fenestrae and
ular volume reflecting the degree of endotheliosis and cystatin
subendothelial accumulation of fibrinoid deposits severely
C (42), suggesting that the basis for the hypofiltration in pre-
lowered glomerular hydraulic permeability in patients with
eclampsia is largely secondary to structural changes in the
preeclampsia. Mesangial cell interposition also decreased avail-
glomerulus as opposed to renal vasoconstriction and a depres-
able surface area for filtration, thereby resulting in a cumulative
sion in RPF. However, the utility of cystatin C as a marker of
depression of K
GFR is unclear in this patient population. A recent study found
f that was exactly proportional to the GFR. A
more controversial conclusion was that the hypofiltration in
that cystatin C correlated poorly with third-trimester creatinine
preeclampsia does not have a hemodynamic basis.
clearance (r
0.27) (45), and another study that used inulin
A recent study used a semiquantitative scale to grade the
clearances for comparison found that the measurement is not
endotheliosis that was present on biopsy specimens that were
independent of body composition as previously assumed (46).
taken from women with preeclampsia approximately 1 wk
To date, cystatin C has not been validated as a marker of GFR
before delivery (42,43). They noted moderate to severe endo-
in pregnancy, with several studies suggesting that it may be
theliosis in all women with significant hypertension and pro-
imprecise.
teinuria before delivery. Of interest, women with nonprotein-
uric gestational hypertension and normal pregnant women also
Proteinuria
exhibited endotheliosis but to lesser degrees, suggesting that
In 1843, John Lever of Guy’s Hospital in London discovered
pregnancy-induced hypertension may in some cases reflect an
the presence of albumin by boiling the urine from pregnant
women with puerperal convulsions. Preeclampsia is differen-
tiated from gestational hypertension by the presence of protein-
uria and is the most common cause of nephrotic syndrome in
pregnancy. The quantity of protein that is excreted in the urine
varies widely. Significant protein excretion is defined as
300
mg in a 24-h urine collection or 1
or greater on urine dipstick
testing of two random urine samples that are collected at least
4 h apart (47).
Numerous studies have used a variety of methods to exam-
ine the biochemical constitution of preeclamptic urine, includ-
ing protein selectivity indices, with variable results. Generally,
urine from preeclampsia has demonstrated poor selectivity and
has not differed significantly from other forms of primary renal
disease (48). Glomerular proteins of intermediate size, such as
albumin, have been identified alone or in combination with
varying degrees of tubular proteins, such as B2-microglobulin,
reflecting the tubular damage that can occur in severe pre-
eclampsia (49,50).
Unfortunately, the exact role of the endothelial cell layer in
the regulation of glomerular permselectivity remains the least
well defined. Endothelial cells are difficult to acquire for in vitro
studies, and, unlike the podocyte, there are no specific markers
for this cell line. Perforated by large fenestrae, the endothelial
cell layer does not contribute to size selectivity, allowing the
passage of neutral molecules with a radius up to approximately
375 Å. Therefore, the mechanism for proteinuria in preeclamp-
sia is not well understood. The glomerular basement membrane
and podocytes typically appear normal (33,36). Few investiga-
tors have used dextran-sieving techniques to elucidate the
Figure 1. Transmission electron microscopy of a representative
properties of the glomerular filtration barrier in women with
glomerular capillary enumerating pathologic changes associ-
preeclampsia. In the 1970s, MacLean et al. (51) confirmed the
ated with preeclampsia: 1, endothelial cell body; 2, swollen,
nonfenestrated endothelium; 3, subendothelial fibrinoid depo-
glomerular origin of proteinuria in preeclampsia demonstrat-
sition; 4, mesangial cell interposition.
ing dextran-sieving coefficients in the intermediate range. This

---

546
Clinical Journal of the American Society of Nephrology
Clin J Am Soc Nephrol 2: 543-549, 2007
finding was corroborated by a more recent study that demon-
membrane-bound receptor. Circulating in the blood, it acts as a
strated a loss of size selectivity significant for bands 31 to 39 Å
potent antagonist to VEGF and placental growth factor (PlGF).
(P
0.0001) as well as 41 to 49 Å (P
0.01) (52). Without more
Both VEGF and PlGF are made by the placenta and circulate in
specific studies, the authors alluded to the fact that loss of
high concentration during pregnancy. Circulating sFlt1 levels
charge selectivity was likely the primary defect in the glomer-
are greatly increased in women with preeclampsia even before
ular filtration barrier in women with preeclampsia. New in-
the onset of clinical symptoms (64). Consistent with the action
sights into the role of angiogenic factors in the maintenance of
of the circulating protein to bind PlGF, free PlGF levels are also
an intact glomerular filtration barrier may reconcile the pres-
decreased in preeclamptic women before the onset of clinical
ence of nephrotic-range proteinuria in an endothelial cell dis-
symptoms (64). When administered to pregnant and nonpreg-
ease (see Circulating Angiogenic Factors in Preeclampsia).
nant rats, sFlt1 produces a syndrome of hypertension, protein-
uria, and glomerular endotheliosis that resembles preeclampsia
Coagulopathy and HELLP Syndrome
(62). It has also been shown that VEGF induces endothelial
In preeclampsia, endothelial injury may also become mani-
fenestrae in vitro, and the loss of 50% of VEGF production in the
fest as a low-grade coagulopathy with increased fibronectin,
mouse glomerulus leads not only to glomerular endotheliosis
increased platelet aggregation, shortened platelet survival, and
but also to loss of glomerular endothelial fenestrae similar to
depressed antithrombin III levels (53). The HELLP syndrome
what is noted in human preeclampsia (65). Antagonists of
develops in up to 10% of pregnancies with severe preeclampsia,
VEGF, used in antiangiogenic oncology trials, sometimes pro-
and evidence exists to suggest that it is not simply an epiphe-
duce hypertension and proteinuria in humans (66,67). Finally,
nomenon of extreme hypertension. Plasma concentrations of
higher circulating levels of the chromosome 13– encoded gene
cellular fibronectin have been shown to be consistently higher
product sFlt1 in pregnancies with trisomy 13 may explain the
throughout pregnancy in woman who develop preeclampsia
increased risk for preeclampsia in women who carry fetuses
compared with healthy control subjects. In addition, markers of
with trisomy 13 (68).
platelet activation, including
-thromboglobulin, as well as
In addition to its role in the pathogenesis of preeclampsia,
assays of platelet aggregation have been demonstrated to pre-
circulating concentration of sFlt1 and PlGF may have important
cede the clinical manifestations of the disease (54,55).
predictive and diagnostic implications. The concentration of
sFlt1 starts to rise near the end of the second trimester in
Eclampsia
women who are destined to have preeclampsia, a full 4 to 5 wk
Seizures with other neurologic symptoms, including head-
before clinical manifestations are first detected (64). By the time
ache and visual disturbances, complicate approximately 5 of
preeclamptic manifestations are pronounced, plasma concen-
every 10,000 live births, with a declining incidence as a result of
trations of sFlt1 are greatly elevated, from two to four times the
improved prenatal care with expedited delivery and, possibly,
levels found in normal pregnancy, and are greatest in patients
the widespread use of magnesium sulfate (56). The precise
with severe preeclampsia. In women who develop preeclamp-
mechanism that is responsible for the development of seizures
sia, there is a modest but significant decrease in PlGF levels
is not clear, but proposed theories include cerebral vasospasm,
beginning as early as the first trimester. From midpregnancy
edema, and the possibility that severe hypertension might dis-
onward, the concentration of unbound PlGF in plasma falls
turb cerebral autoregulation and disrupt the blood– brain bar-
significantly lower at the time when sFlt1 levels are rising.
rier. The cerebral edema of eclampsia predominantly involves
Unbound PlGF is also freely filtered into the urine and thus
the posterior, parieto-occipital lobes and is similar to images
may also serve to predict the subsequent development of pre-
described in reversible posterior leukoencephalopathy syn-
eclampsia (69).
drome (57). This finding on magnetic resonance imaging has
Endoglin (Eng) is an angiogenic receptor that is expressed on
been noted to correlate better with markers of endothelial dys-
the surface of endothelial cells and placental syncytiotropho-
function, including lactate dehydrogenase, red blood cell mor-
blasts. Eng acts as a co-receptor for TGF- , a potent proangio-
phology, and creatinine than the level of hypertension (58,59).
genic molecule. Eng mRNA is upregulated in the preeclamptic
Of interest, reversible posterior leukoencephalopathy syn-
placenta (63). Moreover, the extracellular region of Eng is pro-
drome in patients with thrombotic thrombocytopenic purpura
teolytically cleaved, and soluble Eng (sEng) is released in excess
has also been found to be independent of the level of hyper-
quantities into the circulation of preeclamptic patients. In preg-
tension in some cases (60).
nant rats, sEng exacerbates the vascular damage that is medi-
ated by sFlt1, resulting in severe preeclampsia-like illness, in-
Circulating Angiogenic Factors in
cluding the development of a HELLP-like syndrome and fetal
Preeclampsia
growth restriction (63). In explant cultures of trophoblasts from
Recently, two endogenous antiangiogenic proteins of placen-
5 to 8 wk of gestation, mAb to Eng and antisense Eng oligonu-
tal origin— circulating soluble fms-like tyrosine kinase 1 (sFlt1)
cleotides stimulated trophoblast outgrowth and migration (70).
and soluble endoglin (61)— have been suggested, on the basis
TGF 1 and/or TGF- 3 inhibits trophoblast migration and in-
of rodent models, to play a causal role in the pathogenesis of
vasion, and it seems that Eng mediates this effect. Therefore, it
preeclampsia (62,63). sFlt1 is a secreted protein, a splice variant
has been speculated that production of sEng by the placenta
of the vascular endothelial growth factor (VEGF) receptor Flt1,
may be a compensatory mechanism to limit the effects of sur-
which lacks the transmembrane and cytoplasmic domain of the
face Eng. In recent clinical studies, sEng was elevated not only

---

Clin J Am Soc Nephrol 2: 543-549, 2007
Pathophysiology of the Clinical Manifestations of Preeclampsia
547
during the disease but also before onset of symptoms (71).
the clinical manifestations of the disease. Recent findings on the
Elevations in sEng were particularly pronounced—and, there-
role of circulating antiangiogenic factors have generated great
fore, potentially most useful for prediction—in women who
optimism for being able to predict better the disease and de-
developed preterm preeclampsia or preeclampsia with an in-
velop therapeutic advances. If subsequent trials validate these
fant who was small for gestational age. Although the gesta-
theories, then future work should lead to renewed efforts fi-
tional pattern of sEng concentration tended to parallel the
nally to explain and treat this complex disease.
trajectory of the sFlt1/PlGF ratio, multivariate analysis indi-
cated that each was significantly associated with preeclampsia.
Disclosures
Indeed, a composite measure that incorporated all three angio-
Dr. Karumanchi is listed as co-inventor on a patent filed by the Beth
genic molecules (sFlt1, sEng, and PlGF) was more strongly
Israel Deaconess Medical Center for the use of angiogenic proteins for
predictive of preeclampsia than the individual biomarkers (71)
the diagnosis and treatment of preeclampsia. Dr. Karumanchi is a
(Figure 2).
consultant for Johnson & Johnson, Abbott, and Beckman-Coulter.
Conclusion
Preeclampsia remains a common complication of pregnancy
References
that leads to unacceptable increases in fetal and maternal mor-
1. Roberts JM: Preeclampsia: What we know and what we do
bidity and mortality, particularly in less developed nations.
not know. Semin Perinatol 24: 24 –28, 2000
Efforts continue to understand better the pathophysiology of
2. Lim KH, Zhou Y, Janatpour M, McMaster M, Bass K, Chun
SH, Fisher SJ: Human cytotrophoblast differentiation/in-
vasion is abnormal in pre-eclampsia. Am J Pathol 151: 1809 –
1818, 1997
3. Hershkovitz R, de Swiet M, Kingdom J: Mid-trimester
placentation assessment in high-risk pregnancies using
maternal serum screening and uterine artery Doppler. Hy-
pertens Pregnancy 24: 273–280, 2005
4. Gomez O, Figueras F, Martinez JM, Del Rio M, Palacio M,
Eixarch E, Puerto B, Coll O, Cararach V, Vanrell JA: Se-
quential changes in uterine artery blood flow pattern be-
tween the first and second trimesters of gestation in rela-
tion to pregnancy outcome. Ultrasound Obstet Gynecol 28:
802– 808, 2006
5. Li H, Gudnason H, Olofsson P, Dubiel M, Gudmundsson
S: Increased uterine artery vascular impedance is related to
adverse outcome of pregnancy but is present in only one-
third of late third-trimester pre-eclamptic women. Ultra-
sound Obstet Gynecol 25: 459 – 463, 2005
6. Alexander BT, Llinas MT, Kruckeberg WC, Granger JP:
L-arginine attenuates hypertension in pregnant rats with
reduced uterine perfusion pressure. Hypertension 43: 832–
836, 2004
7. Zhou Y, Damsky CH, Fisher SJ: Preeclampsia is associated
with failure of human cytotrophoblasts to mimic a vascular
adhesion phenotype. One cause of defective endovascular
invasion in this syndrome? J Clin Invest 99: 2152–2164, 1997
8. Zhou Y, Fisher SJ, Janatpour M, Genbacev O, Dejana E,
Wheelock M, Damsky CH: Human cytotrophoblasts adopt
a vascular phenotype as they differentiate. A strategy for
successful endovascular invasion? J Clin Invest 99: 2139 –
2151, 1997
9. Nevo O, Soleymanlou N, Wu Y, Xu J, Kingdom J, Many A,
Zamudio S, Caniggia I: Increased expression of sFlt-1 in in
vivo and in vitro models of human placental hypoxia is
mediated by HIF-1. Am J Physiol Regul Integr Comp Physiol
291: R1085–R1093, 2006
10. Cowden Dahl KD, Fryer BH, Mack FA, Compernolle V,
Maltepe E, Adelman DM, Carmeliet P, Simon MC: Hy-
poxia-inducible factors 1alpha and 2alpha regulate tropho-
Figure 2. Adjusted odds ratios for preterm (A) or term (B)
blast differentiation. Mol Cell Biol 25: 10479 –10491, 2005
preeclampsia according to soluble fms-like tyrosine kinase
11. Fisher SJ: The placental problem: Linking abnormal cy-
1:placental growth factor (sFlt1:PlGF) ratios and soluble endog-
totrophoblast differentiation to the maternal symptoms of
lin levels.
preeclampsia. Reprod Biol Endocrinol 2: 53, 2004

---

548
Clinical Journal of the American Society of Nephrology
Clin J Am Soc Nephrol 2: 543-549, 2007
12. Fujiyama S, Matsubara H, Nozawa Y, Maruyama K, Mori
27. Easterling TR, Brateng D, Schmucker B, Brown Z, Millard
Y, Tsutsumi Y, Masaki H, Uchiyama Y, Koyama Y, Nose A,
SP: Prevention of preeclampsia: A randomized trial of
Iba O, Tateishi E, Ogata N, Jyo N, Higashiyama S, Iwasaka
atenolol in hyperdynamic patients before onset of hyper-
T: Angiotensin AT(1) and AT(2) receptors differentially
tension. Obstet Gynecol 93: 725–733, 1999
regulate angiopoietin-2 and vascular endothelial growth
28. Novak J, Reckelhoff J, Bumgarner L, Cockrell K, Kassab S,
factor expression and angiogenesis by modulating heparin
Granger JP: Reduced sensitivity of the renal circulation to
binding-epidermal growth factor (EGF)-mediated EGF re-
angiotensin II in pregnant rats. Hypertension 30: 580 –584,
ceptor transactivation. Circ Res 88: 22–29, 2001
1997
13. Jeyabalan A, Novak J, Danielson LA, Kerchner LJ, Opett
29. Merrill DC, Karoly M, Chen K, Ferrario CM, Brosnihan KB:
SL, Conrad KP: Essential role for vascular gelatinase activ-
Angiotensin-(1-7) in normal and preeclamptic pregnancy.
ity in relaxin-induced renal vasodilation, hyperfiltration,
Endocrine 18: 239 –245, 2002
and reduced myogenic reactivity of small arteries. Circ Res
30. Valdes G, Germain AM, Corthorn J, Berrios C, Foradori
93: 1249 –1257, 2003
AC, Ferrario CM, Brosnihan KB: Urinary vasodilator and
14. Conrad KP, Vernier KA: Plasma level, urinary excretion,
vasoconstrictor angiotensins during menstrual cycle, preg-
and metabolic production of cGMP during gestation in
nancy, and lactation. Endocrine 16: 117–122, 2001
rats. Am J Physiol 257: R847–R853, 1989
31. Brown MA, Wang J, Whitworth JA: The renin-angiotensin-
15. Conrad KP, Joffe GM, Kruszyna H, Kruszyna R, Rochelle
aldosterone system in pre-eclampsia. Clin Exp Hypertens
LG, Smith RP, Chavez JE, Mosher MD: Identification of
19: 713–726, 1997
increased nitric oxide biosynthesis during pregnancy in
32. Brown CE, Gant NF, Cox K, Spitz B, Rosenfeld CR, Mag-
rats. FASEB J 7: 566 –571, 1993
ness RR: Low-dose aspirin. II. Relationship of angiotensin
16. Danielson LA, Conrad KP: Acute blockade of nitric oxide
II pressor responses, circulating eicosanoids, and preg-
synthase inhibits renal vasodilation and hyperfiltration
nancy outcome. Am J Obstet Gynecol 163: 1853–1861, 1990
during pregnancy in chronically instrumented conscious
33. Sanchez-Ramos L, Briones DK, Kaunitz AM, Delvalle GO,
rats. J Clin Invest 96: 482– 490, 1995
Gaudier FL, Walker CD: Prevention of pregnancy-induced
17. Helmbrecht GD, Farhat MY, Lochbaum L, Brown HE,
hypertension by calcium supplementation in angiotensin
Yadgarova KT, Eglinton GS, Ramwell PW: L-arginine re-
II-sensitive patients. Obstet Gynecol 84: 349 –353, 1994
verses the adverse pregnancy changes induced by nitric
34. Wallukat G, Homuth V, Fischer T, Lindschau C, Horst-
oxide synthase inhibition in the rat. Am J Obstet Gynecol
kamp B, Jupner A, Baur E, Nissen E, Vetter K, Neichel D,
175: 800 – 805, 1996
Dudenhausen JW, Haller H, Luft FC: Patients with pre-
18. Holden DP, Fickling SA, Whitley GS, Nussey SS: Plasma
eclampsia develop agonistic autoantibodies against the an-
concentrations of asymmetric dimethylarginine, a natural
giotensin AT1 receptor. J Clin Invest 103: 945–952, 1999
inhibitor of nitric oxide synthase, in normal pregnancy and
35. Wallukat G, Neichel D, Nissen E, Homuth V, Luft FC:
preeclampsia. Am J Obstet Gynecol 178: 551–556, 1998
Agonistic autoantibodies directed against the angiotensin
19. Pettersson A, Hedner T, Milsom I: Increased circulating
II AT1 receptor in patients with preeclampsia. Can J Physiol
concentrations of asymmetric dimethyl arginine (ADMA),
Pharmacol 81: 79 – 83, 2003
an endogenous inhibitor of nitric oxide synthesis, in pre-
36. AbdAlla S, Lother H, el Massiery A, Quitterer U: Increased
eclampsia. Acta Obstet Gynecol Scand 77: 808 – 813, 1998
AT(1) receptor heterodimers in preeclampsia mediate en-
20. Teerlink T: HPLC analysis of ADMA and other methylated
hanced angiotensin II responsiveness. Nat Med 7: 1003–
l-arginine analogs in biological fluids. J Chromatogr B Ana-
1009, 2001
lyt Technol Biomed Life Sci August 21, 2006 [epub ahead of
37. Xia Y, Wen H, Bobst S, Day MC, Kellems RE: Maternal
print]
autoantibodies from preeclamptic patients activate angio-
21. Hladunewich MA, Derby GC, Lafayette RA, Blouch KL,
tensin receptors on human trophoblast cells. J Soc Gynecol
Druzin ML, Myers BD: Effect of L-arginine therapy on the
Invest 10: 82–93, 2003
glomerular injury of preeclampsia: A randomized con-
38. Dragun D, Muller DN, Brasen JH, Fritsche L, Nieminen-
trolled trial. Obstet Gynecol 107: 886 – 895, 2006
Kelha M, Dechend R, Kintscher U, Rudolph B, Hoebeke J,
22. Staff AC, Berge L, Haugen G, Lorentzen B, Mikkelsen B,
Eckert D, Mazak I, Plehm R, Schonemann C, Unger T,
Henriksen T: Dietary supplementation with L-arginine or
Budde K, Neumayer HH, Luft FC, Wallukat G: Angioten-
placebo in women with pre-eclampsia. Acta Obstet Gynecol
sin II type 1-receptor activating antibodies in renal-allo-
Scand 83: 103–107, 2004
graft rejection. N Engl J Med 352: 558 –569, 2005
23. Hibbard JU, Shroff SG, Lang RM: Cardiovascular changes
39. de Alvarez RR: Renal glomerular tubular mechanisms dur-
in preeclampsia. Semin Nephrol 24: 580 –587, 2004
ing normal pregnancy. I. Glomerular filtration rate, Renal
24. Bosio PM, McKenna PJ, Conroy R, O’Herlihy C: Maternal
plasma flow and creatinine clearance. Am J Obstet Gynecol
central hemodynamics in hypertensive disorders of preg-
75: 931–944, 1958
nancy. Obstet Gynecol 94: 978 –984, 1999
40. Chapman AB, Abraham WT, Zamudio S, Coffin C, Mer-
25. Carr DB, McDonald GB, Brateng D, Desai M, Thach CT,
ouani A, Young D, Johnson A, Osorio F, Goldberg C,
Easterling TR: The relationship between hemodynamics
Moore LG, Dahms T, Schrier RW: Temporal relationships
and inflammatory activation in women at risk for pre-
between hormonal and hemodynamic changes in early
eclampsia. Obstet Gynecol 98: 1109 –1116, 2001
human pregnancy. Kidney Int 54: 2056 –2063, 1998
26. Easterling TR, Carr DB, Brateng D, Diederichs C,
41. Lafayette RA, Druzin M, Sibley R, Derby G, Malik T, Huie
Schmucker B: Treatment of hypertension in pregnancy:
P, Polhemus C, Deen WM, Myers BD: Nature of glomeru-
Effect of atenolol on maternal disease, preterm delivery,
lar dysfunction in pre-eclampsia. Kidney Int 54: 1240 –1249,
and fetal growth. Obstet Gynecol 98: 427– 433, 2001
1998

---

Clin J Am Soc Nephrol 2: 543-549, 2007
Pathophysiology of the Clinical Manifestations of Preeclampsia
549
42. Strevens H, Wide-Swensson D, Grubb A, Hansen A, Horn
59. Demirtas O, Gelal F, Vidinli BD, Demirtas LO, Uluc E,
T, Ingemarsson I, Larsen S, Nyengaard JR, Torffvit O,
Baloglu A: Cranial MR imaging with clinical correlation in
Willner J, Olsen S: Serum cystatin C reflects glomerular
preeclampsia and eclampsia. Diagn Interv Radiol 11: 189 –
endotheliosis in normal, hypertensive and pre-eclamptic
194, 2005
pregnancies. BJOG 110: 825– 830, 2003
60. Bakshi R, Shaikh ZA, Bates VE, Kinkel PR: Thrombotic
43. Strevens H, Wide-Swensson D, Hansen A, Horn T, Inge-
thrombocytopenic purpura: Brain CT and MRI findings in
marsson I, Larsen S, Willner J, Olsen S: Glomerular endo-
12 patients. Neurology 52: 1285–1288, 1999
theliosis in normal pregnancy and pre-eclampsia. BJOG
61. Ito M, Itakura A, Ohno Y, Nomura M, Senga T, Nagasaka
110: 831– 836, 2003
T, Mizutani S: Possible activation of the renin-angiotensin
44. Fisher KA, Luger A, Spargo BH, Lindheimer MD: Hyperten-
system in the feto-placental unit in preeclampsia. J Clin
sion in pregnancy: Clinical-pathological correlations and re-
Endocrinol Metab 87: 1871–1878, 2002
mote prognosis. Medicine (Baltimore) 60: 267–276, 1981
62. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S,
45. Akbari A, Lepage N, Keely E, Clark HD, Jaffey J, MacKin-
Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein
non M, Filler G: Cystatin-C and beta trace protein as mark-
FH, Sukhatme VP, Karumanchi SA: Excess placental solu-
ers of renal function in pregnancy. BJOG 112: 575–578, 2005
ble fms-like tyrosine kinase 1 (sFlt1) may contribute to
46. Macdonald J, Marcora S, Jibani M, Roberts G, Kumwenda
endothelial dysfunction, hypertension, and proteinuria in
M, Glover R, Barron J, Lemmey A: GFR estimation using
preeclampsia. J Clin Invest 111: 649 – 658, 2003
cystatin C is not independent of body composition. Am J
63. Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T,
Kidney Dis 48: 712–719, 2006
47. Brown MA, Lindheimer MD, de Swiet M, Van Assche A,
Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA,
Moutquin JM: The classification and diagnosis of the hy-
Stillman IE, Roberts D, D’Amore PA, Epstein FH, Sellke
pertensive disorders of pregnancy: Statement from the In-
FW, Romero R, Sukhatme VP, Letarte M, Karumanchi SA:
ternational Society for the Study of Hypertension in Preg-
Soluble endoglin contributes to the pathogenesis of pre-
nancy (ISSHP). Hypertens Pregnancy 20: IX–XIV, 2001
eclampsia. Nat Med 12: 642– 649, 2006
48. Simanowitz MD, MacGregor WG: A critical evaluation of
64. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu
renal protein selectivity in pregnancy. J Obstet Gynaecol Br
KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH,
Commonw 81: 196 –200, 1974
Sibai BM, Sukhatme VP, Karumanchi SA: Circulating an-
49. Winkler U, Lison AE, Seitzer B, Niedner W: Urinary pro-
giogenic factors and the risk of preeclampsia. N Engl J Med
tein patterns for early detection of preeclampsia. Contrib
350: 672– 683, 2004
Nephrol 68: 227–229, 1988
65. Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N,
50. Quaas L, Wilhelm C, Klosa W, Hillemanns HG, Thaiss F:
Gerber HP, Kikkawa Y, Miner JH, Quaggin SE: Glomeru-
Urinary protein patterns and EPH-gestosis. Clin Nephrol 27:
lar-specific alterations of VEGF-A expression lead to dis-
107–110, 1987
tinct congenital and acquired renal diseases. J Clin Invest
51. MacLean PR, Paterson WG, Smart GE, Petrie JJ, Robson JS,
111: 707–716, 2003
Thomson D: Proteinuria in toxaemia and abruptio placen-
66. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentru-
tae. J Obstet Gynaecol Br Commonw 79: 321–326, 1972
ber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg
52. Moran P, Baylis PH, Lindheimer MD, Davison JM: Glo-
SA: A randomized trial of bevacizumab, an anti-vascular
merular ultrafiltration in normal and preeclamptic preg-
endothelial growth factor antibody, for metastatic renal
nancy. J Am Soc Nephrol 14: 648 – 652, 2003
cancer. N Engl J Med 349: 427– 434, 2003
53. Roberts JM: Endothelial dysfunction in preeclampsia. Se-
67. Sugimoto H, Hamano Y, Charytan D, Cosgrove D, Kieran
min Reprod Endocrinol 16: 5–15, 1998
M, Sudhakar A, Kalluri R: Neutralization of circulating
54. Felfernig-Boehm D, Salat A, Vogl SE, Murabito M,
vascular endothelial growth factor (VEGF) by anti-VEGF
Felfernig M, Schmidt D, Mittlboeck M, Husslein P, Mueller
antibodies and soluble VEGF receptor 1 (sFlt-1) induces
MR: Early detection of preeclampsia by determination of
proteinuria. J Biol Chem 278: 12605–12608, 2003
platelet aggregability. Thromb Res 98: 139 –146, 2000
68. Bdolah Y, Palomaki GE, Yaron Y, Bdolah-Abram T, Gold-
55. Ballegeer VC, Spitz B, De Baene LA, Van Assche AF,
man M, Levine RJ, Sachs BP, Haddow JE, Karumanchi SA:
Hidajat M, Criel AM: Platelet activation and vascular dam-
Circulating angiogenic proteins in trisomy 13. Am J Obstet
age in gestational hypertension. Am J Obstet Gynecol 166:
Gynecol 194: 239 –245, 2006
629 – 633, 1992
69. Buhimschi CS, Norwitz ER, Funai E, Richman S, Guller S,
56. Altman D, Carroli G, Duley L, Farrell B, Moodley J, Neil-
son J, Smith D: Do women with pre-eclampsia, and their
Lockwood CJ, Buhimschi IA: Urinary angiogenic factors
babies, benefit from magnesium sulphate? The Magpie
cluster hypertensive disorders and identify women with
Trial: A randomised placebo-controlled trial. Lancet 359:
severe preeclampsia. Am J Obstet Gynecol 192: 734 –741,
1877–1890, 2002
2005
57 Manfredi M, Beltramello A, Bongiovanni LG, Polo A, Pistoia
70. Caniggia I, Taylor CV, Ritchie JW, Lye SJ, Letarte M: En-
L, Rizzuto N: Eclamptic encephalopathy: Imaging and patho-
doglin regulates trophoblast differentiation along the inva-
genetic considerations. Acta Neurol Scand 96: 277–282, 1997
sive pathway in human placental villous explants. Endocri-
58. Schwartz RB, Feske SK, Polak JF, DeGirolami U, Iaia A,
nology 138: 4977– 4988, 1997
Beckner KM, Bravo SM, Klufas RA, Chai RY, Repke JT:
71. Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP,
Preeclampsia-eclampsia: Clinical and neuroradiographic
Sibai BM, Epstein FH, Romero R, Thadhani R, Karumanchi
correlates and insights into the pathogenesis of hyperten-
SA: Soluble endoglin and other circulating antiangiogenic
sive encephalopathy. Radiology 217: 371–376, 2000
factors in preeclampsia. N Engl J Med 355: 992–1005, 2006

---