Medico

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

ive to 7% of all pregnancies are complicated by preeclampsia. Proteinuria and hypertension dominate the
clinical picture, because the chief target organ is the
kidney (glomerular endotheliosis). The pathogenesis of preeclampsia is complex; numerous genetic, immunologic, and
environmental factors interact.It has been suggested that preeclampsia is a two-stage disease (1). The first stage is asymptomatic, characterized by abnormal placental development during the first trimester resulting in placental insufficiency and
the release of excessive amounts of placental materials into the
maternal circulation. This in turn leads to the second, symptomatic stage, wherein the pregnant woman developscharacteristic hypertension, renal impairment, and proteinuria and is
at risk for the HELLP syndrome (hemolysis, elevated liver
function enzymes and low platelets), eclampsia, and other endorgan damage. This review focuses on the pathophysiology of
stages 1 and 2 and then considers the potential that changes in
soluble angiogenic factors may underlie much of the disease
process.

PlacentationAbnormalities (Stage I)
On the basis of the observation that the only definitive cure
for preeclampsia is delivery of the placenta and that women
who experience a molar pregnancy, in which a placenta develops without a fetus, frequently develop severe preeclampsia, it
is reasonable to assume that the placenta plays a central role in
the pathogenesis of the disease. Pathologic examination ofplacentas from preeclamptic pregnancies generally reveals placental infarcts and sclerotic narrowing of arteries and arterioles,
with characteristic diminished endovascular invasion by cytotrophoblasts and inadequate remodeling of the uterine spiral
arterioles (2). Although gross pathologic changes are not always seen in the placentas of women with preeclampsia, placental profiles includingabnormal uterine artery Doppler and
placental morphology have been used to identify a subset from
a cohort of high-risk women who go on to develop the syndrome (3). Uterine artery Doppler studies that assess the pul-

Published online ahead of print. Publication date available at www.cjasn.org.
Address correspondence to: Dr Richard A. Lafayette, Stanford University, Division of Nephrology, 300Pasteur Drive, Stanford, CA 94305. Phone: 650-723-6247;
Fax: 650-723-7917; E-mail: czar@stanford.edu.
Copyright © 2007 by the American Society of Nephrology

satility index (PI) reveal increased uterine vascular resistance
well before the clinical signs and symptoms arise (4,5). Moreover, mechanical constriction of the uterine arteries produces
hypertension, proteinuria, and, in some species,glomerular
endotheliosis, supporting an causative role for placental ischemia in the pathogenesis of preeclampsia (6).
Mammalian placentation requires extensive angiogenesis to
establish a suitable network for the supply of oxygen and
nutrients in the fetus. A variety of pro- and antiangiogenic
factors are elaborated by developing placentas. It is believed
that placental angiogenesis isdefective in preeclampsia, as
evidenced by failure of the cytotrophoblasts to convert from a
more epithelial to endothelial phenotype, based on cell surface
marker studies (6,7). Normally, invasive cytotrophoblasts
downregulate the expression of adhesion molecules that are
characteristic of their epithelial cell origin and adopt a cellsurface adhesion phenotype that is typical of endothelial...