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Bahan Bacaan Preeklampsia
Bahan Bacaan Preeklampsia
Manifestations of Preeclampsia
1. Michelle Hladunewich*,
2. S. Ananth Karumanchi ,
3. Richard Lafayette
+ Author Affiliations
1. *
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
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Hypertension
Normal pregnancy in the rat is accompanied by increased production of NO and its second
messenger, cyclic guanosine 35 monophosphate (14) with a parallel increase in renal
expression of constitutive NOS (12,15). In the pregnant rat, an infusion of NG-nitro-l-
arginine methyl ester (L-NAME), an exogenous inhibitor of NOS, has been shown to
replicate some of the hemodynamic features of preeclampsia (16). l-Arginine
supplementation reversed these adverse effects of L-NAME on pregnancy, attenuating
hypertension, significantly decreasing proteinuria, and reducing the proportion of injured
glomeruli (17). However, in humans, evidence to support a role of NO deficiency in the
pathogenesis of the hypertension in preeclampsia has been conflicting. Although elevated
circulating levels of asymmetric dimethyl arginine, an endogenous inhibitor of NOS, has
been a consistent finding in pregnancies that are complicated by preeclampsia, plasma
concentrations are typically very low with a narrow distribution among healthy adults,
making quantification extremely challenging and the clinical significance of the finding
uncertain (1820). Furthermore, l-arginine supplementation has not conferred significant
benefit in women with pregnancies that are complicated by preeclampsia (21,22).
Another hypothesis considered the possibility that an early gestational exaggeration of the
normal accommodation to pregnancy can be used to identify and may be pathogenic in
preeclampsia (23). A longitudinal study that used Doppler echocardiography in 400
primigravidas throughout pregnancy noted a significantly increased cardiac output without
any difference in peripheral vascular resistance in the 24 women who eventually developed
preeclampsia compared with healthy control subjects (24). This increased cardiac output was
followed by a marked reduction in the cardiac output and increased peripheral vascular
resistance with the onset of the clinical syndrome. This notion of a crossover in the
hemodynamic profile in women who develop preeclampsia resulted in a handful of studies
that used blockers in a preventive manner (2527). These studies were typically small
and/or uncontrolled. Furthermore, reduced fetal growth was noted in the women who
received the blockers, possibly because of an overaggressive decrease in the cardiac output
(26,27).
More recently, attention has again turned to the renin-angiotensin system (RAS) to provide a
pathophysiologic understanding for the hypertension of preeclampsia. In normal pregnancy,
all components of the RAS are upregulated, but resistance to the pressor effects of
angiotensin II (AngII) allows for normal to low BP (18,19). Similarly, reduced sensitivity of
the renal circulation has been demonstrated in pregnant rats as AngII infusion failed to
decrease GFR, renal plasma flow (RPF), and urine flow (28). One explanation may be
increased plasma levels and urinary excretion rates of Ang(1-7), a potent counterregulator of
AngII, documented in human pregnancy (29,30). Ang(1-7) was demonstrated to be
significantly decreased in women with preeclampsia compared with normal pregnant control
subjects (29).
It is interesting that evidence supports decreased levels of renin, AngI, and AngII in women
with preeclampsia compared with normal pregnancy (31). Despite this, enhanced vascular
sensitivity to components of the RAS is seen in women with preeclampsia. Enhanced
vascular sensitivity to an angiotensin infusion can identify women who are at increased risk
for the development of preeclampsia (32,33).
Recent studies have identified an autoantibody of the IgG subclass in the plasma of women
with preeclampsia that is capable of stimulating the AT1 receptor (34). When serum from
preeclamptic women was added to cultured neonatal rat cardiac myocytes, the chronotropic
effect could be blocked by losartan, confirming the effect was mediated via the AT1 receptor
(35). Furthermore, the autoantibody might stimulate heterodimerization between the AT1
receptor and the B2 receptor for bradykinin (36). This may play an important role in the
enhanced vascular sensitivity to angiotensin. It might also induce the production of reactive
oxygen species, which block cytotrophoblast invasion in vitro and may relate to shallow
trophoblastic implantation, thus accounting for several of the clinical features of preeclampsia
(37). This autoimmune activity wanes after delivery (34). More recently, these antibodies
also were found in patients with acute vascular rejection (38), suggesting that they may play a
role in other forms of endothelial injury as well.
Decreased GFR
Healthy pregnant women exhibit marked glomerular hyperfiltration, peaking above normal,
nongravid levels by 40 to 60% (39,40). This hyperfiltration seems to result primarily from
depression of the plasma oncotic pressure (GC) in the glomerular capillaries. The reduction
of GC in pregnancy is attributable to two phenomena. The first is a hypervolemia-induced
hemodilution that lowers the protein concentration of plasma that enters the glomerular
microcirculation. The second is an elevated rate of RPF. Hyperperfusion of glomeruli blunts
the extent to which the oncotic pressure can increase along the glomerular capillaries during
filtrate formation. In preeclampsia, variable degrees of renal insufficiency are associated with
a characteristic glomerular lesion, glomerular endotheliosis.
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Figure 1.
A recent study used a semiquantitative scale to grade the endotheliosis that was present on
biopsy specimens that were taken from women with preeclampsia approximately 1 wk before
delivery (42,43). They noted moderate to severe endotheliosis in all women with significant
hypertension and proteinuria before delivery. Of interest, women with nonproteinuric
gestational hypertension and normal pregnant women also exhibited endotheliosis but to
lesser degrees, suggesting that pregnancy-induced hypertension may in some cases reflect an
earlier or milder form of the same pathology (44). Subendothelial fibrinoid deposits and
mesangial cell interposition were found only in women with preeclampsia. Unfortunately, the
authors never published any images or acquired confirmation from a second blinded
pathologist to ensure interobserver reliability. In a second article that examined the same
patient population, the authors found a linear trend between glomerular volume reflecting the
degree of endotheliosis and cystatin C (42), suggesting that the basis for the hypofiltration in
preeclampsia is largely secondary to structural changes in the glomerulus as opposed to renal
vasoconstriction and a depression in RPF. However, the utility of cystatin C as a marker of
GFR is unclear in this patient population. A recent study found that cystatin C correlated
poorly with third-trimester creatinine clearance (r = 0.27) (45), and another study that used
inulin clearances for comparison found that the measurement is not independent of body
composition as previously assumed (46). To date, cystatin C has not been validated as a
marker of GFR in pregnancy, with several studies suggesting that it may be imprecise.
Proteinuria
In 1843, John Lever of Guy's Hospital in London discovered the presence of albumin by
boiling the urine from pregnant women with puerperal convulsions. Preeclampsia is
differentiated from gestational hypertension by the presence of proteinuria 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 examine the biochemical constitution of
preeclamptic urine, including 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 preeclampsia (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 .
Therefore, the mechanism for proteinuria in preeclampsia is not well understood. The
glomerular basement membrane and podocytes typically appear normal (33,36). Few
investigators have used dextran-sieving techniques to elucidate the properties of the
glomerular filtration barrier in women with preeclampsia. In the 1970s, MacLean et al. (51)
confirmed the glomerular origin of proteinuria in preeclampsia demonstrating dextran-sieving
coefficients in the intermediate range. This finding was corroborated by a more recent study
that demonstrated a loss of size selectivity significant for bands 31 to 39 (P < 0.0001) as
well as 41 to 49 (P < 0.01) (52). Without more specific studies, the authors alluded to the
fact that loss of charge selectivity was likely the primary defect in the glomerular filtration
barrier in women with preeclampsia. New insights into the role of angiogenic factors in the
maintenance of an intact glomerular filtration barrier may reconcile the presence of
nephrotic-range proteinuria in an endothelial cell disease (see Circulating Angiogenic Factors
in Preeclampsia).
Eclampsia
Seizures with other neurologic symptoms, including headache and visual disturbances,
complicate approximately 5 of every 10,000 live births, with a declining incidence as a result
of improved prenatal care with expedited delivery and, possibly, the widespread use of
magnesium sulfate (56). The precise mechanism that is responsible for the development of
seizures is not clear, but proposed theories include cerebral vasospasm, edema, and the
possibility that severe hypertension might disturb cerebral autoregulation and disrupt the
bloodbrain barrier. The cerebral edema of eclampsia predominantly involves the posterior,
parieto-occipital lobes and is similar to images described in reversible posterior
leukoencephalopathy syndrome (57). This finding on magnetic resonance imaging has been
noted to correlate better with markers of endothelial dysfunction, including lactate
dehydrogenase, red blood cell morphology, and creatinine than the level of hypertension
(58,59). Of interest, reversible posterior leukoencephalopathy syndrome in patients with
thrombotic thrombocytopenic purpura has also been found to be independent of the level of
hypertension in some cases (60).
Endoglin (Eng) is an angiogenic receptor that is expressed on the surface of endothelial cells
and placental syncytiotrophoblasts. Eng acts as a co-receptor for TGF-, a potent
proangiogenic molecule. Eng mRNA is upregulated in the preeclamptic placenta (63).
Moreover, the extracellular region of Eng is proteolytically cleaved, and soluble Eng (sEng)
is released in excess quantities into the circulation of preeclamptic patients. In pregnant rats,
sEng exacerbates the vascular damage that is mediated by sFlt1, resulting in severe
preeclampsia-like illness, including the development of a HELLP-like syndrome and fetal
growth restriction (63). In explant cultures of trophoblasts from 5 to 8 wk of gestation, mAb
to Eng and antisense Eng oligonucleotides stimulated trophoblast outgrowth and migration
(70). TGF1 and/or TGF-3 inhibits trophoblast migration and invasion, and it seems that
Eng mediates this effect. Therefore, it has been speculated that production of sEng by the
placenta may be a compensatory mechanism to limit the effects of surface Eng. In recent
clinical studies, sEng was elevated not only during the disease but also before onset of
symptoms (71). Elevations in sEng were particularly pronouncedand, therefore, potentially
most useful for predictionin women who developed preterm preeclampsia or preeclampsia
with an infant who was small for gestational age. Although the gestational pattern of sEng
concentration tended to parallel the trajectory of the sFlt1/PlGF ratio, multivariate analysis
indicated that each was significantly associated with preeclampsia. Indeed, a composite
measure that incorporated all three angiogenic molecules (sFlt1, sEng, and PlGF) was more
strongly predictive of preeclampsia than the individual biomarkers (71) (Figure 2).
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Figure 2.
Adjusted odds ratios for preterm (A) or term (B) preeclampsia according to soluble fms-like
tyrosine kinase 1:placental growth factor (sFlt1:PlGF) ratios and soluble endoglin levels.
Conclusion
Preeclampsia remains a common complication of pregnancy that leads to unacceptable
increases in fetal and maternal morbidity and mortality, particularly in less developed nations.
Efforts continue to understand better the pathophysiology of the clinical manifestations of the
disease. Recent findings on the role of circulating antiangiogenic factors have generated great
optimism for being able to predict better the disease and develop therapeutic advances. If
subsequent trials validate these theories, then future work should lead to renewed efforts
finally to explain and treat this complex disease.