Case 5 -
J. Charles Jennette
University of North Carolina School of Medicine
Chapel Hill, NC
Click on each slide thumbnail image for an enlarged view
Case Summary Prior to Renal Biopsy:
A 28 year old Hispanic female developed
trace proteinuria and hypertension (blood pressure 120/90 mmHg) 8 weeks into a pregnancy. She had no
history of hypertension prior to the pregnancy and no family history of kidney disease or hypertension.
Laboratory data at that time included serum creatinine 0.7, normal liver function tests and normal
platelet count. Anti-hypertensive therapy was begun with labetalol. At 19 weeks gestation, her
hypertension had worsened to 160/100 mmHg and she had developed 2+ lower extremity edema, malaise and
headaches. The hypertension could not be controlled with a calcium channel blocker, labetalol and
magnesium. Laboratory results at that time included 19 g/day proteinuria, oval fat bodies and fatty
casts in the urine, 1+ hematuria with no RBC casts, serum creatinine 0.6, BUN 7, albumin 2.3, glucose 81,
negative ANA, normal C3, slightly low C4, platelet count 80K, elevated LDH, no anemia, no schistocytes,
and mildly elevated liver function tests. The following were negative or normal: lupus anticoagulant,
anti-cardiolipin antibodies, factor V Leiden, HIV testing, and hepatitis A/B/C serology. Fetal and
placental ultrasound was unremarkable. The clinical differential diagnosis was early onset
preeclampsia/HELLP syndrome versus thrombotic microangiopathy versus other kidney disease (possibly
preexisting disease exacerbated by pregnancy). A renal biopsy was performed.
Case 5 - Figure 1 -
Two "bloodless" glomeruli with obliteration of capillary lumens caused by swollen endothelial cells and expansion of the subendothelial zone. Note the unremarkable tubulointerstitial compartment. (H&E stain)
Case 5 - Figure 2 -
This higher magnification of one of the glomeruli in figure 5-1 shows the pale acidophilic consolidation with slight vacuolization that is characteristic for eclampsia/preeclampsia. (H&E stain)
Case 5 - Figure 3 -
Masson trichrome stained glomeruli with obscured capillary lumens, but no hypercellularity. Note again the unremarkable tubulointerstitial compartment.
Case 5 - Figure 4 -
This higher magnification of one of the glomeruli in figure 5-3 revealing the somewhat "bubbly" appearance in the consolidated areas. This is caused more by swollen endothelial cells and podocytes rather than increase in matrix material and thus does not stain as intensely blue as increased matrix would. (Masson trichrome stain)
Case 5 - Figure 5 -
PAS-stained glomerulus showing extensive delicate replication of glomerular basement membranes, which forms some clear ovals that resemble "pearls".
Case 5 - Figure 6 -
Jones silver methenamine stain showing the same glomerular changes illustrated in figure 5-5 as well as herniation of the tip of the swollen glomerulus into the proximal tubule, which is a characteristic but not specific feature of preeclampsia/eclampsia.
Case 5 - Figure 7 -
High magnification of a Jones silver methenamine stain-stained glomerulus showing extensive remodeling of glomerular basement membranes.
Case 5 - Figure 8 -
Masson trichrome stain showing profiles of small arteries and arterioles that have no changes indicative of a thrombotic microangiopathy or of chronic hypertension.
Case 5 - Figure 9 -
Electron micrograph showing obliteration of a glomerular capillary lumen by a combination of endothelial swelling and expansion of the subendothelial zone by slightly electron-dense material.
Case 5 - Figure 10 -
Electron micrograph showing marked narrowing of a glomerular capillary lumen predominantly by endothelial swelling (endotheliosis).
Case 5 - Figure 11 -
Electron micrograph of a capillary wall that is thickened by multiple events, including endothelial swelling and subendothelial invagination, subendothelial mesangial interposition, and accumulation of subendothelial extracellular material. These ultrastructural changes are the basis for the light microscopic capillary wall abnormalities seen in figure 5-7.
Renal Biopsy Diagnosis: Preeclampsia/Eclampsia
Clinical Course after Renal Biopsy:
Based on the renal biopsy findings and
the clinical course, a diagnosis of preeclampsia with HELLP syndrome was made and the difficult decision
was reached to terminate the pregnancy for the safety of the mother. Within days after delivery, liver
function test results and platelet count normalized, and the blood pressure was controllable at 130/80
with labetalol alone. Proteinuria and edema subsequently cleared.
Preeclampsia occurs in approximately 5% to 10% of pregnancies in more developed countries
and a much higher percent in less developed countries
Preeclampsia often is defined as the presence of
hypertension, edema, and proteinuria after 20 weeks of pregnancy in a previously normotensive woman.
However, this syndrome can be superimposed on pre-existing hypertension and may rarely occur earlier than
20 weeks of gestation, as in the case reported above. Preeclampsia also can occur in a woman with a
molar pregnancy, and in this setting more often manifests before 20 weeks gestation. Eclampsia is the
occurrence of convulsions in a woman with preeclampsia. Reduced glomerular filtration rate often occurs
in preeclampsia, however, this may be offset by the elevated creatinine clearance that occurs during
pregnancy. Thrombocytopenia and schistocytosis occasionally are observed but typically are less
pronounced than in an overt thrombotic microangiopathy. HELLP syndrome may accompany preeclampsia and is
characterized by hemolysis, elevated liver enzymes and low platelet count . The patient under
consideration had findings consistent with preeclampsia with HELLP.
Treatment with magnesium sulfate usually is effective for controlling the hypertension of
preeclampsia, reducing the risk of progressing from preeclampsia to eclampsia, and reducing the number
convulsions in women with eclampsia. Delivery is the definitive treatment for preeclampsia. Early
delivery of the fetus because of preeclampsia accounts for 15% of premature births in the US .
The typical histologic lesion is glomerular endothelial
swelling (endotheliosis) resulting in narrowing or occlusion of lumens
This causes a
characteristic "bloodless" appearance to glomeruli. Glomeruli are enlarged and occasionally the tip of
the glomerulus herniates into the lumen of the proximal tubule. Special stains that demarcate basement
membrane material often reveal glomerular basement membrane replication or fine trabeculation.
Glomerular capillary thrombi are rare. Podocytes may be swollen and often contain prominent lipid or
protein resorption droplets. Arterioles and arteries are unremarkable.
Irregular, low intensity immunostaining for
fibrin, IgM and complement components is identified in glomerular capillary walls and/or mesangium is
approximately half of specimens . Staining for IgG and IgA is negative.
Glomerular capillary endothelial swelling
(endotheliosis) is the hallmark ultrastructural finding
Endothelial fenestrations usually are
lost. Lumens often are difficult to identify. Extensive endothelial lipid accumulation may occur.
There may be irregular focal expansion of the subendothelial zone, which may contain moderately
electron-dense material. In older lesions, new basement membrane material surrounds invaginations of
endothelial cytoplasm into the subendothelial zone producing the layering of basement membrane material.
Podocyte foot processes usually are focally effaced and podocyte cytoplasm may contain increased numbers
of lucent or electron-dense resorption vacuoles.
The major clinical
differential diagnostic consideration is between preeclampsia versus thrombotic microangiopathy (TMA)
. A diagnosis of preeclampsia prompts consideration of early delivery and has a good prognosis
whereas a diagnosis of TMA has a bad prognosis and prompts consideration of plasma exchange.
Microangiopathic hemolytic anemia and thrombocytopenia occurring during the first trimester along with
proteinuria and hypertension supports a diagnosis of TMA rather than preeclampsia (which typically occurs
after 20 weeks). In some patients, the overlap in clinical and laboratory features between preeclampsia
and TMA does not allow a definitive clinical diagnosis. Usually, however, the distinctions can be made
readily by renal biopsy evaluation.
Glomeruli affected by preeclampsia have predominantly endotheliosis (endothelial swelling)
with focal subendothelial expansion by moderately electron-dense material. In contrast, glomeruli
affected by TMA have less pronounced endothelial swelling, but much more extensive subendothelial
expansion by electron-lucent material, and a higher frequency of thrombosis. Renal biopsy specimens from
patients with preeclampsia almost never have microangiopathic lesions in arterioles or arteries, whereas
specimens with TMA often have lesions such as arteriolar fibrinoid necrosis, arterial edematous (myxoid)
intima thickening and thrombosis.
The light microscopic and electron microscopic images that were available for review with
this case show the classic lesions of preeclampsia.
The pathogenesis of preeclampsia appears to occur in two
phases: abnormal implantation of the placenta leading to impaired placental blood flow, which in turn
induces the release of pathogenic factors from the placenta into the maternal circulation (e.g. sFlt1)
and/or the development of pathogenic autoantibodies (e.g. AT1R-AA). Release or generation of toxic
factors in the maternal circulation results in endothelial injury in many maternal organs, especially the
kidneys, liver, brain and lungs . The occurrence of preeclampsia in molar pregnancies proves that
toxic factors from the fetus are not required to cause preeclampsia.
Maynard et al.  compared the gene expression profile in placental tissue from women
with and without preeclampsia and identified soluble Flt1 (sFlt1) as a potential pathogenic factor.
sFlt-1 is a soluble form of the receptor for vascular endothelial growth factor (VEGF) and placental
growth factor (PlGF). sFlt-1 is highly expressed in placentas of women with preeclampsia. It is a
truncated form of Flt-1 (fms-related tyrosine kinase) that is secreted into the circulation because it
lacks transmembrane and cytosolic domains. However, it still binds to its ligands, VEGF and PlGF, thus
reducing the chance that these ligands can react with full length Flt-1. Therefore, sFlt-1 works as a
VEGF/PlGF antagonist. There is evidence that trophoblastic injury enhances placental sFlt1 production.
sFlt1 antagonizes the protective effects of VEGF and placental growth factor on endothelial cells. Thus
impaired placental blood flow could cause placental injury with release of sFlt1 that in turn sets the
stage for endothelial damage.
Maynard et al  also provided strong evidence for the pathogenicity of sFlt-1 by causing
disease in rats by intravenous injection of an adenovirus vector that expressed sFlt-1. These rats
developed renal disease that closely mimicked human preeclampsia clinically and pathologically
At UNC, Nobuyuki Takahashi, in collaboration with Oliver Smithies, has developed a similar
model in mice by intravenous injection of an adenovirus that expresses sFlt-1 (unpublished data). This
causes marked proteinuria, hypertension and decreased urine volume. Kidneys from these mice have light
microscopic and electron microscopic abnormalities that are virtually identical to those of human
Hertig et al.  measured sFlt1 concentrations in serial serum samples from pregnant
women with normal pregnancy or pregnancy complicated by gestational or chronic hypertension but without
preeclampsia at the time of recruitment. They observed that maternal serum sFlt1 level was markedly
increased at delivery in women with preeclampsia and was increased as early as 6.5 weeks prior to the
clinical onset of preeclampsia. They concluded that measurement of sFlt1 could identify women at risk of
developing preeclampsia. Their observations also support a role for sFlt1 in the pathogenesis of
Luft and his associates have identified an autoimmune phrnomenon in patients with
preeclampsia but the pathogenic significance of this finding are unresolved. They demonstrated that
agonistic (activating) antibodies that bind the second extracellular loop of the angiotensin II AT1
receptor (AT1R-AA) appear with the development of preeclampsia and disappear by 6 weeks after delivery.
AT1R-AA induce signaling in vascular cells and trophoblasts, including activation of AP-1 and nuclear
factor-kappa B (NF-κB). This signaling results in tissue factor production and reactive oxygen
species generation, which have been implicated in the pathogenesis of preeclampsia.
Dechend et al.  crossed rats transgenic for the human angiotensinogen
with rats transgenic for the human renin (hRen) gene. The female hAogen x male hRen cross had severe
hypertension and proteinuria that developed during the last trimester of pregnancy and subsided after
delivery. The converse cross did not. The female hAogen x male hRen cross developed AT1R-AA and renal
lesions similar to human preeclampsia as well as placental atherosis-like lesion in the spiral arteries.
Gack et al. compared gene expression profiles from placentas from controls and from
patients with preeclampsia using DNA microarray analysis. The soluble form of the disintegrin
metalloprotease ADAM 12 was the most upregulated transcript. This was confirmed by in situ hybridization
of sections of placentas from patients with preeclampsia and by analysis of serum from patients with
preeclampsia . ADAM proteases snip off the ends of membrane proteins resulting in the shedding of
A possible unifying concept that would move preeclampsia into the autoimmune disease
category is that AT1R-AA cause placental throphoblasts to release sFlt-1 (maybe with the help of ADAM 12)
that in turn causes endothelial injury. But this is only gross conjecture.
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