nephrology digest
REFERENCES
1
Department of Medicine,
Division of Nephrology; Ohio
State University Wexner Medical
Center, Columbus, Ohio, USA
Correspondence: Salem J.
Almaani, Department of
Medicine, Division of
Nephrology; Ohio State
University Wexner Medical
Center, 395 W 12th Ave, Ground
Floor, Columbus, Ohio 43210,
USA.
E-mail: salem.almaani@osumc.
edu
730
6. KDIGO Anemia Work group. KDIGO Clinical Practice
1. Fishbane S, Spinowitz B. Update on anemia in ESRD and
earlier stages of CKD: core curriculum 2018. Am J Kidney
Dis. 2018;71:423–435.
2. Schwartz AJ, Das NK, Ramakrishnan SK, et al. Hepatic
hepcidin/intestinal HIF-2alpha axis maintains iron
absorption during iron deficiency and overload. J Clin
Invest. 2019;129(1):336–348.
3. Nakanishi T, Kuragano T, Nanami M, et al.
Misdistribution of iron and oxidative stress in chronic
kidney disease. Free Radic Biol Med. 2019;133:248–253.
4. Macdougall IC. Intravenous iron therapy in patients
with chronic kidney disease: recent evidence and future
directions. Clin Kidney J. 2017;10:i16–i24.
5. Drueke TB, Massy ZA. Oral or intravenous iron for
anemia correction in chronic kidney disease? Kidney Int.
2015;88:673–675.
translational science
Placental growth factor in
pre-eclampsia: friend or foe?
Salem J. Almaani1
Refers to: Parchem JG, Kanasaki K, Kanasaki M, et al. Loss of placental growth factor ameliorates maternal
hypertension and preeclampsia in mice. J Clin Invest. 2018;128:5008–5017
Kidney International (2019) 95, 730–732; https://doi.org/10.1016/j.kint.2019.02.002
KEYWORDS: gene expression; microbiology; preeclampsia
Copyright ª 2019, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
reeclampsia is a hypertensive disorder of
P pregnancy that can present with pro-
teinuria or end-organ damage. Preeclamp-
sia occurs in approximately 5% of pregnancies
and is associated with significant fetal and
maternal morbidity that can extend beyond the
period of pregnancy. The exact pathogenesis of
preeclampsia is still unclear; however, evidence
supports a role for placental ischemia and disor-
dered development and remodeling of the
placental vasculature.1 These processes are espe-
cially relevant in “placental” or “early” pre-
eclampsia, in which they are thought to
contribute to an altered repertoire of placenta-
derived factors that promote maternal endothelial
dysfunction.2 Those placenta-derived factors
include members of the vascular endothelium
growth factor (VEGF) family and their receptors,
including placental growth factor (PlGF) and its
receptor fms-like tyrosine kinase 1 (Flt-1).
Multiple epidemiologic studies have demon-
strated an association between preeclampsia and
decreased PlGF levels, elevated soluble Flt-1
(sFlt-1) levels, or an increase in the ratio of
sFlt-1 to PlGF, and use of these measures as
biomarkers for preeclampsia is being evaluated.3
Guideline for Anemia in Chronic Kidney Disease. Kidney
Int Suppl. 2012;2(suppl):279–335.
7. Bailie GR, Larkina M, Goodkin DA, et al. Variation
in intravenous iron use internationally and over time:
the Dialysis Outcomes and Practice Patterns
Study (DOPPS). Nephrol Dial Transplant. 2013;28:
2570–2579.
8. Macdougall IC, White C, Anker SD, et al. Intravenous
iron in patients undergoing maintenance
hemodialysis. [published correction appears in N Engl
J Med. 2019;380:502]. N Engl J Med. 2019;380:
447–458.
9. Kalantar-Zadeh K, Regidor DL, McAllister CJ, et al. Time-
dependent associations between iron and mortality in
hemodialysis patients. J Am Soc Nephrol. 2005;16:
3070–3080.
In experimental models, administration of re-
combinant VEGF or PlGF decreased mean arte-
rial pressure, and it improved glomerular
filtration rate in a rat model of preeclampsia.4,5
Recombinant VEGF also improved6 systolic
blood pressure, proteinuria, and endotheliosis in
mice with adenovirus-induced overexpression of
sFLT-1. Taken together, these studies suggest a
causative role for low VEGF or PlGF levels in the
development of preeclampsia.
A recent article7 published in the Journal of
Clinical Investigation challenges this paradigm.
Parchem and colleagues7 first compared preg-
nant PlGF knockout and wild-type mice and
found no evidence of preeclampsia, despite an
increase in serum sFlt-1 levels, a decrease in
serum VEGF levels, and an increase in placental
Flt-1 expression in the knockout animals.
Modest histologic alterations, including an in-
crease in junctional zone glycogen, were
accompanied by increased placental weight and
a decreased embryo:placenta weight ratio in
knockout mice.
Parchem et al.7 next evaluated the impact of
PlGF deficiency in an established mouse model
of preeclampsia. Catechol-O-methyltransferase
Kidney International (2019) 95, 727–732
 nephrology digest

Genetic Environmental Immunological ? Metabolic

factors factors factors factors

Placenta
Abnormal trophoblast
invasion and differentiation

Decidua
Trophoblasts
Placental
Ischemia/hypoxia

Angiogenic factor imbalance

VEGF

Myometrium
PlGF Spiral
PlGF absence*
artery
sFlt

Endothelial dysfunction
Nonpregnant Preeclampsia Normal pregnancy

Activated
coagulation
Hypertension system
Proteinuria
Edema Hepatic
ischemia Cerebral
edema
Figure 1 | The current understanding of the pathogenesis of preeclampsia. *Incorporating the findings of Parchem et al.7 PlGF, placental
growth factor; sFlt, soluble fms-like tyrosine kinase; VEGF, vascular endothelium growth factor.

(COMT) knockout mice develop preeclampsia
that can be rescued by administration of
2-methoxyestradiol (2-ME), an estradiol
metabolite generated by COMT activity. They
generated PlGF/COMT double-knockout mice,
and then bred double-knockout females with
double-knockout or COMT knockout males.
Pregnant females carrying placentas with either
complete knockout of both COMT and PlGF or
complete knockout of COMT and heterozygous
expression of PlGF were compared. Females
carrying placentas with complete knockout of
both COMT and PlGF had lower systolic blood
pressure and a trend toward decreased pro-
teinuria, suggesting that the complete absence
of PlGF partially rescued the mice from pre-
eclampsia despite a nonsignificant increase in
serum sFlt. These mice also had a decreased
embryo:placenta ratio, which was driven by
smaller embryos as opposed to increased
placental weight. Histologically, an increase in
junctional zone glycogen was also found in
placentas with complete knockout of both
COMT and PlGF relative to placentas with
heterozygous expression of PlGF, and the latter
more closely resembled the placentas from
COMT knockout mice.
To determine the relevance of the murine
findings to human preeclampsia, plasma 2-ME
and PlGF levels were measured and found to be
lower in patients with preeclampsia, compared
with those with normal pregnancies, with a
linear correlation between the levels of 2-ME
and PlGF in patients with preeclampsia.
Based on their results, Parchem et al.7
speculated that PlGF deficiency may be pro-
tective against preeclampsia through alterations
in placental metabolism, including an increase
in placental glycogen. The data from Parchem
et al.7 add another layer of complexity to the
role of PlGF in preeclampsia and challenge the
premise that PlGF is involved in the patho-
genesis of preeclampsia solely through its
angiogenic role.
As with previous studies, including those
demonstrating favorable outcomes after

Kidney International (2019) 95, 727–732 731

nephrology digest
treatment with PlGF or VEGF, these results
should be interpreted in light of the inherent
limitations of the murine models of pre-
eclampsia. In humans, 4 different PlGF splice
variants are found, and PlGF levels are
decreased but not entirely depleted in women
with preeclampsia. Additionally, PlGF may
respond to hypoxia or ischemia in a tissue- and
situation-specific fashion, and other comor-
bidities may influence the relationship between
preeclampsia and PlGF in women. For
example, there is an association between low
PlGF levels and preeclampsia in obese women,
which is not observed in those with concomi-
tant gestational diabetes.8 The protective effect
of PlGF deficiency in the COMT knockout
model of preeclampsia suggests that the low
plasma PlGF levels observed in women with
preeclampsia could reflect a compensatory
response, rather than a pathogenic role as
previously hypothesized. In addition, studies of
preeclampsia in women must acknowledge the
complexity and heterogeneity of this popula-
tion. For example, early-stage chronic kidney
disease (CKD) is often unrecognized prior to
pregnancy and is associated with a higher risk
of preeclampsia, probably due to maternal and
not placental factors. Healthy kidney donors
represent a prime example, carrying a higher
risk of preeclampsia and other hypertensive
diseases of pregnancy.9 Thus, careful pheno-
typing of women included in studies of pre-
eclampsia is of paramount importance.
In summary, the unexpected results of the
study by Parchem et al.7 highlight the complex
pathogenesis of preeclampsia (Figure 1), with
732
contributions from both metabolic and angio-
genic processes, and should prompt future
translational studies that include the collection
of data in pregnant women.
DISCLOSURE
The author declared no competing interests.
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placental growth factor ameliorates maternal
hypertension and preeclampsia in mice. J Clin Invest.
2018;128:5008–5017.
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Kidney International (2019) 95, 727–732