Current Hypertension Reports (2020) 22:36

https://doi.org/10.1007/s11906-020-1033-9

PREECLAMPSIA (V GAROVIC, SECTION EDITOR)

Preeclampsia and Glomerulonephritis: A Bidirectional Association

Vincenzo Di Leo 1 & Flavia Capaccio 1 & Loreto Gesualdo 1

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Purpose of Review We focus on the current understanding of preeclampsia (PE) in order to examine how it mediates glomerular
injury and affects the course of glomerulonephritis (GNs). In addition, this review discusses the role of GNs on the development
of PE.
Recent Findings In PE, the dysfunctional utero-placental perfusion causes the release into the mother’s circulation of anti-
angiogenic substances, leading to systemic endotheliosis. In preeclamptic patients, the imbalance between pro- and anti-
angiogenic factors is responsible for the kidney injury, and PE may reveal a silent pre-existent GN or may induce the development
of the disease. Moreover, in women with chronic kidney disease (CKD), it could accelerate the disease progression. In any case,
GNs compromise renal function, making the kidney less responsive to physiological changes that occur during pregnancy and, at
the same time, cause maternal vascular inflammation, representing a risk factor for PE development.
Summary Although a bidirectional correlation between GNs and PE has been demonstrated, the data are limited, and further
large studies are warranted. Close collaboration between a multidisciplinary team of obstetricians and nephrologists is essential to
establish the correct diagnosis and safely manage these vulnerable women and their fetuses.

Keywords Preeclampsia . Glomerulonephritis . IgA nephropathy . Focal segmental glomerulosclerosis . Lupus nephritis .
Diabetic nephropathy . Chronic kidney disease

Introduction 34 weeks of gestation) is associated with a high rate of fetal

Preeclampsia: The Crosstalk Between Kidney
and Placenta
PE is a gestational disorder that complicates approximately
5% of all pregnancies and is also a cause of about 15% of
cases of maternal morbidity and mortality [1, 2]. It begins after
20 weeks of gestation and is characterized by new onset hy-
pertension and proteinuria (≥ 300 mg/day) or new-onset pre-
eclampsia associated signs without proteinuria [3].
There are two subtypes of PE, classified by the time of
delivery: early onset preeclampsia (EO-PE) and late onset
preeclampsia (LO-PE). The EO form (delivery before
This article is part of the Topical Collection on Preeclampsia
* Loreto Gesualdo
loreto.gesualdo@uniba.it
1
Nephrology, Dialysis and Transplantation Unit, Department of
Emergency and Organ Transplantation, University of Bari Aldo
Moro, Bari, Italy
growth restriction (FGR), and it is also known as a “placental”
type, in contrast to the LO form (delivery after 34 weeks),
defined as “maternal” type, in which neonates generally do
not have a growth restriction and may even be large for ges-
tational age [4–6].
The placenta represents the focus of the pathogenesis of
PE, but we are far from understanding all the aspects of this
intricate disease. In 1991, Redman at al. [7] proposed the two-
stage model of PE: an abnormal formation of the uterine spiral
arteries, due to a superficial invasion of trophoblast during the
first half of pregnancy, represents the placental stage (stage 1).
This abrupt remodeling of the blood vessels leads to an
ischemia-reperfusion injury and to a placental oxidative stress,
which stimulate the release of pro-hypertensive and anti-
angiogenic factors bringing about systemic endothelial injury
and clinically overt maternal illness (stage 2) [8, 9]. Although
this model can well explain the development of EO-PE, it is
less applicable to LO-PE.
To overcome this problem, the same authors suggested a
second placental etiology of PE [10] (without considering
poor placentation) in which the alteration in placental
 36 Page 2 of 7
perfusion occurs later when the placenta outgrows the uterine
capacity (“constrained placenta”), in which terminal villi are
compressed, impeding intervillous perfusion and causing hyp-
oxia and stress in the same way as the dysfunctional perfusion
associated with EO-PE acts [4].
The main substances implicated in this imbalance between
angiogenic and anti-angiogenic factors are: vascular endothe-
lial growth factor (VEGF), placenta growth factor (PlGF),
soluble fms-like tyrosine kinase-1 (sFlt-1) and endoglin
(ENG). VEGF, binding to its receptors, can activate endothe-
lial nitric oxide synthase (eNOS); it is essential for angiogen-
esis of the placental vasculature and for endothelial function.
PlGF is expressed by the placenta and has an angiogenic effect
on the development of the placental vascular system.
Conversely, sFlt-1, a potent scavenger of VEGF and PlGF,
and sENG, the extracellular domain of ENG, have anti-
angiogenic properties and are overexpressed in preeclamptic
patients [11].
During normal pregnancy, the kidney undergoes important
anatomic and physiologic adaptive changes playing a key role
in pregnancy. Therefore, it is one of the organs most vulnera-
ble to events occurring in PE, and at the same time, kidney
malfunction in CKD and GNs influences pregnancy and, in
particular, the development of complications.
This mechanism can be well explained from the new multi-
step model proposed by Staff et al. [4], in which the maternal
factors that can affect multiple steps in the pathway leading to
PE have been integrated with the original two-step model [7].
Indeed, pre-pregnancy conditions that cause maternal vascular
inflammation (including renal disease, chronic hypertension,
some autoimmune disorders, and diabetes) may impact mul-
tiple the aspects of placentation (stage 1) or may also lead to a
“constrained placenta” or affect maternal vascular responsive-
ness to inflammatory factors produced by the placenta in late
pregnancy (stage 2) [12].
The Glomerular Damage in Preeclamptic Patients
The main characteristic glomerular lesions of PE are
endotheliosis and podocytopathy [13].
Glomerular endotheliosis (a term coined by Spargo et al.
[14]) is characterized by enlarged glomeruli, glomerular en-
dothelial swelling, and vacuolization, with the loss of endo-
thelial fenestrations and evident glomerular capillary occlu-
sion, but it is not usually accompanied by prominent capillary
thrombi [15, 16]. The swollen endothelial cytoplasm en-
croaches upon the lumen of the glomerular capillaries, con-
tributing to tuft ischemia. Double contours of the basement
membrane are seen by light microscopy and electron micros-
copy, and the immunofluorescence may reveal fibrin deposits
in glomeruli [17].
The link between endotheliosis and the development of
proteinuria is not completely clear, but a central role seems
Curr Hypertens Rep (2020) 22:36
to be played from VEGF, that is an angiogenic and survival
factor for endothelial cells and, in the kidney, is primarily
produced by glomerular podocytes, through paracrine and au-
tocrine secretion [13]. Podocyte-derived VEGF and its bind-
ing to VEGFR on endothelial cells (ECs) induces their matu-
rity and is required for structural integrity of the glomerular
endothelium, while its binding on podocytes is essential in
preserving glomerular filter integrity [18, 19].
The down-regulation of circulating VEGF, or its neutraliza-
tion by antagonist (sFlt-1), is responsible for damage of the ECs
and, subsequently, glomeruli [20]; it is one of the pathophysio-
logic mechanisms involved in the development of proteinuria.
In addition, it has been postulated that damaged ECs induce
clotting and vessel occlusion, as well as starting to produce
endothelin-1 (ET1), a strong vasoconstrictor agent that is a
possible link between endothelial dysfunction and altered
podocytes integrity and function. Indeed, its release leads to
consequent nephrin shedding from podocytes [21–23••].
Nephrin is a specific podocyte slit-diaphragm protein involved
in the regulation of cell polarity and cytoskeletal stabilization;
its loss in the urine of preeclamptic patients is associated with
increased oxidative stress, a factor contributing to podocyte
injury and podocyte protein shedding in PE [23••].
As revealed by Wang et al. [24, 25], this podocyte shedding
is associated with the disease severity, and the urine levels of
nephrin and of other podocyte-associated proteins are corre-
lated with the amount of proteinuria in women with PE.
Preeclampsia and Chronic Kidney Disease
A major problem in the mother is the long-term consequences
of PE on the kidney. Indeed, PE may lead to permanent kidney
damage in women without pre-existing CKD [26], and as
shown by Covella et al. [27••], preeclamptic women have an
increased risk of development of end-stage renal disease
(ESRD) in the long term.
On the other hand, as described in Fig. 1, women with GNs
and/or chronic kidney disease have a substantially increased
risk for the development of placental disease, and hence, PE.
[28–30].
Glomerulonephritis
IgA Nephropathy: The most Common Primary
Glomerulonephritis in Pregnancy
Immunoglobulin A nephropathy (IgAN) is the most common
GN in developed countries [31]. The peak incidence of IgAN
is in young adults aged 20–30 years, so patients with IgAN
commonly become pregnant.
Curr Hypertens Rep (2020) 22:36
Preeclampsia
Systemic endotheliosis
Increased circulating
sFlt-1 and sENG
Decreased circulating
VEGF and PlGF
Reduced placental
perfusion
Shallow Constrained Maternal vascular
placentation placenta hyperresponsiveness
(EO-PE) (LO-PE) (LO-PE)
Excessive pre-pregrancy maternal
vascular inflammation
Glomerulonephritis
Fig. 1. in PE, the dysfunctional utero-placental perfusion leads to an
imbalance between angiogenic and anti-angiogenic factors producing
systemic endotheliosis and kidney damage. Glomerular endotheliosis
and podocyte shedding could be responsible of the onset of GNs, or
flares or CKD progression. At the same time, renal diseases (e.g., GNs)
Although the impact of IgAN on pregnancy outcomes,
among which PE, is well described, there are no data about
the specific effect of PE on the progression of IgAN.
Wang at al. [32••] conducted a meta-analysis of the renal
and pregnancy outcomes in women with IgAN. The study
included more than 1000 participants, from 9 cohort or case-
control studies (8 of which were conducted in Asia). They
evaluated the effect of pregnancy on IgAN progression, as
well as the effect of kidney disease on pregnancy outcomes.
Results showed that pregnancy in CKD stages 1–3 did not
increase the risk for kidney disease progression in IgAN pa-
tients, but they could not conclude that gestation has no ad-
verse effects on the renal progression of IgAN patients with
CKD 4–5 due to the lack of relevant studies. Finally, in this
study, women with IgAN had higher rates of PE compared
with the general population (9.2 vs 1.9%) [32••].
Other data on the link between IgAN and PE were reported
in a recent systematic review by Piccoli et al. [33]. In this
meta-analysis the authors included 13 case series reporting
on 581 IgAN women with 729 pregnancies and 562 non-
pregnant controls. Results showed that pregnancy in women
with IgAN was not associated with a higher risk of progres-
sion of kidney disease, possibly due to the overall preserved
kidney function at baseline.
However, this meta-analysis identified a particularly high
risk of PE in women with IgAN, showing an over ten-fold
increase compared to the low-risk population, while the in-
creased risk of preterm birth and the incidence of newborns
Page 3 of 7 36
Glomerular endotheliosis Podocyte shedding
Kidney damage
Glomerulonephritis
represent a pre-pregnancy condition that cause maternal vascular
inflammation. This can impact multiple aspects of placentation (EO-PE)
as well as may affect maternal vascular responsiveness to inflammatory
factors produced by the placenta, especially in the third trimester of
pregnancy, or can lead to a constrained placenta (LO-PE) [12].
with low birth weight were doubled, suggesting that PE oc-
curred later (LO-PE or “maternal” form of PE) [33, 34].
This increased risk of PE in IgAN patients could be ex-
plained by considering that this GN is characterized by elevat-
ed sFlt-1 plasma levels, a factor responsible for systemic en-
dothelial cell injury, but further research is needed to better
understand this relationship [35•].
Against this scenario, although the risk for adverse mater-
nal or fetal outcomes is higher compared with the general
population, pregnancy can be considered in patients with
IgAN, especially in those with preserved kidney function,
but they need close monitoring by a nephrologist and an ob-
stetrician, in particular in the late phases of pregnancy.
Focal Segmental Glomerulosclerosis
and Preeclampsia: Which Came First?
The link between focal segmental glomerulosclerosis (FSGS)
and PE has long been known [36]. Traditionally, it is generally
asserted that PE resolves some days to weeks after delivery.
However, in some women, the kidney injury persists even
after the pregnancy.
Suzuki et al. conducted a retrospective cohort study includ-
ing 133 renal biopsies performed in postmenopausal women
(between the ages of 45–60). They discovered 37 women with
a history of PE, and of these, 8 demonstrated FSGS on renal
biopsy. By contrast, of the 96 women with no history of PE,
only one FSGS was recorded as the final biopsy diagnosis,
 36 Page 4 of 7
demonstrating a strong link between PE and FSGS in post-
menopausal woman with kidney disease [37].
Although the mechanism underlying the relationship be-
tween FSGS and PE is unclear, hyperfiltration stress, which
characterizes pregnancy, has been identified as a potential risk
factor for the development of FSGS, mostly in women born
with very low birth weight, a population known to have a
reduced number of nephrons [38].
Furthermore, although PE is characterized by an increased
shedding of podocytes into the urine, the number of glomer-
ular podocytes is unaffected, suggesting an increased
podocytes turnover [39]. Indeed, Penning et al. showed that
the lost podocytes were replaced by progenitor cells of the
parietal epithelial cells, but they supposed that under certain
conditions such as PE, this replacement mechanism cannot
compensate fully, leading to FSGS [40].
On the other hand, FSGS with initial and indolent features,
presenting for the first time during pregnancy, may be masked
and misdiagnosed as PE, and moreover, the latter may make
manifest or be superimposed upon a pre-existing GN [41].
Lupus Nephritis: A Challenge for the Nephrologist
Systemic lupus erythematosus (SLE) is an autoimmune dis-
ease that mostly affects women of child-bearing age. The
changing immunological status occurring in pregnant women
may influence the outcome of patients with lupus nephritis
(LN) [42]. Over time, pregnancy outcomes in SLE patients
have improved thanks to multidisciplinary management, preg-
nancy planning, and monitoring [43••]. However LN, espe-
cially in its active phase, is still considered predictive of a poor
pregnancy and maternal outcome [44]. In both LES and pre-
eclampsia, similar histopathological placental findings are ob-
served, suggestive of the derangements in implantation, vas-
cular remodeling, and immune regulation. Histological data
show a large neutrophilic infiltrate in the placental tissue of
SLE pregnancies, as well as in preeclamptic women, while
this common feature of both processes is not present in
healthy pregnancies. This is related to placenta inflammation
and vasculopathy [45] and could explain how SLE increases
the risk of PE.
An Italian prospective multicenter study, conducted in 61
pregnant women affected by LN, showed that PE developed
in six pregnancies (8.4%) and was predicted by prior LN,
longer disease duration, and hypertension [46, 47].
Moreover, the incidence of PE seems to be correlated with
the histological LN class: patients with proliferative disease
on renal biopsy (class III or IV) have a higher incidence of PE
compared to those with non-proliferative disease (class II or
V) and to pregnant lupus patients without nephropathy [48,
49].
Differentiating LN, or a flare, from PE is often challenging
for the nephrologist, but usually in LN, the new onset
Curr Hypertens Rep (2020) 22:36
hypertension and proteinuria are accompanied by a reduction
of complement levels and increased double stranded DNA
(dsDNA) antibody levels [50]. The percentage of flares inci-
dence in pregnant women with LN depends on the study, but
some have reported values as high as 19.7% [46] or 25.6%
[51]. In any case, prior LN and a flare during pregnancy in-
crease the risk of PE [50, 51].
In regards to the impact of pregnancy on the long-term
outcome of LN, Gianfreda et al. [52••] conducted a retrospec-
tive study including 32 women with LN with a 10-year fol-
low-up after their first pregnancy and 64 matched controls
with the same follow-up, who had never had a pregnancy.
Between the two groups, there was no difference in CKD free
survival curves during the 10-year follow-up. In both groups
the temporal trend, based on the annual evaluation of the glo-
merular filtration rate (GFR) and serum creatinine, shows that
women who gave birth persistently maintained better values
of renal function than controls.
In conclusion, even if pregnancy in SLE women is still not
risk-free for either the mother or the baby, thanks to precon-
ception counseling, planned pregnancies, an early detection
and treatment of complications, women with LES can have
safe and successful pregnancies [53].
Diabetic Nephropathy and Preeclampsia: A Close
Relationship
Women affected by type 1 or type 2 diabetes mellitus (DM)
still have high rates of adverse pregnancy outcomes compared
with the general population [54]. Women with diabetic ne-
phropathy (DN) are more likely to have an increased risk of
hypertensive disorders of pregnancy, and of fetal preterm
birth, intrauterine growth restriction, and perinatal mortality
[55].
In particular, the prevalence of PE in diabetic women with
DN is 35–64% [56], compared with 9–17% in women with
DM without nephropathy [57].
Poor glycemic control, nulliparity, reduced kidney func-
tion, and elevated blood pressure are risk factors for PE [58].
In addition, a pre-existing endothelial injury in women with
DM, manifesting with microalbuminuria, appears to be related
to the development of PE [59].
How the onset of PE can affect DM has been described in a
retrospective study by Gordin et al. [60]. The authors enrolled
203 women with type 1 DM and examined the long-term
effects of PE in the development of diabetic complications
later in life. Women who had PE were more likely to manifest
DN compared to women who had a regular pregnancy course
(42% vs 9%).
A faster decline in renal function was observed in a small
retrospective case series of diabetic women with GFR <
40 mL/min/1.73 m2 and proteinuria > 1 g/die, compared with
before conception. The presence of both risk factors, but not
Curr Hypertens Rep (2020) 22:36
Table 1. the effect of PE/pregnancy on maternal renal disease and the effect of specific GN on PE.
GN The effect of specific GN on PE
IgAN The presence of IgAN is associated with a specifically
high risk of PE (incidence: ~ 9%) [32••, 33, 34].
FSGS FSGS is the most common diagnosis in postpartum-related
biopsies [66, 67••].
LN Pregnant women with LN show an increased incidence
of PE (~ 8%) [46, 47]
DN DN is associated with high rates of PE (35%–64%)
[56] versus a PE incidence in women with DM without
nephropathy of 9–17% [57].
GN: glomerulonephritis; IgAN: IgA Nephropathy; FSGS: focal segmental glomerulosclerosis; LN: lupus nephritis; DM: diabetic nephropathy.
of either alone, also predicted a shorter time to dialysis therapy
or GFR halving, and low fetal birth weight [61].
Other Glomerulonephritis Forms and Preeclampsia
The literature assessing pregnancy risk associated with other
forms of primary GNs is limited and dated [62–64]. In gener-
al, severe hypertension, advanced CKD, and active nephritis
are associated with higher rates of PE, increased premature
delivery, small for gestational age births, and accelerated loss
of renal function [65].
In view of these data, in women affected by GN, with or
without CKD, control of the glomerular disease is desirable
before planning a pregnancy. However, even if some studies
have been conducted, additional research about the correlation
between these primary GNs and PE is needed.
Conclusions
In women with underlying renal disease, both the effects of
pregnancy on the maternal renal disease and the effect of the
renal disease on the pregnancy outcome should be considered
(Table 1). The incidence of PE secondary to primary glomer-
ular disease is uncertain and changes according to the histo-
logical findings and severity of the renal dysfunction, also due
to the difficulty in diagnosing and differentiating these dis-
eases, that can also be coexisting.
On the other hand, pregnancy and particularly PE may also
accelerate the progression of the maternal GN, due to this
“stress test” for the kidney. Although a bidirectional correla-
tion between some GNs (e.g., IgAN, FSGS, LN, and DN) and
PE is demonstrated, the data for other forms of primary GNs
are limited and further large studies are warranted.
Undoubtedly, close collaboration between a multidisciplinary
team of obstetricians and nephrologists is essential to establish
the correct diagnosis and safely manage these vulnerable
women and fetuses: an incorrect diagnosis of PE will result
in an unnecessarily urgent and premature delivery, and the
Page 5 of 7 36
The effect of PE/Pregnancy on GNs
Pregnancy does not increase renal progression in patients
with IgAN-CKD stages 1–3 [33].
PE may induce the development of FSGS [38].
The percentage of flares incidence in pregnant women with
LN reaches values of 19.7% [46] or 25.6% [51].
Women with DM without renal involvement and pregnancies
complicated by PE were more likely to develop DN than
women with DM and uncomplicated pregnancies [60].
failure to detect an overlapping PE may have severe maternal
and fetal outcomes.
Compliance with Ethical Standards
Conflict of Interest The authors declare no conflicts of interest relevant
to this manuscript.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
References
Papers of particular interest, published recently, have been
highlighted as:
• Of importance
•• Of major importance
1. Say L, et al. Global causes of maternal death: a WHO systematic
analysis. Lancet Glob Health. 2014;2(6):e323–33.
2. Kongwattanakul K, et al. Incidence, characteristics, maternal com-
plications, and perinatal outcomes associated with preeclampsia
with severe features and HELLP syndrome. Int J Womens Health.
2018;10:371–7.
3. Phipps E, et al. Preeclampsia: updates in pathogenesis, definitions,
and guidelines. Clin J Am Soc Nephrol. 2016;11(6):1102–13.
4. Staff AC. The two-stage placental model of preeclampsia: an
update. J Reprod Immunol. 2019;134–135:1–10.
5. Xiong X, et al. Impact of preeclampsia and gestational hyperten-
sion on birth weight by gestational age. Am J Epidemiol.
2002;155(3):203–9.
6. Ness RB, Roberts JM. Heterogeneous causes constituting the single
syndrome of preeclampsia: a hypothesis and its implications. Am J
Obstet Gynecol. 1996;175(5):1365–70.
7. Redman CW. Current topic: pre-eclampsia and the placenta.
Placenta. 1991;12(4):301–8.
8. Armaly Z, et al. Preeclampsia: novel mechanisms and potential
therapeutic approaches. Front Physiol. 2018;9:973.
9. Burton GJ, et al. Rheological and physiological consequences of
conversion of the maternal spiral arteries for uteroplacental blood
flow during human pregnancy. Placenta. 2009;30(6):473–82.
 36 Page 6 of 7
10. Redman CW, Sargent IL, Staff AC. IFPA Senior Award Lecture:
making sense of pre-eclampsia - two placental causes of
preeclampsia? Placenta. 2014;35(Suppl):S20–5.
11. Sircar M, Thadhani R, Karumanchi SA. Pathogenesis of
preeclampsia. Curr Opin Nephrol Hypertens. 2015;24(2):131–8.
12. Staff AC, et al. Preeclampsia and uteroplacental acute atherosis:
immune and inflammatory factors. J Reprod Immunol. 2014;101–
102:120–6.
13. Moghaddas Sani H, Vahed SZ, Ardalan M. Preeclampsia: a close
look at renal dysfunction. Biomed Pharmacother. 2019;109:408–
16.
14. Spargo BH, et al. The renal lesion in preeclampsia. Perspect
Nephrol Hypertens. 1976;5:129–37.
15. Stillman IE, Karumanchi SA. The glomerular injury of
preeclampsia. J Am Soc Nephrol. 2007;18(8):2281–4.
16. Hussein W, Lafayette RA. Renal function in normal and disordered
pregnancy. Curr Opin Nephrol Hypertens. 2014;23(1):46–53.
17. Johnson, RJ. Comprehensive clinical nephrology 6th Edition.
Elsevier. 2019. SECTION VIII Pregnancy and Renal Disease,
Chapter 42 - 43, p. 502–522.
18. Eremina V, et al. Glomerular-specific alterations of VEGF-A ex-
pression lead to distinct congenital and acquired renal diseases. J
Clin Invest. 2003;111(5):707–16.
19. Eremina V, et al. VEGF inhibition and renal thrombotic
microangiopathy. N Engl J Med. 2008;358(11):1129–36.
20. Galvis-Ramirez MF, Quintana-Castillo JC, Bueno-Sanchez JC.
Novel insights into the role of glycans in the pathophysiology of
glomerular endotheliosis in preeclampsia. Front Physiol. 2018;9:
1470.
21. Collino F, et al. Preeclamptic sera induce nephrin shedding from
podocytes through endothelin-1 release by endothelial glomerular
cells. Am J Physiol Renal Physiol. 2008;294(5):F1185–94.
22. Craici IM, et al. Advances in the pathophysiology of pre-eclampsia
and related podocyte injury. Kidney Int. 2014;86(2):275–85.
23.•• Wang Y, et al. Loss of slit protein nephrin is associated with re-
duced antioxidant superoxide dismutase expression in podocytes
shed from women with preeclampsia. Physiol Rep. 2018;6(13):
e13785 This paper shows that reduced nephrin and podoplanin
expression is associated with increased oxidative stress, that
plays a significant role in inducing podocyte protein shedding
in PE.
24. Wang Y, et al. Increased urinary levels of podocyte glycoproteins,
matrix metallopeptidases, inflammatory cytokines, and kidney inju-
ry biomarkers in women with preeclampsia. Am J Physiol Renal
Physiol. 2015;309(12):F1009–17.
25. Zhao S, et al. Altered nephrin and podoplanin distribution is asso-
ciated with disturbed polarity protein PARD-3 and PARD-6 expres-
sions in podocytes from preeclampsia. Reprod Sci. 2011;18(8):
772–80.
26. Ponticelli C, Moroni G. Is preeclampsia a risk for end-stage renal
disease? Kidney Int. 2019;96(3):547–9.
27.•• Covella B, et al. A systematic review and meta-analysis indicates
long-term risk of chronic and end-stage kidney disease after
preeclampsia. Kidney Int. 2019;96(3):711–27 This is a very useful
systematic review and a meta-analysis. The authors report that
the relative risk of ESRD was significantly greater (6.35) in 110,
803 women who had PE in comparison with 2,680,929 control
subjects without PE.
28. Di Marco GS, et al. The soluble VEGF receptor sFlt1 contributes to
endothelial dysfunction in CKD. J Am Soc Nephrol. 2009;20(10):
2235–45.
29. Foster RR. The importance of cellular VEGF bioactivity in the
development of glomerular disease. Nephron Exp Nephrol.
2009;113(1):e8–e15.
Curr Hypertens Rep (2020) 22:36
30. Zhang JJ, et al. A systematic review and meta-analysis of outcomes
of pregnancy in CKD and CKD outcomes in pregnancy. Clin J Am
Soc Nephrol. 2015;10(11):1964–78.
31. Floege J, Amann K. Primary glomerulonephritides. Lancet.
2016;387(10032):2036–48.
32.•• Wang F, et al. Renal outcomes of pregnant patients with immuno-
globulin A nephropathy: a systematic review and meta-analysis.
Am J Nephrol. 2019;49(3):214–24 This is a large recent meta-
analysis including 145 renal events in 1198 participants, in
which the authors concluded that pregnancy did not accelerate
kidney disease deterioration in women with IgAN in stages of
chronic kidney disease 1–3.
33. Piccoli GB, et al. A systematic review on materno-foetal outcomes
in pregnant women with IgA nephropathy: a case of "late-mater-
nal" preeclampsia? J Clin Med. 2018;7(8).
34. Piccoli GB, et al. Maternal-foetal outcomes in pregnant women
with glomerulonephritides. Are all glomerulonephritides alike in
pregnancy? J Autoimmun. 2017;79:91–8.
35.• Zhai YL, et al. Elevated soluble VEGF receptor sFlt-1 correlates
with endothelial injury in IgA nephropathy. PLoS One. 2014;9(7):
e101779 This is a very interesting study, in which the authors
show that VEGF/sFlt-1 levels are significantly lower in IgAN
patients than healthy volunteers. The plasma sFlt-1 levels are
significantly elevated and correlated with proteinuria, hyper-
tension, and vWF levels.
36. Gaber LW, Spargo BH. Pregnancy-induced nephropathy: the sig-
nificance of focal segmental glomerulosclerosis. Am J Kidney Dis.
1987;9(4):317–23.
37. Suzuki H, Inoue T. Renal diseases associated with pre-eclampsia in
postmenopausal women. J Clin Nephrol Res. 2014;1(2):1011.
38. Orozco Guillen OA, et al. Collapsing lesions and focal segmental
glomerulosclerosis in pregnancy: a report of 3 cases. Am J Kidney
Dis. 2019;74(6):837–43.
39. Garovic VD. The role of the podocyte in preeclampsia. Clin J Am
Soc Nephrol. 2014;9(8):1337–40.
40. Penning ME, et al. Association of preeclampsia with podocyte
turnover. Clin J Am Soc Nephrol. 2014;9(8):1377–85.
41. Oliverio AL, et al. Renal complications in pregnancy preceding
glomerulonephropathy diagnosis. Kidney Int Rep. 2019;4(1):
159–62.
42. Jara LJ, et al. Risk factors of systemic lupus erythematosus flares
during pregnancy. Immunol Res. 2014;60(2–3):184–92.
43.•• Andreoli L, et al. EULAR recommendations for women's health and
the management of family planning, assisted reproduction, preg-
nancy and menopause in patients with systemic lupus erythemato-
sus and/or antiphospholipid syndrome. Ann Rheum Dis.
2017;76(3):476–85 This systematic review of evidence provides
recommendations for women's health issues in SLE and was
developed using an evidence-based approach followed by ex-
pert consensus.
44. Yang H, et al. Pregnancy-related systemic lupus erythematosus:
clinical features, outcome and risk factors of disease flares–a case
control study. PLoS One. 2014;9(8):e104375.
45. Marder W, et al. Placental histology and neutrophil extracellular
traps in lupus and pre-eclampsia pregnancies. Lupus Sci Med.
2016;3(1):e000134.
46. Moroni G, et al. Maternal outcome in pregnant women with lupus
nephritis. a prospective multicenter study. J Autoimmun. 2016;74:
194–200.
47. Moroni G, et al. Fetal outcome and recommendations of pregnan-
cies in lupus nephritis in the 21st century. a prospective multicenter
study. J Autoimmun. 2016;74:6–12.
48. Carmona F, et al. Class III-IV proliferative lupus nephritis and
pregnancy: a study of 42 cases. Am J Reprod Immunol.
2005;53(4):182–8.
Curr Hypertens Rep (2020) 22:36
49. Rodrigues BC, et al. The impact of different classes of lupus nephri-
tis on maternal and fetal outcomes: a cohort study of 147
pregnancies. Lupus. 2019;28(4):492–500.
50. Lightstone L, Hladunewich MA. Lupus nephritis and pregnancy:
concerns and management. Semin Nephrol. 2017;37(4):347–53.
51. Smyth A, et al. A systematic review and meta-analysis of pregnancy
outcomes in patients with systemic lupus erythematosus and lupus
nephritis. Clin J Am Soc Nephrol. 2010;5(11):2060–8.
52.•• Gianfreda D, et al. Does pregnancy have any impact on long term
damage accrual and on the outcome of lupus nephritis? J
Autoimmun. 2017;84:46–54 This retrospective cohort study
aims at establishing the long-term impact of pregnancy on renal
and extra renal SLE activity, on the development of CKD, and
on the increase of damage in LN patients.
53. Mecacci F, et al. Preeclampsia in pregnancies complicated by sys-
temic lupus erythematosus (SLE) nephritis: prophylactic treatment
with multidisciplinary approach are important keys to prevent ad-
verse obstetric outcomes. J Matern Fetal Neonatal Med.
2019;32(8):1292–8.
54. Berger H, Gagnon R, Sermer M. Guideline No. 393-diabetes in
pregnancy. J Obstet Gynaecol Can. 2019;41(12):1814–25 e1.
55. Bramham K. Diabetic nephropathy and pregnancy. Semin
Nephrol. 2017;37(4):362–9.
56. Klemetti MM, et al. Obstetric and perinatal outcome in type 1
diabetes patients with diabetic nephropathy during 1988–2011.
Diabetologia. 2015;58(4):678–86.
57. Bell R, et al. Trends in prevalence and outcomes of pregnancy in
women with pre-existing type I and type II diabetes. BJOG.
2008;115(4):445–52.
58. Damm JA, et al. Diabetic nephropathy and microalbuminuria in
pregnant women with type 1 and type 2 diabetes: prevalence, anti-
hypertensive strategy, and pregnancy outcome. Diabetes Care.
2013;36(11):3489–94.
Page 7 of 7 36
59. Jensen DM, et al. Microalbuminuria, preeclampsia, and preterm
delivery in pregnant women with type 1 diabetes: results from a
nationwide Danish study. Diabetes Care. 2010;33(1):90–4.
60. Gordin D, et al. Pre-eclampsia but not pregnancy-induced hyper-
tension is a risk factor for diabetic nephropathy in type 1 diabetic
women. Diabetologia. 2007;50(3):516–22.
61. Imbasciati E, et al. Pregnancy in CKD stages 3 to 5: fetal and
maternal outcomes. Am J Kidney Dis. 2007;49(6):753–62.
62. Uchino E, et al. Membranous nephropathy associated with preg-
nancy: an anti-phospholipase A2 receptor antibody-positive case
report. CEN Case Rep. 2018;7(1):101–6.
63. Ope-Adenuga S, Moretti M, Lakhi N. Management of membranous
glomerulonephritis in pregnancy: A multidisciplinary challenge.
Case Rep Obstet Gynecol. 2015;2015:839376.
64. De Castro I, et al. Nephrotic syndrome in pregnancy poses risks
with both maternal and fetal complications. Kidney Int.
2017;91(6):1464–72.
65. Blom K, et al. Pregnancy and glomerular disease: a systematic
review of the literature with management guidelines. Clin J Am
Soc Nephrol. 2017;12(11):1862–72.
66. Day C, et al. The role of renal biopsy in women with kidney disease
identified in pregnancy. Nephrol Dial Transplant. 2008;23(1):201–
6.
67.•• Webster P, et al. A multicenter cohort study of histologic findings
and long-term outcomes of kidney disease in women who have been
pregnant. Clin J Am Soc Nephrol. 2017;12(3):408–16 This study
compares causes and long-term renal outcomes of biopsy-
proven renal disease identified during pregnancy or within 1
year postpartum, with non those in pregnant women.
Publisher’s Note Springer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.