Pediatr Nephrol (2012) 27:1213–1219
DOI 10.1007/s00467-011-1963-1
REVIEW
The influence of gender and sexual hormones on incidence
and outcome of chronic kidney disease
Sebastian Kummer & Gero von Gersdorff &
Markus J. Kemper & Jun Oh
Received: 28 April 2011 / Revised: 19 June 2011 / Accepted: 19 June 2011 / Published online: 16 July 2011
# IPNA 2011
Abstract It has long been known that the female sex is
associated with a better clinical outcome in chronic renal
diseases. Although many experimental, clinical, and epide-
miological studies in adults have attempted to explain the
difference in disease progression between females and
males, a definitive understanding of the underlying mech-
anisms is still lacking. Hormone-modulating therapies are
being increasingly used for various indications (such as
post-menopausal hormone replacement, estrogen- or
androgen-receptor antagonists for cancer therapy). There-
fore, a deeper knowledge of the interaction between sexual
hormones and progression of kidney disease is important,
as hormone-modulating therapy for non-renal indication
may influence both kidney structure and function. In
addition, specific modulation of the sexual hormone
system, such as the use of selective estrogen receptor
modulators, may represent a therapeutic option for patients
with renal diseases. Although conclusive data on this topic
in the pediatric population are still lacking, the aim of this
review is to familiarize pediatric nephrologists with gender-
specific differences in renal physiology, pathophysiology,
S. Kummer (*)
Department of General Pediatrics, University Children’s Hospital,
Moorenstr. 5,
40225 Duesseldorf, Germany
e-mail: sebastian.kummer@med.uni-duesseldorf.de
G. von Gersdorff
Renal Division, Department of Medicine,
University Hospital Cologne,
Cologne, Germany
M. J. Kemper : J. Oh
Department of Pediatric Nephrology,
University Medical Center Hamburg-Eppendorf,
Hamburg, Germany
and the progression of kidney diseases. Experimental
models that analyze the effects of sexual hormones on
renal structure and function are discussed. It is hoped that
this review will stimulate researchers to focus on pediatric
studies that will provide a deeper insight into the interaction
of gender hormones and the kidney both before and during
puberty.
Keywords Sex . Disease progression . Risk factor . FSGS .
Renal disease
Epidemiology: gender-dependent incidence
and progression of chronic renal diseases
In patients with chronic renal diseases, the prevalence of
end-stage renal disease (ESRD) is higher in males than in
females (Fig. 1). These gender differences show remarkable
variations with age: when the male-to-female ratio of ESRD
is plotted as a function of age (Fig. 2), there are two peaks.
The first peak appears during infancy and early childhood
and most likely represents renal failure due to congenital
urologic anomalies, which are predominantly seen in boys.
A second peak appears between ages 40–50 years, when
the activity of gender hormones in women begins to
decline. These gender-linked differences disappear after
the beginning of the menopausal years.
Thus, two different mechanisms can be distinguished,
which may cause the gender differences in renal diseases:
a) Gender-specific incidence of congenital anomalies of
the kidney and urinary tract (CAKUT). These differ-
ences are presumably due to genetic factors. Hormonal
influences are of minor importance since maternal sex
hormones cross the placental barrier easily, thus
1214
Fig. 1 Prevalence of end-stage renal disease in the USA depending
on age and gender (data are taken from the U.S. Renal Data System
2000 Annual Data Report. The National Institutes of Health, NIDDK,
Bethesda, MD)
overriding gender differences in fetal hormone produc-
tion. Therefore, this group of patients is of minor
relevance for the subject of this review.
b) Influences of gender hormones on renal structure and
function. These may either directly affect renal struc-
tures (e.g., via gender hormone receptors on renal cells)
or indirectly via secondary influence factors (e.g.
cardiovascular system).
A multitude of epidemiologic studies have analyzed the
interplay of gender and chronic renal diseases. Berg et al.
demonstrated that the physiological decline of renal
function during aging is significantly slower in healthy
females than in males [loss of glomerular filtration rate
(GFR) of 1.4 ml/min/1.73 m2 per decade in healthy female
kidney donors compared to 8.7 ml/min/1.73 m2 per decade
in males, as measured by inulin clearance] [1]. These
Fig. 2 Male-to-female ratio of end-stage renal disease as a function of
age. The first peak during early infancy is caused by a male
predominance in congenital anomalies of the kidney and urinary tract
(CAKUT), representing the most frequent cause for end-stage disease
in infancy. The second peak is located between menarche and
menopause, when hormonal influences are the most pronounced (data
taken from the U.S. Renal Data System 2000 Annual Data Report.
The National Institutes of Health, NIDDK, Bethesda, MD)
Pediatr Nephrol (2012) 27:1213–1219
differences were detectable through the whole age spectrum
(21.5–67.1 years, median 38.5 years).
The largest meta-analysis investigating gender differ-
ences in chronic renal diseases compared data collected on
11,345 patients participating in a total of 68 studies [2].
Female patients with polycystic kidney diseases, membra-
nous glomerulonephritis (MGN), and nephropathies of
unknown etiology had a favorable renal outcome compared
to their male counterparts. The clinical outcomes were
ESRD requiring renal replacement therapy, age of initiation
of renal replacement therapy, and changes in measured
GFR. The influence of menopause was not addressed in
this study due to the heterogeneous patient population.
Cattran and colleagues further showed a significant
benefit of female gender in 395 patients with MGN and
370 patients with focal-segmental glomerulosclerosis
(FSGS) [3]. They measured the decrease in creatinine-
based clearance and the overall survival of renal function.
In particular, the negative impact of proteinuria on the rate
of disease progression was clearly lower in women, and this
interaction was independent of blood pressure.
Renal involvement in several systemic diseases also
shows distinct gender-dependent features. For example, renal
involvement occurs more frequently and more severely in
males with systemic lupus erythematodes (SLE), although
SLE incidence is considerably higher in females [4]. Data on
renal involvement in diabetes mellitus (DM) type 2 are
conflicting, likely due to the lack of multivariate analyses of
blood pressure and pre-/postmenopausal age influencing
gender-dependent factors. Therefore, consistent evidence is
still missing on potential gender differences in the renal
involvement of DM type 2 patients.
A large meta-analysis of 27,805 adult patients with type
I DM showed an association of male gender with an
increased risk for an early development of diabetic
nephropathy [5]. Renal involvement was further dependent
on pre- or postpubertal onset of diabetes in children.
Prepubertal diagnosis of diabetes leads to significantly
prolonged latency until the first manifestation of nephrop-
athy. However, gender influences were not studied in this
trial [6].
Epidemiologic studies published to date which have
examined gender differences in renal diseases did not
analyze different racial groups separately. In turn, studies
demonstrating an increased risk of renal disease for several
ethnic groups, such as African Americans, Hispanics,
Native Americans, or Asians, have not specifically
addressed gender differences in these populations [7].
Therefore, it remains unclear whether gender differences
in renal diseases are also dependent on racial background.
Interestingly, the female advantage largely disappears
after the initiation of dialysis therapy, with women having
as poor survival as men despite the continuing worse risk
Pediatr Nephrol (2012) 27:1213–1219
profile of men also during dialysis therapy. The reasons for
this observation have not as yet been fully elucidated, but
may be due to—among others—a more severe impact of
several risk factors on the overall prognosis of women
despite a less frequent occurrence (see [8] for an overview
of this topic).
Gender differences associated with renal
transplantation
It has long been noted that the outcome and survival of
renal grafts is much better in female than in male recipients
[9], suggesting that the influence of the female recipient’s
‘environment’ is protective of the transplanted graft.
In contrast, renal grafts from female donors have been
reported to have an inferior survival rate compared to those
from male donors [10]. Interestingly, in this study, the effect
was observed to be even more pronounced for younger
donors (16–45 years) than for older donors (>45 years). As
an explanation for this finding, the rapid loss of high
premenopausal estrogen levels of the female donor
organism on the removed kidney may compromise graft
function and survival after transplantation into a male
recipient. Another explanation for the inferior survival of
grafts from female donors is provided by the concept of
‘nephron underdosing’: fewer and smaller nephrons may
compromise organ function and survival by overloading the
capacity of individual nephrons. In contrast to early
anatomic studies suggesting larger kidney weight in men,
more recent data do not show any significant differences in
kidney weight when corrected for body weight [11].
Furthermore, the number of glomeruli in females seems to
be equal to that in males [12]. Thus, ‘nephron underdosing’
seems to be of minor importance in terms of gender
differences in renal transplantation. This conclusion is also
supported by a study showing that other transplanted organs
(e.g. heart) show similar drawbacks when taken from
female donors [10]. The same study demonstrated that the
frequency of rejection treatments 1 year after transplanta-
tion was higher when the kidneys were taken from female
donors. Consistent with these findings, Vereerstraten and
coworkers saw a higher incidence of acute rejection
episodes in female kidneys [13]. Both findings point to an
immunological effect, for example, increased immunoge-
nicity of female grafts by the higher expression of HLA
antigens [14].
Gender differences in pediatric renal disease
In children, the prevalence of glomerular diseases, such as
minimal-change glomerulonephritis (MCGN), is slightly
1215
higher in boys than in girls [15]. Furthermore, girls with
steroid-sensitive nephrotic syndrome show a trend towards
less frequent post-pubertal recurrences than males (43 vs.
83%) [16]. However, the general frequency of MCGN
relapses reported in this study was higher than that found in
other studies in which relapses were reported in only 30%
of patients after the initiation of puberty [17].
Kyrieleis et al. demonstrated that therapy with cyclo-
phosphamide of steroid-dependent and frequently relapsing
MCGN in prepubertal girls achieved definite remission
more often compared with boys, although this trend did not
reach statistical significance [18]. Examination of the same
patients again after puberty revealed that, interestingly, of
the 29% patients who developed a relapse, nine were boys
and only three were girls [19]. These data suggest a similar
trend towards a clinical advantage of female gender in
pediatric glomerular diseases.
A retrospective analysis of 4,166 children with chronic
kidney disease (CKD) of different etiologies identified an
association between CKD progression (among others) and
male gender [20]. However, this finding did not show
statistical significance in the multivariate analysis, possibly
due to the heterogeneous spectrum of disease etiologies.
Surprisingly, to the best of our knowledge, there have not
been any subsequent studies specifically focusing on
gender differences in pediatric patients with chronic
glomerular diseases.
Taken together, the available epidemiological data show
a significant benefit of female gender for the prognosis of
renal diseases. In the following part of this review, different
experimental models explaining these gender differences
will be discussed.
Influences of hormones on experimental models of renal
function and disease
Various animal models of renal disease (hypertensive, age-
related, polycystic, and renal mass-reduction) have shown
that the progression of renal injury is faster in male animals
than in their female littermates: as early as 1975 Elma and
colleagues were able to show that male rats spontaneously
develop proteinuria and glomerulosclerosis during aging,
whereas female animals were remarkably resistant against
these changes [21]. In another experiment, disease progres-
sion in male rats could be slowed by estrogen substitution
or orchiectomy [22], suggesting a protective influence of
estrogens and adverse effects of androgens. Similarly,
experimental castration of 5/6 nephrectomized rats pro-
tected male animals against proteinuria, tubulointerstitial
damage, and renal accumulation of fibronectin, whereas
female animals did not show any protective effect after
removal of estrogen influence by ovariectomy [23].
1216
In several other studies reviewed by Neugarten et al.,
estrogen application reduced proteinuria and glomerular
fibrosis after experimental renal damage in different animal
models [24]. In addition, the expression of glomerular
damage markers, such as desmin, in spontaneously hyper-
tensive rats and rats after puromycin treatment could be
attenuated by estrogen treatment [25, 26].
Thus, female sexual hormones generally exhibit protec-
tive effects, while androgens often accelerate disease
progress in animal models of renal disease.
Possible mechanisms explaining gender differences
in the progression of renal disease
Lifestyle factors and nutritional profile
Factors such as physical and psychological stress, smoking,
and especially nutritional factors seem to have a significant
impact on the progression of renal diseases [27]. In
particular, an excessive consumption of protein, sodium,
and phosphate has been shown to be harmful. Dyslipidemia
with high low-density lipoprotein (LDL), low high-density
lipoprotein (HDL), and hypertriglyceridemia [28], as well
as obesity in general [29], further facilitate disease
progression. Compared to men, women have a more
favorable nutritional profile, with higher intakes of fruit,
vegetables, and dietary fibers and lower intakes of fat and
protein [30], and a beneficial serum lipid profile [31, 32].
This may provide significant benefit for the prognosis of
renal diseases.
Uric acid has recently turned out to be another risk factor
for accelerated kidney disease progression—probably me-
diated by increasing the incidence of arterial hypertension
[33]. As uric acid levels are known to be higher in males
than in females [34], this may further contribute to a faster
progression of CKD in men
Blood pressure and intrarenal hemodynamics
Arterial hypertension is significantly associated with a
worse prognosis in CKD [35]. Various studies have shown
that women have a lower mean arterial blood pressure [36]
and a lower incidence of arterial hypertension than age- and
weight-matched men [37]. Interestingly, these differences in
blood pressure level between men and women disappear
after the onset of the menopause [37]. Therefore, hormonal
influences on blood pressure level may substantially affect
the outcome of renal diseases [15].
When adjusted for body weight and body surface, GFR
is identical for both genders in humans and rats [38].
However, intrarenal hemodynamics show gender-specific
reactions on numerous variables. The administration of
Pediatr Nephrol (2012) 27:1213–1219
angiotensin II induced an increase of GFR in men, but not
in women [39]. This difference was explained by the
authors in terms of an enhanced glomerular capillary
pressure as a response to angiotensin II in men, which
was reduced or even absent in women. One possible
molecular mechanism might be that estrogens and andro-
gens both modulate the expression of angiotensinogen,
angiotensin II, angiotensin II receptor, renin, and angioten-
sinogen converting enzyme (ACE) in multiple different cell
types, as shown in cell cultures and animal models [40, 41].
Correspondingly, human studies show an impact of estro-
gens and oral contraceptives on the regulation of the renin–
angiontensin–aldosterone system (RAAS) [42, 43]. In
contrast, endogenous increases in estrogen levels (e.g.,
during pregnancy) are associated with a decrease in arterial
blood pressure despite the activation of RAAS [44]. Taken
together, these data show gender-specific influences on both
the regulation of systemic blood pressure and intrarenal
hemodynamics.
Other influences of the hormonal milieu
Premenopausal application of oral contraceptives as well as
postmenopausal hormone replacement therapy (HRT)
increases microalbuminuria, a marker of early glomerular
damage [45]. In 5,845 postmenopausal women older than
65 years, HRT was also associated with a significantly faster
decline of renal function compared to women without any
HRT [46]. In a subgroup analysis, this effect was limited to
the estrogen monotherapy (additional decline of 1.21 ml/
min/1.73 m2 compared to non-substituted individuals).
Progesterone alone or in combination with estrogens did
not induce an accelerated decline of kidney function.
Moreover, the effect was detectable only for oral adminis-
tration, not for vaginal application, and was independent of
any other co-medications (such as non-steroidal antiphlo-
gistics, ACE inhibitors, angiotensin receptor blockers,
glucocorticoids, cyclosporine, etc.). Unfortunately, it was
not documented whether the therapy was initiated before or
during menopause.
In contrast, other studies have detected a reduced risk
for albuminuria in postmenopausal women on HRT
without further differentiation for the subtype of medica-
tion [47]. In postmenopausal women with DM, HRT also
did not show any effect on albuminuria compared to
women without HRT [48], whereas in premenopausal
patients with DM, HRT was clearly associated with
albuminuria [43]. Experimental data reveal similar dis-
crepancies as epidemiological studies: in animal models,
only continuous application of estrogen throughout a 9-
month period was able to reduce experimentally induced
glomerulosclerosis, while intermittent application every 3
months had no effect [49].
Pediatr Nephrol (2012) 27:1213–1219
One possible explanation for this inconsistency in
experimental and clinical data is the high degree of
heterogeneity in the therapeutic approach to HRT, with a
variety of different hormone subtypes, application forms,
and timing of therapy initiation.
Cellular pathways of sexual hormones and selective
estrogen receptor modulators (SERM)
Numerous studies have shown that gender hormones, in
particular estrogens, have pleiotropic effects on different
cell types through specific cellular receptors. Extensive
investigations in this field have been performed, especially
for neuronal cells and skeletal muscle cells. For example,
the transcription of genes encoding mitochondrial proteins
is modified by estrogen receptor (ER) activation, represent-
ing a strong link between ER signaling and intact
mitochondrial function [50]. One specific example is the
estrogen-induced expression of nuclear respiratory factor-1
(NRF-1), a transcriptional factor that regulates the expres-
sion of nuclear-encoded mitochondrial genes, such as
mitochondrial transcription factor A (TFAM) [51]. This
pathway leads to a coordinated increase in the expression of
the mitochondrial genome and thereby the stimulation of
mitochondrial biogenesis and function. This cellular path-
way could explain why skeletal muscle cells are stabilized
against oxidative damage by estrogens [52] and why
degenerative diseases of muscle cells are associated with a
decrease of estrogen levels [53]. The stabilization of
mitochondrial function has also been shown in ocular lens
epithelium, where estrogen was found to reduce destabili-
zation of mitochondrial membrane potential by oxidative
stress [54]. In addition to these genomic ER effects, ‘non-
classical’ actions via membrane-associated ER are also able
to activate cytoplasmic signaling pathways in a G-protein-
coupled manner. For example, activation of mitogen-
activated protein kinase (MAPK) or phosphatidylinositol
3-OH kinase (PI3K) pathways appears within minutes after
estrogen administration [55, 56]. The MAPK pathway
involves a group of intracellular signaling molecules
comprising three major families with different downstream
effects: extracellular signal-regulated kinase (ERK1/2), p38
MAPK, and c-Jun N-terminal kinases. These pathways
involve a group of intracellular signaling molecules with
impacts on cell proliferation, survival, apoptosis, differen-
tiation, motility, among others. One example of protective
estrogen action is the reduction of apoptotic cell death of
neurons following ischemia by an estrogen-induced activa-
tion of the Raf–MEK–ERK–p90RSK cascade [56]. Inter-
estingly, similar pathways have recently been shown to be
active in podocytes: podocytes isolated, immortalized, and
subsequently analyzed in vitro were observed to show
estrogen-induced modulation of TGFβ- and MAPK-
1217
pathways [57]. Doublier and colleagues demonstrated that
this mechanism also leads to a protection of podocytes
against transforming growth factor beta 1 (TGFβ1)- or
tumor necrosis factor alpha (TNFα)-induced apoptosis in
vitro and in vivo, while testosterone induces podocyte
apoptosis by signaling via androgen receptors [58]. Un-
published data from our group show a corresponding
estrogen-induced protection of podocytes in the model of
puromycin-induced apoptosis. Studies on metastatic cancer
have implicated a novel set of signaling molecules as
potential mediators of estrogens, namely, focal adhesion
kinase (FAK) and paxillin. Both regulate cell adhesion and
the interaction of cytoskeletal components with the extra-
cellular matrix. In podocytes, these proteins have been
shown to be critical for the maintenance of cellular
structures: The interactions of podocytes with the glomer-
ular basement membrane result in increased stability
against proteinuria in FAK knockout mice [59]. Recent
data also show a complex interaction of estrogen signaling
with the activity of FAK, thereby modulating cell motility
via control of the focal adhesion complex turnover in
endothelial cells, breast cancer cells, and endometrial cells.
Further protective influences of estrogens are an inhibited
production of matrix proteins, such as collagen type I and
IV, and stimulation of matrix-degrading enzymes, thereby
reducing glomeruloslerosis [60, 61]. In TGF-β-transgenic
mice, which have an increased susceptibility to extensive
glomerulosclerosis, estrogen substitution significantly
reduces sclerosis [62]. Protective effects have also been
shown for SERM such as tamoxifen and raloxifene. These
substances bind to estrogen receptors with tissue-specific
effects and different binding specificities for ERα or ERβ:
for example, raloxifene has a fourfold higher affinity for
ERα than for ERβ and does not induce endometrial
hyperplasia. In vitro, SERM are able to reduce collagen
synthesis, similar to estrogen [60]. In vivo, renal prognosis
is improved by SERM: raloxifene has very recently been
found to be significantly renoprotective in postmenopausal
women that were treated with this medication for reduction
of bone fractures. In this study, raloxifene-treated women
developed a significantly slower annual increase in serum
creatinine and a lower decrease in GFR [63]. Several
estrogenic effects can also be induced by metabolites of
estradiol, such as catecholestradioles (e.g. 2-hydroxyestradiol
and 4-hydroxyestradiol) [25]. Interestingly, these effects are
independent of ER activation, indicating that additional
independent mechanisms must be involved.
Summary/conclusion
In terms of the incidence and progression of chronic renal
diseases, epidemiological data demonstrate that the female
1218
gender endows patients with significant benefits compared
to the male gender.
In this review, we have presented several factors that
have been evaluated extensively (lifestyle, blood pressure,
and hemodynamics). More recent data also show direct
actions of sexual hormones in the kidney at a cellular level
(e.g., regulation of apoptosis, cytoskeletal dynamics, mito-
chondrial function, nitric oxide signaling). Taken together, a
complex interaction of estrogen effects in combination with
partly adverse androgen effects seems likely, with the
balance of both contributing decisively to the overall renal
prognosis.
However, the clinically most relevant question still
remains to be answered: will this knowledge find any
therapeutic application in the near future? A first attempt
was published in 1955 [64]. Three patients with severe
nephrotic syndrome had complete resolution of symptoms
when treated with an initial course of estrogen application,
but proteinuria recurred after the discontinuation of the
medication. Two women had another course of therapy and
achieved remission again, while the male patient refused to
take these hormones again and died in nephrotic crisis.
Although the substitution of 17β-estradiol does not
provide a reasonable therapeutic option due to significant
side-effects (such as possible tumor induction and femini-
zation), SERM or non-receptor mediated estrogen metabo-
lites may offer promising options for a targeted therapy of
renal diseases. Whether such an approach might also be
extended to the pediatric population with a reasonable
balanced risk profile regarding specific problems of
prepubertal/pubertal patients remains to be determined.
However, increasing awareness of gender aspects may
encourage pediatric nephrologists to consider them as risk
factors and prognostic indicators for renal diseases in the
pediatric population.
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