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American National Kidney Foundation

Journal of
Kidney
Diseases VOL 25, NO 4, APRIL 1995

IN-DEPTH REVIEW

The Impact of Gender on the Progression of Chronic Renal Disease

Sharon R. Silbiger, MD, and Joel Neugarten, MD

0 Observations in experimental animals and in humans have shown that the rate of progression of renal disease
is influenced by gender. Deterioration of renal function in patients with chronic renal disease is more rapid in men
than in women, independent of dices in blood pressure or serum cholesterol levels. In addiion to genetically
determined differences between the sexes in renal structure and function, sex hormones may directly influence
many of the processes implicated in the pathogenesis of renal disease progression. Potential mechanisms include
receptor-mediated effects of sex hormones on glomerular hemodynamics and mesangial cell prolii and
matrix accumulation as well as effects on the synthesis and release of cytokines, vasoactlve agents, and growth
factors. In addition, estrogens may exert potent antioxidant actions in the mesanglal microenvironment, which
may contribute to the protective effect of female gender.
0 19s5 by the National Kidney FQundation, Inc.

INDEX WORDS Gender; kidney disease; mesangial cell; lipids.

T HE RATE OF progression of chronic renal

disease is more rapid in men than in women,
independent of blood pressure or serum choles-
tions in the mesangial microenvironment that
may contribute to the protective effect of female
gender. Similar factors may contribute to gender-
terol levels.lm7 Although the protective effect of associated differences in renal allograft survivaL8
female gender on the development and progres-
sion of atherosclerosis and coronary artery dis- GENDER AND THE PREVALENCE
OF RENAL DISEASE
ease in premenopausal women has been the sub-
ject of extensive clinical and basic science The age- and race-adjusted incidence and
investigation, the relationship between renal dis- prevalence of end-stage renal disease is greater
ease and gender has not been studied in detail. in men than in women9 (Table 1). In particular,
Experimental data do suggest, however, that the men show a higher incidence of end-stage renal
impact of gender on renal disease progression failure caused by glomerulonephritis and hyper-
may reflect both genetically determined differ- tensive glomerulosclerosis.‘”
ences between the sexes in renal structure and
function as well as receptor-mediated direct ef-
fects of sex hormones on mesangial cells. Sex From the Nephrology Division, Department of Medicine,
Montefiore Medical Center, ana’ the Albert Einstein College
hormones may directly influence many of the
of Medicine, Bronx, NY.
processes implicated in the pathogenesis of renal Received June 21, 1994; accepted in revisedform Septem-
disease progression. Potential mechanisms in- ber 12, 1994.
clude receptor-mediated effects of sex hormones Supported by a grant-in-aid from the American Heart As-
on glomerular hemodynamics and mesangial cell sociation, NY-NJ AfJiliate, New York, NY.
Address reprint requests to Joel Neugarten, MD, JD, Mon-
proliferation and matrix accumulation as well as
tejiore Medical Center, Renal Laboratory, Moses 605, I I1
effects on the synthesis and release of cytokines, East 210 St, Bronx, NY 10467.
vasoactive agents, and growth factors. In addi- 0 1995 by the National Kidney Foundation, Inc.
tion, estrogens may exert potent antioxidant ac- 0272-6386/95n504-ooO1$3.oo/o

American Journal of Kidney Diseases, Vol25, No 4 (April), 1995: pp 515-533 515

516 SILBIGER AND NEUGARTEN

Table 1. Influence of Gender on the Prevalence of Renal Disease

Male:Female Ratio Reference

End-stage renal disease 1.4:1 9

ESRD due to glomerulonephritis 1.6:1* 10
ESRD due to hypertensive glomerulosclerosis 1.4-l .6:1’ 10
Minimal change nephrotic syndrome in children 2:l 16,17
Minimal change nephrotic syndrome in adults Equal 16,17
Idiopathic focal glomenrlar sclerosis Slight male predominance 294
Membranous nephropathy 2-3:l 11-13
IgA nephropathy 2.2:1 14,15
Goodpasture’s syndrome 2-3:l 16-20
Membranoproliferative glomerulonephritis Equal 295

Abbreviations: ESRD, end-stage renal disease.

’ Incidence data.

Most immune-mediated primary glomendar
diseases have a predilection for men (Table 1).
Among patients with idiopathic membranous ne-
phropathy,’ l-l3 IgA nephropathy,‘4*15 and minimal
change nephrotic syndrome in children,‘6*‘7 men
and boys outnumber women and girls by two to
three to one. Although the gender distribution of
idiopathic crescentic glomerulonephritis varies in
different series, more than two thirds of those
with pulmonary hemorrhage are male.‘8-20 The
mechanisms responsible for the greater preva-
lence of immune-mediated primary glomerular
disease in men is unclear. Most studies show
that male animals exhibit suppressed rather than
enhanced immune responsiveness and that ad-
ministration of exogenous testosterone is immu-
nodepressing.2’-24 However, these experimental
observations are not amenable to simple interpre-
tations because down-regulation of the immune
response may have differing consequences de-
pending on the nature of the immunologic insult.
Gender and race interact to influence the inci-
dence and prevalence of diabetic nephropathy.
The age-adjusted incidence of end-stage renal
disease attributed to diabetic nephropathy among
persons with diabetes is higher in white men than
in white women but lower in African-American
men than in African-American women.25 The ex-
cess risk in African-American women may re-
flect the extremely high incidence rate of diabetic
renal failure per million population in postmeno-
pausal African-American women.”
It is not known whether greater occupational
exposure to industrial nephrotoxins, such as lead
and hydrocarbons, contributes to the excess risk
for end-stage renal disease in men.26 The resis-
tance of female rats to the development of ne-
phropathy after chronic inhalation of petroleum
products suggests the possibility of gender-re-
lated differences in susceptibility to these
agents.26.27
GENDER AND THE PROGRESSION
OF RENAL DISEASE
Clinical Studies
Female gender confers protection against the
progression of renal disease in humans.lm7 How-
ever, there are insufficient data available to deter-
mine whether gender-related protection occurs at
all ages or selectively in premenopausal women.
Moreover, no data are available regarding the
effects of hormone replacement therapy on the
course of renal disease in women.
Studies of patients with chronic nondiabetic
renal disease suggest that the rate of progression
to end-stage renal failure is more rapid in men
than women (Table 2).le5 Those studies that as-
sess the rate of decline in renal function by mea-
Table 2. Renal Diseases Shown to Progrem
More Rapldly in Men
Reference
Chronic renal disease 1-5
Membranous nephropathy’ 29-40
IgA nephropathy’ 5,47-61
Polycystic kidney disease 71-77
l Not all studies are in agreement.
GENDER AND RENAL DISEASE
suring serum creatinine levels or time until dial-
ysis must be interpreted cautiously. Men ingest
more protein and have a larger muscle mass than
women, which is reflected in an increased rate
of creatinine generation. Thus, differences in cre-
atinine metabolism may contribute to apparent
gender-related differences in renal disease pro-
gression in studies relying only on serum creati-
nine measurements to assess renal function.2s
In a prospective study of 62 men and 51
women with chronic renal disease and a creati-
nine clearance on entry of 10 to 60 mL/min,
Rosman et al2 found that the creatinine clearance
declined 50% more rapidly in men than in
women. Similarly, in a retrospective study of 95
men and 79 women with nondiabetic renal dis-
ease admitted to an end-stage renal disease pro-
gram, Hannedouche et al’ found that men pro-
gressed to renal failure more rapidly than women.
After adjustment for age, blood pressure, and
type of nephropathy, the rate of decline of creati-
nine clearance was nearly 50% more rapid in
men than in women. The Modification of Diet in
Renal Disease Study confirmed the deleterious
effect of male gender on the progression of
chronic renal diseases.4 In this prospective,
multicenter study of 840 primarily nondiabetic
subjects with chronic renal disease who under-
went serial measurements of iothalamate clear-
ance over a mean of 2.2 years, male gender was
identified as a risk factor for more rapid decline
in renal function.4
Most studies suggest that the prognosis of
membranous nephropathy is more favorable in
women than in men.29a Male gender is associ-
ated with a more rapid rate of decline in renal
function and more frequent development of end-
stage renal failure.29V3’-35*37-40 In several other
studies, there was a trend toward more rapid pro-
gression in men, although the number of patients
studied was insufficient to achieve statistical sig-
nificance.30’36 In contrast, a few other studies
failed to find any difference in the rate of progres-
sion of membranous nephropathy between men
and women.4’a Inconsistent results may be ex-
plained by the fact that many of the studies in
both groups were retrospective in nature, did not
use rigorous statistical analysis, or included both
treated and untreated patients followed for vary-
ing periods. However, the adverse effect of male
gender on the outcome of membranous nephrop-
517
athy has recently been confirmed. In a prospec-
tive study of 100 untreated patients with mem-
branous nephropathy, Schieppati et al39 showed
that the probability of retaining renal function
after 8 years of observation was significantly
greater in women than in men.
Numerous studies have evaluated the influence
of gender on the progression of IgA nephropathy;
however, the results are conflicting. Although
many studies suggest that the rate of progression
of IgA nepbropathy is more rapid in men than in
women, 5*474’other studies fail to show an adverse
effect of male gender on the course of the dis-
ease. ‘5*62-70
In a study of 106 men and 47 women
with IgA nephropathy who underwent serial iso-
topic clearance measurements over approxi-
mately 4 years, renal function declined in 57%
of the men, but in only 36% of the women.5
Gender influences both the renal and extram-
nal manifestations of adult polycystic kidney dis-
ease. With one exception, all studies have found
that the rate at which renal failure progresses is
more rapid in affected men.7’-77 Accordingly,
men require maintenance hemodialysis on aver-
age 5.5 years earlier than do women.7’*75 Al-
though the prevalence of hypertension is greater
in affected men, male gender and hypertension
each independently contribute to the more ag-
gressive course observed in men.7’*73
Progressive glomerulosclerosis that accompa-
nies aging may be more pronounced in men than
women; however, not all studies are in
agreement. 78-8oFew data are available regarding
the rate of loss of renal function in aging women.
Animal Models of Renal Injury
Aging male rats develop spontaneous protein-
uria and glomerulosclerosis, whereas females, es-
trogen-treated males, and orchiectomized males
are remarkably resistant to the development of
these abnormalities.8’-88 In contrast to the pro-
gressive age-related loss of renal function seen
in male rats, renal function is well preserved in
aging female rats throughout adulthood and be-
gins to decline only late in life.86*89~90
Ablation of
renal mass greatly accelerates glomerular sclero-
sis and proteinuria in aging male rats. However,
the rate at which renal injury develops is mark-
edly less in ablated females.8’*9’-w Moreover, or-
chiectomy retards and androgen replacement ac-
celerates the development of glomerular injury
518
in male rats subjected to renal ablation (see Ad-
dendum).W7”*95
Studies in the spontaneously hyperlipidemic
Imai rat indicate that male gender may interact
with hyperlipidemia to accelerate renal in-
jury- %.97Despite similar blood pressure and se-
rum cholesterol levels, aging hyperlipidemic
male Imai rats develop proteinuria and progres-
sive glomerular sclerosis at an accelerated rate,
whereas female Imai rats do not develop glomer-
ular injury.% Moreover, administration of estro-
gen to male rats ameliorates renal injury in this
model.%
Conversely, in the Cohen diabetic rat and the
analbuminemic rat, renal disease progression is
more rapid in females and is ameliorated by
ovariectomy or accelerated by estrogen replace-
ment.98-‘0’
GENDER AND RENAL STRUCTURE
AND FUNCTION
Kidney Size
Administration of androgens to some but not
all species of animals causes an increase in kid-
ney weight’02~“9 (reviewed in references 118 and
119). The increase in kidney weight is primarily
attributable to an increase in cortical volume that draw definitive conclusions78~‘35’143*144 (Table 3).
correlates with the preferential induction by an-
drogens of proximal tubular cell hypertro-
phy -92~106~1zo
Androgen-induced renal hypertrophy
is accompanied by increased renal RNA content
and renal protein synthesis.‘03~‘18 Conversely,
castration reduces kidney weight, RNA content,
and protein synthesis.1’4~‘15~118~121 These castra- though the regression lines for glomerular num-
tion-induced changes are reversed by androgen
replacement.‘18~‘21
Kidneys from male animals are larger and
weigh more than female kidneys.106~“7~122~126 tional studies using larger numbers of kidneys
Most animal studies indicate that this gender dif-
ference persists even after correction for differ-
ences in body weight.106,123-125 A preferential in-
crease in renal cortical and proximal tubular
volumes in male rats accounts for most of the
gender-related difference in kidney size and
weight.lM
The influence of androgens on compensatory
renal hypertrophy in animals is modest.127-131An-
drogens cause small increases in compensatory
renal growth when administered to uninephrec-
tomized animals.127*13’ Moreover, castrated rats
and rats with a congenital deficiency of func-
SILBIGER AND NEUGARTEN
tional testosterone receptors exhibit normal com-
pensatory renal gro~th.‘~‘*‘~~*‘~~ In addition, re-
cent studies suggest that the basic mechanisms
involved in compensatory hypertrophy may dif-
fer between the sexes.‘32*133Compensatory renal
growth is growth hormone independent in female
rats, whereas the hypertrophic response is growth
hormone dependent in males.‘32
Men have larger kidneys that women.131~134’40
However, it is unclear whether gender indepen-
dently influences kidney weight after differences
in body surface area are taken into account. Kasi-
ske and Umen134 and Moe11’38 found that after
adjustment for body surface area, corrected kid-
ney weight is identical in men and women. In
contrast, Lattimer’3’ found that corrected kidney
weight was greater in adult men than in adult
women.
Glomerular Number and Size
Whether gender-related differences in glomer-
ular number exist is an issue that may impact on
renal disease progression. In several strains of
rats, no gender difference in glomerular number
has been observed.122*141*‘42Early postmortem
studies in humans analyzed too few kidneys to
In addition, the race of the subjects was not speci-
fied. A more recent study by Nyengaard and
Bendtsen’45 found that kidneys from men had
11% more glomeruli than did kidneys from
women (one outlier excluded; standard error of
the mean approximately 6% in each group). Al-
ber versus age for men and women were not
significantly different, this may merely reflect the
small number of kidneys studied. Thus, addi-
are needed to determine whether gender-related
differences in glomerular number exist.
A recently advanced hypothesis links glomer-
ular hypertrophy to the development of glomeru-
lar sclerosis.146Whether gender differences in the
development of glomerular hypertrophy contrib-
ute to the increased susceptibility of male ani-
mals to renal injury remains to be shown. Despite
the more rapid development of glomerular scle-
rosis in aging male rats and after ablation of renal
mass, several studies have failed to find gender-
related differences in glomerular diameter in in-
tact or ablated animals.91X106+122 In contrast, other
GENDER AND RENAL DISEASE 519

Table 3. Number of Glomeruli in Kidneys from Men and Women

Male Female

No. of Glometuli No. of Glomeruli

n (Xl03 n (x10-3

Hayman and Johnston’” 8 1,173 + 96 3 1,185 ? 61

Moritz and Hayman’ 9 1,320 2 65 5 1,214 2 64
Moore’35 19 730 2 49 10 811 2 48
McLachlan et al.” 19 1,364 2 85 13 1,229 2 94
Nyengaard and Bendtsen’“’ 18 650 2 39 18 584*33

l One outlier value obtained from a male kidney was excluded.

investigators have found that intact and ablated
male animals have larger glomeruli than their
female counterparts’47”48 and that glomerular size
is reduced by castration.“‘95’97”2’,‘47 Moreover,
data are contradictory as to whether administra-
tion of exogenous testosterone induces glomeru-
lar hype~ophy.89,“.95,‘~.‘~‘~‘~’
In studies of human kidneys, one group of
investigators found no gender-associated differ-
ences in glomerular diameter or total glomerular
volume.78,‘36 In contrast, Nyengaard and Bendt-
sen’45 found that glomerular diameter was 20%
larger and total glomerular volume 34% greater
in men than in women. Thus, whether gender
impacts on glomerular number or size to influ-
ence the rate of progression of renal disease is
an unsettled issue.
Renal Hemodynamics
An increase in the glomerular capillary pres-
sure has been linked to hyperfiltration-induced
glomerular injury and progressive deterioration
in renal function.‘49 Thus, gender-related differ-
ences in glomerular hemodynamics might con-
tribute to differential susceptibility to progressive
renal injury. Short-term administration of andro-
gens to oophorectomized female rats increases
glomerular size, glomerular ultrafiltration coef-
ficient, whole-kidney and single-nephron glo-
merular filtration rate, and single-nephron blood
flow in the absence of differences in arterial or
glomerular capillary pressure~.~~However, after
prolonged androgen administration, these changes
plateau or reverse.89
Baylis and co-workers’4’~‘50-‘52 found that, in
comparison with male rats, females have lower
whole-kidney and single-nephron glomerular fil-
tration rates and blood flows and higher afferent
and efferent arteriolar resistances in the absence
of differences in arterial or glomerular capillary
pressures (Table 4). Ovariectomy reduced renal
vascular resistance and increased renal function
to values intermediate between those of male rats
and intact female rats.14’ In addition, gender-re-
lated differences in the response of the renal vas-
culature to cyclooxygenase inhibition were ob-
served in anesthetized animals.‘4’9150~‘5’
On the basis of these observations, Baylis and
Wilson93 suggested that the increased renal vas-
cular resistance seen in female rats may protect
their glomeruli from hyperfiltration-induced in-
jury by blunting elevations in glometular capil-
lary pressure associated with various renal in-
sults. In this regard, female rats subjected to
unilateral nephrectomy and fed a high-protein
diet excrete less protein and have lower glomeru-
lar capillary pressures than similarly treated male
rats.93 Remuzzi et a1,‘22 however, failed to find
any difference in afferent or efferent arteriolar
resistances between male and female rats. These
investigators found that the arterial pressure, re-
nal blood flow, glomerular ultrafiltration coeffi-
cient, and whole-kidney and single-nephron glo-
merular filtration rates were higher in male than
in female rats (Table 4).‘22 Gender-related differ-
ences in renal function persisted after correction
of whole-kidney data for kidney weight.‘22 In
contrast, corrected values did not differ between
the sexes in Baylis’ study.‘22*‘4’
Gender also influences regional renal blood
flow autoregulation in the rat.‘53-‘s5 Autoregula-
tion of outer medullary renal blood flow is im-
paired in female rats compared with males.‘55 In
addition, autoregulation of juxtamedullary glo-
520
Table 4. Glomerular Hemadynamice
AP GFR GFWKW
Remuui et al’22 t t t t
Munger and Baylis’4’ +, t *
Abbreviations: t, increased in males compared
difference between the sexes.
merular blood flow in bydronephrotic kidneys is
also less efficient in females.‘” It also has been
observed that papillary blood flow is lower in
male rats than in female rats or in castrated
males.‘56 In addition, replacement testosterone
reverses the increase in papillary flow associated
with castration.‘53 A role for vasodilatory prosta-
glandins in mediating these phenomena is sug-
gested by the finding that cyclooxygenase inhibi-
tion abolishes gender-associated differences in
regional autoregulatory capacity and in papillary
blood flo~.‘~~-‘~’
Administration of exogenous testosterone to in-
tact dogs does not alter glomerular filtration rate
or renal blood flow and has a variable effect on
tubular excretory capacity.‘os*‘57 The suggestion
that testosterone may increase glomerular filtration
rate during compensatory renal hypertrophy after
uninephrectomy requires confirmation.‘3’ In fe-
male dogs, ovariectomy does not alter renal hemo-
dynamics, whereas administration of exogenous
estrogen has variable effects.‘05~‘58“60In humans,
neither testosterone, estrogen, orchiectomy, or
ovariectomy has any influence on glomerular fil-
tration rate, renal blood flow, or tubular excretory
capacity. 1200.131.161-163
Glomerular filtration rate and renal blood flow
are higher in men than in women.‘40,‘64-‘66 In
comparing renal function in men and women,
results should theoretically be corrected for glo-
merular basement membrane surface area. Cor-
rection for lean body mass or body surface area
is a poor surrogate. In this regard, Smith’40 and
later WessotP5 compiled all studies of renal he-
modynamics performed in humans during the
1940s and 1950s and concluded that glomerular
filtration rate and renal blood flow were lower in
normal women than in normal men, even after
correction for body surface area. However, such
an analysis is flawed by the lack of clear criteria
to exclude renal disease in the original studies
and because the analysis combined data obtained
SILBIGER AND NEUGARTEN
in Male Rate Compared With Females
RBF RBF/KW SNGFR Qn POC KF S RE
t* t ++++te+o
t c* t t ++ 1 1
with females; 1, decreased in males compared with females; ++, no
under differing conditions in many different lab-
oratories over nearly two decades.‘@’ In a more
recent study that evaluated renal function in nor-
mal subjects before kidney donation, there was
no gender difference in glomerular filtration or
renal blood flow after correction for body surface
area. ‘@
MECHANISMS THAT MAY CONTRIBUTE TO
GENDER-RELATED DIFFERENCES IN RENAL
DISEASE PROGRESSION
Hypertension
In experimental models of hypertension in the
rat and mouse, elevated blood pressure develops
at an earlier age and becomes more severe in
male than in female animals.‘67~‘75 In addition,
most studies indicate that the early development
of hypertension in the spontaneous hypertensive
rat is androgen dependent.‘7’~‘73-175 It has been
suggested that these effects are mediated by an-
drogen-induced activation of the renin-angioten-
sin system. ‘76~L77However, these experimental
observations may not be directly applicable to
humans.
A recent report that analyzed all published
clinical trials of antihypertensive therapy and epi-
demiologic surveys of hypertension concluded
that the prevalence of hypertension is greater in
black women than in black men and nearly equal
in white men and women.L78 However, uncon-
trolled hypertension is more common in men.‘78
In addition, men appear to be more susceptible
to the deleterious effects of hypertension on the
kidney and thus more prone to develop hyperten-
sive nephrosclerosis and end-stage renal fail-
ure. 6*7~‘o
Data relating to gender differences in the
prevalence and severity of hypertension among
patients with renal disease other than hyperten-
sive nephrosclerosis are limited.‘79 Moreover,
few studies have addressed gender-related differ-
ences in the impact of hypertension or in the
GENDER AND RENAL DISEASE
impact of antihypertensive therapy on the pro-
gression of primary renal disease.3,6*72~73*‘8
The prevalence of hypertension in adult poly-
cystic kidney disease is greater in affected
men.7’-73 In this disorder, male gender and hyper-
tension each independently contribute to the
more aggressive course observed in men.72*73
Other studies of chronic renal disease have also
identified male gender, independent of blood
pressure, as a risk factor for more rapid decline
in renal function.1*4 However, additional studies
in humans are required to precisely define the
interactions between gender and hypertension in
primary renal disease.
Dietary Factors
Food and protein intake are greater in men
than in women.2**1s1 In experimental models of
renal disease, increased dietary intake of protein,
phosphorus, and other nutrients may contribute
to enhanced renal injury in males.81~181~1s3In fact,
restriction of food intake reduces the severity of
glomerular sclerosis in aging male rats to a level
comparable to that observed in aging female rats
fed an unrestricted diet.18* Thus, gender differ-
ences in dietary intake of protein and other nutri-
ents may contribute to gender-associated differ-
ences in the course of renal disease.2*180
Direct Cellular Effects of Sex Hormones
Direct effects of sex hormones on mesangial
cells may contribute to gender-related differences
in the rate of progression of renal disease (Table
5). Testosterone and estrogen influence many of
the processes implicated in the pathogenesis of
renal disease progression, including mesangial
cell proliferation and matrix accumulation, as
well as the synthesis and release of cytokines,
vasoactive agents, and growth factors (Table 6).
If the impact of gender on renal disease is medi-
ated through direct effects of sex hormones on
Table 5. Receptor-mediated Effects
of sex Hormones
l Cell proliferation1g0~2w
l Collagen synthesis or d~radation’gB~‘w~~-~~z’*~z’4
l Proteoglycan synthesis or degradation
Serum lipoprotein Ievels2rr278
l
l Cellular lipid metabolism289-283
521
Table 6. Influence of Sex Hormones on the
Synthesis and Release of Vasoactive Agents,
Growth Factors, and Cytokines
l Renin-angiotensin system176~‘77~2’6~232
l Cyclooxygenase products23g25’
l Cytokines and growth facto~‘g0~‘g2~197~254-268
TGF-fl 1W197.254.255.263.2b(
IGF-I 191,256,2&3
EGF'92.257-?62.26.-2%?
l Endothelin233.234
Abbreviations: TGF-p, transforming growth factor beta;
IGF, insulin-like growth factor; EGF, epidermal growth fac-
tor.
renal cell biology, then receptors for these hor-
mones must exist in the kidney. In fact, cytosolic
and nuclear receptors for estradiol and testoster-
one have been demonstrated in homogenates of
renal tissue.1M‘188 In addition, autoradiographic
studies have shown binding of estradiol and tes-
tosterone to glomeruli, arterioles, and tubular
cells.189
The effects of sex hormones on cell proliferation
reported in various studies are conflicting, most
likely related to variable cell culture condi-
tions.‘%‘” In aortic smooth muscle cells, which
are similar in structure and function to renal mes-
angial cells, estradiol has no specific mitogenic
effect.‘% Androgens have also been reported to be
either pro-proliferative or anti-proliferative, de-
pending on cell type and culture conditions.‘97-199
We have studied the direct effects of estradiol,
estriol, and testosterone on the proliferation of cul-
tured rat mesangial cells.*@’ Both estrogens and
testosterone were found to have marked pro-prolif-
erative effects. Although cell proliferation may
contribute to progressive renal injury, it is unlikely
that gender differences in renal disease progression
can be explained on this basis, given the similar
effects of estrogens and testosterone.
It has been suggested that the accumulation of
glomerular extracellular matrix may be a precur-
sor to the development of glomerular sclerosis.*”
The direct effects of estrogens and testosterone
on these processes depend on cell type and cul-
ture conditions. In cultured bovine aortic smooth
muscle cells, estradiol decreases synthesis of pro-
collagen type III and in high concentrations also
decreases synthesis of procollagen type I.196~202
In addition, estradiol and female gender are

associated with increased collagen degradation
by vascular smooth muscle and connective
tissue.203-zo5In vivo, estrogen administration re-
duces the accumulation of collagen and elastin
in the aorta of normal, hypertensive, and choles-
terol-fed animals.2w208
The direct effects of testosterone on cellular
collagen synthesis have not been extensively
studied. However, available data suggest a stimu-
latory effect.‘97*‘99.209Testosterone increases col-
lagen synthesis by vascular smooth muscle cells
in culture and stimulates the activity of the en-
zyme responsible for collagen cross-linking.2’0~2”
In vivo, administration of testosterone increases
the accumulationof collagen and elastin in aortas
of normal and cholesterol-fed animals.206720792’2
We have studied the direct effects of estradiol
and testosterone on collagen synthesis by cul-
tured rat mesangial cells. We found that estradiol
in micromolar concentrations suppressed the ac-
cumulation of total collagen, including types I
and IV collagen.200 Estradiol also decreased the
steady state message for type I collagen.200 In
contrast, testosterone had no effect on total colla-
gen accumulation.200
Collagen-degrading metalloproteases, synthe-
sized and secreted by resident glomerular epithe-
lial and mesangial cells, play an important role
in limiting glomerular matrix accumulation.2’3
Whereas glomerular metalloprotease activity was
found to be similar in young male and female
rats, activity increased in aging female rats but
not in aging males.2’3 Glomerular metallopro-
tease activity was found to correlate inversely
with glomerular sclerosis, suggesting that it may
play an important role in protecting aging fe-
males from glomerular injury.2’3 However, other
investigators have concluded the opposite, find-
ing that urinary proteinase activity increased with
age in male but not female rats.2’4 These authors
suggested that enhanced glomerular proteinase
activity may damage glomerular basement mem-
brane proteins and contribute to glomerular in-
jury in aging male rats.*14
Renin-Angiotensin System
The renin-angiotensin system plays a key role
in modulating renal hemodynamics and also in-
fluences mesangial cell proliferation and matrix
production.2’5 Because these processes may con-
tribute to glomerular injury, gender-related dif-
SILBIGER AND NEUGARTEN
ferences in renal disease progression may reflect
alterations in the renin-angiotensin system.2o’*2’5
Administration of exogenous estrogen raises
the plasma concentration of renin substrate,
which results in increased generation of angio-
tensin II, which in turn increases secretion of
aldosterone2’6-227 (reviewed in reference 228).
Notwithstanding early studies to the contrary,
plasma levels of angiotensinogen, angiotensin I
and II, and aldosterone are also increased by ex-
ogenously administered testosterone.‘76~229*230 In
addition, exogenous testosterone increases renin
mRNA and renin activity in peripheral tissues.23’
Moreover, renal and hepatic angiotensinogen
levels are higher in male rats than in female rats
and are reduced by castration.‘76.‘77 Thus, ele-
vated intrarenal angiotensin levels may acceler-
ate the progression of renal disease in males
through the hemodynamic and direct cellular ef-
fects of angiotensin.
Sex hormones may also directly affect angio-
tensin receptor number. However, this effect ap-
pears to be tissue specific.232 In the kidney, the
direct effect of estradiol on AI1 receptor number
is controversial, increasing the number of glo-
merular AI1 receptors in one study and reducing
them in another study.216.232No information is
available as to whether testosterone has any di-
rect effects on glomerular AI1 receptor number
or affinity.
Endothelin is a potent vasoconstrictor, with
mitogenic activity in mesangial cells, which has
been implicated in the pathogenesis of athero-
sclerosis.233 Recent studies show that endothelin
levels are higher in men than in women and in-
crease in women after administration of testoster-
one.233 In addition, regulation of endothelin re-
lease may differ between the sexes.234
Prostaglandins
Products of the cyclooxygenase and lipoxy-
genase pathways have been implicated in the de-
velopment and progression of numerous models
of renal disease. 235Both the vasodilatory prosta-
glandin, PGE2, and inhibitors of thromboxane A2
have a protective effect on the progression of
renal disease in these models.235 Data examining
the relationship between sex hormones and renal
prostaglandin synthesis are conflicting. Some
studies have found that urinary excretion of pros-
taglandins is greater in female rats than in males,
GENDER AND RENAL DISEASE
but other studies have found no difference.236-2”9
Renal medullary microsomal fractions from male
rats show higher PGEz synthetic rates than frac-
tions obtained from female rats because of en-
hanced activity of prostaglandin synthase.240*24’
In contrast, renal papillary slices from female
rats show higher PGE2 synthetic rates than do
papillary slices from males.242 In other studies,
PGE2 synthesis by renal microsomal fractions
was increased in estradiol-treated rats compared
with untreated controls.243,2““ Gender also influ-
ences the rate at which prostaglandins are de-
graded. 236.237,24’~244
The activity of prostaglandin
dehydrogenase, the primary enzyme that catabo-
lizes PGE2 and PGEh in the kidney, is lower in
the kidneys of female rats compared with males
and is suppressed by the administration of exoge-
nous estradiol in both sexes.236,237*24’.24
Although the effects of gender and of sex hor-
mones on the renal synthesis of thromboxane A2,
prostacyclin, and lipoxygenase products have not
been studied, sex hormones affect the synthesis
of these compounds in nonrenal tissues that bear
similarities to either renal mesangial cells or glo-
merular capillary endothelial cells. For example,
estradiol increases prostacyclin synthesis by aor-
tic smooth muscle cells and vascular endothelial
cells. 245-248This effect is mediated by increased
activity of prostacyclin synthase.245’246*24xStudies
examining the effect of testosterone on prosta-
cyclin synthesis show conflicting results.245,249-25’
Thus, further studies are needed to determine
whether differences in renal prostaglandin syn-
thesis or content exist in men versus women.
Cytokines and Growth Factors
Various cytokines and growth factors have di-
rect effects on the kidney that may influence the
rate of progression of renal injury. In particular,
transforming growth factor beta regulates glo-
merular extracellular matrix protein synthesis
and degradation and has been implicated in the
pathogenesis and progression of several models
of experimental glomerular disease.252 Insulin-
like growth factor is mitogenic to mesangial cells
and affects renal hypertrophy and renal hemody-
namics under various experimental circum-
stances, whereas epidermal growth factor stimu-
lates cellular proliferation and suppresses matrix
synthesis.253
Few studies have addressed the effects of gen-
523
der or of sex hormones on the renal synthesis
and availability of these cytokines and growth
factors. However, sex hormones have been
shown to modulate cytokine levels in various
nonrenal tissues. For example, estradiol increases
the synthesis and release of transforming growth
factor beta, insulinlike growth factor, and epider-
ma1 growth factor in cell lines derived from vari-
ous female reproductive organs.‘W.254-262The
ability of estradiol to enhance cell proliferation
and increase procollagen type I synthesis by os-
teosarcoma cells may be mediated by trans-
forming growth factor beta.‘W*254In addition, the
mitogenic activity of estradiol in certain other
cell types appears to be mediated by increases in
insulin-like growth factor or epidermal growth
factor. ‘9’~‘92*263*264
Similarly, testosterone has been
shown to stimulate the synthesis and release of
transforming growth factor beta in nonrenal tis-
sues. 19’ However, the data are conflicting as to
the effects of sex hormones on renal epidermal
growth factor synthesis.‘88.265-268
If sex hormones affect the level or availability
of these or other cytokines and growth factors in
the kidney as they appear to do in various nonre-
nal tissues, then alterations in cytokine levels
may contribute to gender-related differences in
renal disease progression.
Estrogens as Antioxidant Agents
It has been suggested that oxidative stress,
caused by overproduction of reactive oxygen
species or decreased efficiency of scavenger
mechanisms, may contribute to glomerular and
tubular injury after ischemic, toxic, and immune
renal insults.269-27’ In numerous experimental
models of renal disease, antioxidant agents re-
duce renal injury.269-27’ In addition, other experi-
mental observations suggest that enhanced oxi-
dative stress may play a role in mediating
progressive renal disease after a reduction in
nephron mass.269In this regard, estradiol contains
a phenolic hydroxyl group that confers potent
antioxidant activity272 (reviewed in reference
273). Accordingly, the potent antioxidant proper-
ties of estrogens may confer protection in chronic
renal disease by reducing oxidative tissue injury.
Estrogen’s Interaction With Lipids in Renal
Disease
Recent experimental evidence suggests a role
for hyperlipidemia in the development of glomer-
524
ular sclerosis and the progression of renal in-
jury.274 Morphologic similarities between scle-
rosing glomerular lesions and atherosclerotic
lesions have been observed, and similarities in
the pathogenesis of these disorders have been
proposed.274 Factors predisposing to atheroscle-
rosis in blood vessels may have similar impor-
tance in the development of glomerular sclerosis.
The development of atherosclerotic lesions has
been linked to local accumulation of low-density
lipoprotein (LDL) and its oxidation in the micro-
environment of the vessel wa11.275Oxidized LDL
may play an analogous role in the evolution of
glomerular sclerosis (reviewed in reference 276).
Premenopausal women have higher levels of
high-density lipoprotein, particularly high-den-
sity lipoprotein2 and lower total cholesterol and
LDL levels than do men.“’ Levels of LDL in-
crease and those of high-density lipoprotein de-
cline after menopause.“’ Estrogen replacement
therapy reverses postmenopausal alterations in
serum lipoproteins to restore the beneficial pat-
tern seen in premenopausal women.277~278
It is also relevant that only 50% of the cardio-
vascular protection afforded by estrogen is medi-
ated by alterations in serum lipoproteins.“’ Di-
rect effects of estrogen on the atherogenic
process in vessel walls contribute to estrogen’s
cardioprotective effects and may play a similar
role in retarding progressive glomemlar in-
jury. 279*280 In experimental models of atheroscle-
rosis in ovariectomized animals, estrogen in a
dose that does not alter serum lipoprotein levels
reduces accumulation of LDL in vessel walls and
retards the development of atherosclerosis.279*280
In an analogous manner, it is possible that recep-
tor-mediated and other direct effects of estrogen
on the glomerular mesangium may contribute to
the protective effects of female gender on the
development of glomerulosclerosis.
Gender-related differences in LDL oxidation
also may contribute to differences in renal dis-
ease progression. Estradiol contains a phenolic
hydroxyl group that confers potent antioxidant
properties.272 Estradiol can insert into the lipid
core of LDL and donate hydrogen atoms from
its phenolic hydroxyl group to lipid radicals to
inhibit lipid peroxidation.272*28’~288Thus, estradiol
is a potent inhibitor of LDL oxidation by cultured
macrophages and endothelial ce11s.282~283 In addi-
tion, we have shown that mesangial cell-medi-
SILBIGER AND NEUGARTEN
ated oxidation of LDL is also suppressed by es-
tradio1.2W In contrast, testosterone, which lacks a
phenolic hydroxyl group, is devoid of antioxidant
properties in all systems studied.282-284
In addition to inhibiting oxidation of LDL,
estrogens modulate the level of cellular LDL
receptors and influence the activity of intra-
cellular enzymes involved in lipoprotein metabo-
lism.289q293Pharmacologic doses of estrogen in-
crease both LDL receptor mRNA and the number
of LDL receptors in the liver of normal ani-
ma1s.289-291
These changes enhance the clearance
of LDL from the plasma and lower serum choles-
terol levels.289 In contrast, hepatic uptake of oxi-
dized LDL is not increased, suggesting that estro-
gen does not up-regulate the scavenger LDL
receptor.2W*29’ In vascular smooth muscle cells,
estrogen has been shown to decrease the activity
of cholesteryl ester synthetic enzymes and to in-
crease cholesteryl ester degradory enzymes, lead-
ing to reduced aortic cholesteryl ester accumula-
tion.292 Thus, by altering the serum lipoprotein
profile, inhibiting the oxidation of LDL, and in-
fluencing lipoprotein metabolism, estrogens may
confer protection against the development of glo-
merular sclerosis in a manner analogous to their
protective effect in atherosclerosis.
CONCLUSION
Gender has a major impact on the development
and progression of renal disease. Deterioration
of renal function in patients with chronic renal
disease is more rapid in men than in women,
independent of differences in blood pressure or
serum cholesterol levels. Experimental observa-
tions suggest that many of the known mecha-
nisms of renal injury may contribute to gender-
related differences in renal disease progression.
In addition to genetically determined differences
between the sexes in renal structure and function,
direct receptor-mediated effects of sex hormones
on mesangial cells may play an important role
in determining the differential susceptibility to
renal injury. Sex hormones directly influence
many of the processes implicated in the patho-
genesis of renal disease progression, including
mesangial cell proliferation and matrix accumu-
lation as well as the synthesis and release of cyto-
kines, vasoactive agents, and growth factors. In
addition, estrogens may exert potent antioxidant
actions in the mesangial microenvironment,
GENDER AND RENAL DISEASE
whichmaycontributeto theprotectiveeffectof
female gender on renal disease progression.
However, the precise mechanisms underlying
gender-related differences in renal disease pro-
gression remain to be elucidated.
ADDENDUM
Since submission of this report, Baylis*% studied glomeru-
losclerosis in aging rats and found that intact males developed
progressive glomerular damage, whereas castrated males and
intact or ovariectomized females were protected from renal
injury. Neither glomendar hypertrophy nor glomerular hyper-
tension correlated with glomerular injury. The investigator
concluded that the presence of androgens rather than the
absence of estrogens promotes glomerular injury in aging
male rats. However, the animals were not pair-fed, and body
weight in ovariectomized females was 22% to 34% greater
than in intact females. In view of the deleterious effects of
increased dietary protein and total calorie consumption on
the progression of glomerular injury, differences in dietary
intake complicate interpretation of these data vis-a-vis the
influence of estrogen withdrawal on disease progression.
Moreover, other studies have shown that exogenous estrogens
ameliorate glomerulosclerosis in aging male rat~.~~.%How-
ever, these studies are also flawed by reduced caloric intake
in estrogen-treated animals and by suppression of testosterone
levels.
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