B-CRF : rheumatological and mineral complications
B- CRF : metabolic and endocrine complications
Gender and the Prevalence and Progression of Renal Disease
Joel Neugartene, Ladan Golestaneh
Advances in Chronic Kidney Disease
Volume 20, Issue 5 , Pages 390-395, September 2013
ABSTRACT
In most experimental models of CKD, male animals progress more rapidly than females.
Modulation of the hormonal milieu can replicate the effects of gender on the course of kidney
disease. These observations suggest that sex hormones per se may be important
determinants of the greater susceptibility of males to progressive kidney injury. The
predominance of data in humans suggests that the course of nondiabetic kidney disease is
more aggressive in men than women. Male gender is arguably also a risk factor for
progression of diabetic nephropathy. Sex hormones directly or indirectly affect many cellular
processes by modulating the synthesis of various cytokines, growth factors, and vasoactive
agents. In particular, estrogen acts in a receptor-dependent mechanism to regulate genes
involved in extracellular matrix metabolism. Estrogen has profound effects on transforming
growth factor-β signal transduction and on the renin-angiotensin system. These effects may
contribute to alterations in kidney hemodynamics and affect kidney disease progression.
Selective estrogen receptor modulators, agents that mimic many of the beneficial effects of
estrogen without reproducing estrogen's deleterious effects on reproductive tissue,
ameliorate the course of kidney disease in animal models and in postmenopausal women.
Key Words: Gender, Sex, CKD, Estrogen, Testosterone
COMMENTS
The mechanisms underlying the gender disparity observed in the incidence, prevalence, and
progression rate of kidney disease has not been fully elucidated. In most experimental
models of kidney disease, male animals show accelerated progression.1 Hormonal
manipulations replicate the effects of gender on the course of experimental kidney disease,
suggesting that female sex hormones may slow progression of kidney disease whereas male
hormones may accelerate progression.1 These observations also suggest that sex
hormones per se, rather than genetically determined structural differences, determine the
greater susceptibility of the male kidney to progressive kidney injury.
Unlike experimental models, studies describing the relationship between gender and kidney
disease progression in humans have yielded conflicting data. To further evaluate these
discrepant data, the authors performed a meta-analysis involving 11,345 patients from 68
studies to determine the effect of gender on the progression of nondiabetic kidney disease.
In men with autosomal dominant polycystic kidney disease, immunoglobulin A (IgA)
nephropathy, membranous nephropathy, or CKD of unspecified etiology, progression was
more rapid than in women. The Modification of Diet in Renal Disease Study also found that
the rate of deterioration of glomerular filtration rate (GFR) was slower in younger women as
compared with men, but this difference was no longer significant after adjusting for
differences in blood pressure, urinary protein excretion, and high-density lipoprotein levels.
Numerous cross-sectional and longitudinal studies in persons with type I diabetes show a
greater prevalence of micro- and macroalbuminuria in men vs women or an increased risk of
developing microalbuminuria and progressing to macroalbuminuria. In particular, a large
study from Germany of 27,805 type I diabetics reported that male sex was associated with
the development of microalbuminuria. (Raile K, Galler A, Hoffer S, et al. Diabetic
nephropathy in 27,805 children, adolescents, and adults with type 1 diabetes. Effect of
diabetes duration, A1C, hypertension, dyslipidemia, diabetes onset, and sex. Diabetes Care.
2007;30(10):2523–2528)
Numerous mechanisms have been suggested to explain the protective effect of female
gender on the progression of kidney diseases. These include differences between the sexes
in kidney structure, systemic and kidney hemodynamics, diet, lipid metabolism, and blood
pressure. Sex hormones also affect numerous cellular either directly or indirectly by
regulating the synthesis and release of cytokines, vasoactive agents, and growth factors.
Selective estrogen receptor modulators are agents that mimic many of the beneficial effects
of estrogen on bone and vascular tissue without reproducing estrogens deleterious effects on
reproductive tissue. Selective estrogen receptor modulators inhibit mesangial cell matrix
synthesis and ameliorate kidney injury in numerous experimental models of kidney disease.
A recent post hoc analysis of the Multiple Outcomes of Raloxifene Evaluation study, a
multicenter, randomized, double-blind trial of Raloxifene vs placebo on the risk of fractures in
postmenopausal women, found that women in the group that received Raloxifene had a
slower yearly rate of increase in creatinine and a significantly slower yearly rate of decline in
eGFR over 3 years of follow-up. (Melamed ML, Blackwell T, Neugarten J, et al. Raloxifene, a
selective estrogen receptor modulator, is renoprotective: a post-hoc analysis. Kidney Int.
2011;79(2):241–249)
Towards a general protection using selective oestrogen receptors modulators in
postmenopausal women with early stages of CKD ?
Pr. Jacques CHANARD
Professor of Nephrology