Summary
Recently, a group of Korean internists published a paper in the journal Scientific Reports describing the results of their analysis of the national health insurance database focusing on the effects of menopausal hormone therapy (MHT) on the incidence of end-stage renal disease (ESRD)[1]. As a total, 4,905 Korean postmenopausal women developed ESRD, among the 1.46 million followed-up for 9 years since 2009. Adjusted hazard ratios (HRs) [95% confidence interval] for ESRD development according to their MHT duration were: no MHT, reference; MHT < 2 years; 0.634 [0.556-0.723]; 2-5 years, 0.721 [0.597-0.871]; > 5 years, 0.654 [0.531-0.806], implying that MHT protects kidneys irrespective of its duration, with ~30% reduced risk of ESRD. Subgroup analyses showed that the beneficial effect of MHT was more pronounced in women aged <65 years and those with diabetes or hypertension, whereas MHT was associated with reduced risk of ESRD similarly in women with body mass index (BMI) < 25 or > 25, or in those with or without pre-existing chronic kidney diseases. The study showed a protective effect of MHT on kidneys on the largest scale ever reported.
Commentary
For many decades, the discussion about the benefits of MHT to prevent chronic diseases in postmenopausal women has centered around cardiovascular diseases and osteoporosis. The effects of MHT on metabolic disorders related to the former, such as dyslipidemia and diabetes, has also been intensively studied, whereas kidneys have hardly been paid enough attention. For example, words “kidney” or “kidneys” cannot be found in the encyclopedic “2016 IMS Recommendations on women’s midlife health and menopause hormone therapy”, which seems to cover almost all the aspects of life that MHT could have any effects on [2]. The negligence may partly be due to the discrepancy found in the past few papers with smaller scales than the present one on the effects of MHT on kidney functions: one study reported a higher prevalence of microalbuminuria in MHT users than non-users [3], while another found that MHT was associated with better estimated glomerular filtration rate (eGFR) and blood pressure (BP) levels than non-users [4].
In a paper recently published from Iran, the authors investigated the relationship between the incidence of chronic kidney disease (CKD) and endogenous estrogen exposure (EEE), defined as the time interval between age at menarche and menopause, in a 15-year prospective cohort study [5]. They found that the HRs for CKD incidence in women with EEE < 11 compared to those with EEE ≥ 11 years was 2.7 [CI 95%, 2.2-3.2] in women aged <45 years and 1.2 [CI 95%, 1.0-1.4] in those aged ≥45 years, implying the protective effect of endogenous estrogen on kidneys. The present paper which is being commented [1] is in line with their findings.
If estrogen has any beneficial effects on kidneys, what would be the possible mechanisms? According to previous reports estrogen: (1) attenuates diabetic kidney disease by regulating extracellular matrix and transforming growth factor β-1 (TGF-β-1) [6], (2) protects podocytes from apoptosis [7], and (3) regulates renal sodium/potassium homeostasis and renin-angiotensin pathway [8]. These pathways could collectively help kidneys maintain their functions. The remaining question is whether the “timing hypothesis” would also apply to the beneficial effects of MHT on kidneys or not, as the information concerning the relationship between ESRD incidence and the time gap between menopause and the initiation of MHT are not presented in the current paper. A report of a secondary analysis of this huge nation-wide health insurance database is much anticipated.
Prof. Masakazu Terauchi, MD, PhD
Department of Women’s Health, Tokyo Medical and Dental University, Tokyo, Japan
References
- Ahn SY, Choi YJ, Kim J, Ko GJ, Kwon YJ, Han K. The beneficial effects of menopausal hormone therapy on renal survival in postmenopausal Korean women from a nationwide health survey. Sci Rep. 2021;11(1):15418.
https://pubmed.ncbi.nlm.nih.gov/34326358/ - Baber RJ, Panay N, Fenton A; IMS Writing Group. 2016 IMS Recommendations on women’s midlife health and menopause hormone therapy. Climacteric. 2016;19(2):109-50.
https://pubmed.ncbi.nlm.nih.gov/26872610/ - Monster TB, Janssen WM, de Jong PE, de Jong-van den Berg LT; Prevention of Renal and Vascular End Stage Disease Study Group. Oral contraceptive use and hormone replacement therapy are associated with microalbuminuria. Arch Intern Med. 2001;161(16):2000-5.
https://pubmed.ncbi.nlm.nih.gov/11525702/ - Fung MM, Poddar S, Bettencourt R, Jassal SK, Barrett-Connor E. A cross-sectional and 10-year prospective study of postmenopausal estrogen therapy and blood pressure, renal function, and albuminuria: the Rancho Bernardo Study. Menopause. 2011;18(6):629-37.
https://pubmed.ncbi.nlm.nih.gov/21326121/ - Farahmand M, Ramezani Tehrani F, Khalili D, Cheraghi L, Azizi F. Endogenous estrogen exposure and chronic kidney disease; a 15-year prospective cohort study. BMC Endocr Disord. 2021;21(1):155.
https://pubmed.ncbi.nlm.nih.gov/34348694/ - Dixon A, Maric C. 17beta-Estradiol attenuates diabetic kidney disease by regulating extracellular matrix and transforming growth factor-beta protein expression and signaling. Am J Physiol Renal Physiol. 2007;293(5):F1678-90.
https://pubmed.ncbi.nlm.nih.gov/17686959/ - Kummer S, Jeruschke S, Wegerich LV, et al. Estrogen receptor alpha expression in podocytes mediates protection against apoptosis in-vitro and in-vivo. PLoS One. 2011;6(11):e27457.
https://pubmed.ncbi.nlm.nih.gov/22096576/ - Tremblay AM, Dufour CR, Ghahremani M, Reudelhuber TL, Giguère V. Physiological genomics identifies estrogen-related receptor alpha as a regulator of renal sodium and potassium homeostasis and the renin-angiotensin pathway. Mol Endocrinol. 2010;24(1):22-32.
https://pubmed.ncbi.nlm.nih.gov/19901197/
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