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CKD in Patients with Bilateral Oophorectomy

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CKD in Patients with Bilateral Oophorectomy CJASN ePress. Published on September 19, 2018 as doi: 10.2215/CJN.03990318 Article CKD in Patients with Bilateral Oophorectomy Andrea G. Kattah,1 Carin Y. Smith ,2 Liliana Gazzuola Rocca,3 Brandon R. Grossardt,2 Vesna D. Garovic,1 and Walter A. Rocca3,4 Abstract Background and objectives Premenopausal women who undergo bilateral oophorectomy are at a higher risk of morbidity and mortality. Given the potential benefits of estrogen on kidney function, we hypothesized that women who undergo bilateral oophorectomy are at higher risk of CKD. 1Division of Nephrology and Design, setting, participants, & measurements We performed a population-based cohort study of 1653 women Hypertension, residing inOlmstedCounty, Minnesota whounderwent bilateral oophorectomy before age 50 years oldand before Department of Internal 2 the onset of menopause from 1988 to 2007. These women were matched by age (61 year) to 1653 referent women Medicine, Divisions who did not undergo oophorectomy. Women were followed over a median of 14 years to assess the incidence of of Biomedical Statistics and fi , 2 . CKD. CKD was primarily de ned using eGFR (eGFR 60 ml/min per 1.73 m on two occasions 90 days apart). Informatics and Hazard ratios were derived using Cox proportional hazards models, and absolute risk increases were derived 3Epidemiology, using Kaplan–Meier curves at 20 years. All analyses were adjusted for 17 chronic conditions present at index date, Department of Health race, education, body mass index, smoking, age, and calendar year. Sciences Research, and 4Department of Neurology, Mayo Results Women who underwent bilateral oophorectomy had a higher risk of eGFR-based CKD (211 events for Clinic, Rochester, oophorectomy and 131 for referent women; adjusted hazard ratio, 1.42; 95% confidence interval, 1.14 to 1.77; Minnesota absolute risk increase, 6.6%). The risk was higher in women who underwent oophorectomy at age #45 years old (110 events for oophorectomy and 60 for referent women; adjusted hazard ratio, 1.59; 95% confidence interval, 1.15 Correspondence: to 2.19; absolute risk increase, 7.5%). Dr.WalterA.Rocca, Division of # Epidemiology, ConclusionsPremenopausal women who undergo bilateral oophorectomy, particularly those 45 years old, are at Department of Health higher risk of developing CKD, even after adjusting for multiple chronic conditions and other possible Sciences Research, confounders present at index date. Mayo Clinic, 200 First ccc–ccc Street SW, Rochester, Clin J Am Soc Nephrol 13: , 2018. doi: https://doi.org/10.2215/CJN.03990318 MN 55905. Email: [email protected] Introduction Women who undergo bilateral oophorectomy be- Estrogen has shown protective effects on the kidneys fore natural menopause (often performed concur- in both animal models and observational human rently with hysterectomy) may have a particularly studies. In particular, estrogen reduced glomerulo- high risk of harm from prolonged estrogen depriva- sclerosis and glomerular permeability in ischemia- tion (12). There is increasing evidence that premeno- reperfusion injury in various animal models (1). In one pausal women who undergo bilateral oophorectomy model of sclerosis-prone mice, ovariectomy caused may be at a higher risk for significant morbidity and severe glomerulosclerosis and kidney dysfunction mortality, particularly if they are younger than age 46 that was then corrected by continuous estrogen re- years old at the time of oophorectomy and do not placement (2,3). Younger women have a lower in- receive adequate estrogen therapy (13–16). Studying cidence of ESKD and slower progression of CKD than this population of women who become acutely and men; however, that advantage disappears after men- surgically menopausal offers a unique opportunity to opause (4–6). In addition, women may have a steeper identify the precise onset of estrogen deprivation as increase in risk of cardiovascular and all-cause mor- well as adjust for the comorbidities and other possible tality for a given lower GFR or higher albuminuria confounders that are present at the index date (time of compared with men (7). Observational studies of oophorectomy). estrogen therapy in women have had variable results, The long-term risk of CKD in women undergoing with some studies showing beneficial effects of estro- bilateral oophorectomy has not been explored pre- genonmarkersofkidneydysfunction,suchas viously. In this population-based cohort study, we albuminuria (8,9), and some other studies showing evaluated the long-term risk of developing CKD in potential harm (10,11). These discrepant studies have women who underwent bilateral oophorectomy com- had significant methodologic differences, including pared with age-matched referent women without the ages of the women studied and the methods of oophorectomy after adjusting for potential con- assessing kidney function. founders, including cardiovascular, metabolic, and www.cjasn.org Vol 13 November, 2018 Copyright © 2018 by the American Society of Nephrology 1 2 Clinical Journal of the American Society of Nephrology other chronic conditions present at the index date. We also identified the women with two or more codes .30 days apart assessed whether age at the time of oophorectomy and the assigned at any time (before or after the index date). The use of estrogen therapy may modify this risk. complete medical records of these women were then re- viewed, and the Kidney Disease: Improving Global Out- comes criteria for CKD stages 1, 2, and 3b–5wereapplied Materials and Methods (24). These criteria required an eGFR,45 ml/min per 1.73 m2 Cohort Definition and Comorbidities at Index Date and/or the presence of markers of kidney damage (pro- fi Women were identi ed as part of the Mayo Clinic Cohort teinuria or abnormal urinary sediment) over a 3-month Study of Oophorectomy and Aging-2 (MOA-2) as de- period. We excluded stage 3a (defined as an eGFR of 45–60 – scribed extensively elsewhere (15 17). All of the data used ml/min per 1.73 m2 in the absence of proteinuria or abnormal for this study were derived from the medical records urinary sediment), because during the pilot phase of the linkage system of the Rochester Epidemiology Project, study, we noted that patients with stage 3a often went – which has been described elsewhere (18 21). All research undiagnosed by providers and therefore, would have been activities were approved by the Mayo Clinic and Olmsted missed by our targeted chart review. The rationale for adding Medical Center Institutional Review Boards. The cohort this secondary definition was that CKD as defined by eGFR study included women who underwent bilateral oophorec- could be evaluated using laboratory values extracted elec- tomy or second unilateral oophorectomy from January 1, tronically alone, whereas review of urine protein and 1988 to December 31, 2007 and age-matched referent women sediment requires the clinical context for interpretation. from the same population. The oophorectomy had to be Unfortunately, reviewing the medical records of the entire performed before the onset of menopause and before age 50 cohort was not feasible. We wanted to include CKD stages 1 years old. The date of the surgical procedure was considered and 2 in our analysis, because many of the studies the index date, and simple random sampling was used to suggesting a relationship between estrogen and the kidney identify referent women from the same Olmsted County, evaluated proteinuria as an outcome. Minnesota population born in the same year (61 year) who had not undergone bilateral oophorectomy before the index Statistical Analyses date. Referent women did not have to be menopausal at the Each definition of CKD (eGFR and adjudicated diagnos- index date and remained eligible if they underwent bilateral tic codes) was considered separately for the cohort anal- oophorectomy after the index date. yses, and women with CKD onset before the index date Medical comorbidities present at the index date were were excluded from the corresponding outcome analysis fi electronically abstracted using selected International Classi - (only incident outcomes were assessed). Women were cation of Diseases (ICD) diagnosis codes (ICD-8 or ICD-9) (22). followed from index date to the date of CKD onset, or Womenneededtohaveatleasttwodiagnosticcodesina they were censored at the earliest of death, time of last visit . given category separated by 30 days to avoid false positive with a Rochester Epidemiology Project provider (lost to diagnoses (17). Medical records were manually reviewed, and follow-up), or end of the study (December 31, 2014). We fi oophorectomy status was con rmed by trained study person- estimated unadjusted and adjusted hazard ratios (HRs) and nel (primarily L.G.R.). In addition, extensive clinical informa- 95% confidence intervals (95% CIs) using Cox proportional tion was manually abstracted from the medical records, hazards models, with age as the timescale. Cumulative including demographic and reproductive characteristics and incidence curves were estimated using the Kaplan–Meier systemic estrogen therapy after the index date. method, and absolute risks were obtained from the Kaplan– Meier curves at 20 years after oophorectomy or index. Assessment of CKD during Follow-Up Differences between the two cohorts were also measured CKD was defined in two different ways—primarily using using the absolute risk increase (ARI) or absolute risk eGFR values and in a secondary analysis, using adjudicated reduction obtained by subtracting the two absolute risks. diagnostic codes. The primary
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