Kidney Structure and Reproductive History Among Healthy Female Kidney Donors

Sex hormones may play an important role in the kidney.1Coggins C.H. Breyer Lewis J. Caggiula A.W. Castaldo L.S. Klahr S. Wang S.R. Differences between women and men with chronic renal disease.Nephrol Dial Transplant. 1998; 13: 1430-1437https://doi.org/10.1093/ndt/13.6.1430Crossref PubMed Scopus (123) Google Scholar,2Neugarten J. Gender and the progression of chronic kidney disease.Mayo Clin Proc. 2020; 95: 2582-2584https://doi.org/10.1016/j.mayocp.2020.10.013Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Shorter duration of a woman’s reproductive lifespan, or the time from menarche to menopause, has been associated with cardiovascular disease and chronic kidney disease (CKD).3Feng Y. Hong X. Wilker E. et al.Effects of age at menarche, reproductive years, and menopause on metabolic risk factors for cardiovascular diseases.Atherosclerosis. 2008; 196: 590-597https://doi.org/10.1016/j.atherosclerosis.2007.06.016Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar,4Kang S.C. Jhee J.H. Joo Y.S. et al.Association of reproductive lifespan duration and chronic kidney disease in postmenopausal women.Mayo Clin Proc. 2020; 95: 2621-2632https://doi.org/10.1016/j.mayocp.2020.02.034Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar We have recently demonstrated that women with bilateral oophorectomy before the natural age of menopause are at an increased risk of CKD.5Kattah A.G. Smith C.Y. Gazzuola Rocca L. Grossardt B.R. Garovic V.D. Rocca W.A. CKD in patients with bilateral oophorectomy.Clin J Am Soc Nephrol. 2018; 13: 1649-1658https://doi.org/10.2215/CJN.03990318Crossref PubMed Scopus (28) Google Scholar Pregnancy also causes significant physiologic changes in kidney function, including hypertrophy, hyperfiltration, and proteinuria, though it is not clear if these changes persist.6Odutayo A. Hladunewich M. Obstetric nephrology: renal hemodynamic and metabolic physiology in normal pregnancy.Clin J Am Soc Nephrol. 2012; 7: 2073-2080https://doi.org/10.2215/CJN.00470112Crossref PubMed Scopus (126) Google Scholar The objective of our study was to determine how past reproductive history can impact kidney function and structure. We sent surveys on reproductive history to women enrolled in the Aging Kidney Anatomy cohort, which has been previously described.7Denic A. Alexander M.P. Kaushik V. et al.Detection and clinical patterns of nephron hypertrophy and nephrosclerosis among apparently healthy adults.Am J Kidney Dis. 2016; 68: 58-67https://doi.org/10.1053/j.ajkd.2015.12.029Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar The cohort includes living kidney donors at the Scottsdale, AZ, and Rochester, MN, sites of the Mayo Clinic, and for this analysis, included donors from January 2000 to December 2017.8Merzkani M.A. Denic A. Narasimhan R. et al.Kidney microstructural features at the time of donation predict long-term risk of chronic kidney disease in living kidney donors.Mayo Clin Proc. 2021; 96: 40-51https://doi.org/10.1016/j.mayocp.2020.08.041Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Generally, all prospective donors undergo a thorough medical evaluation, including iothalamate clearance to measure glomerular filtration rate, 24-hour albumin excretion, computed tomography (CT) angiography, and a biopsy of the donated kidney at the time of surgery. Morphometric analysis of kidney biopsies and calculations of kidney volumes on CT are then performed. Survey questions were grouped into 3 areas: menstrual, pregnancy, and menopausal history (Item S1). Using a retrospective cohort study design, we determined whether past reproductive factors were predictive of kidney function and structure outcomes at donation. Among postmenopausal women at the time of donation, differences in kidney structure were compared by years since menopause, years of reproductive lifespan, and years of endogenous estrogen exposure. Endogenous estrogen exposure was calculated as previously described9de Kleijn M.J. van der Schouw Y.T. Verbeek A.L. Peeters P.H. Banga J.D. van der Graaf Y. Endogenous estrogen exposure and cardiovascular mortality risk in postmenopausal women.Am J Epidemiol. 2002; 155: 339-345https://doi.org/10.1093/aje/155.4.339Crossref PubMed Scopus (172) Google Scholar and was defined as the portion of a woman’s reproductive lifespan with elevated levels of endogenous estrogen, unopposed by progesterone. Analyses were performed using logistic regression for binary outcomes and linear regression for continuous outcomes and were adjusted for age, body mass index (BMI), and hypertension at donation. Differences by past reproductive factors were reported as percent differences. There were 1,870 female kidney donors, and 673 women completed the survey and were included in the cohort (Item S1 and Table S1). Clinical and kidney characteristics at donation and reproductive history results by survey are listed in Table S2. Women with at least 1 predonation pregnancy resulting in a delivery (n = 498) had significantly larger cortex per glomerulus on biopsy in unadjusted analysis and larger total kidney volume and cortical kidney volume on CT after adjusting for age, BMI, and hypertension (Table 1). Time from last pregnancy to donation was not associated with kidney structural findings in adjusted analyses.Table 1Association of At Least 1 Past Pregnancy Resulting in a Delivery (Parous State) With Clinical and Kidney Characteristics at the Time of Donation (N = 673 Donors)Patient Characteristics at DonationaWhen listed, units apply to mean (SD) values only.Mean (SD) or No. (%)UnadjustedAdjustedbAdjusted for age, body mass index, and hypertension.NulliparousParous% Diff. or OR (95% CI)P Value% Diff. or OR (95% CI)P ValueKidney volumes by CT angiogramTotal kidney volume, mm3265,395 (53,508)266,594 (42,371)1.5% (˗2.7% to 5.8%)0.54.3% (0.3% to 8.4%)0.03cValues are statistically significant at P<0.05.Total cortex volume, mm3184,486 (34,119)185,608 (32,549)1.1% (˗3.4% to 5.8%)0.64.5% (0.3% to 8.9%)0.03cValues are statistically significant at P<0.05.Total medulla volume, mm377,164 (18,466)80,319 (18,248)6.3% (0.2% to 12.9%)0.04cValues are statistically significant at P<0.05.6.0% (˗0.4% to 12.7%)0.07Kidney biopsy featuresGlomerular volume, mm30.0023 (0.0009)0.0024 (0.0009)7.6% (˗2.7% to 19.1%)0.27.8% (˗2.8% to 19.6%)0.2Cortex per glomerulus, mm30.061 (0.035)0.066 (0.034)12.3% (0.2% to 25.9%)0.05cValues are statistically significant at P<0.05.12.0% (˗0.5% to 26.0%)0.06Percent GSG3.4 (6.0)4.4 (7.8)18.6% (˗9.4% to 55.3%)0.2-6.1% (˗28.3% to 22.8%)0.6Percent IFTA0.33 (1.95)0.42 (0.77)55.9% (6.2% to 129.9%)0.02cValues are statistically significant at P<0.05.15.2% (˗21.6% to 69.3%)0.5Percent IFTA >0%30 (17.1%)124 (24.9%)1.66 (1.07 to 2.63)0.03cValues are statistically significant at P<0.05.1.29 (0.81 to 2.09)0.3IFTA density, foci per mm2 cortex10.7 (32.2)11.6 (24.4)25.5% (˗2.6% to 61.7%)0.081.8% (˗20.9% to 31.1%)0.9Percent luminal stenosis >50%30 (17.1%)96 (19.3%)1.11 (0.74 to 1.80)0.60.86 (0.53 to 1.42)0.5Kidney function measurementsMeasured GFR, mL/min/1.73 m2109.5 (31.1)100.8 (19.8)˗10.0% (˗14.4% to -5.3%)<0.001cValues are statistically significant at P<0.05.˗3.9% (˗8.6% to 1.0%)0.124 h urine albumin, mg5.7 (6.1)4.8 (22.3)˗10.8% (-36.6% to 25.5%)0.53.3% (˗27.7% to 47.6%)0.9Nephron number2,302,358 (890,383)2,099,534 (825,643)˗6.4% (˗15.6% to 3.8%)0.2˗6.8% (˗16.0% to 3.4%)0.2Single-nephron GFR, µL/min55.5 (24.0)56.9 (21.8)7.1% (˗3.6% to 19.1%)0.26.7% (˗4.1% to 18.6%)0.2Abbreviations: CT, computed tomography; GFR, glomerular filtration rate; GSG, global glomerulosclerosis; IFTA, interstitial fibrosis tubular atrophy; OR, odds ratio.a When listed, units apply to mean (SD) values only.b Adjusted for age, body mass index, and hypertension.c Values are statistically significant at P < 0.05. Open table in a new tab Abbreviations: CT, computed tomography; GFR, glomerular filtration rate; GSG, global glomerulosclerosis; IFTA, interstitial fibrosis tubular atrophy; OR, odds ratio. There were 218 women (32.4%) who were postmenopausal at the time of kidney donation. After adjustment for age, BMI, and hypertension, each year since menopause was associated with increased percentage of interstitial fibrosis and tubular atrophy (%IFTA), each 5-year increase in reproductive lifespan was associated with decreased %IFTA, and each year of endogenous estrogen exposure was associated with decreased %IFTA and decreased IFTA foci density (Table 2, Fig S1). The amount of %IFTA by morphometry in these kidney donors is quite low, though still visible on representative samples (Fig S2).Table 2Age-, BMI-, and Hypertension-Adjusted Association of Reproductive History Factors With Clinical and Kidney Characteristics at the Time of Donation Among Postmenopausal Women (N = 218)Patient Characteristics at DonationPer Year Since MenopausePer 5 Years of Reproductive LifespanPer Year of Endogenous Estrogen ExposureDiff. or OR (95% CI)P ValueDiff. or OR (95% CI)P ValueDiff. or OR (95% CI)P ValueKidney volumes by CT angiogramTotal kidney volume (%)0.0% (˗0.4% to 0.5%)0.90.0% (˗2.0% to 2.0%)0.90.2% (˗0.5% to 0.9%)0.5Total cortex volume (%)0.1% (˗0.4% to 0.6%)0.7˗0.5% (˗2.7% to 1.7%)0.6˗0.2% (˗0.8% to 0.6%)0.8Total medulla volume (%)˗0.2% (˗0.9% to 0.5%)0.61.2% (˗2.0% to 4.4%)0.51.0% (˗0.1% to 2.0%)0.06Kidney biopsy featuresGlomerular volume (%)˗0.6% (˗1.7% to 0.5%)0.33.9% (˗1.3% to 9.4%)0.10.8% (˗0.8% to 2.4%)0.3Cortex per glomerulus (%)0.5% (˗1.0% to 2.0%)0.3˗1.9% (˗8.3% to 5.0%)0.6˗1.6% (˗3.7% to 0.6%)0.1Percent GSG (%)1.8% (˗1.6% to 5.3%)0.3˗2.5% (˗16.7% to 14.2%)0.8˗3.8% (˗8.5% to 1.1%)0.1Percent IFTA (%)5.9% (0.5% to 11.5%)0.03aValues are statistically significant at P<0.05.˗20.2% (˗37.3% to -0.1%)0.05aValues are statistically significant at P<0.05.˗10.1% (˗16.8% to -2.9%)0.008aValues are statistically significant at P<0.05.Percent IFTA >0% (OR)1.05 (1.00 to 1.10)0.05aValues are statistically significant at P<0.05.0.83 (0.66 to 1.03)0.090.91 (0.84 to 0.98)0.01aValues are statistically significant at P<0.05.IFTA density (%)3.1% (˗0.4% to 6.7%)0.08˗11.5% (˗24.5% to 3.7%)0.1˗6.7% (˗11.3% to -1.8%)0.009aValues are statistically significant at P<0.05.Percent luminal stenosis >50% (OR)1.03 (0.98 to 1.09)0.20.81 (0.64 to 1.04)0.090.98 (0.90 to 1.06)0.6Kidney function measurementsMeasured GFR (%)˗0.5% (˗1.1% to 0.1%)0.092.4% (˗0.3% to 5.2%)0.080.5% (˗0.3% to 1.2%)0.224 h urine albumin (%)˗1.6% (˗5.2% to 2.1%)0.41.8% (˗14.3% to 21.0%)0.84.1% (˗1.7% to 10.3%)0.2Nephron number (%)0.2% (˗1.1% to 1.5%)0.8˗2.3% (˗7.8% to 3.6%)0.40.9% (˗0.9% to 2.8%)0.3Single-nephron GFR (%)˗0.5% (˗1.7% to 0.7%)0.43.9% (˗1.8% to 10.1%)0.2˗0.5% (˗2.3% to 1.3%)0.6Abbreviations: BMI, body mass index; CT, computed tomography; GFR, glomerular filtration rate; GSG, global glomerulosclerosis; IFTA, interstitial fibrosis tubular atrophy; OR, odds ratio.a Values are statistically significant at P < 0.05. Open table in a new tab Abbreviations: BMI, body mass index; CT, computed tomography; GFR, glomerular filtration rate; GSG, global glomerulosclerosis; IFTA, interstitial fibrosis tubular atrophy; OR, odds ratio. Our study demonstrates that reproductive history does have a measurable impact on kidney structure. Past pregnancy was associated with larger kidney volumes on imaging, as well as larger cortical volume per glomerulus on kidney biopsy. Nephron hypertrophy is known to occur during pregnancy, but it has not been clear whether this hypertrophy persists after delivery in humans. We observed an increase in cortical volume per glomerulus, but not an increase in glomerular volume, suggesting that an increase in the tubular volume accounts for this observation and does not fully regress after delivery. We did not find any significant impact of pregnancy complications (n = 45 women) on kidney structural findings. This could be due not only to the small sample size but to the requirement of normal kidney function and the lack of certain CKD risk factors to be a donor. We found that among postmenopausal women, those with a longer duration of menopause were more likely to have detectable IFTA on biopsy than women with a shorter duration of menopause, after adjusting for age, BMI, and hypertension. Similarly, those with longer reproductive lifespans and endogenous estrogen exposure were less likely to have detectable IFTA on biopsy. Women generally have a slower progression of CKD than men, as well as a lower risk of developing end-stage kidney disease, possibly owing to estrogen effects.10Ricardo A.C. Yang W. Sha D. et al.Sex-related disparities in CKD progression.J Am Soc Nephrol. 2019; 30: 137-146https://doi.org/10.1681/ASN.2018030296Crossref PubMed Scopus (111) Google Scholar Our study supports the hypothesis that estrogen is nephroprotective and also suggests a role for the duration of estrogen deficiency. Our study has limitations. The survey response rate was modest at 37.5%, and responses may be subject to recall bias. We also evaluated multiple parameters, which increases the potential for a type I error. These are all subclinical findings. However, this study confirms that reproductive factors warrant consideration when evaluating the effects of disease and aging on kidney health. Conceived the study idea: AGK, VDG, ADR; collected the data and performed the analysis: AGK, ADR, AFM, AD; helped interpret results: all authors. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual’s own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate. This study was supported by a Mayo Clinic Department of Medicine Catalyst Award (Dr Kattah), Mayo CCaTS grant number UL1TR002377, and the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK090358). The funders had no role in study design, data collection, data analysis, interpretation of data, or writing of the report, nor the decision to submit for publication. The authors declare that they have no relevant financial interests. We thank the Mayo Clinic Survey Research Center for their help in survey design, planning, testing, and implementing the survey, as well as data collection. Our data cannot be shared. This patient data contains highly personal information relating to reproductive history. We are open to collaboration with de-identified data and IRB-approved protocols. Received July 4, 2022. Evaluated by 2 external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form December 27, 2022. This article was corrected online on March 31, 2023 to correct units listed in Table 1. Download .pdf (2.39 MB) Help with pdf files Supplementary File (PDF)Figures S1-S2; Item S1; Tables S1-S2.