Sex Differences in Age-Related Loss of Kidney Function

Abstract

Background - CKD is more prevalent in women, but more men receive kidney replacement therapy for kidney failure. This apparent contradiction is not well understood.<p>

<p>Methods - We investigated sex differences in the loss of kidney function and whether any sex disparities could be explained by comorbidity or CKD risk factors. In the Renal Iohexol Clearance Survey (RENIS) in northern Europe, we recruited 1837 persons (53% women, aged 50–62 years) representative of the general population and without self-reported diabetes, CKD, or cardiovascular disease. Participants’ GFR was measured by plasma iohexol clearance in 2007–2009 (n=1627), 2013–2015 (n=1324), and 2018–2020 (n=1384). At each study visit, healthy persons were defined as having no major chronic diseases or risk factors for CKD. We used generalized additive mixed models to assess age- and sex-specific GFR decline rates.<p>

<p>Results - Women had a lower GFR than men at baseline (mean [SD], 90.0 [14.0] versus 98.0 [13.7] ml/min per 1.73 m²; P<0.001). The mean GFR change rate was −0.96 (95% confidence interval [CI], −0.88 to −1.04) ml/min per 1.73 m² per year in women and −1.20 (95% confidence interval [CI], −1.12 to −1.28) in men. Although the relationship between age and GFR was very close to linear in women, it was curvilinear in men, with steeper GFR slopes at older ages (nonlinear effect; P<0.001). Healthy persons had a slower GFR decline, but health status did not explain the sex difference in the GFR decline.<p>

<p>Conclusion - Among middle-aged and elderly individuals in the general population, decline in the mean GFR in women was slower than in men, independent of health status. <p>

<p>CKD is projected to become the fifth leading cause of years of life lost in 2040. In most countries, more women than men develop CKD stage G3, which is defined as a reduced GFR, whereas more men start RRT. This apparent contradiction is poorly understood, but proposed explanations include gender disparities in access to health care and RRT, biologic differences between women and men leading to different GFR decline rates, bias in creatinine-based formulas to estimate the GFR, and overestimation of the CKD prevalence in women. In addition, sex and gender disparities in health status could cause differences in GFR loss. For example, women have a lower prevalence of myocardial infarction and a longer life expectancy than men. However, although cross-sectional population studies have found a higher mean GFR in healthy than in unhealthy persons, it is unknown whether good health is associated with preserved GFR during aging at the individual level, and whether this can explain the sex difference in CKD prevalence.<p>

<p>Population-based longitudinal studies with repeated assessments of GFR in the same individuals are necessary to investigate the associations between sex, health status, and age-related GFR decline. The few existing studies on GFR change rates were not population based, did not investigate the association with health status, or used equations to calculate the eGFR on the basis of endogenous substances. These eGFR equations are biased by non–GFR-related factors, such as muscle mass, affecting men and women differently, particularly during aging. Measurements of GFR by an exogenous filtration marker, e.g., iohexol, avoid these methodologic problems.<p>

<p>Accordingly, we investigated age- and sex-specific GFR decline rates in the Renal Iohexol Clearance Survey (RENIS), which is the only general population cohort with repeated measurements of GFR.The aim of the study was to report a reference range for age-related GFR decline in the general population and to investigate possible sex disparities in GFR decline rates by health status.