Unravelling the sex differences and decline in kidney health after 73 years of age

There are about 850 million people in the world living with chronic kidney disease (CKD). Of these, approximately 380 million are male, 470 million are female and about 85 million will ultimately develop end-stage renal disease (ESRD) requiring renal replacement therapy or kidney transplantation.^1,2 As the ageing population and global prevalence of conditions such diabetes, cardiovascular disease (CVD) and obesity increase, the number of complex, multimorbid patients with CKD is expected to rise.³ Although CKD is more prevalent in women, there is a noticeable male predominance in ESRD owing to their higher risk of disease progression. The mechanisms underlying the observed sexual dimorphism in CKD, however, are not fully understood. 

As we navigate an era where the focus has shifted towards preventive and precision medicine, there is an ever-increasing need to recognise the different phenotypes that exist within disease populations. This encompasses establishing age- and sex-based differences, particularly as seminal studies from which conclusions are drawn have significant imbalances in age and sex distribution. This is crucial to aid early detection, prevent complications and manage patients using approaches tailored to their needs. A uniform strategy no longer meets the diverse needs of today's complex challenges. 

In their recently published work in the American Journal of Kidney Diseases, Sullivan and colleagues⁴ attempt to provide some insight into sex-specific differences in the relationships between cardiometabolic risk factors and estimated glomerular filtration rate (eGFR). Welsh individuals from the Secure Anonymised Information Linkage Databank were included if they had three or more eGFR values with at least 90 days between the first and last measurement, at least one eGFR value >15 mL/min/1.73 m², blood results leading up to kidney replacement therapy (KRT) – either kidney transplantation or maintenance dialysis – and were >18 years old. eGFR was calculated using the 2009 CKD-EPI equation, without the race coefficient. The primary outcome was the annual decline in eGFR in males and females, and in those with and without cardiometabolic risk factors. The effect of socioeconomic status was also studied, with patients categorised into quintiles according to the Welsh Index of Deprivation. 

Of the 1,127,731 included, 629,046 (55.8%) were females and 498,685 (44.2%) were males. At baseline, the men were older, and had higher systolic blood pressure, BMI and HbA_1c. They were also more likely to smoke and have cardiovascular conditions, such as hypertension, heart failure, peripheral vascular disease or stroke/TIA, and had a coronary artery disease prevalence that was twice as high as women. After adjusting for these risk factors, the average annual decline in eGFR was similar for men and women, until the age of about 73 years (73.8 years for men and 72.6 years for women), after which the rate was disproportionately higher in men compared to women (−1.26 mL/min/1.73 m²  [95% CI, −1.26 to −1.25] vs −1.03 mL/min/1.73 m² [−1.03 to −1.03]). 

The authors also examined decline in renal function stratified by sex and according to each risk factor. Overall, men and women with cardiometabolic risk factors had a higher rate of decline compared to their counterparts without them. Beyond the age of 73 years, eGFR drop was greater in men compared to women, regardless of the presence or absence of a risk factor. 

For both sexes, the factors associated with the greatest decrease in eGFR per year were current smoking (males, −1.58 [−1.60 to −1.55]; females, −1.27 [−1.29 to −1.25]) and diabetes (males, −1.44 [−1.45 to −1.43]; females, −1.21 [−1.22 to −1.20]). The distinction, however, was in the third factor which was peripheral vascular disease for males (−1.31 [−1.32 to −1.29]) and socioeconomic deprivation for females (−1.06 [−1.07 to −1.05]). The higher the socioeconomic class (i.e. lesser deprivation), the smaller the reduction in renal function was. While this was also generally true for men, the graded response was not observed in the middle 3 quintiles, suggesting there are other, more influential factors (potentially cardiometabolic) at play for these middle-income households. 

In the secondary analysis, which looked at the risk of incident renal failure (defined by a persistently reduced eGFR of <15 mL/min/1.73 m² for ≥3 months or need for long-term KRT), males were shown to have incident rates that were about twice as high compared to females. After adjusting for confounders, the risk of kidney failure was nearly two-fold (adjusted HR, 1.83 [1.70 to 1.97]) in males. Although the overall mortality rate was higher for men, the mortality rate in those commencing KRT and those with incident kidney failure not commencing KRT was higher in women. Lastly, a higher baseline eGFR and older age were associated with a lower risk of kidney failure for both sexes, though this was more pronounced in women (P<0.001).

This real-world study offers valuable thoughts for consideration. Despite demonstrating a strong association between the presence of various cardiometabolic risk factors and declining eGFR, this alone was not enough to explain the accelerated renal function decline in men. Indeed, similar findings have also been observed in other studies. Notably, in an analysis from the Renal Iohexol Clearance Survey (RENIS) on a healthy cohort without CKD, diabetes or CVD, women still had a slower reduction in eGFR.⁵ 

This then raises the question: do men have an inherently higher risk of kidney failure? While genetic variants have been associated with a number of kidney pathologies, and polygenic risk scores have been used to predict CKD risk, studies to date are yet to identify a male genetic predisposition.⁶ Sex hormones are thought to play a role through their direct effects on the kidneys as well as on conditions, such as diabetes and CVD, that modulate kidney disease. High oestrogen levels have been regarded as protective, but views on testosterone levels are more varied, with both high and low levels linked to disease progression, indicating that further investigation is required.⁷ 

Though the decline in eGFR was more pronounced after the age of 73 years, it is crucial to highlight that this observation was likely influenced by a combination of factors, including the onset and accumulation of comorbidities well before this age, disease-related mechanisms and age-related effects, such as inflammation, diminished physiological reserve and altered metabolism. Thus, adequate management of these comorbidities (including the cardiometabolic ones) and engaging in healthy lifestyles to promote healthy ageing may delay onset of this deterioration. 

The most important take-home message from this study, however, is that there is scope to modify the risk of progression of CKD, and potentially prevent ESRD in men and women. This may be achieved by specifically targeting areas associated with the greatest risk to kidney health. For men, more stringent management of cardiometabolic risk factors may be required, with consideration to lowering referral thresholds for specialist management as well as the upper limit for treatment targets (e.g. stricter control of blood pressure and blood glucose levels). While those who are healthcare avoidant or non-compliant may be overlooked, additional efforts by healthcare professionals to understand reasons behind this may help. 

Undoubtedly, women also need attention with regards to the above, but findings from this study highlight the relevance of the social determinants of health (SDOH), even in developed countries. Though females are more likely to be health conscious and healthcare seeking, limitations in factors such as education, income, access to basic amenities and support with family responsibilities can act as barriers to accessing healthcare or receiving treatment effectively, increasing gender disparities.² 

This may, in part, explain the higher mortality rates in women who required KRT in the study. SDOH are influenced by several factors, including cultural elements, and improving these requires collaboration from policymakers at local, national and international levels. From a healthcare-provider perspective, proactively addressing the social components and working with patients (both women and men) to overcome any barriers, whether through improving health literacy or facilitating access to sources of support, can have a huge impact. 

One criticism of the study is the use of creatinine-based eGFR calculation in an analysis looking at sex-specific differences, given the distinction in muscle mass between males and females that can confound the results. The results may also be less applicable to other populations with differing prevalences of cardiometabolic conditions, and regions where susceptibility to the SDOH are greater. Nonetheless, this important study underscores the need for specific strategies that combine a cardio-renal-metabolic approach, taking into account patients’ biopsychosocial circumstances, to reduce the burden of CKD.

A digest of the study can be read here.

References

1. Carrero JJ, Hecking M, Chesnaye NC, Jager KJ (2018) Sex and gender disparities in the epidemiology and outcomes of chronic kidney disease. Nat Rev Nephrol 14: 151–64
2. Tong A, Evangelidis N, Kurnikowski A et al (2022). Nephrologists’ perspectives on gender disparities in CKD and dialysis. Kidney Int Rep 7: 424–35
3. Stevens PE, Ahmed SB, Carrero JJ, et al (2024) KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int 105: S117–314
4. Sullivan MK, Lees JS, Rosales BM et al. Sex and the relationship between cardiometabolic risk factors and estimated GFR decline: A population-based cohort study. Am J Kidney Dis 23 Jul [ Epub ahead of print]
5. Melsom T, Norvik JV, Enoksen IT et al (2022) Sex differences in age-related loss of kidney function. J Am Soc Nephrol 33: 1891–902
6. Sawaf H, Gudura TT, Dorobisz S et al (2023) Genetic susceptibility to chronic kidney disease: Links, risks and management. Int J Nephrol Renovasc Dis 16: 1–15
7. Conte C, Antonelli G, Melica ME et al (2023) Role of sex hormones in prevalent kidney diseases. Int J Mol Sci 24: 8244