Gender Differences in Kidney Stone Disease (KSD): Findings from a Systematic Review

Seven studies have been reported since 2015, which offer up-to-date epidemiological perspectives on gender differences in KSD [10‐16]. Abufraj et al. evaluated data from the US National Health and Nutrition Examination Survey (NHNES), and this revealed that between 2008 and 2018, the prevalence of KSD increased significantly among women (6.5% vs. 9.3%, (p_trend = 0.001) [10]. However, there was no significant increase among men. Risk factors specific to women were identified and included increasing number of previous pregnancies (2 pregnancies — OR 1.64, CI 1.1–2.23; 3 or more pregnancies — OR 2.17, CI 1.63–2.88), menopause (OR 1.61, CI 1.21–2.15) and female hormone use (OR 1.38, CI 1.15–1.65). Two further groups reported on the same national database [11, 12]. Tundo et al. focused their analysis on adults younger than 50 years of age in order to better understand the burden of the disease on working age group [12]. The authors determined that women of working age were just as likely as men to develop KSD. All the analysis carried out by the separate groups consistently reported that amongst adolescent females, the rate of increase was the greatest. Hsi et al. performed analysis of data from a prospective sample, the South Community Cohort Study, which also has confirmed the rise in female KSD [13].

In another retrospective review, Masterson et al. looked at over half a million Navy personnel and found the incidence of KSD in women was in fact higher than men (OR 1.17, p < 0.0001) [14]. Given the strict medical work up required in this area of work, to ensure safe flight status, this analysis included a large number of asymptomatic stones. It has been postulated that this may be one of the explanations why the rising trend is seen in the female population. Indeed, recent follow up data made available from the Olmsted County study reveals that women were more likely to be asymptomatic stone formers [15]. Vaughan et al. reviewed nearly 5000 stone episodes at a US centre and found that compared to women, men were significantly more likely to have a symptomatic recurrence following their initial presentation with stones (HR 1.25, p = 0.002) [16].

As part of the evolution for patient centred and holistic care, an increasing number of studies now include quality of life (QoL) as an outcome measure [17]. Four recent studies were identified, which explored this theme [18‐21]. Stern et al. evaluated data from the North American Stone Quality of Life Consortium and found that younger, stone patients tolerated stone events less favourably than men [18]. Younger women had a significantly lower health-related quality of life (HRQoL) scores compared to older men (OR 1.56, p = 0.0003). Moreover, this difference was consistent across all four domains measured (social functioning, stone related impact, vitality and emotional functioning). This would be consistent with recent data from a study by Maccraith et al., which recorded that this group was most likely to have a re-admission to the emergency department after ureteroscopy (URS) [19]. Patel et al. carried out a survey to explore the impact of KSD on QoL and recorded a worsening trend in females under 40 years of age [20]. Previous evidence has shown that KSD impacts more negatively on care givers than primary income earners, and some author groups have speculated that this may offer some explanation to the above findings [18]. Islamoglu evaluated the role of menopause on pain experienced during shockwave lithotripsy (SWL) and reported women post menopause to have significantly lower pain scores than younger women (p < 0.001) [21].

It has been hypothesised that sex hormones may have a significant role in gender differences for KSD, and 5 studies were identified which investigated this further [22‐24, 26]. Peerapen et al. investigated the effects of oestrogen in the kidney [22]. They demonstrated that oestrogen (i) reduces surface expression of two calcium oxalate crystal receptors, (ii) reduces crystal binding capability and (iii) reduces intracellular ATP in renal tubular cells. These may all contribute to a favourable environment within the kidney, thus reducing the risk of stone formation in women of reproductive age. Zhu et al. used rodent models to demonstrate that oestrogen receptor knock-out mice and rats treated with an oestrogen receptor antagonist had increased renal calcium oxalate deposition and increased urinary oxalate excretion, and as a result, the activity of oestrogen in healthy females may be protective against KSD [23].

Conversely, Nackeeran et al. examined the possible role of sex hormones on the risk of stone formation by measuring the testosterone and oestrogen levels in over 10,000 American patients who self-reported a history of KSD [24]. They concluded that abnormal testosterone levels (both high and low) did not significantly increase the risk of stone formation. They also found no correlation between low oestrogen (in both genders) and KSD. However, given the timings of the study, the sex hormone levels were likely measured after some duration of the stone episode, so does not necessarily represent the levels at the time of stone formation.

There is some evidence to support a protective role of ACE-inhibitors on stone formation [25]. Xiao et al. performed a cross-sectional analysis in order to investigate this further amongst a population with type 2 diabetes mellitus (DM) [26]. The protection achieved among women was superior to men. This may be due to androgen-mediated calcium excretion in male kidneys counteracting the protection derived from ACE inhibitors.

Three studies were identified which investigated the association of stone composition and gender [27‐29]. Kravdal et al. analysed a series of over 1250 stones collected at surgery from a Norwegian population [27]. They found that men were more likely to have calcium oxalate monohydrate stones than women (males, 57.3% vs females, 47.1%, p < 0.001), and women were more likely to have carbonate apatite (females, 16.2% vs males, 7.8%, p < 0.001) and struvite (females, 10.6% vs males, 3.0%, p < 0.001) stones. Wang et al. performed a similar analysis of over 1500 stones collected at their tertiary centre [28]. Women were more likely to have mixed composition stones (females, 70.9% vs males, 57.0%, p < 0.001) and more likely to have a history of urinary tract infection (UTI) (females, 39.1% vs males, 35.7%, p = 0.042). They also found that women were statistically more likely to have renal as opposed to ureteric stones (females, 85.2% vs males, 77.4%, p < 0.001).

Wood et al. published an analysis of over 500 stone patients who had 24-h urine collections performed [29]. This showed that men excreted more calcium (mg/day) (males, 217.7 vs females, 180.1, p = 0.0002) and oxalate (mg/day) (males, 43.2 vs females, 34.20, p < 0.0001) into their urine than women, had a lower pH than women (males, 6.03 vs females, 6.20, p = 0.0001) and were more likely to have supersaturation of uric acid in their urine than women (mg/day) (males, 1.03 vs females, 0.70, p < 0.0001). The latter is consistent with existing literature highlighting that women are less at risk of high urate levels than men, resulting in a male predominance in uric acid stones and gout [30]. The basis for this may be hormonal, and they found multiple mechanisms by which the expression and activity of uric acid transporters are affected by oestrogen, which goes some way to explain the gender difference in pathology related to hyperuricaemia.

Sepsis is the leading cause of KSD-related mortality [31]. Seven studies were identified, which investigated sepsis post-KSD intervention [32‐38]. It has previously been demonstrated that women have higher sepsis rates after ureteroscopy (URS) than men [39]. Southern et al. confirmed this in a retrospective analysis of over 3000 URS cases (OR 1.6, CI 1.19–2.15) [32]. Another study recorded a significantly higher rate of post-operative sepsis after percutaneous nephrolithotomy (PCNL) in women (OR 7.8, p = 0.001) [33]. Overall, all the studies determined female gender to be a risk factor for developing sepsis post-stone surgery [32‐38].

The prevalence of KSD is also increasing in the paediatric setting [40]. A large contributing factor for this is considered to be the paralleled rise of body mass index (BMI) in this age group [41]. Three studies were identified, which investigated gender differences in paediatric KSD [42‐44]. Taisan et al. reported findings from a longitudinal study over a 30-year period and found the overall risk of KSD doubled in children [42]. Furthermore, the lifetime risk of developing KSD among females increased by 45% during the study period (1997–2012). Both this study and one by Schwadrerer et al. recorded that girls were most likely to experience KSD in adolescence [42, 43]. This age group is increasingly affected by KSD which is consistent with findings from NHNES [10]. Meiouiet et al. studied stone composition in 432 paediatric calculi [44]. Girls had calcium oxalate stones in 72.3% of cases compared to 42.7% in boys (p < 0.00001).

Three studies were identified, which investigated gender differences in the setting of warmer seasons [45, 47, 48]. Vicedo-Cabrera et al. analysed data from admission to emergency department (ED) across 68 centres in a US state between 1997 and 2015 [45]. When the highest ambient temperatures were recorded, a significantly higher proportion of men were admitted with KSD (males, RR 1.73 vs females, RR 1.15, p < 0.001). This is consistent with previous evidence highlighting the seasonal variation in KSD events as well as a recent population-based time series analysis in Canada (RR = 1.64 vs 1.22, p = 0.006) [46, 47]. Fukuhara et al. also reported that more ageing and male patients presented with acute stone disease when the ambient temperature was high [48]. It is difficult however to determine whether the cause is related to occupational behaviour or whether there may be a truly physiological cause. The latter may be because there are more aquaporin channels in the proximal collecting tubule and thin descending loop of Henle in men, which causes greater water reabsorption and therefore more concentrated urine [49]. This is consistent with a previous study which showed that men have a lower urine volume in hot weather than women [46].

This review offers insight into the evolving changes in the global burden of KSD and the gender differences that exist within it (Table 2). The heterogeneity of studies precludes a formal meta-analysis. Furthermore, the nature of included studies introduces several limitations. Cause-effect conclusions are difficult to establish in cross-sectional studies and case control studies, such as where patients record stone events are subject to recall bias.

In addition to the abovementioned possible causes for the changes to the gender gap, the rise in obesity among women, which is greater than among men, is likely a contributing factor. Studies have shown obesity in women leads to significantly greater supersaturation of calcium oxalate [50]. Goldfarb et al. reported findings from a twin registry and revealed the heritable component of KSD to be greater in men than women [51]. Their findings support the theory that environmental risk factors play a greater role in women.

Data from the Nurses’ Health Study (NHS) I and II showed long-term (> 2 months) antibiotic usage is an independent risk factor for KSD [52]. Given the proportionally higher volume of women who require long-term antibiotics for chronic UTI, this may be another under-recognized contributor to the epidemiological changes observed. More needs to be done on standardizing the outcome parameters and evaluating the QoL of these patients [53].