The worldwide incidence of UTUC is less common in women [3–7]. However, an epidemiological study in Taiwan showed a higher prevalence of UTUC in women than in men [9, 11, 12, 14, 15]. The Taiwan Cancer Registry Annual Report [15] in 2018 also revealed that the crude incidence rate was higher in women (male-to-female ratio = 1:1.3). Clearly, the sex-based distributions of UTUC in Taiwan differ from those in other regions in the world. Chen et al. [16] attribute the progressive increase in the high incidence of UTUC, especially among women, in part to the systematic replacement of traditionally used Chinese herbs with aristolochic acid based on aristolactam-DNA adducts and TP53 mutations, which are identical to those observed in UTUC associated with Balkan endemic nephropathy. A previous report indicated a higher incidence of using alternative therapies for special conditions in women. One of the culturally based reasons is that women consume special nourishment and diets involving herbal medicines daily for at least 1 month after each pregnancy [14]. The exposure to aristolochic acid contributes significantly to the high incidence of UTUC in women in Taiwan. Another study showed a higher proportion of pT3 and advanced-grade UTUC reported in women undergoing nephroureterectomy [4]. The diagnosis of metastatic UTUC was also higher in women [6]. Male patients with UTUC thus have better pathologic outcomes than female patients for the same disease, which may be explained by inequalities in health care between the sexes. A trend toward a more inferior quality of care for women might be an additional possible cause of the sex inequalities [17]. However, no differences were observed between the sexes in CSS in most studies [4–7, 9].
Preoperative CKD was reported as an independent risk factor for higher renal and urothelial cancer rates, but not for prostate, colorectal, lung, breast, or all cancers combined [18]. A national cohort study showed that CKD, the female sex, age, hematuria, bladder cancer history, and end-stage renal disease were significantly associated with UTUC [12]. A study from Japan on UBUC oncologic outcomes in patients with CKD showed that these patients presented with more aggressive cancer behaviors leading to disease progression and recurrence [19]. In our study cohort, the incidence of advanced pT stage (T3, T4) tumor in patients with advanced CKD was 40.0%, which is significantly higher than that in patients with non-advanced CKD (19.4%; p = 0.001). Preoperative CKD was also associated with higher metastatic features in survival analysis. Several studies have proven an association between CKD and cancer outcomes related to the effects of chronic inflammation, oxidative stress, and uremia-related immune deficiency [20–23]. The immune deficiency may increase the risk of cancer, especially virus-associated cancers [20].
As the tumor continues to grow in UTUC, the cancer cells can create a physical obstruction that may put pressure on the urinary tract, subsequently leading to nephron and kidney dysfunction [24]. Some reports believed that renal impairment mechanisms differ between the sexes [12, 19]. A recent report by Schneider et al. [25] showed that the availability of nitric oxide in renal circulation is greater in female patients with type 2 diabetes, which is associated with reduced levels of oxidative stress in women. Another study demonstrated significant sex differences in renal vascular function in patients with CKD [26]. Although the effects are canceled out by age, younger women (< 55 years) exhibit both better endothelium-dependent and endothelium-independent dilation than men of the same age. Convincing evidence has shown that renal endothelial dilatory function can predict susceptibility to renal damage [27]. Therefore, the sex differences observed in our data may be due to lower oxidative stress and better renal vascular function in women.
In the present study, two major differences between the sexes were identified: the high prevalence of CKD and dialysis in women and the high smoking rate in men.
In Taiwan, women use more traditional Chinese medicine treatments than men [28]. These treatments include herbal medicines, acupuncture, moxibustion, and other therapies, which are all covered by the national health insurance system [28]. Sex differences persisted across the age groups. The regular consumption of herbal medicines in Taiwan is very common. Previous studies have reported a high national prevalence of UC in the country, which is associated with the use of carcinogenic remedies containing aristolochic acid [14, 16]. Moreover, Taiwanese women have a higher tendency to self-medicate than men and are higher users of healthcare services in general [28]. The high prevalence and low awareness of CKD in Taiwan have also been reported [29]. The need to advocate more strongly for CKD prevention and education for both physicians and the populace is urgently needed.
Unlike previous studies, we demonstrated that the female sex was not an unfavorable prognostic factor for UTUC. Considering the higher rate of CKD among women with UTUC, we hypothesized that CKD status may also influence previous results. Few reports have demonstrated the difference in CKD rates between the sexes. In this study, we showed that after adjusting for CKD status, women had better metastasis outcomes. Other potential contributing factors to the unique presentations of female cases need further identification and investigation in Taiwan. Theories elucidating the differences in incidence, severity, and prognosis of UTUC between the sexes have not been established. Differences between sexes in carcinogenic exposures, routes of entry, or enzymatic processing of environmental substances may account for the clinical discrepancies.
This study had several limitations. First, this was a retrospective analysis of a single-center series. Second, the enrolled patients were treated by different surgeons over a 13-year period. Third, we could not exclude all possible factors that potentially contributed to CKD. Thus, in order to eliminate the confounders, we took CKD stages into consideration and determine the effects on UTUC outcomes. However, further meta-analysis is needed to compare our findings with those of other published reports with larger populations.