The Impact of Sex Differences on Renal Function Outcomes After Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Retrospective Study

Background: Upper tract urothelial carcinoma (UTUC) is a relatively rare type of urothelial carcinoma. Additionally, only few reports have examined the sex differences in patients with UTUC. Therefore, the present study aimed to identify the sex factors affecting renal function in patients with UTUC. Methods: Patients who underwent radical nephroureterectomy for non-metastatic UTUC between 2000 and 2013 were retrospectively reviewed and divided into two groups by sex. The Kaplan–Meier method was applied to evaluate the effects of sex on survival, whereas for the other clinicopathological parameters, hazard ratios were evaluated using the Cox regression model. The analyses were also performed in patients with different chronic kidney disease (CKD) stages. Results: A total of 368 patients were included, 147 men and 221 women. Female patients had a higher rate of anemia, advanced CKD stage, and dialysis. Male patients predominantly had a higher rate of smoking. The Kaplan– Meier analysis revealed no differences between sexes on metastasis-free survival (MFS) and cancer-specic survival. Multivariate analysis conrmed that ureteral tumors, advanced pathological tumor stage, and adjuvant chemotherapy indicated signicantly worse survival outcomes in both sexes. However, only female patients with advanced CKD showed poorer MFS. After adjusting for renal function, the analysis found men had worse MFS. Conclusions: The female sex is signicantly associated with a higher prevalence of advanced CKD among patients with UTUC in Taiwan. The impact of sex differences on renal function needs to be considered when evaluating survival.

and found that sex could not predict the outcomes. Hurel et al. [6] showed that the female sex was an independent factor for predicting nal non-organ-con ned disease (p = 0.007) but not of survival. Xylinas et al. [7] developed nomograms built on a retrospective analysis of 1,839 patients with UTUC and found that men had a higher risk of intravesical recurrence than women. A Taiwanese study noted no differences between the sexes in the clinicopathological characteristics of UBUC; however, female patients with bladder cancer were more prone to have more advanced UTUC and renal impairment than male patients [8]. Li et al. [9] observed that male patients with renal insu ciency have a higher possibility of bladder tumor recurrence after RNU. Nevertheless, the effects of sex in UTUC have still not been established by a global consensus.
In Taiwan, the prevalence and incidence of chronic kidney disease (CKD) are higher compared with those in other countries [10]. Previous reports have shown that the female sex had a higher prevalence of proteinuria and renal impairment than the male sex [10,11]. Chen et al. [12] used the Taiwan Longitudinal Health Insurance Database to demonstrate that CKD is a signi cant factor associated with UTUC. To our knowledge, few reports have analyzed the relationship between sex differences in renal function and their prognosis in Asia. The aim of the present study was to identify the sex-related factors affecting renal function in patients with UTUC who underwent RNU.

Patients
Patients who underwent either open or laparoscopic RNU with bladder cuff excision for non-metastatic UTUC at Kaohsiung Medical University Hospital, Kaohsiung, Taiwan between 2000 and 2013 were included in the study. The present study was approved by the review board of our institution (KMUH-IRB-20120138). Patients were divided into two groups by sex. Clinical parameters including demographic characteristics, pathological features, oncologic follow-up, and the cause leading to mortality were retrospectively collected. Patients with neoadjuvant chemotherapy or radiotherapy, concurrent muscle-invasive bladder tumor, acute blood disorders, bone marrow diseases, and incomplete clinical information were excluded. Tumor stage was evaluated according to the 2002 American Joint Committee Cancer TNM system. All cases were reviewed by two pathologists and re-classi ed as low or high grade using the 2004 World Health Organization grading system. Renal function was evaluated using the estimated glomerular ltration rate based on the Chronic Kidney Disease Epidemiology Collaboration creatinine-based formula [13].

Postoperative follow-up
After the operation, outpatient clinics were arranged every 3 months in the rst 2 years and every 6 months in the subsequent 2 years. From the fth year, annual follow-ups were arranged in patients with no evidence of disease. Detailed history taking, physical examination, urine cytology, cystoscopy, and serial imaging survey were performed following the surveillance guidelines. Metastatic progression was de ned as tumor recurrence at the operation site, regional lymph nodes, and distant organs. Tumors occurring in the bladder or contralateral upper urinary tract were considered metachronous and not categorized as disease progression. Adjuvant chemotherapy and radiation therapy were administered in 71 and 30 patients, respectively, according to pathological stage, performance status, renal function, and consent to treatment.

Statistical analysis
Differences between categorical parameters were assessed using the χ 2 or Fisher's exact test. The Kaplan-Meier method was applied to estimate the effects of sex on metastasis-free survival (MFS) and cancer-speci c survival (CSS). Survival rates were recorded from the day of RNU to metastatic progression, cancer-speci c death, or the latest visit. Survival curves were compared using a log-rank test. Only prognostic factors that were statistically signi cant in univariate analysis were included in the multivariate Cox proportional hazard model to identify independent predictors for MFS and CSS. Statistical signi cance was set at p < 0.05. SPSS 20.0 (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses.

Results
Overall, we included 368 patients, 147 (39.9%) men and 221 (60.1%) women, in the current study. Table 1 shows the patients' clinical and pathologic pro les. The mean ± standard deviation age of patients who underwent RNU was 66.8 ± 10.6 years. The mean follow-up after surgery was 41.7 ± 31.7 months (40.4 ± 30.2 months among men and 42.5 ± 32.7 months among women). No difference in follow-up time was observed between the two groups. Female patients had a higher risk of preoperative anemia (p = 0.047) than male patients. Advanced CKD, which was de ned as CKD in stage 4 or 5 in this study, was signi cantly associated with the female sex (p = 0.008). Therefore, a higher dialysis rate was also noted among female patients (p < 0.001). Male patients had a higher rate of smoking (p < 0.001).

Sex differences
No differences were found between the sexes in MFS (p = 0.093; Fig. 1a) and CSS (p = 0.731; Fig. 1b). The Kaplan-Meier analysis revealed that advanced CKD was associated with worse MFS (p = 0.031; Fig. 1c) but not CSS (p = 0.109; Fig. 1d). We found that women had a higher rate of advanced CKD in our study cohort. Multivariate analysis revealed that advanced CKD was an independent predictor of MFS in women. After adjusting for CKD status, we noted that men had worse MFS (log-rank test, p = 0.019; Fig. 1e). No differences were found in CSS even after adjusting for renal function (log-rank test, p = 0.492; Fig. 1f). This close association between advanced CKD and MFS was only observed in women. Men had a higher rate of smoking, which did not impact the MFS (log-rank test, p = 0.962; Additional le 1: Fig. 1a) and CSS (log-rank test, p = 0.616; Additional le 1: Fig. 1b).

Discussion
The worldwide incidence of UTUC is less common in women [3][4][5][6][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 signi cantly 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][5][6][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 signi cantly 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 signi cantly 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 in ammation, oxidative stress, and uremia-related immune de ciency [20][21][22][23]. The immune de ciency 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 signi cant 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 identi ed: 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 in uence 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 identi cation 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 ndings with those of other published reports with larger populations.

Conclusions
This study found that women had no inferior surgical outcomes than men in RNU but tended to have poorer MFS with advanced CKD. Conversely, advanced CKD did not in uence MFS in men. However, after adjusting for renal function, women were found to have better MFS than men. Thus, sex differences in renal function are an important factor in considering the outcomes in UTUC in clinical practice.

Declarations
Ethics approval and consent to participate:The present study was approved by the review board of our institution (KMUH-IRB-20120138). All patients signed the informed consent form.  Figure 1