
==== Front
Ren Fail
Ren Fail
Renal Failure
0886-022X
1525-6049
Taylor & Francis

39301874
10.1080/0886022X.2024.2402508
2402508
Version of Record
Research Article
Hemodialysis and Peritoneal Dialysis
Statin therapy and upper tract urothelial carcinoma risk in hyperlipidemic patients with chronic kidney disease and end-stage kidney disease, a population-based 17-year follow-up study
Y.-C. Cheng et al.
https://orcid.org/0009-0004-9076-8925
Cheng Ya-Chi a‡
https://orcid.org/0000-0003-3542-8552
Sung Fung-Chang bcd‡
https://orcid.org/0000-0002-4371-5968
Muo Chih-Hsin be
https://orcid.org/0000-0003-4563-4341
Hsu Chih-Cheng bfgh
https://orcid.org/0000-0002-9684-0789
Tsai Wen-Chen b
https://orcid.org/0000-0003-3619-468X
Hsu Yueh-Han ijk
a Division of Family Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
b Department of Health Services Administration, China Medical University, Taichung, Taiwan
c Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
d Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan
e Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan
f Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan
g Department of Family Medicine, Min-Sheng General Hospital, Taoyuan, Taiwan
h National Center of Geriatrics and Welfare Research, National Health Research Institutes, Yunlin, Taiwan
i Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
j Department of Nursing, Min-Hwei Junior College of Health Care Management, Tainan, Taiwan
k Division of Nephrology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
Supplemental data for this article can be accessed online at https://doi.org/10.1080/0886022X.2024.2402508.

‡ Both authors contributed equally to this work.

CONTACT Yueh-Han Hsu cych07023@gmail.com Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, 539, Zhong-Xiao Road, Chiayi 60002, Taiwan
20 9 2024
2024
20 9 2024
46 2 240250811 1 2024
3 9 2024
4 9 2024
KnowledgeWorks Global Ltd.20 9 2024
published online in a building issue20 9 2024
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
2024
The Author(s)
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

Abstract

Background

The upper tract urothelial carcinoma (UTUC) risk associated with statin therapy in hyperlipidemic patients with chronic kidney disease (CKD) and end-stage kidney disease (ESKD) remains obscure.

Aim

This retrospective cohort study investigated the UTUC risk for hyperlipidemic patients with CKD or ESKD associated with statin therapy.

Methods

From the national insurance claims data of Taiwan, we identified hyperlipidemic patients and established three pairs of statin users and non-users sub-cohorts matched by propensity scores: 401,490 pairs with normal kidney function, 37,734 pairs with CKD, and 6271 pairs with ESKD. Incidence rates and hazard ratio (HR) of UTUC were estimated, by the end of 2016, between statin and non-statin cohorts, and between hydrophilic statins users and lipophilic statins users. Time-dependent model estimated adjusted HR, and sub-distribution HR (sHR) accounting for the competing risk of deaths.

Results

The statin-users with ESKD were at increased UTUC risk (sHR 1.98; 95% confidence interval (CI), 1.28–3.06), significant for younger patients (40–64 years). The incidence was twofold greater in women than in men (31.8 versus 15.9 per 10,000 person-years). Receiving lipophilic statins was associated with increased UTUC risk in CKD and ESKD patients, while receiving hydrophilic statins was associated with increased UTUC risk in ESKD patients.

Conclusions

Patients with ESKD receiving statin were at an increased UTUC risk, significant for younger group (<65 y/o). The positive associations between UTUC and statin persisted in both genders with ESKD, and in therapy with either lipophilic statins or hydrophilic statins. Statin users with ESKD deserve attention for UTUC prevention.

Keywords

Cancer risk
gender
kidney disease
statins
upper tract urothelial carcinoma
Taiwan Ministry of Health and Welfare Clinical Trial Center MOHW109-TDU-B-212-114004 MOST Clinical Trial Consortium for Stroke MOST 109-2321-B-039-002 China Medical University Hospital 10.13039/501100004391 DMR-108-154 Tseng-Lien Lin Foundation of Taichung, Taiwan Ditmanson Medical Foundation Chiayi Christian Hospital R-109-17 This research was funded by Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW109-TDU-B-212-114004), MOST Clinical Trial Consortium for Stroke (MOST 109-2321-B-039-002), China Medical University Hospital (DMR-108-154), Tseng-Lien Lin Foundation of Taichung, Taiwan, and Ditmanson Medical Foundation Chiayi Christian Hospital (R-109-17).
==== Body
pmcIntroduction

Upper tract urothelial carcinoma (UTUC) is a rare urological cancer, receiving less attention. This disease has been on the rise in Taiwan, to 4.07 per 100,000 in 2019, among the highest rates worldwide [1]. Comparing to general population without kidney dysfunction, risks of developing UTUC are 1.72 times greater for patients with chronic kidney disease (CKD) [2], or 11.6–33.3 times greater for patients with end-stage kidney disease (ESKD) or dialysis-dependent patients in Taiwan [3,4]. The cancer is crucial for population in Taiwan due to a high ESKD prevalence. The development of UTUC has also been associated with smoking, female gender, diabetes, arsenic-exposure, traditional Chinese medicine use, analgesic use, and repeated urinary tract infections [5,6].

Statins are currently the most commonly prescribed medications, for patients with hyperlipidemia, which effectively reduce serum low-density lipoprotein levels, cardiovascular events, and mortality in non-dialysis patients. In addition, studies also reported that statins could inhibit cell proliferation in vitro [7,8] and could associate with reduced tumor growth or mortality in patients with cancer [9–11]. Lai et al. in a bench study, claimed a beneficial role of statin in urothelial carcinoma risk [8]. A recent study using insurance claims data found the statin therapy was associated with reduced cancer-related deaths for 17% in women with breast cancer [9]. Evidence also showed that statin therapy had clinical benefits on urological cancers, improving survivals from renal cell carcinoma [10] and prostate cancer [11]. However, studies on the relationship between statin therapy and UTUC risk are sparse.

The mucosal surfaces of the renal pelvis, ureter, and bladder share the same embryologic origin, and thus the term ‘urothelium’ is used to delineate the lining surface epithelium [12]; UTUC and urinary bladder cancer (UBC) were considered as separate twin cancers associated with their biological make-up [13]. For studies on the relation between statins and UBC, an earlier study analyzing 88,125 cancer cases and 362,254 matched controls found that prolonged use of statins over 4 years was related to increased UBC risk (odds ratio 1.29; 95% confidence interval (CI), 1.08–1.54) [14]. A recent population-based cohort study reported that receiving statins was afflicted with an increased risk for UBC (odds ratio 1.23; 95% CI, 1.19–1.27) [15]. However, another observational study [16] and a meta-analysis research [17] failed to prove an association between statin therapy and the UBC risk.

Cancer risk associated with statin therapy in patients with CKD and ESKD has seldom been addressed. We have reported that CKD and ESKD patients receiving statins were benefited with reduced hepatoma risk [18]. Because CKD and/or ESKD patients are at elevated risk of developing UTUC, it is important to investigate whether statin therapy might modify the UTUC risk for these patients. We also aimed to evaluate the UTUC risks by the severity of kidney dysfunction, age, sex, and the type of statin.

Ethics approval

This study was approved by the Research Ethics Committee of China Medical University and Hospital (approval No. CRREC-107-021) and the Research Ethics Committee of Ditmanson Medical Foundation Chiayi Christian Hospital (approval No. CYCH-IRB-2019063).

Methods

Data source

This study established study cohorts using the population-based insurance claims data available at the Health and Welfare Data Science Centers, provided by the Ministry of Health and Welfare of Taiwan. The data bank consisted of the National Health Insurance Research database (NHIRD), Catastrophic illness Registry, Taiwan cancer registry annual report, and death registry. The information available in the insurance claims data included demographic status of insured population, outpatient and inpatient records of medical treatments, medications, and costs. Taiwan cancer registry collected and consolidated records of all types of primary cancer for cancer patients. These data were linked by re-coded identifications to protect the privacy of insured individuals. In the claims data, drugs and disease classifications conformed to the Anatomical Therapeutic Chemical Classification System and the International Statistical Classification of Diseases and Related Health Problems 9th Revision (ICD-9) for diseases diagnosed before 2016, and ICD-10 since 2016.

Study cohorts

From the insurance claims data, we identified 4,638,044 patients with hyperlipidemia (ICD-9: 272/ICD-10: E780-E785) newly diagnosed in 1999–2015, including 3,233,708 patients (∼70%) with statin therapy and 1,404,336 patients without (Figure 1). We identified 1,069,623 patients who had received statin therapy for at least 90 days continuously for the potential statin cohorts (Figure 1). The 91st day of statin therapy was defined as the index date. UTUC was decided by ICD coding (ICD-9: 189.1, 189.2; ICD-10: C65, C66) and cancer registry. After excluding 447,521 hyperlipidemic patients, ineligible for this study, we identified 622,102 patients remained in the statin cohort. We further identified three subgroups consisting of 565,384 patients with normal kidney function (90.9%), 47,357 CKD patients without dialysis (7.61%), and 9,361 patients with ESKD (1.50%).

Figure 1. Flowchart for establishing study sub-cohorts with and without statins therapy in patients with hyperlipidemia among groups of normal kidney function, chronic kidney disease, and end-stage kidney disease.

From 1,404,336 hyperlipidemic patients without statin therapy before 2015, we identified 863,410 patients for the non-statin cohort after exclusions according to the same criteria that were used for the statin cohort. This cohort consisted of three subgroups: 792,793 patients with normal kidney function (91.8%), 62,717 patients with non-dialysis CKD (7.26%), and 7,900 patients with ESKD (0.91%). From subgroups of both the statin cohort and the non-statin cohort, we randomly selected three pairs of sub-cohorts matched by propensity score with same sizes. Multivariable logistic regression was used to calculate propensity score for each person. For the normal kidney function pairs, the propensity score match adjustments included variables of age, gender, monthly income, living areas, comorbidity, tradition Chinese medicine use, use of non-steroid anti-inflammatory drugs (NSAIDs), frequency of urinary tract infection, and hyperlipidemia diagnosis date. For the CKD pairs, the CKD diagnosis date was added for adjustment. For the ESKD pairs, the ESKD diagnosis date was added for adjustment.

Outcome and comorbidity

The study population were followed from the date being included in their study cohorts to the date with UTUC diagnosed or death, or the end of 2015 for estimating the incidence of UTUC for each sub-cohort as the primary outcome. The secondary outcome was to compare UTUC occurrences by age, gender, and the type of statin used, in which we compared the effectiveness between hydrophilic statin and lipophilic statin.

Comorbidities that we considered as potential covariates associated with developing UTUC were diabetes, hypertension, peripheral arterial occlusive disease, ischemic heart disease, and stroke. All comorbidities were defined by clinical diagnosis within one year before the index date. The frequency of urinary tract infection per year was defined within 180 days before the end point. We also included the use of traditional Chinese medicine and NSAIDs as potential covariates, which were also defined within one year before the index date.

Statistical analysis

Number and percentage were used to present distributions of categorical variables. Mean and standard deviation of age were presented. We used standardized differences to compare mean and prevalence of baseline characteristics between two sub-cohorts for each pair group. If the standardized difference was larger than 0.1, we considered that the covariate balance was not achieved. The UTUC incidence rate was calculated with the sum of UTUC events divided by the sum of follow-up person-years in each cohort. We used standard Cox proportional hazards regression model to estimate the adjusted hazard ratio (aHR) and 95% CI of UTUC for statin users compared to non-users after controlling for the matched pairs (model 1). The status of receiving statins might change during the study period, we used time-dependent Cox proportional hazards regression analysis to assess the aHR of UTUC (model 2). We also accounted for the competing risk of death using Fine–Gray analysis model (model 3) to estimate the sub-distribution hazard ratio (sHR). We assessed the incidence and HRs of UTUC by sex and age. For comparing the effectiveness between hydrophilic statins and lipophilic statins, we included Pravastatin and Rosuvastatin in lipophilic statins, and Simvastatin, Lovastatin, Fluvastatin, Atorvastatin, Cerivastatin, and Pitavastatin in hydrophilic statins to compare to non-users.

All statistical tests were two-sided, and the statistical significance was defined as p value <.05. We used SAS, version 9.4 (SAS Institute, Cary, NC), for data analyses.

Results

Study population characteristics

Among population included in this study, the sample sizes were the largest in sub-cohorts of normal kidney function group (401,490 pairs of persons), followed by the CKD group (37,734 pairs of patients) and ESKD group the least (6,271 pairs of patients) (Table 1). The normal kidney function cohorts were younger with more women, and the CKD cohort was older with more men among the three groups. The CKD cohorts and ESKD cohorts had lower income, more likely lived in southern areas and more prevalent with comorbidities. The CKD group had higher portions of using the traditional Chinese medicine and NSAIDs.

Table 1. Distribution of demographic status and comorbidity compared between propensity score matched statin and non-statin cohorts in three study groups.

 	Normal kidney function	 	Chronic kidney disease	 	End-stage kidney disease	 	
Variable	Non-statin
N = 401,490	Statin
N = 401,490	Standardized difference	Non-statin
N = 37,734	Statin
N = 37,734	Standardized difference	Non-statin
N = 6271	Statin
N = 6271	Standardized difference	
Age, mean (SD)	58.4	(10.5)	58.5	(9.78)	0.012	64.5	(10.7)	64.5	(9.93)	0.002	63.2	(10.5)	62.5	(9.66)	0.063	
Men, n (%)	195,578	48.7	194,287	48.4	0.006	20,844	55.2	20,575	54.5	0.014	3223	51.4	2984	47.6	0.076	
Income, NTD	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	
 ≤19,200	142,652	35.5	142,675	35.5	0.000	14,522	38.5	14,930	39.6	0.022	2723	43.4	2765	44.1	0.014	
 19,201–21,900	71,984	17.9	71,885	17.9	0.001	7544	20.0	7325	19.4	0.015	1279	20.4	1254	20.0	0.010	
 21,901–36,300	93,146	23.2	92,024	22.9	0.007	8396	22.3	8249	21.9	0.009	1282	20.4	1267	20.2	0.006	
 >36,300	93,698	23.3	94,906	23.6	0.007	7272	19.3	7230	19.2	0.003	987	15.7	985	15.7	0.001	
Living area	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	
 Northern	184,714	46.0	185,975	46.3	0.006	14,245	37.8	14,198	37.6	0.003	2390	38.1	2458	39.2	0.022	
 Central	75,624	18.8	75,127	18.7	0.003	7966	21.1	8011	21.2	0.003	1297	20.7	1250	19.9	0.019	
 Southern	116,301	29.0	115,171	28.7	0.006	13,301	35.3	13,238	35.1	0.003	2222	35.4	2204	35.2	0.006	
 Eastern and off-shore islands	24,851	6.19	25,217	6.28	0.004	2222	5.89	2287	6.06	0.007	362	5.77	359	5.72	0.002	
Comorbidity, n (%)	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	
 Diabetes	61,195	15.2	71,874	17.9	0.072	7949	21.1	8962	23.8	0.064	2050	32.7	2097	33.4	0.016	
 Hypertension	109,671	27.3	117,107	29.2	0.041	14,278	37.8	15,515	41.1	0.067	2447	39.0	2555	40.7	0.035	
 PAOD	5191	1.29	5929	1.48	0.016	868	2.30	943	2.50	0.013	303	4.83	329	5.25	0.019	
 IHD	31,080	7.74	38,806	9.67	0.068	4835	12.8	5703	15.1	0.066	1192	19.0	1277	20.4	0.034	
 Stroke	10,305	2.57	14,174	3.53	0.056	2054	5.44	2294	6.08	0.027	342	5.45	339	5.41	0.002	
UTI frequency per year	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	
 Median (Q1, Q3)	0	(0, 0.09)	0	(0, 0.09)	 	0	(0, 0.26)	0	(0, 0.24)	 	0	(0, 0)	0	(0, 0.14)	 	
 Mean (SD)	0.23	(2.81)	0.19	(2.67)	0.013	0.48	(4.19)	0.37	(4.10)	0.026	0.43	(1.86)	0.31	(1.73)	0.071	
TCM use	94,941	23.7	94,524	23.5	0.002	9722	25.8	9706	25.7	0.001	744	11.9	760	12.1	0.008	
NSAID used	296,263	73.8	296,802	73.9	0.003	28,463	75.4	28,920	76.6	0.028	4101	65.4	4059	64.7	0.014	
Hemodialysis	 	 	 	 	 	 	 	 	 	 	5769	92.0	5659	90.2	0.062	
PAOD: peripheral artery occlusive disease; IHD: ischemic heart disease; UTI: urinary tract infection; TCM: traditional Chinese medicine; NSAID: non-steroid anti-inflammatory drugs.

Risk of UTUC by age and sex

By the end of follow-up, the UTUC incidence rate was lower in statin users than in non-users among those with normal kidney function or with CKD, but the stain users had higher UTUC incidence than the non-users for those with ESKD (Table 2). HRs showed no significant differences between the users and non-users, but the sHR (1.98; 95% CI, 1.28–3.06) shows the risk was significant for the users with ESKD after controlling for competing risk of deaths. Compared with the normal kidney function group, the UTUC incidence rates were near fourfold higher for CKD patients and over 20-fold higher for ESKD patients. Table 2 also shows that women had higher incident UTUC than men among all three groups, the differences were greater for those with ESKD, 31.8 versus 15.9 per 10,000 person-years in the statin users and 28.6 versus 10.3 per 10,000 person-years in the non-users.

Table 2. Incidence of upper tract urothelial carcinoma and statin cohort to non-statin cohort hazard ratio by sex in three groups.

 	Non-statin	Statin	Hazard ratio (95% confidence interval)	
Outcome	Event, n	PYs	Rate	Event, n	PYs	Rate	Model 1	p	Model 2	p	Model 3	p	
NKF	290	2,118,588	1.37	274	2,483,371	1.10	0.79 (0.67–0.93)	.005	0.84 (0.52–1.38)	.502	0.97 (0.68–1.37)	.842	
 Men	118	1,012,854	1.17	104	1,170,414	0.89	0.74 (0.57–0.96)	.002	1.03 (0.48–2.22)	.937	0.78 (0.43–1.40)	.396	
 Women	172	1,105,734	1.56	170	1,312,958	1.29	0.82 (0.67–1.01)	.066	0.74 (0.39–1.42)	.368	1.10 (0.71–1.72)	.663	
CKD	76	154,818	4.91	105	218,116	4.81	0.95 (0.71–1.27)	.724	0.90 (0.62–1.30)	.572	1.29 (0.96–1.73)	.090	
 Men	34	85,101	4.00	38	117,900	3.22	0.78 (0.49–1.24)	.293	1.02 (0.56–1.83)	.953	1.15 (0.73–1.82)	.553	
 Women	42	69,716	6.02	67	100,216	6.69	1.07 (0.73–1.58)	.718	0.87 (0.54–1.40)	.563	1.41 (0.96–2.07)	.078	
ESKD	29	15,098	19.2	66	26,677	24.7	1.20 (0.77–1.86)	.424	1.42 (0.91–2.21)	.118	1.98 (1.28–3.06)	.002	
 Men	8	7764	10.3	19	11,918	15.9	1.43 (0.63–3.24)	.398	0.47 (0.14–1.59)	.227	2.34 (1.02–5.37)	.045	
 Women	21	7334	28.6	47	14,758	31.8	1.04 (0.62–1.76)	.883	1.82 (1.10–3.01)	.019	1.89 (1.13–3.15)	.015	
PYs: person-years; rate: per 10,000 PYs; NKF: normal kidney function; CKD: chronic kidney disease; ESKD: end-stage kidney disease; model 1: adjusted for matched pairs; model 2: in time-dependent model after controlling for all comorbidities; model 3: in competing risk model after controlling for all comorbidities and deaths.

Models 2 and 3 in normal kidney function were conducted by 20% random sampling of the whole cohort.

Table 3 shows that the UTUC incidence rates were all lower in the younger than in the elderly, but no aHR showed significant statin therapy effectiveness for users. On the other hand, statin users in the ESKD group were at a sHR of 1.98 (95% CI, 1.28–3.06) for UTUC after controlling for comorbidities and deaths, mainly due to the younger group with an aHR of 2.63 (95% CI, 1.31–5.27).

Table 3. Incidence of upper tract urothelial carcinoma and statin cohort to non-statin cohort hazard ratio by age in three groups.

 	Non-statin	Statin	Hazard ratio (95% confidence interval)	
Study
Group age	Event, n	PYs	Rate	Event, n	PYs	Rate	Model 1	p	Model 2	p	Model 3	p	
NKF	290	2,118,588	1.37	274	2,483,371	1.10	0.79 (0.67–0.93)	.005	0.84 (0.52–1.38)	.502	0.97 (0.68–1.37)	.842	
 40–64	114	1,571,071	0.73	127	1,832,329	0.69	0.92 (0.72–1.18)	.499	1.13 (0.56–2.29)	.727	1.10 (0.63–1.91)	.736	
 65–80	176	547,517	3.21	147	651,043	2.26	0.69 (0.56–0.86)	.001	0.63 (0.31–1.27)	.197	0.82 (0.51–1.30)	.393	
CKD	76	154,818	4.91	105	218,116	4.81	0.95 (0.71–1.27)	.724	0.90 (0.62–1.30)	.572	1.29 (0.96–1.73)	.090	
 40–64	16	77,310	2.07	25	77,507	3.23	0.98 (0.52–1.85)	.937	1.07 (0.79–1.47)	.642	1.21 (0.63–2.34)	.566	
 65–80	60	77,507	7.74	80	109,058	7.34	0.93 (0.67–1.30)	.677	0.98 (0.65–1.48)	.940	1.28 (0.92–1.78)	.147	
ESKD	29	15,098	19.2	66	26,677	24.7	1.20 (0.77–1.86)	.424	1.42 (0.91–2.21)	.118	1.98 (1.28–3.06)	.002	
 40–64	10	8741	11.4	40	16,764	23.9	1.89 (0.94–3.80)	.076	1.07 (0.58–2.00)	.821	2.63 (1.31–5.27)	.007	
 65–80	19	6357	29.9	26	9913	26.2	0.83 (0.46–1.51)	.544	1.78 (0.94–3.37)	.078	1.41 (0.77–2.62)	.269	
PYs: person-years; rate: per 10:000 PYs; NKF: normal kidney function; CKD: chronic kidney disease; ESKD: end-stage kidney disease; model 1: adjusted for matched pair; model 2: using time-dependent model after controlling for all comorbidities; model 3: using competing risk model after controlling for all comorbidities and deaths.

Models 2 and 3 in normal kidney function were conducted by 20% random sampling of the whole cohort.

Comparison of effectiveness between lipophilic statins and hydrophilic statins uses

Figure 2 depicts the incident UTUC for patients with normal kidney function, CKD and ESKD using lipophilic statins and hydrophilic statins, compared to non-users. The incidence, 0.94 per 10,000 person-years, was the lowest in hydrophilic statin users with normal kidney function, which increased to 3.10 per 10,000 person-years in patients with CKD and reached to the highest of 32.8 per 10,000 person-years in those with ESKD. Compared to non-statin users, the sHRs showed significant elevated hazards for lipophilic statin users with CKD (1.39; 95% CI, 1.02–1.90) and ESKD patients (1.75; 95% CI, 1.10–2.79), and for hydrophilic statin users with ESKD (2.76; 95% CI, 1.57–4.86).

Figure 2. Incidence rates of UTUC in patients with chronic kidney disease and end-stage kidney disease associated with using lipophilic statin and hydrophilic statin, compared with non-statin users. LS: lipophilic statins; HS: hydrophilic statins; CKD: chronic kidney disease; ESKD: end-stage kidney disease: UTUC: upper tract urothelial carcinoma.

Discussion

This is the first study has ever used a complicated design to investigate the UTUC risk associated with the treatment effectiveness of statin therapy for hyperlipidemic patients with different stages of kidney diseases. Our study showed that the statin therapy was associated with a 98% increase in UTUC risk for ESKD patients, with a greater impact for female patients. The incidence in younger users (40–64 y/o) was twofold greater than non-users. Using lipophilic statin was associated with increased risks of UTUC in both CKD and ESKD groups, while using hydrophilic statin was associated with increased risk of UTUC in the ESKD group, implying potential safety of using hydrophilic statins in CKD patients. Our findings were consistent with evidence in previous studies [2–4].

Age and sex are also important factors associated with the UTUC risk. The UTUC incidence rates were higher in the elderly than in the younger in all three groups for both statin users and non-users (Table 3), interpreting that the risk was greater for the elderly, particularly for patients with ESKD. Among the statin users with ESKD, the UTUC incidence was near 12-fold greater in the elderly or near 35-fold greater in the younger, compared to the corresponding age groups with normal kidney function. The data indicated that younger hyperlipidemic patients with ESKD are at a high risk of UTUC, even under the statin therapy. Wang et al. have also reported a sharp inverse relationship between age and the standardized incidence ratio of UTUC, which supported our findings [3].

It is also important to note that the UTUC incidence rates were consistently higher in women than in men among all three groups (Table 2). The gap was higher for patients with ESKD of both statin users and non-users. The malignancy of UTUC is relatively less common in Western than in Taiwan. No study using a design similar to ours. The international study investigating outcomes after radical nephroureterectomy for UTUC found no gender differences on incidence and progression outcomes [19]. Lin et al. have reported that the risk of UTUC was over twofold higher in women than in men in Taiwan [5]. Chung et al. found the HR of all cancers 2.5-fold greater in women than in men with kidney transplant, a gender gap much greater than those without [20]. For patients with UTUC, an Austria study found female tended to have advanced tumor staging and worse survival conditions [21]. Findings in these studies reflect that Asian women should be on higher alert for the risk of developing UTUC, particularly for those with kidney disorders.

The carcinogenic characteristics of UTUC and UBC may have divergence between Asian and Western. Western population are more prevalent with UBC associated with Lynch syndrome [22], whereas in Taiwan, the occurrence of UBC and other UTUC has been suspected for association with aristolochic acid in patients using herbs [1,5]. UTUC and UBC are considered as separate twins based on differences in the mutational profiles [13]. The Lynch syndrome is more prevalent in UTUC patients than in UBC patients in Western [22]. In an earlier study, Chen et al. reported that 61.2% (93/152) of UTUC patients in Taiwan had exposed to aristolochic acid leading to mutations in TP53 gene [23], which provided solid evidence in the carcinogenesis of UTUC, at least in Taiwan.

Recent studies have reported that statins may lead to mitochondrial changes or immune-modulation effects [15,24]. A Swedish nationwide register study reported that statins are associated with metabolic changes in the mitochondria, affecting the urothelial epithelial cells of the urinary bladder [15]. The initial positive statin therapy effects in lowering serum lipids through the mitochondria might change after a long-term use, leading to an increased risk of developing UBC. Statins may play the role of immune-modulation by reducing the effects of BCG in the UBC treatment, worsening the treatment prognosis [25].

Previous studies comparing the treatment effectiveness between lipophilic and hydrophilic statins appeared mainly for relevant cardiovascular effects with adverse outcome [26]. Limited studies have reported the comparison for the risk of cancer development relating to their kidney function. Because using statins to control low-density lipoprotein levels has become a crucial part of daily practice, the clinicians need more information to provide precise treatments. In our study, the elevated risk of UTUC seemed stronger for statin therapy using lipophilic statin (in statin-users of both CKD and ESKD) than using hydrophilic statin (in ESKD statin-users only). Several studies reported that statin therapy with lipophilic statin superior to hydrophilic statin in reducing risks of hepatoma [27], endometrial cancer [28], and colon cancer [29]. However, these reports did not bring kidney function status into study designs. We previously reported the superiority of hydrophilic statins over lipophilic statins in risk reduction of hepatoma in hyperlipidemic patients with CKD and ESKD [18]. Whether kidney function status had an influence on developing cancers associated with hydrophilic or lipophilic statins deserves further investigation.

Limited studies have linked the UTUC risk to both statin therapy and kidney dysfunction. It has been a constant challenge in investigating factors associated with UTUC in Taiwan as of the relationship with aristolochic acid. Researchers might consider herbs used in Taiwan play a crucial role in the cancer pathogenesis [1]. In 2003, the Taiwan government has banned herbal prescriptions containing aristolochic acid. The database used in the present study consisted of claims data from 1999 to 2015. In most claims data, the information on aristolochic acid exposure was not reported from clinics of Chinese medicine and herbal stores. We, thus, were unable to investigate whether patients had the aristolochic acid exposure, which is one of our study limitations. However, our study design has considered the prescribed traditional Chinese medicine uses as the potential risk factor associated with UTUC and had this factor controlled for in the multivariable analysis. There were about 23.5% of our study population had used traditional Chinese medicine, similar in both statin cohort and non-statin cohort. We were therefore reluctant to consider aristolochic acid caused bias in the risk evaluation in this study.

There are some other limitations in this study. Due to characteristics of our database, we have no access to some patient information on laboratory data for kidney disease stages, lifestyles, and diet habits. Due to the nature of observational study, potential bias existed such as prescription bias. Job history and chemical exposures might play a role in the risk of UTUC but was not included in the adjustment as well. Our cohorts with normal kidney function are younger than cohorts with CKD and ESKD, which might lead potential bias in the analysis. Lastly, although this is a well-focused nation-wide study conducted under the setting of national health insurance database, generalization to be made to other health-care settings might be limited.

Even though, our study has certain strengths. We conducted multiple efforts to reduce the confounding effects, such as propensity-score match, time-dependent model analysis and competing analysis against death. Our study design addressed immortal time bias as well. With a large population data, we were able to establish six study cohorts (statin users and non-users in three different kidney function status), without jeopardizing the statistical power in further stratification analyses. The study designs compared the associations of incident UTUC with different kidney function status. The increased UTUC risks in patients with CKD and ESKD are consistent with current evidence. In addition to comparing the differences with age and sex, we compared the treatment effectiveness between hydrophilic statin and lipophilic statin for incident UTUC. Statins might be associated with reduced cancer risk in other organs such as with prostate cancer [11] and hepatoma [18], yet with elevated risk in UTUC. Altogether, our study expanded our notion and hinted the possibility of diverse risk association of statin therapy with different cancers. Our reports could arouse attentions on the adverse impact of statin therapy for hyperlipidemic patients with kidney dysfunction. Further prospective investigations are needed to delineate such associations.

Conclusions

We reported a positive association with the risk of UTUC in hyperlipidemic patients with ESKD receiving statin therapy compared with those without the therapy. Further subgroup analyses found persistent positive associations in ESKD patients below 65 y/o, and in both genders. Lipophilic statins had elevated risk association with UTUC in patients with CKD and ESKD, while hydrophilic statins were associated with UTUC in patients with ESKD.

Supplementary Material

Fig 2 ESKD ST UTUC.tiff

Fig 1 ESKD ST UTUC.tiff

Acknowledgements

We are grateful to Health Data Science Center, China Medical University Hospital, and Ditmanson Medical Foundation Chiayi Christian Hospital for providing administrative, technical, and funding supports, and to Ministry of Health and Welfare for providing data.

Author contributions

Yueh-Han Hsu had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Yueh-Han Hsu: study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, obtaining funding, administrative, technical, or material support, supervision. Ya-Chi Cheng: analysis and interpretation of data, critical revision of the manuscript for important intellectual content. Fung-Chang Sung: study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, obtaining funding, administrative, technical, or material support, supervision. Chih-Hsin Muo: study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, statistical analysis, obtaining funding, administrative, technical, or material support. Chih-Cheng Hsu: study concept and design, analysis and interpretation of data, critical revision of the manuscript for important intellectual content, supervision. Wen-Chen Tsai: analysis and interpretation of data, critical revision of the manuscript for important intellectual content, supervision.

Disclosure statement

No potential conflict of interest was reported by the author(s).
==== Refs
References

1 Dickman KG, Chen CH, Grollman AP, et al. Aristolochic acid-containing Chinese herbal medicine and upper urinary tract urothelial carcinoma in Taiwan: a narrative review. World J Urol. 2023;41 (4 ):899–907. doi: 10.1007/s00345-022-04100-5.35867141
2 Chen JS, Lu CL, Huang LC, et al. Chronic kidney disease is associated with upper tract urothelial carcinoma: a nationwide population-based cohort study in Taiwan. Medicine. 2016;95 (14 ):e3255. doi: 10.1097/MD.0000000000003255.27057873
3 Wang SM, Lai MN, Chen PC, et al. Increased risk of urothelial cancer in young and middle aged patients with end-stage renal disease. J Formos Med Assoc. 2015;114 (1 ):52–57. doi: 10.1016/j.jfma.2013.10.022.24360022
4 Hsiao PJ, Hsieh PF, Chang CH, et al. Higher risk of urothelial carcinoma in the upper urinary tract than in the urinary bladder in hemodialysis patients. Ren Fail. 2016;38 (5 ):663–670. doi: 10.3109/0886022X.2016.1155392.26956094
5 Lin MY, Niu SW, Li WM, et al. Incidence and survival variations of upper tract urothelial cancer in Taiwan (2001–2010). Int J Urol. 2022;29 (2 ):121–127. doi: 10.1111/iju.14731.34708447
6 Palvio DH, Andersen JC, Falk E. Transitional cell tumors of the renal pelvis and ureter associated with capillarosclerosis indicating analgesic abuse. Cancer. 1987;59 (5 ):972–976. doi: 10.1002/1097-0142(19870301)59:5<972::AID-CNCR2820590520>3.0.CO;2-Y.3815276
7 Sheikholeslami K, Ali Sher A, Lockman S, et al. Simvastatin induces apoptosis in medulloblastoma brain tumor cells via mevalonate cascade prenylation substrates. Cancers. 2019;11 (7 ):994. doi: 10.3390/cancers11070994.31319483
8 Lai CR, Tsai YL, Tsai WC, et al. Farnesoid X receptor overexpression decreases the migration, invasion and angiogenesis of human bladder cancers via AMPK activation and cholesterol biosynthesis inhibition. Cancers. 2022;14 (18 ):4398. doi: 10.3390/cancers14184398.36139556
9 Chang WT, Lin HW, Lin SH, et al. Association of statin use with cancer- and noncancer-associated survival among patients with breast cancer in Asia. JAMA Netw Open. 2023;6 (4 ):e239515. doi: 10.1001/jamanetworkopen.2023.9515.37083661
10 Nayan M, Macdonald EM, Juurlink DN, et al. Medication use and survival in diabetic patients with kidney cancer: a population-based cohort study. Pharmacol Res. 2016;113 (Pt A ):468–474. doi: 10.1016/j.phrs.2016.09.027.27678041
11 Raval AD, Thakker D, Negi H, et al. Association between statins and clinical outcomes among men with prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2016;19 (2 ):151–162. doi: 10.1038/pcan.2015.58.26782711
12 Melicow MM. Tumors of the urinary drainage tract: urothelial tumors. J Urol. 1945;54 (2 ):186–193. doi: 10.1016/S0022-5347(17)70066-3.
13 Green DA, Rink M, Xylinas E, et al. Urothelial carcinoma of the bladder and the upper tract: disparate twins. J Urol. 2013;189 (4 ):1214–1221. doi: 10.1016/j.juro.2012.05.079.23023150
14 Vinogradova Y, Coupland C, Hippisley-Cox J. Exposure to statins and risk of common cancers: a series of nested case-control studies. BMC Cancer. 2011;11 (1 ):409. doi: 10.1186/1471-2407-11-409.21943022
15 Lundberg E, Hagberg O, Jahnson S, et al. Association between occurrence of urinary bladder cancer and treatment with statin medication. Turk J Urol. 2019;45 (2 ):97–102. doi: 10.5152/tud.2019.94495.30875287
16 Kuo CC, Chiu HF, Lee IM, et al. Statin use and the risk of bladder cancer: a population-based case-control study. Expert Opin Drug Saf. 2012;11 (5 ):733–738. doi: 10.1517/14740338.2012.712960.22849562
17 Zhang XL, Geng J, Zhang XP, et al. Statin use and risk of bladder cancer: a meta-analysis. Cancer Causes Control. 2013;24 (4 ):769–776. doi: 10.1007/s10552-013-0159-3.23361339
18 Sung FC, Yeh YT, Muo CH, et al. Statins reduce hepatocellular carcinoma risk in patients with chronic kidney disease and end-stage renal disease: a 17-year longitudinal study. Cancers. 2022;14 (3 ):825. doi: 10.3390/cancers14030825.35159093
19 Shariat SF, Favaretto RL, Gupta A, et al. Gender differences in radical nephroureterectomy for upper tract urothelial carcinoma. World J Urol. 2011;29 (4 ):481–486. doi: 10.1007/s00345-010-0594-7.20886219
20 Chung CJ, Huang CY, Tsai HB, et al. Sex differences in the development of malignancies among end-stage renal disease patients: a nationwide population-based follow-up study in Taiwan. PLOS One. 2012;7 (9 ):e44675. doi: 10.1371/journal.pone.0044675.22957098
21 Mohamad Al-Ali B, Madersbacher S, Zielonke N, et al. Impact of gender on tumor stage and survival of upper urinary tract urothelial cancer: a population-based study. Wien Klin Wochenschr. 2017;129 (11–12 ):385–390. doi: 10.1007/s00508-016-1088-4.27670858
22 Therkildsen C, Eriksson P, Höglund M, et al. Molecular subtype classification of urothelial carcinoma in Lynch syndrome. Mol Oncol. 2018;12 (8 ):1286–1295. doi: 10.1002/1878-0261.12325.29791078
23 Chen CH, Dickman KG, Huang CY, et al. Aristolochic acid-induced upper tract urothelial carcinoma in Taiwan: clinical characteristics and outcomes. Int J Cancer. 2013;133 (1 ):14–20. doi: 10.1002/ijc.28013.23292929
24 Karanović S, Ardin M, Tang Z, et al. Molecular profiles and urinary biomarkers of upper tract urothelial carcinomas associated with aristolochic acid exposure. Int J Cancer. 2022;150 (2 ):374–386. doi: 10.1002/ijc.33827.34569060
25 Berglund RK, Savage CJ, Vora KC, et al. An analysis of the effect of statin use on the efficacy of Bacillus Calmette-Guerin treatment for transitional cell carcinoma of the bladder. J Urol. 2008;180 (4 ):1297–1300; discussion 1300. doi: 10.1016/j.juro.2008.06.034.18707737
26 Climent E, Benaiges D, Pedro-Botet J. Hydrophilic or lipophilic statins? Front Cardiovasc Med. 2021;8 :687585. doi: 10.3389/fcvm.2021.687585.34095267
27 Simon TG, Duberg AS, Aleman S, et al. Lipophilic statins and risk for hepatocellular carcinoma and death in patients with chronic viral hepatitis: results from a nationwide Swedish population. Ann Intern Med. 2019;171 (5 ):318–327. doi: 10.7326/M18-2753.31426090
28 Desai P, Wallace R, Anderson ML, et al. An analysis of the association between statin use and risk of endometrial and ovarian cancers in the women’s health initiative. Gynecol Oncol. 2018;148 (3 ):540–546. doi: 10.1016/j.ygyno.2018.01.006.29422345
29 Liu Y, Tang W, Wang J, et al. Association between statin use and colorectal cancer risk: a meta-analysis of 42 studies. Cancer Causes Control. 2014;25 (2 ):237–249. doi: 10.1007/s10552-013-0326-6.24265089
