Role of Aristolochic Acid, Statins, and Aspirin on the Risk of Urothelial Cancer in Patients With End-Stage Renal Disease

Background and Purpose: Both end-stage renal disease (ESRD) and upper tract urothelial cancer (UTUC) bear high incidence rates in Taiwan. Female is also observed higher in development of urinary tract cancer (UTC). We can use National Health Research Institute database (NHRID) to calculate incidence and prevalence rate, and to deduce possible caution and prevention factor, including relation disease and consumption of medicine. Arsenic is a potential confounder although more than 99% of UC cases resided in area out of 4 traditional endemic areas of arsenic in Southwest Taiwan. Other possible predisposing factors include analgesics, aristolochic acid (AA) containing Chinese herbal products (CHP). Some anti-inflammation agents are also potential chemoprevention for occurrence of UC in chronic dialysis patient. Otherwise, in Nov 2003 prohibition of 5 herbal components containing AA was promulgated by the Department of Health. This policy may have impact on development of UC.
Methods: We used NHIRD 1997-2002, 1997-2008 and 1,000,000 randomized samples as our study database. There are four designs to answer different questions. First, we used 1997-2002 NHIRD data to calculate standardized incidence ratios (SIRs) of urinary tract cancer among ESRD and general population as reference. Second, cox-regression model to calculate hazard ratios of UC in ESRD with factors of AA-CHP, analgesics and acetaminophen from NHIRD claims. Third, using 1997-2008 NHIRD, we calculated 40-84 y/o cumulative incidence rate (CIR40-84) and SIR40-84 and tested trend by calendar year. Fourth, using 1997-2008 NHIRD we put potential caution and prevention agents on UC among ESRD.
Results: Using 1997-2002 NHIRD, there are 687 new developed UTC among 58,739 patients with ESRD. Using the general population as the reference group, SIRs were 12.9 (95% CI (confidence interval): 12.0-13.9) for all UTC cases. SIRs are disproportionate high in female of 22.1 (95% CI: 20.1, 24.3) and younger, namely, less than 50 y/o of 74.5 (95% CI: 1.8, 41.2). Another similar period study sorting 320 patients developed UC after ESRD from 38,995 ESRD patients. Having been prescribed Mu Tong or an estimated consumption of aristolochic acid (esAA) more than 1-100 mg, were both associated with an increased risk of UC in the multivariable analyses. Analgesic consumption of more than 150 pills was also associated with an increased risk of UC.
Another study sorting 2,708 new developed UC from 90,477 ESRD between1997 and 2008 covering the patients aged 40-85. The time trends of CIR40-84 and SIR40-84 of UTUC in females appear to decline after calendar year 2000. These trends may be related to AA-associated herbal products after 1998.
Moreover, during 1998-2008 data, 1,243 new developed UC were sorted from 98,243 ESRD patients. Having been prescribed of esAA and acetaminophen increased risk significantly for UC. Significantly increased risk of lower tract UC if Mu Tong ever been prescribed, and at upper tract UC became significant at consumption more than 60 g. At chemoprevention agents, significant reduced hazard of UC in cases having been prescribed statin and aspirin in cases without exposure or less than esAA of 100 mg. More than 100 mg consumption the benefit will become marginal.
Conclusions: Consumption of aristolochic acid-related Chinese herbal products was associated with an increased risk of developing UC in ESRD patients. After decline in prescription of AA-CHP during study period, we found a similar trend in female UTUC incidence. The time trends associate with the consumption of aristolochic acid. Exception to AA-CHP consumption, acetaminophen is also a potential causal factor. Promising chemopreventive effect is found at aspirin and statin usage, but more than 100 mg AA consumption this effect is not promising. In conclusion, although AA-CHP consumption is decreasing, hazard of UC in ESRD patients was still high in end of 2008. Consumption of aristolochic acid herbal products implicitly impact public health in this generation. Although more understanding of causal and prevention factors are encouraging, developing practically regulations are indeed urgent.