Association Between Urothelial Carcinoma After Kidney Transplantation and Aristolochic Acid Exposure: The Potential Role of Aristolochic Acid in HRas and TP53 Gene Mutations

Xiao, Jing; Zhu, Xu-Dong; Hao, Gangyue; Zhu, Yichen; Hou, Hongping; Zhang, J.; Ma, Lin; Tian, Ye; Zhang, Y.H.

doi:10.1016/j.transproceed.2011.09.069

Cited by 12 publications

(16 citation statements)

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“…Four studies were conducted in Taiwan; three in China; and one across Croatia, Bosnia, and Serbia. Four ORs and the corresponding confidence intervals were calculated using the data provided in the articles (20, 24–26). One of the case-control studies investigated the risk of UUC at two AA exposure levels (151–250 mg; >250 mg) (23).…”

Section: Resultsmentioning

confidence: 99%

Risk Assessment of Upper Tract Urothelial Carcinoma Related to Aristolochic Acid

Wang

2013

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background Aristolochic acid (AA) is a toxin found in plants of the genus Aristolochia, to which humans can be exposed either through certain Chinese herbal medicines or through inadvertent commingling with food crops. Our objective was to estimate cumulative exposures of AA associated with increased risk of end stage renal disease (ESRD), and to conduct a systematic review and meta-analysis on AA-induced upper tract urothelial carcinoma (UUC). Methods Using epidemiological studies on AA-related disease from multiple different world regions, a systematic review was performed in which relative risks, hazard ratios, and odds ratios were derived or extracted directly; and a meta-analysis was conducted. One study was used to estimate a benchmark dose lower confidence limit (BMDL) for AA-related ESRD. Results Mean values for risk ratios - odds ratios, relative risks, or hazard ratios - of UUC caused by AA ranged from 1 to 49. A meta-analysis of these studies resulted in a pooled odds ratio of 5.97 (95% CI: 2.78–12.84) for this AA-related cancer. The obtained BMDL for AA-related ESRD was 0.42 g cumulative aristolochic acid exposure. Conclusions Aristolochic acid exposure is significantly associated with an increased risk of UUC, and there is a dose-dependent relationship between cumulative AA exposure and end stage renal disease risk. Impact Individuals who use certain Chinese herbal medicines may significantly increase their risk of developing UUC and/or ESRD, as would individuals who are inadvertently exposed to aristolochic acid through commingling of Aristolochia plants with harvested food crops.

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Section: Resultsmentioning

confidence: 99%

Risk Assessment of Upper Tract Urothelial Carcinoma Related to Aristolochic Acid

Wang

2013

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…In addition to the high rate of postoperative recurrence, the high risk of death from other diseases was considered to be owing to the various cardiovascular and cerebrovascular complications of AAN, especially in patients receiving maintenance dialysis. 56 Among the 16 studies identifying the molecular alterations in AA-UTC, 10,13,14,22,[57][58][59][60][61][62][63][64][65][66][67][68] eight studies assessed AA exposure by WGS/WES through NGS approaches. 13,14,22,[58][59][60]67,68 WGS was performed on AA-UTUC in one study 68 and AA-RCC in one study.…”

Section: Discussionmentioning

confidence: 99%

“…Characteristics of the included studies reporting risk or oncologic outcomes of AA-UTC Tables 1 and 2 summarize the characteristics of the 25 studies reporting risk or oncologic outcomes of AA-UTC. [66][67][68] Twenty-four were peer-reviewed articles published from 1991 to 2020, [35][36][37][38][39][40][41][42][44][45][46][47][48][49][50][51][52][53][54][55][56][66][67][68] and one was a master's thesis completed in 2011. 43 Among them, 18 were cohort studies 37,38,[40][41][42][43][44]46,[48][49][50][51][52][53][54][55]56,68 and seven were case-control studies.…”

Section: Comparison Of the Included Studies Between The Present And Previous Systematic Reviewsmentioning

confidence: 99%

“…43 Among them, 18 were cohort studies 37,38,[40][41][42][43][44]46,[48][49][50][51][52][53][54][55]56,68 and seven were case-control studies. 35,36,39,66,45,67,47 Study locations included Taiwan, 39,[45][46]49,52,67 mainland China, 36,38,[40][41][42][43][44]48,51,[53][54][55][56]68 Croatia, 35,37 and Serbia. 47,50 Baseline renal functions of study participants included chronic kidney disease (CKD) stages 0-5, 35,…”

Section: Comparison Of the Included Studies Between The Present And Previous Systematic Reviewsmentioning

confidence: 99%

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Aristolochic acid-associated urinary tract cancers: an updated meta-analysis of risk and oncologic outcomes after surgery and systematic review of molecular alterations observed in human studies

Kang

Chen

Lin

et al. 2021

Therapeutic Advances in Drug Safety

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Background: The risk of primary aristolochic acid (AA)-associated urothelial carcinoma (AA-UC) has been summarized by a 2013-published meta-analysis. Given that additional evidence has been continuously reported by original studies, an updated meta-analysis is needed. Meanwhile, to complete the whole picture, a systematic review of molecular alterations observed in AA-urinary tract cancers (AA-UTC) was also performed. Methods: We searched PubMed, Embase and four Chinese databases up to October 2020. Observational studies comparing risk or oncologic outcomes of UTC between patients with and without AA exposure were eligible for systematic review and meta-analysis. Studies investigating molecular alterations in AA-UTC using human tissue samples were eligible for systematic review. Results: In total, 38 and 20 studies were included in the systematic review and meta-analysis, respectively. Exposure to AA led to an overall increased risks of primary UTC [UC and renal cell carcinoma (RCC)] (OR 6.085, 95% CI 3.045–12.160) and postoperatively recurrent UC (RR 1.831, 95% CI 1.528–2.194). Subgroup analysis of postoperative primary AA-upper tract UC (AA-UTUC) showed increased risks of bladder recurrence (adjusted RR 1.949, 95% CI 1.462–2.597) and contralateral UTUC recurrence (crude RR 3.760, 95% CI 2.225–6.353), worse overall survival (adjusted HR 2.025, 95% CI 1.432–2.865) and worse disease-specific survival (adjusted HR 3.061, 95% CI 1.190–7.872), but no effect on cancer-specific survival (adjusted HR 0.772, 95% CI 0.269–2.215). High mutation load with AA mutational signature presenting largely in the putative driver genes was observed in AA-UTUC. In contrast, AA mutational signature is rarely found in the mutated RCC driver genes and the mutation load in AA-RCC is low. Therefore, AA has different roles in the genesis of UTUC and RCC. Conclusions: Implementing effective strategies to completely protect people from exposure to AA is urgently needed. Additionally, more effort should be made in identifying the precise carcinogenic mechanisms of AA to determine the future treatment strategies. Plain language summary Risk, recurrence and survival outcomes after surgery and molecular changes possibly involved in the genesis of aristolochic acid-associated urinary tract cancers Background: The association between aristolochic acid (AA) and primary urothelial carcinoma (UC) has been summarized by a 2013-published meta-analysis. Given that additional evidence has been reported in the past 7 years, an updated meta-analysis is needed. Meanwhile, to complete the whole picture, a systematic review of molecular changes possibly involved in AA-mediated urinary tract carcinogenesis was also performed. Methods: We searched PubMed, Embase and four Chinese databases for human studies up to October 2020. Studies comparing the risk of urinary tract cancer (UTC) between patients with and without AA exposure and studies investigating the molecular changes in AA-associated UTC (AA-UTC) using human tissue samples were eligible for inclusion. Thirty-eight studies were finally included. Results: The results showed that exposure to AA was associated with a 6-fold increased risk of primary UTC (UC and renal cell carcinoma, RCC) and a 1.8-fold increased risk of postoperatively recurrent UC. After studies reporting primary AA-upper tract UC (AA-UTUC) were analyzed, a 1.9-fold increased risk of bladder recurrence and a 3.8-fold increased risk of contralateral UTUC recurrence was observed. Additionally, exposure to AA worsened the postoperative survival of patients with UTUC by a 2-fold increased risk of overall death and a 3-fold increased risk of death from other diseases and recurrences. However, there was no effect on death due to cancer. Lastly, AA seemed to play different roles in the etiology of UTUC and RCC based on the observations of different mutation loads and different distributions of AA-induced mutations in AA-UTUC and AA-RCC samples. Conclusions: Implementing effective strategies to completely protect people from exposure to AA is urgently needed. Moreover, more effort should be made in identifying the precise carcinogenic mechanisms of AA-UTC to determine the future treatment strategies.

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“…China has experienced a similar trend. Indeed, according to our published data, urothelial carcinoma (UC) is the predominant malignancy among Chinese RT patients (6)(7)(8)(9). This is quite different from Western countries, in which non-melanoma skin cancer and post-transplantation lymphoproliferative disorder (PTLD) are the most common malignancies (10,11).…”

Section: Introductionmentioning

confidence: 99%

Chemotherapy for urothelial carcinoma in renal transplantation patients: Initial results from a single center

Zhu

Xiao

Guo

et al. 2015

Molecular and Clinical Oncology

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The aim of this study was to assess the safety and efficacy of gemcitabine plus cisplatin/carboplatin (GC/GCa) chemotherapy in renal transplantation (RT) patients with urothelial carcinoma (UC). We reviewed the records of 12 RT patients with metastatic or locally advanced UC who received chemotherapy at our institution since January, 2013. All the patients received intravenous gemcitabine (800 mg/m) on days 1, 8 and 15, plus cisplatin (70 mg/m) or carboplatin (area under the curve = 5) on day 2, every 28 days. A total of 10 patients completed all the cycles, while 1 patient discontinued treatment due to disease progression and 1 patient discontinued due to non-medical reasons. In total, 12 patients received a median of four cycles of chemotherapy. The overall response rate was 50% (4/8 cases) in patients with measurable lesions. At the time of the study, 5 patients had succumbed to the disease (overall survival, 9.2 months), while 7 patients remained alive (follow-up time, 13.3 months). The most common toxicities were myelosuppression and gastrointestinal effects. Therefore, the GC/GCa regimen was found to be effective and tolerable in RT patients with UC. However, further studies involving more patients and control groups are required to confirm our results.

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Association Between Urothelial Carcinoma After Kidney Transplantation and Aristolochic Acid Exposure: The Potential Role of Aristolochic Acid in HRas and TP53 Gene Mutations

Cited by 12 publications

References 12 publications

Risk Assessment of Upper Tract Urothelial Carcinoma Related to Aristolochic Acid

Risk Assessment of Upper Tract Urothelial Carcinoma Related to Aristolochic Acid

Aristolochic acid-associated urinary tract cancers: an updated meta-analysis of risk and oncologic outcomes after surgery and systematic review of molecular alterations observed in human studies

Chemotherapy for urothelial carcinoma in renal transplantation patients: Initial results from a single center

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