尿液中無機砷代謝物種及腎臟皮質、腎盂、輸尿管金屬分布與腎臟癌關係之探討

Abstract

背景：泌尿上皮移形細胞癌在台灣的發生率較西方國家高，佔台灣地區的腎臟癌發生率一半以上。先前研究顯示，鉻、錳、銅、砷、鎘、鉛及鎳金屬對腎臟及泌尿道系統會產生不良健康效應，有高砷暴露且砷代謝功能較差的人，其發展為周邊血管系統疾病的危險性較高。本研究目的在探討腎臟癌發生是否與腎臟各部位組織內之砷濃度或是其他金屬濃度有關。此外，也比較砷代謝功能的差異是否與腎臟癌發病有關。 方法：本研究收集102名進行腎臟器官摘除手術的個案，包括腎細胞癌個案、泌尿上皮移形細胞癌個案及對照個案。收取研究個案尿液樣本，並從摘除的腎臟器官取得腎臟皮質、腎盂、輸尿管等組織樣本，各樣本再以感應耦合電漿質譜儀分析，分析金屬包括鉻、錳、銅、砷、硒、鍶、鎘、鉛、鎳等元素；並利用液相層析儀串聯感應耦合電漿質譜儀分析尿液中之砷物種，包括三價砷、五價砷、單甲基砷酸、雙甲基砷酸等。另以問卷調查方式收集個案的基本資料及影響環境金屬暴露因子資料，以與各種腎臟組織樣本中金屬濃度進行相關性比較。 結果：腎細胞癌個案尿液中鎘平均濃度為6.77 ± 13.3 µg / L，泌尿上皮移形細胞癌個案為2.30 ± 4.60 µg / L，兩組研究個案間具統計上顯著差異。腎細胞癌個案腎臟皮質中的錳與銅的平均濃度分別為3.24 ± 2.05 µg / g、9.51 ± 3.98 µg / g，皆顯著高於泌尿上皮移形細胞癌個案腎臟皮質的錳濃度2.07 ± 1.52 µg / g、銅濃度6.10 ± 4.84 µg / g。另外，腎細胞癌個案組中腎臟皮質腫瘤組織的銅、硒、鎘與鉛濃度皆小於其週邊正常組織中的相對應金屬濃度，其濃度差值平均分別是-6.21 ± 6.46 µg / g (p = 0.01)、-2.65 ± 2.81 µg / g (p = 0.01)、-87.5 ± 73.8 µg / g (p = 0.003)、-1.97 ± 2.69 µg / g (p = 0.04)。此外，各種腎臟組織樣本與尿液中總砷濃度、砷物種比例及PMI、SMI兩項指標等，在三組研究個案間沒有達到統計上的顯著差異。 結論：過往研究指出，暴露到鉻、錳、銅、砷、鎘、鉛及鎳金屬可能與泌尿道系統病變有關，而本研究結果雖有發現尿液中的鎘濃度及腎臟皮質組織中的錳、銅濃度在腎細胞癌與泌尿上皮移行細胞癌二組研究個案間有統計差異，但並未發現尿液中的總砷與砷物種濃度在個案間有顯著差異，因此本研究結果尚不足以說明尿液中總砷與砷物種作為腎臟癌相關風險指標的可行性。另外，銅、硒、鎘、鉛等金屬濃度在腎細胞癌腫瘤組織高於正常組織，這些不同類別金屬濃度在腎臟腫瘤組織與正常組織間分布差異的影響機制值得進一步深入探討。

Background：The upper tract urothelial carcinoma accounted for more than half of kidney cancer in Taiwan, and its incidence was higher than those of the western countries. Previous studies indicated that chromium, manganese, copper, arsenic, cadmium, lead and nickel may cause adverse health effects in kidney and urinary tract. People with deficit in arsenic metabolism tended to develop peripheral vascular disease after exposing to high level of arsenic. The goals of this study were set to explore the association between the occurrence of kidney cancers and the concentrations of arsenic or other relevant metals in various kidney tissues, and between the occurrence of kidney cancers and the efficacy of arsenic metabolism in human body. Methods：One hundred and two patients with excision surgery for kidney cancers, including renal cell carcinoma, upper tract urothelial cancer, and controls were recruited from the National Taiwan University Hospital. Urine samples and renal cortex, pelvis samples and urothelial tract samples from the excised organs were collected from each study subject. Concentrations of chromium, manganese, copper, arsenic, selenium, strontium, cadmium, lead, nickel in the collected tissue and urine samples were analyzed by inductively coupled plasma mass spectrometer while the levels of trivalent arsenic, pentavalent arsenic, monomethylarsonic acid, dimethylarsinic acid in urine samples were analyzed with high performance liquid chromatography along with inductively coupled plasma mass spectrometry. Demographics and environmental metal exposure factors of the study subjects were collected by questionnaire administration in order to compare their effects on the study metal levels in urine and kidney tissue samples. Results: Average cadmium concentration in urine samples of the renal cell carcinoma cases, 6.77 ± 13.3 μg/L, was higher than that of upper tract urothelial cancer cases, 2.30 ± 4.60 μg/L (p <0.05). The average concentrations of manganese and copper in the renal cortex in the cases of renal cell carcinoma were significantly higher than those of the upper tract urothelial cancer cases. Average manganese and copper concentrations in renal cortex samples of the renal cell carcinoma cases were 3.24 ± 2.05 μg/g and 9.51 ± 3.98 μg/g, respectively, both significantly higher than those of the upper tract urothelial cancer cases; 2.07 ± 1.52 μg/g and 6.10 ± 4.84 μg/g, respectively. In addition, concentrations of copper, selenium, cadmium and lead in tumor tissues of the renal cortex samples of the renal cell carcinoma cases were all lower than those in the adjacent normal tissues with differences of 6.21 ± 6.46 &micro;g/g (p=0.01), 2.65±2.81 &micro;g/g (p=0.01), 87.5±73.8 &micro;g/g (p=0.003), 1.97±2.69 &micro;g/g (p=0.04). Furthermore, there was no difference in total arsenic levels in various renal tissue samples, and in proportion of arsenic species, PMI and SMI index for urine samples, among the renal cell carcinoma cases, the upper tract urothelial carcinoma cases, and the controls. Conclusions: Previous studies reported that exposure to chromium, manganese, copper, arsenic, cadmium, lead and nickel might be associated with urinary tract related diseases. However, although this study found there were differences in urinary cadmium concentration and in manganese, copper concentrations in renal cortex samples between renal cell carcinoma cases and upper tract urothelial cancer cases, there was no difference observed for total urinary arsenic levels and urinary arsenic species among the renal cell carcinoma cases, the upper tract urothelial cancer cases and the control cases. Therefore, results of the present study might not be appropriate to support the use of total urinary arsenic level and urinary arsenic species levels as indicators for renal cancer related risk. Besides, the concentrations of copper, selenium, cadmium, lead in tumor tissue of the renal cell carcinoma cases were found higher than those of their adjacent normal tissue. The mechanism leading to such metal concentration gradient between tumor and normal tissues in kidney is deserved of future study for further exploration.