慢性腎臟病（Chronic kidney disease, CKD）已成為全球死亡之主因之一，全世界有超過10% 以上的人受影響，尤其老年人、女性以及患有糖尿病或高血壓之族群更是高危險群。腎臟是重金屬毒性之主要標的器官，因為它具有過濾、濃縮及再吸收二價離子及金屬之能力，亦會透過破壞發炎反應或氧化壓力之平衡，進而影響腎功能，特別是身體機能尚未發展完整之兒童等易感性族群，而且生命早期之環境暴露不僅與兒童時期之疾病有關，還會嚴重影響生命後期之健康狀態。過去大多數研究主要探討受污染地區之高濃度重金屬暴露對腎功能之影響，至於環境暴露對慢性腎臟病影響之研究亦是多以成人為標的，鮮少以兒童為標的進行環境重金屬暴露研究。近期部分研究以迴歸模型分析在多種重金屬暴露下對腎功能之影響，並考慮其作用機制，探討發炎反應、氧化壓力及早期腎損傷指標是否作為中介因子，但尚未確認其影響機制，且有些橫斷性研究在低濃度金屬暴露下，同一種金屬在血液與尿液中觀察到對腎功能影響相反之結果。
因此，本研究擬以兒童作為研究族群，發展具較佳預測能力之新型腎相關指標，進行病例對照研究，自既有之兒童慢性腎臟疾病資料庫與國立成功大學附設醫院小兒腎臟門診招募慢性腎臟病兒童與對照組，因兒童無職業暴露，其主要暴露來自環境暴露，若未居住在受空氣、重金屬嚴重污染之地區，可假設其為低濃度環境重金屬暴露之狀況，同時考慮不同季節，環境污染、兒童活動及飲食習慣之差異，在3-9月（非空污季）及10-2月（空污季）兩個季節皆會收集兒童血液及尿液檢體，檢測其重金屬濃度、發炎因子、氧化壓力、腎小管健康指標及腎功能指標，並以迴歸分析評估多種重金屬暴露對腎功能之影響，同時探討發炎反應及氧化壓力是否具中介作用，以說明重金屬對腎功能之影響。然而，兒童慢性腎臟病多以先天性結構異常為主，即使估計之腎絲球過濾率（eGFR）位於正常範圍，腎臟排除重金屬之能力可能仍不及於一般正常兒童。因此，以重金屬排除、體內累積狀況與對照組兒童之差異性分析進行驗證，同時應用血液及尿液，共同解析重金屬排除及累積之新指標與發炎反應、氧化壓力、腎小管健康指標及腎功能指標間之關係。至於室內空氣中重金屬暴露評估則透過實際採集空氣中細懸浮微粒，以ICP-MS分析其重金屬成分含量，經性別、飲食及時間活動模式等校正後，分析住家臥室細懸浮微粒中重金屬濃度與血液及尿液中重金屬、發炎因子、氧化壓力、腎小管健康指標及腎功能指標之相關性。
本研究排除心臟病及高血壓之患者後，最終分析163人次慢性腎臟病組兒童及76人次對照組兒童，對照組以非腎臟疾病導致輕微血尿就診居多，病例組有85.9% 屬於腎結構性異常，大多皆位於Stage 1（74.2%）及Stage 2（16.6%），表示74.2% 之病例組兒童其eGFR值屬 > 90 mL/min per 1.73 m2之階段，而有15人次屬Stage 4（2.5%）及Stage 5（6.7%），其eGFR平均值為10.5 mL/min per 1.73 m2，且兩組間年齡、性別比例、BMI、血壓、早產比例、服用中西藥比例及魚類攝食量皆無顯著差異，僅居家二手菸暴露以對照組（40%）顯著高於病例組（22.5%），病例組與對照組人次約為2比1。71位受測者臥室中24小時PM2.5之平均濃度為28.6μg/m3，其中82%低於我國空氣品質PM2.5之建議值（35μg/m3）（環境部 2024），而所有PM2.5中成分分析僅檢出鉛及鎳。然而，發現有居家二手菸暴露者其室內空氣品質顯著較差，並且在居家使用線香或蚊香之家戶及距離主要道路較近之家戶室內空氣中PM2.5中之鉛濃度較高，若有使用空氣清淨機確實能降低室內PM2.5之濃度。
受測者血中鎘、鈷及鎳檢出率皆小於40% ，血中砷之檢出率最高（81%），血中總汞次之（69%），血中鉛之檢出率為52%，而尿液中重金屬之檢出率皆大於60%，尿中砷之檢出率為100%，其餘分別為鎘：64%、鈷：98%、汞：75%、鎳： 94%及鉛： 89%，所有血中金屬濃度皆低於參考值，尿中砷、鎘及鉛之濃度高於美國，而與我國其他一般兒童族群之文獻相近，然而血中低濃度金屬長期暴露亦具健康風險，仍不可忽視。本研究發現血中砷在家戶距離廟宇較近者顯著高於距離廟宇較遠者，可能來自廟宇線香或紙錢焚燒所致。其次，居家暴露二手菸之兒童其尿中鎘及鎳之濃度顯著較高，且住家之屋齡大於20年之兒童，其尿中鎘及鈷之濃度顯著較高，亦發現家中有使用空氣清淨機之兒童，其尿中鎘之濃度皆顯著低於未使用者，表示暴露二手菸或老舊房屋建材及金屬表面，可能釋放金屬至室內空氣中。然而，使用空氣清淨機雖能使鎘之暴露顯著減少，但因本研究臥室空氣中金屬之濃度較低，並不足以影響整體金屬暴露情形。此外，發現腎功能良好與否會影響金屬之排除狀況，血液中亦發現金屬累積之情況。進一步以飲食評估其可能之暴露來源，發現有服用中藥者，其血中砷高於未服用者；以瓶裝礦泉水為主要飲用水者血中鎳之濃度最高；海水魚之攝食頻率每週至少食用一次者，其血中砷之濃度及校正後之尿中砷之濃度皆顯著較高；結果發現貝類之攝食頻率每週食用1至3次者，其血中汞之濃度顯著高於每週食用不到1次者，表示魚貝類之攝食頻率較高者須多加留意其金屬暴露。
病例組血中砷及鈷皆與2種eGFR值呈顯著負相關，而血中汞卻與2種eGFR值呈顯著正相關，然而UCr, As、UCr, Co及UCr, Ni則亦與2種eGFR值皆呈顯著正相關，出現反向因果關係，可能之解釋為當腎功能較差時，使得金屬排泄至尿中較少。此外，發現血中砷之濃度與尿中腎小管健康指標內皮生長因子（Epidermal growth factor, EGF）呈顯著負相關，與前述血中砷之濃度與2種eGFR值皆呈顯著負相關之結果相呼應。
然而，從肌酸酐排除率發現在兩組兒童間無顯著差異，但以金屬排除能力之結果卻發現，病例組砷及鎘之清除率顯著低於對照組，而Clearance ratio發現鉛在病例組顯著高於對照組，表示病例組金屬排除能力較差之狀況。相關性分析結果發現對照組及病例組之所有金屬之Clearance ratio皆與2種eGFR呈負相關，表示金屬累積在體內對腎功能具不良影響，進一步結合迴歸分析之結果共同評估，鎘、汞及鎳之Clearance ratio不論是否考慮其他金屬共暴露下與2種eGFR皆呈顯著負相關，而砷、鈷及鉛僅在單一金屬之Clearance ratio與2種eGFR皆呈顯著負相關。
腎功能評估則發現病例組兒童之血清肌酸酐及Cystatin C顯著高於對照組，且2種eGFR值（GFR-Schwartz及eGFR-U25）皆顯著較低，表示即使病例組多為結構性異常，其腎功能仍顯著較差，並在腎相關指標中發現腎小管健康指標EGF病例組顯著低於對照組，且發炎因子腫瘤壞死因子受體 1 & 2（Tumor necrosis factor receptor 1 & 2, TNF-R1 & TNF-R2）顯著較高，此外，血中砷之濃度在考慮其他金屬濃度共暴露下仍與TNF-R1及TNF-R2皆呈顯著正相關，並發現TNF-R1具部分中介效應，能介導砷對GFR-Schwartz之影響，且亦TNF-R2具部分中介效應，介導砷對尿中EGF之影響，此外，亦發現α1-微球蛋白 （Alpha-1-microglobulin, α1-MG）可能具部分中介效應，介導鎘對腎小管健康指標腎臟損傷分子（Kidney Injury Molecule-1, KIM-1）之影響，最後，發炎因子單核細胞趨化蛋白-1（Monocyte Chemoattractant Protein-1, MCP-1）可能具部分中介效應，介導汞累積於體內對GFR-Schwartz之影響。
綜上所述，EGF、 TNF-R1及TNF-R2可能為在觀察兒童早期慢性腎臟病較敏感且較能評估慢性腎臟病早期進展之指標，且在低濃度金屬暴露下，慢性腎臟病兒童可能就具較高之易感性，進而影響腎小管健康，進而導致腎功能不良。此外，以血液檢體較能評估金屬與腎功能之影響，然若能搭配尿液檢體並分析金屬排除能力將有助於提高慢性腎臟病兒童之金屬暴露評估之準確性。除了由環境空氣吸入金屬之暴露外，飲食亦是兒童之主要金屬暴露來源，須注意魚貝類之攝食頻率，若能再減少線香、蚊香及二手菸等，並使用空氣清淨機，將能大幅度地降低兒童金屬暴露。

The purpose of the present study is to investigate new early kidney-related indicators that may have better predictive power to evaluate the relationship between multiple metals exposure and renal function in children with chronic kidney disease. Based on past researches, exposure to multiple metals and the ability of the kidney to excrete metals are used as metal exposure status and body burden of metals. Indicators that related to CKD are angiotensin II (Ang II), tubular health indicators (kidney injury molecule-1 (KIM-1), epidermal growth factor (EGF) and alpha-1-microglobulin (α1-MG), inflammatory factor indicators (tumor necrosis factor receptor 1 & 2 (TNF-R1 & TNF-R2), monocyte chemoattractant protein-1 (MCP-1), C-reactive protein (CRP) and Interleukin 6 (IL-6)) and oxidative stress indicators (8-hydroxy-2-deoxyguanosine (8-OHdG) and Malondialdehyde (MDA) were integrated to evaluate the relationship between these indicators and renal function under multiple metals exposure. 163 CKD children and 76 controls were recruited and accepted the examinations. The serum creatinine and Cystatin C in the case group were significantly higher than control group, and the two eGFR values (GFR-Schwartz and eGFR-U25) were both significantly lower, indicating that even if the case group only had structural abnormalities, their renal function was still significant worse. In addition, EGF in the case group was significantly lower than control group. TNF-R1 and TNF-R2 were significantly higher than control group. Moreover, the concentration of arsenic in the blood was significantly positively correlated with both TNF-R1 and TNF-R2 after adusting the co-exposure to other metal concentrations, and it was found that TNF-R1 has a partial mediating effect and could mediate the impact of arsenic on GFR-Schwartz, and TNF-R2 also has a partial mediating effect, mediating the effect of arsenic on urinary EGF.

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