環境中三聚氰胺暴露可經由氧化壓力引發含鈣尿路結石患者的腎小管傷害:三聚氰胺相關結石生成的可能機轉研究

黃詩婷^1,2、劉家駒^3,4,5、吳佳芳²、謝翠娟^1,2、蔡宜純⁶、黃書彬^3,4、李永進^3,7、黃琮懿⁴、

周以和^3,4、沈榮宗⁷、黃俊農^3,4、阮雍順^3,4、吳文正^3,4、吳明蒼^2,8

¹高雄醫學大學 醫學院 醫學研究所; ²高雄醫學大學 精準環境醫學研究中心; ³高雄醫學大學 醫學院 泌尿學科; ⁴高雄醫學大學附設醫院 泌尿部; ⁵衛生福利部 屏東醫院 泌尿科; ⁶高雄醫學大學附設醫院 內科部 腎臟科; ⁷高雄市立小港醫院 泌尿科; ⁸高雄醫學大學 健康科學院 公共健康學系

Environmental melamine exposure increases renal tubular injury via oxidative stress in patients with calcium urolithiasis: The possible mechanism of melamine associated urolithiasis formation

Shih-Ting Huang^1,2, Chia-Chu Liu^3,4,5, Chia-Fang Wu², Tusty-Jiuan Hsieh^1,2, Yi-Chun Tsai⁶,

Shu-Pin Huang^3,4, Yung-Chin Lee^3,7, Tsung-Yi Huang⁴, Yii-Her Chou^3,4, Jung-Tsung Shen⁷,

Chun-Nung Huang^3,4, Yung-Shun Juan^3,4, Wen-Jeng Wu^3,4, Ming-Tsang Wu^2,8

¹Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University; ²Research Center for Precision Environmental Medicine, Kaohsiung Medical University; ³Department of Urology, College of Medicine, Kaohsiung Medical University; ⁴Department of Urology, Kaohsiung Medical University Hospital; ⁵Depratment of Urology, Pingtung Hospital, Ministry of Health and Welfare; ⁶Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital; ⁷Department of Urology, Kaohsiung Municipal Siaogang Hospital; ⁸Department of Public Health, College of Health Sciences, Kaohsiung Medical University

Purpose: Melamine, a widely used chemical found in many products used daily, is ubiquitously present in our environment. In addition to increase the precipitation of crystals, environmental melamine exposure could induce renal tubular injury which would further increase the risk of urolithiasis formation. It is unclear whether this damage comes about via increased oxidative stress in human. This study investigated the interrelationship of environmental melamine exposure, biomarkers of oxidative stress and renal tubular injury in adult patients with calcium urolithiasis.

Materials and Methods: We recruited adult patients diagnosed with upper urinary tract calcium urolithiasis at Kaohsiung Medical University-affiliated hospitals, all located in south western Taiwan, between November, 2010 and January, 2015. All participants were interviewed by trained researchers using a structured questionnaire to collect detailed demographic data, medical history, and history of substance use. At that time, each participant provided a one-spot overnight urine sample for biochemical evaluation of urinary melamine level, biomarkers of oxidative stress (8-oxo-2'-deoxyguanosine, 8-OHdG, and malondialdehyde, MDA) and renal tubular injury (N-acetyl b-D-glucosaminidase, NAG).

Results: A total of 309 patients (54.7 ± 12.8 years) diagnosed as having calcium urolithiasis were recruited. Their mean urinary melamine level was 3.24 ± 6.66 mg/mmol Cr. Urinary melamine levels were significantly and positively correlated with both urinary biomarkers of oxidative stress, 8-OHdG (r=0.305, p<0.001) and MDA (r = 0.343, p< 0.001), in patients with calcium urolithiasis. All results remain significant after adjusting for other covariates. Additionally, structure equation modeling was used to evaluate relative contribution of melamine-induced oxidative stress on renal tubular injury and found that MDA mediated 36.4 % of the total effect of melamine on a biomarker of renal tubular injury, NAG.

Conclusion: Urinary melamine levels were significantly positive correlated with the urinary biomarkers of oxidative stress, which could mediate the risk of renal tubular injury in patients with calcium urolithiasis. This finding suggests that besides causing the precipitation of crystals, melamine may also increase the risk of calcium urolithiasis by causing renal tubular injury via oxidative stress. Further studies are still needed to detail the underlying mechanisms.