Long-term follow-up of nephrotoxicity in rats administered both melamine and cyanuric acid

BMC Research Notes

Kenjiro Kohri¹  Bing Gao³  Keiichi Tozawa²  Noriyasu Kawai²  Yukihiro Umemoto²  Yasue Kubota²  Kentaro Mizuno²  Masahito Hirose²  Shuzo Hamamoto²  Atsushi Okada²  Takahiro Kobayashi²  Takahiro Yasui¹ 

[1] China-Japan Kidney Stone Research Center, Shenyang, China;Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan;School of Basic Medical Sciences, Shenyang Medical College, Shenyang, China

关键词: Renal calculi;    Renal failure;    Cyanuric acid;    Melamine;   

Others  :  1134496
DOI  :  10.1186/1756-0500-7-87

 received in 2013-06-16, accepted in 2014-02-04,  发布年份 2014

【 摘 要 】

Background

Melamine was recently identified as a risk factor for renal calculi following the milk powder contamination in China. However, the long-term natural history of melamine exposure and its renal effects remain unknown. We evaluated renal function and other adverse health effects using a rat model administered melamine and cyanuric aid, considering age and sex.

Methods

Twelve male F334/N rats each of ages 6, 10, and 26 weeks (N = 36) were equally assigned to Group M + C or controls. Group M + C rats were administered 12 mg · kg^-1 · day^-1 of melamine and cyanuric acid for 28 days. Serum and urine samples and kidney sections were evaluated on day 28. Six-week-old male and female F344/N rats were administered 12 mg of melamine and cyanuric acid for 28 days. Body weights were measured weekly; on days 0, 28, 90, and 180 after the 28-day period of melamine and cyanuric acid administration, serum samples and kidney sections were obtained.

Results

Although the control group had no crystals, 6-week-old Group M + C rats had more crystals compared to the 10- and 26-week old Group M + C rats. Male rats also had significantly more crystals than females of the same age. Male rats were affected to a greater extent than females.

Conclusion

Younger rats experienced more severe renal failure and greater renal crystal deposition following melamine and cyanuric acid administration. However, after melamine and cyanuric acid administration cessation, crystal deposition and renal failure improved and did not cause growth arrest. Therefore, early diagnosis of melamine-associated calculi is critical.

【 授权许可】

   
2014 Yasui et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

【 参考文献 】

• [1]World Health Organaization: Melamine and Cyanuric Acid: Toxicity, Preliminary Risk Assessment and Guideline on Levels in Food. Geneva: WHO; 2008.
• [2]NIH: NTP: carcinogenesis bioassay of melamine (CAS No. 108-78-1) In F344/N rats and B6C3F1 mice (feed study). Nat Toxicol Prog 1983. NIH, Research Triangle Park, NC, NTP Technical Report 245, NIH Publication No. 83–2501
• [3]OECD: The OECD Screening Information Data Sets (SIDS), Melamine CAS No. 108-78-1. Geneva, Switzerland: UNEP Chemicals; http://www.chem.unep.ch/irptc/sids/oecdsids/108781.pdf webcite. Accessed August 13, 2008
• [4]Brown CA, Jeong KS, Poppenga RH, Puschner B, Miller DM, Ellis AE, Kang KI, Sum S, Cistola AM, Brown SA: Outbreaks of renal failure associated with melamine and cyanuric acid in dogs and cats in 2004 and 2007. J Vet Diagn Invest 2007, 19:525-531.
• [5]Burns K: Recall shines spotlight on pet foods. J Am Vet Med Assoc 2007, 230:1285-1286.
• [6]Puschner B, Poppenga RH, Lowenstine LJ, Filigenzi MS, Pesavento PA: Assessment of melamine and cyanuric acid toxicity in cats. J Vet Diagn Invest 2007, 19:616-624.
• [7]Guan N, Fan Q, Ding J, Zhao Y, Lu J, Ai Y, Xu G, Zhu S, Yao C, Jiang L, Miao J, Zhang H, Zhao D, Liu X, Yao Y: Melamine-contaminated powdered formula and urolithiasis in young children. N Engl J Med 2009, 360:1067-1074.
• [8]World Health Organization: Melanmine-contaminated powdered infant formula in China in 2008. http://who.int/csr/don/2008_09_22/en/ webcite. Accessed 22 September, 2008
• [9]World Health Organization: Melamine and cyanuric acid: toxicity, preliminary risk assessment and guidance on levels in food 25 september 2008. WHO. http://www.who.int/foodsafety/fs_management/Melamine.pdf webcite. Accessed 25 September 2008
• [10]Kobayashi T, Okada A, Fujii Y, Niimi K, Hamamoto S, Yasui T, Tozawa K, Kohri K: The mechanism of renal stone formation and renal failure induced by administration of melamine and cyanuric acid. Urol Res 2010, 38:117-125.
• [11]Shackelford C, Long G, Wolf J, Okerberg C, Herbert R: Qualitative and quantitative analysis of nonneoplastic lesions in toxicology studies. Toxicol Pathol 2002, 30:93-96.
• [12]Parry J: China’s tainted infant formula sickens nearly 13,000 babies. BMJ 2008, 337:a1802.
• [13]Cruywagen CW, van de Vyver WF, Stander MA: Quantification of melamine absorption, distribution to tissues and excretion by sheep. J Anim Sci 2011, 89:2164-2169.
• [14]Osborne CA, Lulich JP, Ulrich LK, Koehler LA, Albasan H, Sauer L, Schubert G: Melamine and cyanuric acid-induced crystalluria, uroliths, and nephrotoxicity in dogs and cats. Vet Clin North Am Small Anim Pract 2009, 39:1-14.
• [15]Lu X, Wang J, Cao X, Li M, Xiao C, Yasui T, Gao B: Gender and urinary pH affect melamine-associated kidney stone formation risk. Urol Ann 2011, 3:71-74.
• [16]Zhang Q, Gamboa Da Costa G, Von Tungeln LS, Jacob CC, Brown RP, Goering PL: Urinary biomarker detection of melamine- and cyanuric acid-induced kidney injury in rats. Toxicol Sci 2012, 129:1-8.
• [17]Lu X, Gao B, Wang Y, Liu Z, Yasui T, Liu P, Liu J, Emmanuel N, Zhu Q, Xiao C: Renal tubular epithelial cell injury, apoptosis and inflammation are involved in melamine-related kidney stone formation. Urol Res 2012, 40:717-723.
• [18]Peng J, Li D, Chan YK, Chen Y, Lamb JR, Tam PK, El-Nezami H: Effects of water uptake on melamine renal stone formation in mice. Nephrol Dial Transplant 2012, 27:2225-2231.
• [19]Park D, Kim TK, Choi YJ, Lee SH, Bae DK, Yang G, Yang YH, Joo SS, Choi EK, Ahn B, Kim JC, Kim KS, Kim YB: Increased nephrotoxicity after combined administration of melamine and cyanuric acid in rats. Lab Anim Res 2011, 27:25-28.
• [20]Gao J, Shen Y, Sun N, Jia LQ, Pan YS, Sun Q: Therapeutic effects of potassium sodium hydrogen citrate on melamine-induced urinary calculi in China. Chin Med J (Engl) 2010, 123:1112-1116.
• [21]Langman CB, Alon U, Ingelfinger J, Englund M, Saland JM, Somers MJ, Stapleton FB, Sibú NO, Cochat P, Wong W, Eke FU, Satlin L, Salusky I: A position statement on kidney disease from powdered infant formula-based melamine exposure in Chinese infants. Pediatr Nephrol 2009, 24:1263-1266.
• [22]Nie F, Li XJ, Shang PF, Wang Y: Melamine-induced urinary calculi in infants-sonographic manifestations and outcomes 1 year after exposure. Pediatr Radiol 2013, 43:474-478.
• [23]Sun N, Shen Y, Sun Q, Li XR, Jia LQ, Zhang GJ, Zhang WP, Chen Z, Fan JF, Jiang YP, Feng DC, Zhang RF, Zhu XY, Xiao HZ: Diagnosis and treatment of melamine-associated urinary calculus complicated with acute renal failure in infants and young children. Chin Med J (Engl) 2009, 122:245-251.
• [24]Zhu SL, Li JH, Chen L, Bao ZX, Zhang LJ, Li JP, Chen JH, Ji KM: Conservative management of pediatric nephrolithiasis caused by melamine-contaminated milk powder. Pediatrics 2009, 123:e1099-e1102.
• [25]Zhang L, Wu LL, Wang YP, Liu AM, Zou CC, Zhao ZY: Melamine-contaminated milk products induced urinary tract calculi in children. World J Pediatr 2009, 5:31-35.
• [26]Sun Q, Shen Y, Sun N, Zhang GJ, Chen Z, Fan JF, Jia LQ, Xiao HZ, Li XR, Puschner B: Diagnosis, treatment and follow-up of 25 patients with melamine-induced kidney stones complicated by acute obstructive renal failure in Beijing Children’s hospital. Eur J Pediatr 2010, 169:483-489.