Correspondence

Melamine and Nephrolithiasis in Children in Taiwan

N Engl J Med 2009; 360:1157-1158March 12, 2009

Article

To the Editor:

The adverse renal effects of melamine-tainted formula have raised international concern. To address public concerns about melamine, the department of health in Taiwan initiated services to screen exposed children.

From September 24 through October 23, 2008, we screened 1129 children in Taiwan who had possible exposure to contaminated formula, investigating the clinical symptoms and risk factors for nephrolithiasis. Clinical presentation and urinary calcium and creatinine levels were evaluated, and urinalysis and renal ultrasonography were performed. We categorized our patients into three groups, according to exposure history.1,2 The high-exposure group consisted of children who consumed dairy products from the mainland of China presumed to be highly contaminated (e.g., Sanlu or Mengniu brand, with melamine levels reported as exceeding 2.5 ppm).1 The low-exposure group comprised children who consumed brands of contaminated milk with lower measured melamine levels (e.g., Klim or Neslac imported from the mainland of China, with melamine levels of 0.05 to 2.5 ppm).2 The control group consisted of children who consumed brands of milk without detected melamine levels (<0.05 ppm).2

There were 44 children in the high-exposure group; none had hematuria, hypercalciuria, flank pain, or acute renal failure (Table 1Table 1Baseline Characteristics of the Study Children, According to Melamine Exposure.). Nephrolithiasis and a history of residence in the mainland of China were significantly more frequent in the high-exposure group than in the other two groups (P<0.001). In the high-exposure group, children with nephrolithiasis were younger than those without nephrolithiasis (mean ±SD, 2.33±1.12 vs. 4.83±2.64 years; P=0.009). The mean duration of exposure was 7.19 months (range, 0.67 to 36) in the high-exposure group and 17.40 months (range, 3 to 48) in the low-exposure group.

The most common metabolic risk factor for stone formation is hypercalciuria, which in the past has been described in 75 to 80% of children with nephrolithiasis.3 Hematuria as a presenting symptom for nephrolithiasis is also reported to vary, from 30 to 55%.4 However, neither hypercalciuria nor hematuria was detected in any of the nine children in the high-exposure group with nephrolithiasis associated with the consumption of dairy products from the mainland of China. Plain abdominal radiography in these patients was negative; the stones were detected on ultrasonography. The negative plain films suggest that stones related to melamine ingestion are relatively radiolucent and do not contain substantial amounts of calcium.

Consumption of melamine-contaminated dairy products appeared to be a major factor in the development of nephrolithiasis in the children we screened. Furthermore, the children in the high-exposure group in whom nephrolithiasis developed were all under the age of 3 years. Because of the lack of symptoms and signs, we recommend that ultrasonography be performed in children exposed to melamine-contaminated formula.

I-Jen Wang, M.D., Ph.D.
Taipei Hospital Department of Health, Taipei 242, Taiwan

Pau-Chung Chen, M.D., Ph.D.
National Taiwan University College of Public Health, Taipei 10055, Taiwan

Kung-Chang Hwang, M.D., M.P.H.
Hospital Administration Commission, Taipei 100, Taiwan
r92846001@ntu.edu.tw

Supported by grants from the National Science Council of Taiwan (NSC 97-2314-B-192-001-MY2).

This letter (10.1056/NEJMc0810070) was published at NEJM.org on February 4, 2009.

4 References

1. 1

   List of milk products that are confirmed to be positive for melamine. Geneva: International Food Safety Authorities Network, 2008. (Accessed February 20, 2009, at http://www.moh.gov.bn/download/list-of-confirmed-contaminated-products.pdf.)
   

2. 2

   Results of investigation in dairy products with melamine. Taiwan: Bureau of Health, Taipei City Government, 2008. (Accessed February 20, 2009, at http://www.health.gov.tw/Default.aspx?tabid=546&mid=1287.)
   

3. 3

   Stapleton FB. Clinical approach to children with urolithiasis. Semin Nephrol 1996;16:389-397
   Web of Science | Medline

4. 4

   Coward RJ, Peters CJ, Duffy PG, et al. Epidemiology of paediatric renal stone disease in the UK. Arch Dis Child 2003;88:962-965
   CrossRef | Web of Science | Medline

Citing Articles (18)

Citing Articles

1. 1

   Jian Gao, Hong Xu, Xin-Yu Kuang, Wen-Yan Huang, Nai-Qing Zhao, Jia Rao, Qiang-Ying Qian, Xian-Ying Cheng, Zhi-Min Feng, Jing Xu, Xin Zhang, Xiang Wang. (2011) Follow-up results of children with melamine induced urolithiasis: a prospective observational cohort study. World Journal of Pediatrics 7:3, 232-239
   CrossRef

2. 2

   P. Hu, J. Wang, B. Hu, L. Lu, M. Zhang. (2011) Common Features of Melamine-Associated Urinary Stones: a Summary of Available Information based on Biochemical and Ultrasonographic Evidence. Journal of Tropical Pediatrics
   CrossRef

3. 3

   I.- J. Wang, Y.-C. Huang, P.-C. Chen, T.-N. Wu. (2011) Is Screening Cost-effective for Melamine-associated Nephrolithiasis?. Journal of Tropical Pediatrics 57:2, 141-143
   CrossRef

4. 4

   I.-J. Wang, C.-C. Chen, C.-C. Chan, P.-C. Chen, G. Leonardi, K.-Y. Wu. (2011) A hierarchical Bayesian approach for risk assessment of melamine in infant formula based on cases of related nephrolithiasis in children. Food Additives & Contaminants: Part A 28:4, 384-395
   CrossRef

5. 5

   Jian Guo Wen, Qing Long Chang, An Feng Lou, Zhen Zhen Li, Shan Lu, Yan Wang, Ya Lun Wang, Jin Hua Hu, Shu Ping Mao, Yan Zhang, Rui Xue, Chuanchuan Ren, Lu Xing, Guo Xian Zhang, Shengjun Zhang, Jens Christian Djurhuus, Jørgen Frøkiaer. (2011) Melamine-Related Urinary Stones in 195 Infants and Young Children: Clinical Features within 2 Years of Follow-Up. Urologia Internationalis 87:4, 429-433
   CrossRef

6. 6

   Wenjie Zhou, Yongmei Jiang, Hua Shi, Qingkai Dai, Jinhao Liu, Chuan Shen, Hui Yang. (2010) The characteristics of immune system changes in children who ingested melamine-contaminated powdered formula in China. International Journal of Environmental Health Research 20:4, 289-297
   CrossRef

7. 7

   Manuel Dominguez-Estevez, Anne Constable, Paolo Mazzatorta, Andrew G. Renwick, Benoit Schilter. (2010) Using urinary solubility data to estimate the level of safety concern of low levels of melamine (MEL) and cyanuric acid (CYA) present simultaneously in infant formulas. Regulatory Toxicology and Pharmacology 57:2-3, 247-255
   CrossRef

8. 8

   Virunya S. Bhat, Gwen L. Ball, Clifton J. McLellan. (2010) Derivation of a Melamine Oral Reference Dose (RfD) and Drinking-Water Total Allowable Concentration. Journal of Toxicology and Environmental Health, Part B 13:1, 16-50
   CrossRef

9. 9

   Carl G. Skinner, Jerry D. Thomas, John D. Osterloh. (2010) Melamine Toxicity. Journal of Medical Toxicology 6:1, 50-55
   CrossRef

10. 10

    Wen-Chi Chen, San-Yuan Wu, Hsin-Ping Liu, Chiao-Hui Chang, Huey-Yi Chen, Hsin-Yi Chen, Chou-Huang Tsai, Yi-Chun Chang, Fuu-Jen Tsai, Kee-Ming Man, Po-Len Liu, Feng-Yen Lin, Jui-Lung Shen, Wei-Yong Lin, Yung-Hsiang Chen. (2010) Identification of melamine/cyanuric acid-containing nephrolithiasis by infrared spectroscopy. Journal of Clinical Laboratory Analysis 24:2, 92-99
    CrossRef

11. 11

    Chia-Fang Wu, Chia-Chu Liu, Bai-Hsiun Chen, Shu-Pin Huang, Hei-Hwa Lee, Yii-Her Chou, Wen-Jeng Wu, Ming-Tsang Wu. (2010) Urinary melamine and adult urolithiasis in Taiwan. Clinica Chimica Acta 411:3-4, 184-189
    CrossRef

12. 12

    Gang Li, Shufang Jiao, Xiangjun Yin, Ying Deng, Xinghuo Pang, Yan Wang. (2010) The risk of melamine-induced nephrolithiasis in young children starts at a lower intake level than recommended by the WHO. Pediatric Nephrology 25:1, 135-141
    CrossRef

13. 13

    Bo Chen, Xinyang Liu, Shuguang Li, Ying Zhou, Qingwu Jiang. (2009) Melamine exposure assessment in children with nephrolithiasis. Pediatric Nephrology 24:10, 2065-2067
    CrossRef

14. 14

    Feng Yang, Yu Mao, Xiaodong Zhang, Zhiqiang Ma, Xinrong Zhang. (2009) LC-MS/MS method for the determination of melamine in rat plasma: Toxicokinetic study in Sprague-Dawley rats. Journal of Separation Science 32:17, 2974-2978
    CrossRef

15. 15

    Wei-Chih Cheng, Shu-Kong Chen, Tien-Jen Lin, I-Jen Wang, Ya-Min Kao, Daniel Yang-Chih Shih. (2009) Determination of urine melamine by validated isotopic ultra-performance liquid chromatography/tandem mass spectrometry. Rapid Communications in Mass Spectrometry 23:12, 1776-1782
    CrossRef

16. 16

    (2009) Melamine-Contaminated Powdered Formula and Urolithiasis. New England Journal of Medicine 360:25, 2675-2678
    Full Text

17. 17

    Langman, Craig B., . (2009) Melamine, Powdered Milk, and Nephrolithiasis in Chinese Infants. New England Journal of Medicine 360:11, 1139-1141
    Full Text

18. 18

    Céline Gossner, Jorgen Schlundt, Peter Ben Embarek, Susan Hird, Danilo Lo-Fo-Wong, Jose Ocampo Beltran, Keng Ngee Teoh, Angelika Tritscher. (2009) The Melamine Incident: Implications for International Food and Feed Safety. Environmental Health Perspectives
    CrossRef

Letters