Editorial
Melamine, Powdered Milk, and Nephrolithiasis in Chinese Infants
N Engl J Med 2009; 360:1139-1141March 12, 2009
- Article
Melamine, a synthetic nitrogenous product found in many industrial goods and even in fertilizer destined for use in growing crops for human consumption, was recently found to have been added to foods in China — including many different powdered infant formulas1 — to increase their measured, but not biologically available, protein content. Melamine is largely not degraded in humans, although several other compounds (ammeline, ammelide, and cyanuric acid) may become cocontaminants during the manufacturing process, and the main route of excretion after absorption from the gastrointestinal tract appears to be through the urine.2 The findings of acute kidney failure and symptomatic and asymptomatic kidney stones in infants and children previously exposed to melamine through the consumption of tainted powdered infant formulas have caused great concern. In this issue of the Journal, an original article by Guan et al. from Beijing3 and letters to the editor from Ho et al. from Hong Kong4 and Wang et al. from Taipei5 provide readers with substantial information about the relation between exposure to melamine-containing powdered infant formula and nephrolithiasis in infants and children.
Observational data reported by these authors reveal an association between the prevalence of kidney stones as determined on ultrasonography of the kidney at one point in time and a history of melamine exposure based on the amounts in infant formulas as reported by the Chinese authorities. Guan et al. studied 589 children living in or near Beijing whose parents responded to the offer of a free screening; Wang et al. and Ho et al. studied 651 children residing in Taiwan and 2140 residing in Hong Kong, respectively, who underwent testing including ultrasonography of the kidneys.
However, discrepancies in the numbers of exposed children in whom stones developed (and in the categories of exposure to melamine) are found when comparing the three reports. Kidney stones were seen in nearly 10% of the children studied in Beijing who received formula with a high melamine content (>500 ppm) or a moderate melamine content (<150 ppm), and slightly more than 20% of children residing in Taiwan and fed formula with a melamine content exceeding 2.5 ppm had stones. In contrast, only one child residing in Hong Kong and presumably exposed to melamine had a definite kidney stone. How can we best interpret such data to assess the risks for other infants and children who were fed these melamine-contaminated formulas?
One way is to examine the number of people in whom stones would form in the absence of melamine exposure. The estimated number of adults in the United States between the ages of 20 and 74 years in whom stones developed was 5.2% from 1988 through 1994, an increase over the 3.8% from 1976 through 1980.6 There are no published incidences or prevalences for nephrolithiasis in children, but anecdotal discussions among experts suggest that such rates are currently increasing over those in past decades. In both children and adults, dietary and lifestyle factors appear to play an influential role in stone formation,7 albeit within a background of genetic susceptibility.8 Thus, Guan et al. and Wang et al. report prevalences that appear to be significantly higher than expected on the basis of data for adults and anecdotal data for children in the United States and Western Europe.
Adults with kidney stones, as compared with those without stones, have a higher lifelong likelihood of chronic kidney disease, as judged by reduction in the estimated glomerular filtration rate.9 Surprisingly, Guan et al. found elevated urinary microalbumin levels, a potent indicator of glomerular dysfunction, in the children with stones. The effect of such findings over a child's lifetime is unclear but would be worrisome if persistent and prolonged.
There are several caveats concerning the interpretation of the reports by Guan et al., Wang et al., and Ho et al. One cannot derive from these reports the absolute or relative risks for nephrolithiasis and chronic kidney disease from melamine exposure. The study by Guan et al., in Beijing, involves a strong referral bias, as noted by the authors, since it is not clear how many families of children who ingested contaminated formula were aware of the free screening but did not appear. In addition, the definition of a “suspected” stone is questionable and might not withstand scrutiny based on stricter ultrasonographic definitions of nephrolithiasis. Certainly, the presence of oliguria, unexplained crying, and edema in the group without stones suggests that some children were brought to the Beijing hospital for reasons beyond screening.
Guan et al. also uncovered a significant relationship between nephrolithiasis and prematurity, as well as high exposure to melamine. We know that, in general, premature infants may have high rates of kidney calcifications and nephrocalcinosis,10 related in part to therapies used in their care and also to the relative underexcretion of urinary inhibitors of stone formation. Rates of urinary microalbuminuria are higher among premature neonates than among full-term neonates, and the condition may be persistent. Attainment of the maximal glomerular filtration rate lags in the premature infant as well.11 Thus, the experience in Beijing may reflect combined effects of melamine exposure and prematurity on stone formation.
The report from Taiwan by Wang et al. lacks information about screening criteria. Therefore, a true denominator for calculating the rates of stone development is still elusive.
It is remarkable that all three reports describe the absence of conventional symptoms and signs related to nephrolithiasis in the children with stones. Unlike renal stones with other causes in adults and children, which commonly have well-described urinary symptoms and signs, the children with melamine-related nephrolithiasis in Beijing, Taiwan, and Hong Kong were largely asymptomatic, with detection on ultrasonography the sole indicator of the condition. Since the presence of a kidney stone is generally associated with hematuria, leukocyturia, and other urinary abnormalities, their absence in these children is unexplained. One hypothesis is that a melamine-containing kidney stone that has no proteinaceous matrix and does not react with urinary epithelium will not produce urinary findings.
How should physicians in other parts of the world care for Chinese infants who may have been exposed to melamine-contaminated powdered infant formula? The American Society of Pediatric Nephrology suggests a conservative approach in asymptomatic infants,12 since stones presumed to have been induced by melamine ingestion appear to be passed easily after hydration, and there are currently no follow-up reports on the children studied by Guan et al. and Wang et al. Performance of abdominal ultrasonography in all potentially exposed Chinese children living in the United States would be likely to cost many millions of dollars, an expenditure difficult to justify, given that both unaffected and affected children may have no symptoms and that the meaning of a stone in an asymptomatic child is uncertain.
Without a doubt, we must safeguard our children's food supply to prevent future toxic exposures. However, the critical view of melamine exposure and nephrolithiasis gleaned from the three reports in this issue of the Journal raises many questions that underscore the need for intense and careful study before we know whether apparently thriving children have a major ongoing health risk from previous melamine exposure through their infant formula.
No potential conflict of interest relevant to this article was reported.
This article (10.1056/NEJMe0900361) was published at NEJM.org on February 4, 2009.
Source Information
From the Feinberg School of Medicine, Northwestern University, Children's Memorial Hospital, Chicago.
- References
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- Citing Articles (13)
Citing Articles
1
Abhinandan Rana, Madhusudan Bera, Durga Sankar Chowdhuri, Debdoot Hazari, Swapan Kumar Jana, Ennio Zangrando, Sudipta Dalai. (2011) 3D Coordination Network of Ag(I) Ions with μ 3 -Bridging Melamine Ligands. Journal of Inorganic and Organometallic Polymers and Materials
CrossRef2
Chia-Chu Liu, Chia-Fang Wu, Bai-Hsiun Chen, Shu-Pin Huang, William Goggins, Hei-Hwa Lee, Yii-Her Chou, Wen-Jeng Wu, Chun-Hsiung Huang, Jentaie Shiea, Chien-Hung Lee, Kuen-Yuh Wu, Ming-Tsang Wu. (2011) Low exposure to melamine increases the risk of urolithiasis in adults. Kidney International 80:7, 746-752
CrossRef3
William Cameron. 2010. Cyanamides. .
CrossRef4
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
CrossRef5
Yuchang Qin, Xiaowen Lv, Jun Li, Guanghai Qi, Qiyu Diao, Guohua Liu, Min Xue, Jiaqi Wang, Jianming Tong, Liying Zhang, Keying Zhang. (2010) Assessment of melamine contamination in crop, soil and water in China and risks of melamine accumulation in animal tissues and products. Environment International 36:5, 446-452
CrossRef6
Dante P. Dator. (2010) The Globalization of Medical Care: Managing Rare Diseases From Elsewhere. The Journal of Urology 183:4, 1280-1281
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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
CrossRef8
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
CrossRef9
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
CrossRef10
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
CrossRef11
(2009) Melamine-Contaminated Powdered Formula and Urolithiasis. New England Journal of Medicine 360:25, 2675-2678
Full Text12
Ho, Stella Sin Yee, Chu, Winnie Chiu Wing, Wong, Ka Tak, Li, Chi Kong, Wong, William, Ng, Pak Cheung, Ahuja, Anil T., . (2009) Ultrasonographic Evaluation of Melamine-Exposed Children in Hong Kong. New England Journal of Medicine 360:11, 1156-1157
Full Text13
Wang, I-Jen, , Chen, Pau-Chung, , Hwang, Kung-Chang, . (2009) Melamine and Nephrolithiasis in Children in Taiwan. New England Journal of Medicine 360:11, 1157-1158
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- Letters
