To the Editor: The article by Guan et al.,1 the accompanyingeditorial by Langman,2 and the letter to the Editor by Wanget al.3 (all in the March 12 issue) provide information aboutthe epidemiology of pediatric nephrolithiasis caused by melaminepoisoning. Here we supplement those data and commentary withinformation regarding diagnosis and treatment on the basis ofour clinical experience and the advice of the Chinese Ministryof Health.4,5
Kidney stones that have formed as a result of melamine poisoningdiffer from the more commonly encountered radiopaque stonescontaining calcium oxalate and phosphate in that they are radiolucentand not revealed by standard radiography.4 In light of thesedistinctions, B-scan ultrasonography should be used to detectkidney stones in children who have consumed milk that is suspectedof being contaminated with melamine.4 Kidney stones that areassociated with melamine poisoning commonly affect the collectingsystem and ureters bilaterally, predominantly at the ureteropelvicand ureter–bladder junctions.4 The urinary tract may beextensively obstructed.4 The stones can affect large areas andproduce a light background echo.4 Our recommended courses ofaction, depending on the degree of severity of nephrolithiasis,are summarized in Figure 1.
Figure 1. Treatments for Pediatric Nephrolithiasis Caused by Melamine Poisoning as Recommended by the Chinese Ministry of Health.
Kunmei Ji, Ph.D. Shenzhen University Shenzhen 518060, China
Shenglang Zhu, M.D. Shenzhen Nanshan Hospital Shenzhen 518052, China
Zhigang Liu, M.D. Shenzhen University Shenzhen 518060, China lzg{at}szu.edu.cn
References
Guan N, Fan Q, Ding J, et al. Melamine-contaminated powdered formula and urolithiasis in young children. N Engl J Med 2009;360:1067-1074. [Free Full Text]
Langman CB. Melamine, powdered milk, and nephrolithiasis in Chinese infants. N Engl J Med 2009;360:1139-1141. [Free Full Text]
Wang I-J, Chen P-C, Hwang K-C. Melamine and nephrolithiasis in children in Taiwan. N Engl J Med 2009;360:1157-1158. [Free Full Text]
Ministry of Health of the People's Republic of China. Medical treatment of infants affected by Sanlu melamine-contaminated milk powder. The Chinese Ministry of Health Bulletin. October 15, 2008. (Accessed May 28, 2009, at http://www.moh.gov.cn.) (In Chinese.)
Idem. Proposed therapy for infants affected by melamine-contaminated milk powder. September 12, 2008. (Accessed May 28, 2009, at http://www.moh.gov.cn.) (In Chinese.)
To the Editor: The report by Guan et al. regarding infants whoconsumed melamine-contaminated formula states that the increasein the relative risk of stones was lower in preterm infants(odds ratio, 4.5) than in term infants (odds ratio, 7.0). Asnoted in the accompanying editorial, preterm infants generallyhave a higher risk of stones, in part because of a decreasedrate of excretion of urinary inhibitors of stone formation.If we assume there was an equal likelihood of ingesting thetainted formula and an equal duration of exposure among allinfants, preterm infants in this study should have been at higherrisk than term infants. Were the preterm infants seen at a youngerage than term infants, when they might still be under a gestationalage of 40 weeks? At that stage of development, with lower urine-concentratingcapacity, their ability to exceed solubility products in urinemight be poor. Alternatively, among preterm infants, the durationof exposure, a factor in the study by Wang et al., might havebeen less. It would also be interesting to know whether preterminfants made up a greater proportion of those with glomerulardysfunction, since these infants might have had reversible glomerularalbuminuria from prematurity itself.1
Vikas R. Dharnidharka, M.D., M.P.H. University of Florida Gainesville, FL 32610-0296 vikasmd{at}peds.ufl.edu
References
Tsukahara H, Fujii Y, Tsuchida S, et al. Renal handling of albumin and beta-2-microglobulin in neonates. Nephron 1994;68:212-216. [CrossRef][Web of Science][Medline]
To the Editor: In his editorial, Langman discusses the threereports of renal injury from melamine. Other health effectsmay be worth considering in light of the molecular compositionof melamine (Figure 1). Melamine is a triazine (1,3,5-triazine–2,4,6-triamine).Atrazine is a chlorinated triazine (2-chloro-4-[ethylamine]-6-[isopropylamine]-s-triazine)and is used extensively as a broadleaf herbicide in the Midwestand elsewhere in the world, although its use is banned in Europe.Atrazine has been associated with reproductive malformations,such as hermaphroditism in amphibians.1,2 Long-term screeningfor reproductive ill effects in babies who have been exposedto melamine-adulterated formula may be warranted. Conversely,studies on the health of agricultural workers using atrazineshould include an assessment of renal colic and kidney failure.
Figure 1. Molecular Structures of Melamine and Atrazine.
Bruce Hocking, M.B., B.S. 9 Tyrone St. Camberwell, VIC 3124, Australia bruhoc{at}connexus.net.au
References
Hayes T, Haston K, Tsui M, Hoang A, Haeffele C, Vonk A. Atrazine-induced hermaphroditism at 0.1 ppb in American leopard frogs (Rana pipiens): laboratory and field evidence. Environ Health Perspect 2003;111:568-575. [Web of Science][Medline]
Mizota K, Ueda H. Endocrine disrupting chemical atrazine causes degranulation through Gq/11 protein-coupled neurosteroid receptor in mast cells. Toxicol Sci 2006;90:362-368. [Free Full Text]
The authors reply: Ji et al. state that kidney stones that areassociated with melamine contamination are usually radiolucent,which was the case in our study. We emphasized that melamine-associatedurolithiasis should be diagnosed by ultrasonography rather thanby radiographic studies. Because ureteropelvic and ureterovesicaljunctions are relatively narrow, obstruction occurred more easilyin these regions.1 We believe that this is characteristic ofall types of stones, not just those associated with the ingestionof melamine. For diagnostic purposes, since laboratory investigationoften occurred after obstruction, we believe that imaging withultrasonography is the most important technique for diagnosisand for making clinical decisions. For the children with renalfailure induced by obstruction, the most important action isto relieve the obstruction.2
Dharnidharka notes that preterm infants are generally more proneto all types of stones than are term infants. In our study,7 preterm infants and 29 full-term infants had urinary stones.The average ages were 1.56±0.84 years for preterm infantsand 1.74±0.72 years for full-term infants. There wasno significant difference between the ages of the two groups.However, the percentage of preterm infants who were less than40 weeks old was higher than that of full-term infants (28.6%vs. 3.4%, P=0.09). There was no significant difference betweenpreterm infants and full-term infants in the time of exposureto melamine-contaminated formula. There was also no significantdifference in the rate of glomerular dysfunction between thepreterm infants (4%) and the full-term infants (9%), which suggeststhat glomerular dysfunction was not associated with the immaturityof the preterm infants.
Na Guan, M.D., Ph.D. Jie Ding, M.D., Ph.D. Peking University First Hospital Beijing 100034, China djnc_5855{at}126.com
References
Dursun I, Poyrazoglu HM, Dusunsel R, et al. Pediatric urolithiasis: an 8-year experience of single centre. Int Urol Nephrol 2008;40:3-9. [CrossRef][Web of Science][Medline]
Sarica K. Pediatric urolithiasis: etiology, specific pathogenesis and medical treatment. Urol Res 2006;34:96-101. [CrossRef][Web of Science][Medline]
The editorialist replies: We do not have substantial epidemiologicdata and mechanistic explanations regarding melamine-associatedkidney stones in infants caused by tainted powdered formula.Only very recently has it been feasible to measure urinary melamineand its metabolites easily; such capability may help definethe risk of stones from dietary exposure.1
With respect to the recommendations of Ji and colleagues, Ihave several concerns. I do not expect that a fully obstructedurinary tract with stones would be asymptomatic in young infants.Such affected infants would probably show a lack of normal health,appetite, and growth, with symptoms such as irritability, urinaryinfection, gross hematuria, and stone colic. Certainly, no infantsshould continue to receive tainted formula, and without additionalexposure, newly diagnosed cases will cease, since melamine isnot stored in or released from body tissues.
What then should the medical community do about the infantswho were exposed? Without evidence of an ongoing epidemic ofnew kidney stones or new cases of melamine-related acute kidneyfailure, a conservative approach to care has been supportedby pediatric nephrologists internationally.2
With respect to Hocking's comments: although there are reportsof urinary epithelial neoplasia in rats that receive dietarymelamine in high doses and of its modulation by dietary polyunsaturatedfatty acid,3 we do not have a clear understanding of these relationships.Simple chemical similarities of structure may not predict similaractions (e.g., retinoid compounds in skin disorders).4 A melamine-liketriazine compound may be antineoplastic, and cyanuric acid saltsare nonmutagenic. Atrazine has not been linked to nephrolithiasis.However, experimental studies have shown that atrazine inducesinsulin resistance and alters mitochondrial functions,5 whichmay be associated with an increased risk of kidney stones. Agriculturalworkers may have additional environmental risk factors for kidneystones, including chronic volume depletion and high levels ofdietary fructose.
Craig B. Langman, M.D. Children's Memorial Hospital Chicago,IL 60614
References
Tang HW, Ng KM, Chui SS, et al. Analysis of melamine cyanurate in urine using matrix-assisted laser desorption/ionization mass spectrometry. Anal Chem 2009;81:3676-3682. [Medline]
Langman CB, Alon U, Ingelfinger J, et al. A position statement on kidney disease from powdered infant formula-based melamine exposure in Chinese infants. Pediatr Nephrol 2009 February 7 (Epub ahead of print).
Cremonezzi DC, Díaz MP, Valentich MA, Eynard AR. Neoplastic and preneoplastic lesions induced by melamine in rat urothelium are modulated by dietary polyunsaturated fatty acids. Food Chem Toxicol 2004;42:1999-2007. [CrossRef][Web of Science][Medline]
Desai A, Kartono F, Del Rosso JQ. Systemic retinoid therapy: a status report on optimal use and safety of long-term therapy. Dermatol Clin 2007;25:185-193. [CrossRef][Web of Science][Medline]
Lim S, Ahn SY, Song IC, et al. Chronic exposure to the herbicide, atrazine, causes mitochondrial dysfunction and insulin resistance. PLoS ONE 2009;4:e5186-e5186. [CrossRef][Medline]
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