《外科护理学》课程阅读资料（英文）泌尿系统 urolithiasis

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n engl j med 360;11 nejm.org march 12, 2009 1067 The new england journal of medicine established in 1812 march 12, 2009 vol. 360 no. 11 Melamine-Contaminated Powdered Formula and Urolithiasis in Young Children Na Guan, M.D., Ph.D., Qingfeng Fan, M.D., Ph.D., Jie Ding, M.D., Ph.D., Yiming Zhao, Ph.D., Jingqiao Lu, Ph.D., Yi Ai, M.D., Guobin Xu, M.S., Sainan Zhu, M.S., Chen Yao, M.D., Lina Jiang, M.D., Jing Miao, M.D., Han Zhang, M.D., Dan Zhao, M.D., Xiaoyu Liu, M.D., and Yong Yao, M.D. Abstract From Peking University First Hospital (N.G., Q.F., J.D., Y.A., G.X., S.Z., C.Y., L.J., J.M., H.Z., D.Z., X.L., Y.Y.) and the Research Center of Clinical Epidemiology, Peking University Third Hospital (Y.Z., J.L.) — both in Beijing. Address reprint requests to Dr. Ding at Peking University First Hospital, No. 1, Xi An Men Da Jie, Beijing, 100034, China, or at djnc_5855@126. com. Drs. Guan and Fan contributed equally to this article. This article (10.1056/NEJMoa0809550) was published at NEJM.org on February 4, 2009. N Engl J Med 2009;360:1067-74. Copyright © 2009 Massachusetts Medical Society. Background A recent epidemic of melamine contamination of baby formula in China has been associated with the development of urinary tract stones, though the clinical manifestations and predisposing factors are incompletely delineated. Methods We administered a questionnaire to the parents of children 36 months of age or younger who were being screened for a history of exposure to melamine and symptoms of, and possible predisposing factors for, urinary tract stones. In addition, we performed urinalysis, renal-function and liver-function tests, urinary tests for biochemical markers and the calcium:creatinine ratio, and ultrasonography. Powdered-milk infant formulas were classified as having a high melamine content (>500 ppm), a moderate melamine content (<150 ppm), or no melamine (0 ppm); no formulas contained between 150 and 500 ppm of melamine. Results Contaminated formula was ingested by 421 of 589 children. Fifty had urinary stones, including 8 who had not received melamine-contaminated formula; 112 were suspected to have stones; and 427 had no stones. Among children with stones, 5.9% had hematuria and 2.9% had leukocyturia, percentages that did not differ significantly from those among children who were suspected to have stones or those who did not have stones. Serum creatinine, urea nitrogen, and alanine aminotransferase levels were normal in the 22 children with stones who were tested. Four of the 41 children (9.8%) who had stones and in whom urinary markers of glomerular function were measured had evidence of abnormalities; none had tubular dysfunction. Children exposed to high-melamine formula were 7.0 times as likely to have stones as those exposed to no-melamine formula. Preterm infants were 4.5 times as likely to have stones as term infants. Conclusions Prematurity and exposure to melamine-contaminated formula were associated with urinary stones. Affected children lacked typical signs and symptoms of urolithiasis. The New England Journal of Medicine Downloaded from nejm.org on October 18, 2011. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved

Thr NEW ENGLAND JOURNAL Of MEDICINE in young children,most under 36 months We administered a questionnaire designed to ob ofage,recently occurred in China.On Sep-tain information about demographic characteris- tember 12,2008,the Chinese government an- nounced that the epidemic was most likely relat melamine content,dura ora com 0nofeposure,use on or breas melamine the 3-day period before the visit.Other signs trogen by mass:this covert practice appears to have and symptoms,such as oliguria,unexplained cry- been the cause of the melamine contamination of infant formula.Although an epidemic of rena uarrn ing some occurred i with anin melamine ingestion and urinary stones in hu mans was initially unclear in the recent epidemic Republic of China reported that 22 brands of in among children.The present report details an fant formula were contaminated(with reported investigation of melamine-linked u ary stones concentrations of melamine ranging from 0.1 to in children exposed to contaminated formula. 2500 ppm).On the basis METHODS nt、s00 om)moderate Immediately after the announcement of melamine (150 ppm)and no-melamine formula None of contamination of formula and the government the brands tested contained melamine at a con sponsored screening,we initiated a multidisci centration between 150 and 500 ppm.Children had plinary study.The prespecified pri to have been fed formula for at ast 30 days to be mary was the pre to nave ticle at NEJM.org). We developed a questionnaire that was adminis. tered by several trained investigators.For the other LABORATORY INVESTIGATIONS atory sta to us riaa wer proc aur notra was petb sample 0to19 liter)tra sfarrin (re raphy personnel.The rapid impl erence range,0to 2mg per liter),a-microglobulir tation of this study rendered it likely that some (reference range,0to12mg perliter),and N-acetyl data would be incomplete. B-D-glucosaminidase (reference range,0 to 21 t PATIENTS r urinary stones ber UITRASONOGRAPHY OF THE URINARY TRACT September 17 and October 3.2008.The study was Ultrasonography of the kidneys and lower urinary approved by the hospital's ethics committee.All the tract was performed with the use of an uasono parents or guardians provided written informed raphy system (ProSound SSD-5000SV,Aloka)an consent. an attached scanner monitor (5 to 6 MHz).Assess 1068 N ENGLJ MED 360:11 NEJM.ORG MARCH 12,2006 Downloaded from nejm. The N

The new england journal o f medicine 1068 n engl j med 360;11 nejm.org march 12, 2009 An epidemic of urinary tract stones in young children, most under 36 months of age, recently occurred in China. On September 12, 2008, the Chinese government announced that the epidemic was most likely related to melamine contamination of powdered-milk formula for infants, and a policy of free screening for urinary stones in children was instituted. The addition of melamine to food boosts the apparent protein content, since melamine contains 66% nitrogen by mass; this covert practice appears to have been the cause of the melamine contamination of infant formula. Although an epidemic of renal failure, including some deaths, had occurred in 2007 in animals exposed to pet food contaminated with melamine,1 the relationship between melamine ingestion and urinary stones in humans was initially unclear in the recent epidemic among children. The present report details an investigation of melamine-linked urinary stones in children exposed to contaminated formula. Methods Immediately after the announcement of melamine contamination of formula and the governmentsponsored screening, we initiated a multidisciplinary cross-sectional study. The prespecified primary outcome was the presence of urinary stones. Secondary outcomes were clinical manifestations and laboratory abnormalities, as well as other possible factors, associated with melamine exposure. We developed a questionnaire that was administered by several trained investigators. For the other assessments, all involved investigators, pediatricians, ultrasonographers, and laboratory staff were trained to use uniform criteria and procedures. Identifying information concerning patients and samples was concealed from the laboratory and ultrasonography personnel. The rapid implementation of this study rendered it likely that some data would be incomplete. Patients We studied all children 36 months of age or younger who were brought to Peking University First Hospital for screening for urinary stones between September 17 and October 3, 2008. The study was approved by the hospital’s ethics committee. All the parents or guardians provided written informed consent. Questionnaire We administered a questionnaire designed to obtain information about demographic characteristics, including sex and age; the history of exposure to contaminated formula, including the brand, melamine content, duration of exposure, use of formula alone or a combination of breast milk and formula; birth type (preterm or term); and symptoms such as fever or vomiting and diarrhea within the 3-day period before the visit. Other signs and symptoms, such as oliguria, unexplained crying (especially on urination), and edema, and any history of passing stones were recorded. Categorization of Contaminated Formula The General Administration of Quality Supervision, Inspection, and Quarantine of the People’s Republic of China reported that 22 brands of infant formula were contaminated (with reported concentrations of melamine ranging from 0.1 to 2500 ppm). On the basis of the amount of melamine contamination, we grouped the formulas into three categories: high-melamine formula (melamine content, >500 ppm), moderate-melamine formula (<150 ppm), and no-melamine formula. None of the brands tested contained melamine at a concentration between 150 and 500 ppm. Children had to have been fed formula for at least 30 days to be considered to have been exposed. The content of individual formulas is listed in the Supplementary Appendix (available with the full text of this article at NEJM.org). Laboratory Investigations Routine serum-chemical measurements included blood urea nitrogen, creatinine, and alanine aminotransferase levels. Urinalysis was performed, and we measured levels of urinary microalbumin (reference range, 0 to 19 mg per liter), transferrin (reference range, 0 to 2 mg per liter), α1-microglobulin (reference range, 0 to 12 mg per liter), and N-acetyl- β-d-glucosaminidase (reference range, 0 to 21 U per liter). Urinary calcium and creatinine levels were also measured. Detailed methods are found in the Supplementary Appendix. Ultrasonography of the Urinary Tract Ultrasonography of the kidneys and lower urinary tract was performed with the use of an ultrasonography system (ProSound SSD-5000SV, Aloka) and an attached scanner monitor (5 to 6 MHz). AssessThe New England Journal of Medicine Downloaded from nejm.org on October 18, 2011. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved

MELAMINE-CONTAMINATED POWDERED FORMULA AND UROLITHIASIS ments included renal size;the shape of the pye-an approach that biases the relationship between localyceal region,ureter,and bladder;echogenic covariate and outcome toward the null hypoth- ity;and parenchymal thickness.Findings with hnifoneswereCaegorizaisfol esis.Missing categorical data,such as birth type nd use ormula nilk used inthe del Th who had urinary stones without other urinary tion of other existing variables for each observa- tract abnormalities and who had been exposed to tion and may provide insight into the distribution melamine-contaminated formula for 30 days or of missing data. uoihstrodoharemchmincasoc A less tha reported Pv sided (with ated an0.0 signific adj multipl STATISTICAL ANALYSIS The software program epiData (version 3.0.www. rates of omerular dysfunction between any two epidata.dk)was used for data management.Sta- groups of patients (those who had stones,those tistical analyses were performed with SPSS soft- who were suspected to have stones,and those who ware (,).and percen did not have stones).For this analysis,the P value ages were use the distri used to indicate statis efor the hy diagnoses on u the for formula received clinical manifestations.and labo- a threshold value of 0.017 (0.05+3). ratory results chi-square tests and fisher's exac test were used to compare categorical data.Mul RESULTS tivariate analyses we ere conducted with the use of model,in which age group, use c alone or 3irs42.19. A589 7 en Odds ratios and o5 confidence int vals for risk formed consent had heen t ovided by thei were calculated on the basis of model-variable co- ents or guardians.Characteristics of the children efficients and standard errors,respectively.Patients and the melamine content in the formula they without stones served as the reference group. received are listed in Table 1. were used for analysis. measur el? EXTENT OF EXPOSURE AND PRESENCE OF STONES d by 421 of missing binary data were coded as not present. the 589 children CTable 1):50 of the 589 children Table 1.Melamine Exposure and Other Characteristics of the 58 Children Studied,According to the Presence or Absence of Urinary Tract Group Birth Type Melamine Content in formula 断22海66 number (percent) Children with stones 11(6.9)24(10.刀1573)3088)20(81)79.4296.刀239.019(6.3) 8(4.8) Ch003割36n6）4622到6408周48a9利79到87o习3024周58093)2443到 119(74.4)164(73.2144(70.2)247(72.180(72.6)22(61.1)315(73.1)6856.2)223(74.3)136(81.0 N ENGLJ MED 360,11 NEJM.ORG MARCH 12,2009 06g The New England Joual of Medicine

Melamine-Contaminated Powdered Formula and Urolithiasis n engl j med 360;11 nejm.org march 12, 2009 1069 ments included renal size; the shape of the pyelocalyceal region, ureter, and bladder; echogenicity; and parenchymal thickness. Findings with regard to urinary stones were categorized as follows: definite stones, suspected stones (increased, sporadic, punctiform echogenicity in the kidneys or pyelocalyceal system), or no stones. Patients who had urinary stones without other urinary tract abnormalities and who had been exposed to melamine-contaminated formula for 30 days or more were considered to have melamine-associated urolithiasis. Statistical Analysis The software program EpiData (version 3.0, www. epidata.dk) was used for data management. Statistical analyses were performed with SPSS software (version 14.0, SPSS). Frequencies and percentages were used to describe the distributions of diagnoses on ultrasonography among the children according to sex, age, melamine content in the formula received, clinical manifestations, and laboratory results. Chi-square tests and Fisher’s exact test were used to compare categorical data. Multivariate analyses were conducted with the use of a multinomial logistic model, in which age group, sex, birth type, the use of formula alone or in combination with breast milk, and the melamine content in the formula received were included. Odds ratios and 95% confidence intervals for risk were calculated on the basis of model-variable coefficients and standard errors, respectively. Patients without stones served as the reference group. Two models were used for analysis. In model 1, the missing data from measured variables were excluded, leaving 400 observations. In model 2, missing binary data were coded as not present, an approach that biases the relationship between covariate and outcome toward the null hypothesis. Missing categorical data, such as birth type and use of formula alone or in combination with breast milk, were coded as “unknown”; a total of 589 observations were used in the model. The approach used in model 2 allows for the contribution of other existing variables for each observation and may provide insight into the distribution of missing data.2 All reported P values are two-sided (with values less than 0.05 considered to indicate statistical significance) and were not adjusted for multiple testing except for the evaluation of differences in rates of glomerular dysfunction between any two groups of patients (those who had stones, those who were suspected to have stones, and those who did not have stones). For this analysis, the P value used to indicate statistical significance for the hypothesis tested was adjusted for multiple comparisons by means of the Bonferroni correction, for a threshold value of 0.017 (0.05÷3). Results Study Population In all, 589 children were screened: 341 boys (57.9%) and 248 girls (42.1%). All 589 children were consecutively enrolled in the study after written informed consent had been provided by their parents or guardians. Characteristics of the children and the melamine content in the formula they received are listed in Table 1. Extent of Exposure and Presence of Stones Contaminated formula was ingested by 421 of the 589 children (Table 1); 50 of the 589 children Table 1. Melamine Exposure and Other Characteristics of the 589 Children Studied, According to the Presence or Absence of Urinary Tract Stones. Group Age Sex Birth Type* Melamine Content in Formula 0 to ≤1 Yr (N=160) >1 to ≤2 Yr (N=224) >2 to ≤3 Yr (N=205) Male (N=341) Female (N=248) Preterm (N=36) Term (N=431) High (N=121) Moderate (N=300) None (N=168) number (percent) Children with stones 11 (6.9) 24 (10.7) 15 (7.3) 30 (8.8) 20 (8.1) 7 (19.4) 29 (6.7) 23 (19.0) 19 (6.3) 8 (4.8) Children with suspected stones 30 (18.8) 36 (16.1) 46 (22.4) 64 (18.8) 48 (19.4) 7 (19.4) 87 (20.2) 30 (24.8) 58 (19.3) 24 (14.3) Children without stones 119 (74.4) 164 (73.2) 144 (70.2) 247 (72.4) 180 (72.6) 22 (61.1) 315 (73.1) 68 (56.2) 223 (74.3) 136 (81.0) * Birth type was known for only 467 of the 589 children studied. High melamine content was defined as more than 500 ppm, and moderate content less than 150 ppm. The New England Journal of Medicine Downloaded from nejm.org on October 18, 2011. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved

Thr NEW ENGLAND JOURNAL f MEDICINE did not have stones)(table 3)Hematuria wa es (2 of 34).and leukocvturia in 2.9%d of 34).No child suspected to have stones had hematuria,and only 1of76(1.3%)had leukocyturia.Proteinuria was rare,and its frequency did not differ significant ly among of urir evidence of glomerular dysfunction.Among the children for whom these data were available glomerular dysfunction was found in 4 of the 41 children (9.8%)who had stones,12 of the 88 chil he th glomerular dysfunction amon children suspected to have stones as comnared with children whe did not have stones,was significantly increased (P=0.01).The incidence of renal tubular dystunc graphy in Two Children with Urolithiasis 41 anel A)anda l aminotransferase levels were measured in 56 chil- c punct dren-22 who had stones,21 suspected to have y0.3 stones,and 13 who did not have stones.All 50 0.92 cm sha at is row).dose to the lower pole of her right nes an wh stones (201 and 243 I per liter re had stones (overall prevalence,8.5%):112 were range,0 to 401).Neither of these two children had suspected to have urinary stones,and 427 had no received high-melamine formula,and neither had symptoms of infection such as fever and diarrhea gobbet-shapec ren 1968g obstructiononultrasonographyhoUghaGf of age.14:and 19 months to 078 these children had symptoms of obstruction.Most According to these values,62 of the children in of the children with stones did not have oliguria, our study had hypercalciuria:5 of 42(119%)who crying on urination,edema,or pas sing of stone had stones,13 of 88(14.8%)suspected to have The presence of symptoms d not dis inguish chil stones,and 44 of 274 (16.1%)who did not have ones from t did not P=0.34) FACTORS ASSOCIATED WITH URINARY STONES We considered age sex birth type melamine con LABORATORY EXAMINATIONS tent in the formula received,and use of the for- Urinalysis was performed in 372 children (34 ofmulalone inmbtion with breast milk as the 50 who ha suspected to have stones,and 262 of the 42 tion.Complete data were avail for 400 of th 1070 N ENGLJ MED 360:11 NEJM.ORG MARCH 12,2006 oma

The new england journal o f medicine 1070 n engl j med 360;11 nejm.org march 12, 2009 had stones (overall prevalence, 8.5%); 112 were suspected to have urinary stones, and 427 had no stones. Grossly, the stones were mainly grainy and gobbet-shaped (irregular and nubby) and did not cause shadowing on ultrasonography. Most were localized to the renal pelvis (Fig. 1). Four children who had stones also had evidence of urinary tract obstruction on ultrasonography, though none of these children had symptoms of obstruction. Most of the children with stones did not have oliguria, crying on urination, edema, or passing of stones. The presence of symptoms did not distinguish children who had stones from those who were suspected to have stones or those who did not have stones (Table 2). Laboratory Examinations Urinalysis was performed in 372 children (34 of the 50 who had stones, 76 of the 112 who were suspected to have stones, and 262 of the 427 who did not have stones) (Table 3). Hematuria was present in 5.9% of the children with stones (2 of 34), and leukocyturia in 2.9% (1 of 34). No child suspected to have stones had hematuria, and only 1 of 76 (1.3%) had leukocyturia. Proteinuria was rare, and its frequency did not differ significantly among the groups. We considered the elevation of urinary microalbumin levels, transferrin levels, or both to be evidence of glomerular dysfunction. Among the children for whom these data were available, glomerular dysfunction was found in 4 of the 41 children (9.8%) who had stones, 12 of the 88 children (13.6%) suspected to have stones, and 15 of the 269 (5.6%) who did not have stones (P=0.04 for the three-way comparison). The incidence of glomerular dysfunction among children suspected to have stones, as compared with children who did not have stones, was significantly increased (P=0.01). The incidence of renal tubular dysfunction, as indicated by elevation of the urinary β2- microglobulin level, did not differ significantly among the three groups (P=0.42) (Table 3). Serum creatinine, urea nitrogen, and alanine aminotransferase levels were measured in 56 children — 22 who had stones, 21 suspected to have stones, and 13 who did not have stones. All 56 children had normal serum creatinine and urea nitrogen levels. In one child suspected to have stones and one child who did not have stones, alanine aminotransferase levels were increased (201 and 243 IU per liter, respectively [normal range, 0 to 40]). Neither of these two children had received high-melamine formula, and neither had symptoms of infection such as fever and diarrhea. The urinary calcium:creatinine ratio was measured in 404 children and compared with the published reference values for young children: 7 months of age or younger, 1.96; 8 to 18 months of age, 1.4; and 19 months to 6 years of age, 0.78.3 According to these values, 62 of the children in our study had hypercalciuria: 5 of 42 (11.9%) who had stones, 13 of 88 (14.8%) suspected to have stones, and 44 of 274 (16.1%) who did not have stones (P=0.34). Factors Associated with Urinary Stones We considered age, sex, birth type, melamine content in the formula received, and use of the formula alone or in combination with breast milk as potential factors influencing urinary stone formation. Complete data were available for 400 of the 22p3 B A AUTHOR: FIGURE: JOB: 4-C H/T RETAKE SIZE ICM CASE EMail Line H/T Combo Revised AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset. Please check carefully. REG F Enon 1st 2nd 3rd Ding 1 of 1 03-12-09 ARTIST: ts 36011 ISSUE: Figure 1. Results of Ultrasonography in Two Children with Urolithiasis Induced by Melamine-Tainted Formula. Ultrasonographic images of the abdomen are shown for a 2-year-old boy (Panel A) and a 1-year-old girl (Panel B). Both children had multiple and sporadic punctiform, bilateral hyperechoic areas in the renal sinus. The largest hyperechoic area in the boy (Panel A, arrowhead) is 0.25 cm by 0.31 cm, without any shadow. The girl has a hyperechoic conglomeration that is 0.92 cm by 0.74 cm by 0.33 cm (Panel B, arrowhead) with a shadow (arrow), close to the lower pole of her right renal sinus. The New England Journal of Medicine Downloaded from nejm.org on October 18, 2011. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved

MELAMINE-CONTAMINATED POWDERED FORMULA AND UROLITHIASIS Table2.Signs and Symptoms in the Children Studied,According to the Presenceor Absence of Urinary Tract Stones Group Oliguria Unexplained Crying Edema Passing of Stones number/total number (percent) Children with stones 3/4716.4 0/48 0/48 0/48 Children with suspected 61095.5引 8/1107.3) 11100.9) 1/1100.9y stones Children without stones 10/419(2.4 17/418(4.1 4/416(1.0 1/418(0.2 All children 19/5753.3) 25/576(4.3) 5/5740.9) 2/576(0.3) P valuet 0.20 0.08 1.00 0.47 only occurred on urination caate or the comprithe three subous of children with the use of Fisheat test 589 children and were analyzed with two statisti- suspected stones as those exposed to no-melamine cal models.Model 1 included these 400 patients, formula95%CL,12to4.4:P=0.008). and all 589 patients were included in model 2,ir which the mis data were coded as DIscUSSIOn e In this study,using two differen tical mod. ast milk y els we found that to high-melamine for associated with the presence or absence of stones:mula increased the risk of urolithiasis among however,preterm birth and a high melamine con-young children.The results indicate that most chil tent in the formula received were significantly as- dren with melamine-associated urolithiasis hac sociated witht he presence of stor nonspecific symptoms and urinary find dings.Ines hild were 0 In m en ex to hig h-melamin ast wit likel 1a (058 confidence interval [CI.2.1 to 23.0:P=0.001) ntoms are useful in diagnosing th (unadjusted odds ratio,5.8%Cl.2.4 to 13.2:of stones.Our results indicate that screening for P<0.001),whereas children exposed to moderate- urinary stones should be based on the history of melamine formula did not have an increased like exposure to melamine rather than on the symp lihood of stone formation.Preterm inant tomatology. 45C16o224 D-0003 dy,the incide of hem atio,35,95%CL,1.4to8.8p= o0o In addi tion children exposed to high-melamine formula were suspected to have stones and those who did were 2.6 times as likely as those exposed to no- not have stones.Moreover the incidences of he melamine formula to have suspected stones (95% maturia and leukocyturia in children with uro Cl,1.2 to5.4;P0.01;unadjusted odds ratio,.5; lithiasis were lo wer than t se in the study 05 odel ,who report at55% ren ex vith had u tract nges ns.Sima d c only 5 9%of tones (05 children with stones in our study had hematuria 22 to 12 9:P<o001)whereas children exposed to and only 2 9%had leukocyturia it would appea moderate-melamine formula did not have a sig-that urinalysis is not adequate for screening for nificantly increased likelihood of stone tion. reterm inra nts we 5. none of th ren th urinary t ve st s(95%CL,1 ocumente n0 graphy in ou nelamine formula N ENGLJ MED 360,11 NEJM.ORG MARCH 12,2009 1071 The New Englar nd Journal of Medicine thout permission

Melamine-Contaminated Powdered Formula and Urolithiasis n engl j med 360;11 nejm.org march 12, 2009 1071 589 children and were analyzed with two statistical models. Model 1 included these 400 patients, and all 589 patients were included in model 2, in which the missing categorical data were coded as “unknown” (Table 4). Age, sex, and use of formula alone or in combination with breast milk were not significantly associated with the presence or absence of stones; however, preterm birth and a high melamine content in the formula received were significantly associated with the presence of stones. In model 1, children exposed to high-melamine formula were 7.0 times as likely to have stones as children exposed to no-melamine formula (95% confidence interval [CI], 2.1 to 23.0; P=0.001) (unadjusted odds ratio, 5.8; 95% CI, 2.4 to 13.2; P<0.001), whereas children exposed to moderatemelamine formula did not have an increased likelihood of stone formation. Preterm infants were 4.5 times as likely to have stones as term infants (95% CI, 1.6 to 12.4; P=0.003) (unadjusted odds ratio, 3.5, 95% CI, 1.4 to 8.8; P=0.009). In addition, children exposed to high-melamine formula were 2.6 times as likely as those exposed to nomelamine formula to have suspected stones (95% CI, 1.2 to 5.4; P=0.01; unadjusted odds ratio, 2.5; 95% CI, 1.4 to 4.6; P=0.003). In model 2, children exposed to high-melamine formula were 5.4 times as likely as those exposed to no-melamine formula to have stones (95% CI, 2.2 to 12.9; P<0.001), whereas children exposed to moderate-melamine formula did not have a significantly increased likelihood of stone formation. Preterm infants were 3.7 times as likely as term infants to have stones (95% CI, 1.4 to 9.7; P=0.009). In addition, children exposed to highmelamine formula were 2.3 times as likely to have suspected stones as those exposed to no-melamine formula (95% CI, 1.2 to 4.4; P=0.008). Discussion In this study, using two different statistical models, we found that exposure to high-melamine formula increased the risk of urolithiasis among young children. The results indicate that most children with melamine-associated urolithiasis had nonspecific symptoms and urinary findings. These findings contrast with the present guidelines posted on the Web site of the Ministry of Health of China (www.moh.gov.cn), which suggest that symptoms are useful in diagnosing the presence of stones. Our results indicate that screening for urinary stones should be based on the history of exposure to melamine rather than on the symptomatology. In our study, the incidences of hematuria, leukocyturia, and proteinuria did not differ significantly among children who had stones, those who were suspected to have stones, and those who did not have stones. Moreover, the incidences of hematuria and leukocyturia in children with urolithiasis were lower than those in the study by Coward et al.,3 who reported that 55% of the children with urinary stones had hematuria and 30% had urinary tract infections. Since only 5.9% of children with stones in our study had hematuria and only 2.9% had leukocyturia, it would appear that urinalysis is not adequate for screening for melamine-associated urinary stones. Furthermore, none of the four children with urinary tract obstruction documented on ultrasonography in our study had symptoms of obstruction or hematuria, leukocyturia, or proteinuria. Thus, in our view, Table 2. Signs and Symptoms in the Children Studied, According to the Presence or Absence of Urinary Tract Stones. Group Oliguria Unexplained Crying* Edema Passing of Stones number/total number (percent) Children with stones 3/47 (6.4) 0/48 0/48 0/48 Children with suspected stones 6/109 (5.5) 8/110 (7.3) 1/110 (0.9) 1/110 (0.9) Children without stones 10/419 (2.4) 17/418 (4.1) 4/416 (1.0) 1/418 (0.2) All children 19/575 (3.3) 25/576 (4.3) 5/574 (0.9) 2/576 (0.3) P value† 0.20 0.08 1.00 0.47 * Unexplained crying most commonly occurred on urination. † P values were calculated for the comparison among the three subgroups of children with the use of Fisher’s exact test. The New England Journal of Medicine Downloaded from nejm.org on October 18, 2011. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved

Thr NEW ENGLAND JOURNAL f MEDICINE Table 3.Laboratory Results in the Children Studied,Ac ording to the Presence or Absence ofUrinary Tract Stones Group Hematuria umber/total mber (pern) Children with stones 2/34(5.9) 1/342.9 0/34 4/41(9.8) 0/41 higonhsupead 0/76 1/761.3) 1/76(13 12/88(13.6) 4/884.5) without stone 4126215) 4/2621.5 22620.8 15/269(5.6 8/269(3.0 All children 6/372(1.6 63721.6 3/372(0.8 31/398(78) 12/3983.0 P value 0.10 0.63 0.65 0.04 0,42 s of children with the use of Fisher's exact test.except in the case the diagnosis of melamine-related urinary stones of bion an ultr Unlike typical urinary tract stones.most of the lar dysfunction,but not renal tubular dysfunc melamine-associated stones we detected were not tion,differed significantly among children who characterized by shadowing on ultrasonography. had stones,those who were suspected to have ens of melamin nes,and those who did not have stones.More sto n with renal fa d to h es ha using li nass spe nd tha 13 posed primarily of uric acid and melamine e.Before were no significant differences in the incidenc the announcement of formula contamination. of glomerular dysfunction between children with a 3-month-old boy was admitted to our hospita stones and those without stones (9.8%and 5.6% after presenting with a 2-week history of diarr P=0.37).It is unclear whether th re were other On ultr hhogapmutpe e tiny stones,the larg acto t play,such as othe r renal diseases,among were of to have sto tion of the othe the announcement of melamine contamination studv.se we inquired about exposure to melamine:the boy normal in all but two children,both under 1 yea melamine for 3 months atment have st h included hydration and a ther child nelamine form (0.u in dia Th ry tract in enal nelvis This case s ests that mel e not det ermined related stones may not be dense and may be eas In our study,121 children were exposed to ily passed after hydration and alkalinization find high-melamine formula.but only 23 of these chil ings that are consistent with a urate component Iren had urinary stones.Thu urinary stone Mos ciated sto our se loped in a minority of ch dren wer san ith th nosed to mel indicated that contaminated pet food ter it is not knowr times as likely as term infants to have stones whether melamine or uric acid mixed with mela Gilsanz et al.s reported that preterm infants were mine forms microcrystals that could cause tubu- more susceptible than term infants to the devel lointerstitial injury in humans opment of urinary stones not related to melamine 1072 N ENGLJ MED 360:11 NEJM.ORG MARCH 12,2006 Downloaded from nejm. n Oc r18,2011.Fo

The new england journal o f medicine 1072 n engl j med 360;11 nejm.org march 12, 2009 the diagnosis of melamine-related urinary stones requires an ultrasonographic examination. Unlike typical urinary tract stones, most of the melamine-associated stones we detected were not characterized by shadowing on ultrasonography. Sun et al.4 analyzed specimens of melamine-associated stones from 13 children with renal failure by using liquid chromatography–mass spectrophotometry and found that the stones were composed primarily of uric acid and melamine. Before the announcement of formula contamination, a 3-month-old boy was admitted to our hospital after presenting with a 2-week history of diarrhea. On ultrasonography, multiple tiny stones, the largest of which was 0.3 cm by 0.4 cm, were observed bilaterally in the renal pelvis, without shadowing or obstruction of the urinary tract system. After the announcement of melamine contamination, we inquired about exposure to melamine; the boy had received formula containing 150 ppm of melamine for 3 months. After treatment for 9 days, which included hydration and urine alkalinization, ultrasonography was repeated. Only one stone (0.5 cm in diameter) was detected in his left renal pelvis. This case suggests that melaminerelated stones may not be dense and may be easily passed after hydration and alkalinization, findings that are consistent with a urate component. Most melamine-associated stones in our series were small and sand-like, especially those in the renal pelvis. A previous study showed renal tubular degeneration in dogs exposed to melaminecontaminated pet food.1 However, it is not known whether melamine or uric acid mixed with melamine forms microcrystals that could cause tubulointerstitial injury in humans. In our analysis of biomarkers of early renal injury in 398 children, the incidence of glomerular dysfunction, but not renal tubular dysfunction, differed significantly among children who had stones, those who were suspected to have stones, and those who did not have stones. More children suspected to have stones had apparent glomerular dysfunction than those who did not have stones (13.6% vs. 5.6%, P=0.01), yet there were no significant differences in the incidence of glomerular dysfunction between children with stones and those without stones (9.8% and 5.6%, P=0.37). It is unclear whether there were other factors at play, such as other renal diseases, among the children suspected to have stones. Whether melamine can cause injury of other tissues and organs in humans is unknown. In our study, serum alanine aminotransferase levels were normal in all but two children, both under 1 year of age; one of the two children was suspected to have stones and the other did not have them. Neither child had received high-melamine formula, and neither had symptoms of urinary tract infection. The reasons for the increased serum alanine aminotransferase levels were not determined. In our study, 121 children were exposed to high-melamine formula, but only 23 of these children had urinary stones. Thus, urinary stones developed in a minority of children exposed to high-melamine formula. Multivariate logisticregression analysis with the use of two models indicated that preterm infants were 3.7 to 4.5 times as likely as term infants to have stones. Gilsanz et al.5 reported that preterm infants were more susceptible than term infants to the development of urinary stones not related to melamine, Table 3. Laboratory Results in the Children Studied, According to the Presence or Absence of Urinary Tract Stones. Group Hematuria Leukocyturia Proteinuria Glomerular Dysfunction Renal Tubular Dysfunction number/total number (percent) Children with stones 2/34 (5.9) 1/34 (2.9) 0/34 4/41 (9.8) 0/41 Children with suspected stones 0/76 1/76 (1.3) 1/76 (1.3) 12/88 (13.6) 4/88 (4.5) Children without stones 4/262 (1.5) 4/262 (1.5) 2/262 (0.8) 15/269 (5.6) 8/269 (3.0) All children 6/372 (1.6) 6/372 (1.6) 3/372 (0.8) 31/398 (7.8) 12/398 (3.0) P value* 0.10 0.63 0.65 0.04 0.42 * P values were calculated for the comparisons among the three subgroups of children with the use of Fisher’s exact test, except in the case of glomerular dysfunction, for which Pearson’s chi-square test was used. The New England Journal of Medicine Downloaded from nejm.org on October 18, 2011. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved

MELAMINE-CONTAMINATED POWDERED FORMULA AND UROLITHIASIS Table4.Predisposing Factors and Odds Ratios for the Development of Urinary TractStones Predisposing Factor Model 1 Model 2 Children with Su 95%cC 95%C) Pvolue 95%C) Pvalue 95%C) Pvalue Increasing age-per yr 1.20.7-19 050 1.3(0.9-1.8) 0.13 1.10.7-1.6 0.77 120.9-1.)0.15 Male 0804-1.8 0.66 1.0(0.6-1.6 0.99 0.910.5-171 0.83 0.90.6-15) 0.79 Femal 1.0 10 Birth type Preterm 4.51.6-12.400.0030.9(0.3-2.句0.88 3.7(1.4-9.70 000g 120.5-3.0 0.66 Unknown 190.9-3.9) 0.07 0.80.5-1.4)0.47 Term 1.0 1.0 1.0 1.0 High 7.0(2.1-23.010.0012.6(1.2-5.4 0.01 5.4(2.2-12.9)<0.001 23(1.2-4.4) 0.008 Moderate 2.0(0.6-6.2) 0.25170.9-32) 0101.40.6-3.3)0.44 1.50.9-2.5)0.15 None 1.0 1.0 1.0 1.0 Formula alo 1.40.7-3.00.391.3(0.8-22) 0.26 1.00.5-1.9) 0.10 1.40.9-2.2)0.16 0.30.1-1.0 005 0402-0.9 0.03 a alone 1.0 1.0 ssibly owing to a combination of immature re-dom.untimed urine specimens were obtained in nal function and differences in the regulation of our study,which may have influenced the urinary mineral homeostasis. findings. Our study has certain limitations,in part be A fourth limitation is the lack of data on re- it focused on an accidental outbreak ofre as not data were mis nd childr ital in the dire ot in to enrollment bias for two reasons:screened chil changes in renal pathological characteristics in dren mainly came from nearby provinces,such as only one case,involving an 8-month-old boy with Hebei and Henan,in which the melamine con melamine-associated urinary stones who was hos after prolonged anuria caused by bilat e.mna eral ure blopsy spe stones or w ected of hau tones ma bular epithelial-cell deg ration,ym te in have been sent for further evaluation to our hos-filtration in the renal interstitium,and focal fibro pital,a well-known referral hospital for children,sis;the results of immunofluorescence analysis resulting in referral bias and an overestimate of were normal.However,it is unclear whether the the inc l changes were caused by en,m by the acute ob naly,we were unable N ENGLJ MED 360,11 NEJM.ORG MARCH 12,2009 1073 Dowloadedom11.For pooN CegWhoutpemision

Melamine-Contaminated Powdered Formula and Urolithiasis n engl j med 360;11 nejm.org march 12, 2009 1073 possibly owing to a combination of immature renal function and differences in the regulation of mineral homeostasis. Our study has certain limitations, in part because it focused on an accidental outbreak of renal disease. First, some data were missing among responses to the questionnaire. Second, the geographic location of our hospital, in the center of Beijing, a city in northern China, might have led to enrollment bias for two reasons: screened children mainly came from nearby provinces, such as Hebei and Henan, in which the melamine contamination was reported as being more serious than elsewhere. In addition, children screened in other hospitals, especially those who had urinary stones or were suspected of having stones, may have been sent for further evaluation to our hospital, a well-known referral hospital for children, resulting in referral bias and an overestimate of the incidence of urinary stones. Third, since for some children, morning urine samples were not collected before the visit to the hospital, random, untimed urine specimens were obtained in our study, which may have influenced the urinary findings. A fourth limitation is the lack of data on renal pathological characteristics, since it was not feasible in this situation to perform renal biopsies in children with urolithiasis. Therefore, we could not assess the direct injury of renal tissue by melamine. To date, we have information about changes in renal pathological characteristics in only one case, involving an 8-month-old boy with melamine-associated urinary stones who was hospitalized after prolonged anuria caused by bilateral urethral stones.4 His renal-biopsy specimen revealed sclerosis in 6 of 26 glomeruli, partial tubular epithelial-cell degeneration, lymphocyte infiltration in the renal interstitium, and focal fibrosis; the results of immunofluorescence analysis were normal. However, it is unclear whether the renal histopathological changes were caused by melamine itself or by the acute obstructive uropathy that ensued. Finally, we were unable to test the Table 4. Predisposing Factors and Odds Ratios for the Development of Urinary Tract Stones. Predisposing Factor Model 1 Model 2 Children with Stones Children with Suspected Stones Children with Stones Children with Suspected Stones odds ratio (95% CI) P value odds ratio (95% CI) P value odds ratio (95% CI) P value odds ratio (95% CI) P value Increasing age — per yr 1.2 (0.7–1.9) 0.50 1.3 (0.9–1.8) 0.13 1.1 (0.7–1.6) 0.77 1.2 (0.9–1.6) 0.15 Sex Male 0.8 (0.4–1.8) 0.66 1.0 (0.6–1.6) 0.99 0.9 (0.5–1.7) 0.83 0.9 (0.6–1.5) 0.79 Female 1.0 1.0 1.0 1.0 Birth type Preterm 4.5 (1.6–12.4) 0.003 0.9 (0.3–2.6) 0.88 3.7 (1.4–9.7) 0.009 1.2 (0.5–3.0) 0.66 Unknown 1.9 (0.9–3.9) 0.07 0.8 (0.5–1.4) 0.47 Term 1.0 1.0 1.0 1.0 Melamine content in formula High 7.0 (2.1–23.0) 0.001 2.6 (1.2–5.4) 0.01 5.4 (2.2–12.9) <0.001 2.3 (1.2–4.4) 0.008 Moderate 2.0 (0.6–6.2) 0.25 1.7 (0.9–3.2) 0.10 1.4 (0.6–3.3) 0.44 1.5 (0.9–2.5) 0.15 None 1.0 1.0 1.0 1.0 Formula alone or with breast milk Formula with breast milk 1.4 (0.7–3.0) 0.39 1.3 (0.8–2.2) 0.26 1.0 (0.5–1.9) 0.10 1.4 (0.9–2.2) 0.16 Unknown 0.3 (0.1–1.0) 0.05 0.4 (0.2–0.9) 0.03 Formula alone 1.0 1.0 1.0 1.0 The New England Journal of Medicine Downloaded from nejm.org on October 18, 2011. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved

1074 n engl j med 360;11 nejm.org march 12, 2009 Melamine-Contaminated Powdered Formula and Urolithiasis melamine concentration of milk formulas ourselves; instead, we relied on reported values of the melamine content. In conclusion, we suggest that children with urinary stones induced by melamine-tainted formula require careful ongoing and long-term follow-up. Supported by a grant from the National Key Technology Research and Development Program of China. No potential conflict of interest relevant to this article was reported. We thank all the doctors, nurses, and other staff members of the Departments of Pediatrics, Ultrasonic Medicine, and Laboratory Medicine of Peking University First Hospital who kindly provided their cooperation in this study, and the graduate students of Peking University First Hospital who provided assistance in data management. References 1. Thompson ME, Lewin-Smith MR, Kalasinsky VF, et al. Characterization of melamine-containing and calcium oxalate crystals in three dogs with suspected pet food-induced nephrotoxicosis. Vet Pathol 2008;45:417-26. 2. Chertow GM, Milford EL, Mackenzie HS, Brenner BM. Antigen-independent determinants of cadaveric kidney transplant failure. JAMA 1996;276:1732-6. 3. Coward RJ, Peters CJ, Duffy PG, et al. Epidemiology of paediatric renal stone disease in the UK. Arch Dis Child 2003;88: 962-5. [Erratum, Arch Dis Child 2004;89: 797.] 4. Sun N, Shen Y, Sun Q, et al. Melamine related urinary calculus and acute renal failure in infants. Zhonghua Er Ke Za Zhi 2008;46:810-5. (In Chinese.) 5. Gilsanz V, Fernal W, Reid BS, Stanley P, Ramos A. Nephrolithiasis in premature infants. Radiology 1985;154:107-10. Copyright © 2009 Massachusetts Medical Society. receive immediate notification when a journal article is released early To be notified when an article is released early on the Web and to receive the table of contents of the Journal by e-mail every Wednesday evening, sign up through our Web site at NEJM.org. The New England Journal of Medicine Downloaded from nejm.org on October 18, 2011. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved

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