Chinese Medical Journal 2009;122(3):245-251
Diagnosis and treatment of melamine-associated urinary calculus complicated with acute renal failure in infants and young children

SUN Ning,  SHEN Ying,  SUN Qiang,  LI Xu-ran,  JIA Li-qun,  ZHANG Gui-ju,  ZHANG Wei-ping,  CHEN Zhi,  FAN Jian-feng,  JIANG Ye-ping,  FENG Dong-chuan,  ZHANG Rui-feng,  ZHU Xiao-yu,  XIAO Hong-zhan

SUN Ning (Department of Urology, Beijing Children′s Hospital Affiliated to Capital Medical University, Beijing 100045, China)

SHEN Ying (Department of Nephrology, Beijing Children′s Hospital Affiliated to Capital Medical University, Beijing 100045, China)

SUN Qiang (Department of Nephrology, Beijing Children′s Hospital Affiliated to Capital Medical University, Beijing 100045, China)

LI Xu-ran (Department of Urology, Beijing Children′s Hospital Affiliated to Capital Medical University, Beijing 100045, China)

JIA Li-qun (Diagnostic Imaging Center, Beijing Children′s Hospital Affiliated to Capital Medical University, Beijing 100045, China)

ZHANG Gui-ju (Department of Nephrology, Beijing Children′s Hospital Affiliated to Capital Medical University, Beijing 100045, China)

ZHANG Wei-ping (Department of Urology, Beijing Children′s Hospital Affiliated to Capital Medical University, Beijing 100045, China)

CHEN Zhi (Department of Nephrology, Beijing Children′s Hospital Affiliated to Capital Medical University, Beijing 100045, China)

FAN Jian-feng (Department of Nephrology, Beijing Children′s Hospital Affiliated to Capital Medical University, Beijing 100045, China)

JIANG Ye-ping (Department of Nephrology, Beijing Children′s Hospital Affiliated to Capital Medical University, Beijing 100045, China)

FENG Dong-chuan (Department of Surgery, Xuzhou Children′s Hospital, Xuzhou, Jiangsu 221006, China)

ZHANG Rui-feng (Department of Pediatric Internal Medicine, Xuzhou Children′s Hospital, Xuzhou, Jiangsu 221006, China)

ZHU Xiao-yu (Department of Surgery, Xuzhou Children′s Hospital, Xuzhou, Jiangsu 221006, China)

XIAO Hong-zhan (Beijing Institute of Microchemistry, Beijing 100091, China)

Correspondence to:SHEN Ying,Department of Nephrology, Beijing Children′s Hospital Affiliated to Capital Medical University, Beijing 100045, China (Tel: . Fax:. E-mail:ying_116sh@sohu.com)
Keywords
calculus, urinary; renal failure, acute; melamine; infant; child
Abstract

Background  Infants in some areas of China developed urinary lithiasis after being fed with powdered milk that was tainted with melamine in 2008 and very small proportion of the infants developed acute renal failure caused by urinary tract calculus obstruction. The aim of this article was to summarize clinical characteristics, diagnosis and treatment of infants with urinary calculus and acute renal failure developed after being fed with melamine tainted formula milk.
Methods
  Data of infant patients with urinary calculus and acute renal failure due to melamine tainted formula milk admitted to the Beijing Children′s Hospital Affiliated to the Capital Medical University and the Xuzhou Children′s Hospital in 2008 were used to analyze the epidemiological characteristics, clinical manifestations, imaging features as well as effects of 4 types of therapies.
Results  All the 34 infants with urinary calculus were complicated with acute renal failure, their blood urea nitrogen (BUN) was (24.1±8.2) mmol/L and creatinine (Cr) was (384.2±201.2) μmol/L. The chemical analysis on the urinary calculus sampled from 15 of the infants showed that the calculus contained melamine and acidum uricum. The time needed for the four types of therapies for returning Cr to normal was (3.5±1.9) days for cystoscopy group, (2.7±1.1) days for lithotomy group, (3.8±2.3) days for dialysis group, and (2.7±1.6) days for medical treatment group, which had no statistically significant difference (P=0.508). Renal failure of all the 34 infants was relieved within 1 to 7 days, averaging (3.00±1.78) days.
Conclusions  Melamine tainted formula milk may cause urinary calculus and obstructive acute renal failure. It is suggested that firstly the patients with urinary calculus complicated with acute renal failure should be treated with dialysis or medication to correct electrolyte disturbance, in particular hyperkalemia, and then relieve the obstruction with available medical and surgical methods as soon as possible. It was observed that the short-term prognosis was satisfactory.

Urinary calculus was uncommon among infants and young children, but there is a tendency to increase in a sporadic form.1 However, in 2008, number of cases with urinary lithiasis among infants had suddenly increased, and almost all the cases had a history of being fed with milk powder products which were probably tainted with melamine. In the present study, we summarized and analyzed the clinical data of infants and children who developed acute renal failure induced by urinary lithiasis that was associated with intake of melamine-contaminated milk powder.

METHODS

Clinical data
Totally 34 patients with urinary calculus complicated with acute renal failure associated with ingestion of melamine-tainted milk powder were admitted to Beijing Children′s Hospital Affiliated to Capital Medical University (25 cases) and the Xuzhou Children′s Hospital (9 cases) between January and September, 2008. Of the 34 cases, 24 were boys and 10 were girls, the boys to girls ratio was 2.4:1.0. The age of onset was 6 to 35 months, 27 (79.4%) of the patients were under the age of 1 year, and the median age of the 34 cases was 8.5 months.

Methods
Retrospective analyses were made on the 34 patients′ epidemiologic features, clinical manifestation, the characteristics of imaging findings, as well as the effects of the different interventional measures and prognosis.

Statistical analysis
All data were expressed as mean ± standard deviation (SD). SPSS 14.0 statistical software was applied; Student′s t test, correlation analysis and analysis of variance were used for statistical analyses. P <0.05 was considered statistically significant.

RESULTS

General data
The residential regions of the patients
The patients were from 9 provinces and 1 municipality: 14 were from Hebei, 7 from Jiangsu, 2 from Henan, 2 from Shandong, 2 from Gansu, 2 from Shanxi, 2 from Anhui, 1 from Liaoning, 1 from Qinghai and 1 from Beijing.

Months of admission
All the 34 patients were hospitalized between January and September, 2008. One patient was admitted in March, 2 in April, 2 in May, 8 in June, 10 in July, 10 in August and 1 in September.

Approximate duration of ingesting melamine-tainted milk powder
The mean (±SD) duration was (9.4±4.2) months, median, duration 8.0 months and the range was 0.5 to 30.0 months.

Clinical manifestations
Of the 34 cases, 33 had oliguria or anuria, 15 cases had the following gastrointestinal symptoms: vomiting, diarrhea, anorexia and abdominal distention; 10 cases fever and 3 cases had gross hematuria. All the 34 cases had acute renal failure, urinary calculus and complete or partial obstruction. In one case the ureteric calculus caused rupture of the ureter, the stone was displaced and encapsulated, and there was still adhesion around the ureter after conservative treatment. None of the 34 cases had any definite deformity of the urinary system. The course of the disease was 18 hours to 60 days, mean 4.5 days.

Imaging examinations
Urinary calculus was found in each case by ultrasound examinations of the urinary system. The calculus was located in bilateral kidneys and ureters on both sides in 21 cases, in unilateral kidney and bilateral ureters in 6 cases, in bilateral kidneys and unilateral ureter in 2 cases and in bilateral kidneys only in 3 cases and in bilateral ureters only in 2 cases. The site of obstruction caused by the calculi was the junction of pelvis and ureter in 33 cases, the junction of ureter and urinary bladder in 28 cases and the part of ureter crossing over the iliac blood vessels in 8 cases. Coexistence of obstructions at the junction of pelvis and ureter and at the junction of ureter and bladder was found in 5 cases. Unilateral obstruction at the junction of pelvis and ureter was found in 3 cases (1 of them was complicated with obstruction at distal ureter-bladder junctrion), and unilateral obstruction at the junction of ureter and bladder in 1 case (Figures 1 and 2).


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Figure 1. Urinary system ultrasonogram of the case 16. The patient was a 13-month-old boy. There is a 1.5 cm × 0.5 cm calculus on the right side at the junction of pelvis and ureter with dilation and dropsy of the right pelvis and calices.
Figure 2. Urinary system ultrasonogram of the case 33. The patient was an 11-month-old boy. There is a 1.1 cm × 0.7 cm calculus on the left side at the distal end of the ureter with dilation and dropsy of the left ureter with the inner diameter 0.9 cm.

Blood urea nitrogen and creatinine
All the 34 cases had different degrees of acute renal failure. The mean blood urea nitrogen (BUN) was (24.1±8.2) mmol/L and the creatinine was (384.2±201.2) μmol/L.

Component of the calculi
Urinary calculi specimens were collected from 15 cases and were analyzed as unknown objects for their components at Beijing Institute of Microchemistry using infrared spectroscopy, nuclear magnetic resonance, and high performance liquid chromatography. The result of the analysis proved that the calculus was composed of melamine and uric acid, and the molecular ratio of uric acid to melamine was around 2:1 (Figure 3 and Table 1).


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Figure 3. By infrared spectroscopy analysis, the calculus was composed of melamine and uric acid. The upper graph represents is the component separated from the calculus by using high performance liquid chromatography, and the lower graph represents is the standard melamine.


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Table 1. The main chemical components of the urinary calculi are melamine and uric acid

Treatment and outcome
Of the 25 cases hospitalized in Beijing Children’s Hospital Affiliated to Capital Medical University, 7 were treated with rehydration and alkalization of the urine alone. These cases started to have urine or significantly increased urine volume within 24 hours after the treatment. Eleven cases were treated with retrograde catheterization into the ureter via cystoscopy (in 2 of these cases peritoneal dialysis tube was placed and peritoneal dialysis was attempted, but because of failure in drainage, the treatment was switched to the retrograde catheterization); in 9 of these cases a 3F ureteral catheter was retrogradely inserted into both ureters and retained for drainage, and in one case the catheter could only be inserted into the left ureter, therefore this case only had drainage on the left side; while in another case cystoscopy showed that on insertion of the catheter into the ureter, urine flew out from the orifice of the ureter accompanied by expelling of sand-gravel-like calculi, therefore no drainage catheter was retained. In 10 of the 11 cases the obstruction was relieved immediately and the urine was drained, while one patient still had no urine at 24 hours after the treatment and the patient was treated with hemodialysis. The patient started to have urine at 36 hours after the treatment began. Six cases were treated with peritoneal dialysis and they began to have urine on day 1 to day 3. One case was treated with hemodialysis.

Of the 9 cases hospitalized in Xuzhou Children’s Hospital, 8 cases underwent unilateral pelvic or ureteral lithectomy, and "J" shaped catheters were retained in 6 cases for internal drainage, and perirenal external drainage catheter was placed for 1 case. In 1 case, the contralateral ureter was probed at the same time and bilateral "J" shaped catheters were retained for internal drainage. In another patient cystoscopy showed flowing out of urine with expelling gravel-like calculi, and unilateral "J" shaped catheter was retained for drainage.

All the patients in both hospitals were divided into 4 groups according to the treatment approaches: patients in group 1 (12 cases) were treated with cystoscopy and retrograde catheterization, including 2 cases treated with the cystoscopy and catheterization as major treatment after peritoneal dialysis; patients in group 2 (8 cases) were treated with lithectomy as the major treatment plus drainage as an adjuvant therapy; patients in group 3 (7 cases) were treated dialyses, 6 of them were treated with peritoneal dialysis alone (in 2 of theses cases the treatment was shifted from peritoneal dialysis to cystoscopy plus catheterization because of inefficient dialysis tube drainage) and 1 was treated with hemodialysis; group 4 patients (7 cases) were treated with general medical treatment.

Time to recovery of renal function was not correlated with BUN and creatinine levels determined during the renal failure (P=0.999). The mean time to normalization of creatinine was (3.5±1.9) days in group 1, (2.7±1.1) days in group 2, (3.8±2.3) days in group 3 and (2.7±1.6) days in group 4, the difference among the 4 groups was not significant (P=0.508).

Evaluation of the outcomes
The renal failure in all the 34 cases was cured. The urinary calculi in most of the patients were completely removed and the morphology of kidneys on imaging examinations returned to normal. The mean time to recovery of renal function was (3.0±1.8) days (range from 1 to 7 days). There was no recurrence of the disease in any of these cases till October 2, 2008. The clinical data of these cases are listed in Table 2.


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Table 2. Clinical data of the 34 children with urinary lithiasis complicated with acute renal failure


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Table 2. Clinical data of the 34 children with urinary lithiasis complicated with acute renal failure

DISCUSSION

Melamine is a nitrogen-containing organic heterocyclic compound belonging to trizines. It’s molecular formula is C3N6H6 or C3N3(NH2)3 and its molecular weight is 126.12. This chemical is used in manufacturing of household utensil and surface of ornaments; it should never have been added into any kind of foods or drinks. It was reported in 2007 that in the United States many dogs and cats were poisoned and died, subsequent investigations proved that melamine was added into parts of the wheat and rice protein powder for making feeds for the pets, which caused urinary calculus, renal failure and deaths of the pets.2 According to the data from the General Administration of Quality Supervision, Inspection and Quarantine of the People’s Republic of China, the highest content of melamine in the milk powder formula products for infants and young children is 2563 mg/kg milk powder. All the 34 patients reported in this paper had a history of long-term ingestion of the problematic milk powder, and melamine and uric acid were detected positive from the urinary calculus specimens collected from 15 of these patients. It can basically be confirmed that the urinary lithiasis and the obstructive renal failure are caused by melamine based on the facts that both the milk powder products and the urinary calculi contained melamine plus the ultrasonographic features seen in these patients, although the mechanisms how the melamine and uric acid conjugate and form calculi warrant further studies.

Epidemiologic features
Urinary calculus had been very rare among infants and young children 3 years ago and the age range of patients was from 1 year and 2 months to 11.5 years and the cases were sporadic. However, a report from Beijing Children’s Hospital1 showed that the number of cases with urinary calculus gradually increased during the recent 3 years, and the features of the calculi were similar to those seen in the present series of patients. Since March 2008, number of infants with urinary calculus and obstructive renal failure caused by being fed with melamine contaminated milk powder suddenly increased and reached a peak in June to August.

The analysis of data from the 34 cases showed that the mean time from the beginning of continuous feeding with the problematic milk powder to onset of the disease was 9.4 months, and range for most of the cases was between 5.2 to 13.6 months and the shortest time was 0.5 month and longest 30 months. Formation of the urinary calculus may be complicated, there may be some other factors related to susceptibility or precipitation, therefore, further studies are needed.

Features of the cases
The present study showed that among the cases with urinary calculus and acute renal failure, there were more boys than girls, the male to female ratio was 2.4:1.0. The possible reason is that (1) the boys have longer and narrower urethra than the girls and the urethra in boys has 3 narrow segments and 2 bending parts, and hence it is difficult for calculi to be expelled. A survey on population distribution of urinary calculus in China showed that the male to female ratio of patients with urinary calculus in China was 2–5:1. For calculus in upper urinary tract, the incidence among males is slightly higher than that in females, while for lower urinary tract calculus, the incidence among males is significantly higher than that in females.3 A study from the United Kingdom on 121 children with renal lithiasis found that the male to female ratio was 2.1:1.0,4 which is consistent with the reports from China. (2) Melnick et al5 reported that male animals were more prone to develop urinary calculi than female animals in a subacute and chronic toxicity study in which F344 rats and B6C3F1 mice were given melamine for 13 weeks and 103 weeks, respectively.

Other studies showed that intake of the same dose and same concentration of melamine by young rats shortly after weaning caused significantly higher incidence of urinary calculus as compared with adult rats, and in the young rats the development of calculus had a considerable dose-effect relationship with the quantity of melamine intake, and that over-saturation of melamine in the urinary tract may cause formation of calculus more easily.6 The clinical findings of the present study are consistent with the above-mentioned observations in that the infants and young children seemed to be more susceptible to development of urinary calculus than adults, which might be related to lower ability to absorb fluids, immaturity of renal function and suboptimal nutritional status of infants and young children.

Diagnosis
The overt manifestations of obstructive renal failure are oliguria or anuria, severe patients may have convulsions, edema or hypertension. Most of the infants and young children with urinary calculus without obstruction are asymptomatic, only a small proportion of patients may have symptoms or signs like crying, vomiting and hematuria. Careful parents may find turbid urine or even fine sand gravel-like stones in the patients′ urine. Features of imaging examinations include no visible stones opacity on plain X-ray film and high sensitivity and specificity of ultrasonography. The ultrasound findings of the calculi are characterized by lump-like stones formed by aggregated piecemeal calculi or sand gravel-like aggregation which involve broader range of the urinary tract including the pelvis, calices and ureter, and in many cases the calculi were found bilaterally, and there is a hypoechoic image behind the calculus, and the rear edge of the stone can be detected. The sites of severe obstruction were often found to be the junction of pelvis and ureter, the segment of ureter crossing over the iliac vessels or the junction of ureter and the urinary bladder. In the cases with ureteric obstruction, the upper part of the ureter is dilated, and at the lowest end of the dilated part, the stone can be clearly seen. With complete obstruction, both kidneys are swollen, the echo of the renal parenchyma is stronger with normal thickness of the parenchyma and the pelvis and calices are slightly dilated and the calices appeared to be blunt and round in shape. In a proportion of patients there is edema of the perirenal fascia and periureteral soft tissues; and as the disease proceeded, the walls of the pelvis and ureters show edema and thickening. Intravenous urinary tract radiography is mainly used for judgment of renal function, and the calculi appear as filling defects. Plain CT scan may visualize the stones as high density images, but because of the radiation injury and absence of special advantages in imaging, it is generally not necessary to use CT for diagnosis of urinary calculus. Based on clinical manifestations of obstructive renal failure in infants and young children in combination with the history of the unusual feeding, negative calculi on X-ray plain film and the features of ultrasonographic images, the diagnosis and differential diagnosis of melamine-associated urinary calculus are not difficult in most of the cases.

Treatments
Treatment of the obstructive renal failure should focus on the following two aspects: one is emergency management of hyperkalemia and other electrolyte disturbances; the other is to relieve the obstruction of the urinary tract and drain the urine.

Since the stone is relatively loose, there is a high possibility of spontaneous expulsion of the stones. For patients with shorter history of the disease and better general status and serum potassium lower than 6.5 mmol/L and smaller calculus, the treatment of choice should be medical conservative approaches or dialysis. For cases with severe renal failure, the treatment of choice should be cystoscopy plus retrograde catheterization into the ureters for trying to dredge; if the catheter proceeds over the obstruction site, there will be urine flowing out from the catheter; in this case the intraureteral catheter should be retained and the urethral catheter with balloon should be placed and fixed securely to prevent from dropping out. Flowing out of sand gravel like stones with urine from the ureteral orifice observed via cystoscope signals effective relief of the obstruction. For the critically ill patients who could not tolerate anesthesia and surgery, hyperkalemia and other severe electrolyte disturbances should be first managed and primary resuscitation should be performed if necessary, and then simple and effective measures such as cystoscopy or ureteroscopy for retrograde ureteral catheterization for drainage or renal puncture for nephrostomy should be chosen. For infants at very young age in whom the cystoscope can not be inserted through the urethra into the bladder, and if no suitable endoscope is available for retrograde catheterization, or if drainage is unsatisfactory after the cystoscopy and ureteral catheterization and the recovery of renal function is too slow, peritoneal dialysis can be chosen and thereby to support the patient to obtain sufficient fluid intake, which may help movement of the stones. In the present study we observed in the patients who underwent dialysis the stones were spontaneously expelled and the obstruction was relieved. In the situation where there is neither available endoscope nor blood purification measures are applicable in patients with severe obstruction and renal failure, open lithectomy or cystostomy for retrograde ureteral catheterization may also be an optional method of treatment. The results of treatments of the present series of patients showed that there was no significant difference in the efficacy of different therapeutic approaches for reliving renal failure. The primary principle for selecting different interventional measures is the safety and efficacy, and the next is minimal injury to the patients; selection of methods should be based on comprehensive consideration of the disease status, technical skills of the physicians or surgeons and the medical facilities and equipment. After the renal failure is relieved, the urine output and the status of stone evacuation should be observed, and the expelled stones should be sent for chemical analysis. Evacuation of stones may occur 1 week to 3 months after diagnosis. It remains to be explored how to promote evacuation of the stones that has no change in the shape and site.

Our clinical data suggest that after reasonable treatments, the short-term outcome of the infants with acute obstructive renal failure induced by urinary calculus caused by melamine tainted milk powder formulae for infants is good although further follow-up observations are warranted for long-term outcome. Because of limited number of patients and the short follow-up time, this report provides only some preliminary data. Melamine-caused urinary lithiasis is a newly emerged urologic disease, for which there are very limited clinical and experimental studies in China and overseas countries; further studies are needed for clarifying many relevant problems.

REFERENCES

1. Meng Q, Shen Y, Sun N, Liu ZH. Clinical analyses of urinary calculus and acute renal failure in children. Chin Pediatr Emerg Med (Chin) 2008; 15: 122-124.

2. Dobson RL, Motlagh S, Quijano M, Cambron RT, Baker TR, Pullen AM, et al. Identification and characterization of toxicity of contaminants in pet food leading to an outbreak of renal toxicity in cats and dogs. Toxicol Sci 2008; 106: 251-262.

3. Mi H, Deng Y. Epidemiological characteristics of urinary calculus in China. Chin J Urol (Chin) 2003; 24:715-716.

4. Coward RJ, Peters CJ, Duffy PG, Corry D, Kellett MJ, Choong S, et al. Epidemiology of paediatric renal stone disease in the UK. Arch Dis Child 2003; 88: 962-965.

5. Melnick RL, Boorman GA, Haseman JK, Montali RJ, Huff J. Urolithiasis and bladder carcinogenicity of melamine in rodents. Toxicol Appl Pharmacol 1984; 72: 292-303.

6. Neerman MF, Zhang W, Parrish AR, Simanek EE. In vitro and in vivo evaluation of a melamine dendrimer as a vehicle for drug delivery. Int J Pharm 2004; 281: 129-132.