Melamine is a newly identified cause of urinary lithiasis. Since the events of deaths of 4000 pets (cats and dogs) due to melamine poisoning in North American regions last year,1,2 there have been reports on experimental and pathological studies on renal failure in cats and dogs caused by melamine.3,4 However, no reports on ultrasonographic diagnosis of urinary calculus in human being caused by melamine are available. The aim of the present study was to understand the features of echogenicity of the urinary calculi caused by melamine, the expulsion of the calculi and value of ultrasonography in diagnosis of urinary lithiasis caused by melamine intake in infants and young children.
Ultrasound examination for urinary calculus was performed for 28 332 infants and children who had a history of ingestion of milk powder formulae possibly added with melamine between March 2008 and October 2008 in the Beijing Children's Hospital. Data of 395 cases who were diagnosed as urinary lithiasis were analyzed. Of these cases, 247 were male and 148 were female, the age of these cases ranged from 1 month to 12 years, 35 of the cases were under the age of 6 months, 280 cases were 6 months to 3 years of age and 80 were older than 3 years. The age of the cases that were complicated with urinary tract obstruction was between 5 months and 22 months. The length of period of time for which the infants and children were fed with the problematic milk powder was 2 months to 2 years. Abdominal X-ray plain film was taken for 13 cases and intravenous pyelography (IVP) was performed for 12 cases.
The following ultrasonographs were used in this study: Philips HDI 5000, transducer frequency 2–5 MHz and 5–12 MHz; Philips IU 22, transducer frequency 5–12 MHz and 4–9 MHz; and GE Logic 9, transducer frequency 6–8 MHz and 9–14 MHz.
Method of examination
No fasting was required. For incooperative patients 10% chloral hydrate was given orally at a dose of 0.5 ml/kg body weight. Ultrasound examinations were carried out on kidneys, ureters and urinary bladder at longitudinal and transverse scans. For patients with hydronephrosis or hydroureterosis secondary to obstructions, the anterior and posterior diameters of the renal pelvis and the internal diameter of dilated ureters were measured. For patients with renal failure the sizes of both kidneys were measured and the increased cortical echogenicity of both kidneys was observed. Diagnosis of lump-like calculus was made when strong echogenicity >0.4 cm × 0.4 cm were seen, and diagnosis of gravel-like calculi was made when clustered fine gravel-like strong echogenicity was seen.
Of the 395 cases, 49 (12.4%) were inpatients whose course of disease was 1 day to 20 days, and one of these cases was anuric for 20 days. Twenty-five cases had acute renal failure, and their main clinical manifestations were crying, restlessness, fever and vomiting; 12 of the cases presented with a chief complaint of oliguria or anuria. The remaining 24 inpatients without renal failure had intermittent hematuria (5), reduced frequency of urination (2), crying at urination (2) and visible expelled calculi at the urethral meatus (2), and the rest of patients had no overt clinical symptoms.
Intrarenal lump-like calculi > 0.4 cm × 0.4 cm were found in 231 cases, and in 137 of these cases there was a weak echo image behind the calculi. The largest calculus was 2.2 cm × 2.2 cm. In 142 cases the intrarenal calculi were unilateral (19 of them were complicated with ureteral calculi and 1 case with urethral calculus) and in 57 cases bilateral (18 of them were complicated with ureteral calculi). Simple ureteric calculi were found in 29 cases, urinary bladder calculus in 1 case and urethral calculi in 2 cases. Gravel-like calculi were found in 164 cases, which were unilateral in 127 cases (complicated with ureteral calculi in 2 cases) and bilateral in 36 cases (complicated with ureteral calculus in 1 case), and simple ureteral gravel-like calculi were found in 1 case. Seven patients had underlying congenital hydronephrosis.
Incarceration of ureteric calculi was found in 51 cases (in whom the 7 cases with congenital hydronephrosis. caused by pelvic-ureteral junction obstruction (PUJO), were excluded), which was bilateral in 25 cases and unilateral in 26 cases. Totally 76 ureters were involved. The stones were found incarcerated at one of the three physiological narrow segments of ureter; at the junction of pelvis and ureter in 34 cases, at the distal part of ureter in 30 cases and at the segment of ureter crossing over the iliac vessels in 12 cases. Mild calicealhydroureterosis and mild pelvis dilatation (the anterioposterior diameter was 1.1 cm to 1.8 cm) were detected above the obstruction at the side of incarceration, and caliceal pelvis tension was low in some cases and high in some other cases; the kidney was enlarged as the long diameter reached 8 cm in children 6 months to 2 years of age, and the echogenicity of the renal cortex was markedly increased. The echo intensity of the cortex of right kidney was greater than that of the liver. However, no thinning of the renal parenchyma was seen. The part of ureter above the obstruction was found dilated (the inner diameter was 0.4 cm to 1.0 cm) and the part below the obstruction was withered and flat. Multiple calculi in ureter were seen in 3 cases. Two cases had small amount of ascites and edema of perinephric fat sac.
Abdominal X-ray plain film was taken for 13 cases and dense echo image of relatively low density in the renal area was seen in 4 of the cases. IVP was performed for 12 cases and 5 of them had ureteral filling defects, hydronephrosis and hydroureterosis were shown above the obstruction. X-ray examinations could not reveal any other findings suggestive of urinary calculus.
Ultrasonographic reexaminations were carried out for 116 (29.4%) cases 1 week to 1 month after the first ultrasonography. In 37 of the 46 cases who had gravel-like calculi, no calculi were detectable on reexamination. Of the 26 outpatients who had lump-like calculi without dropsy, none had expulsion of the calculi in spite of increased amount of water intake. In 24 of the 42 inpatients with lump-like calculi (34 of them were complicated with dropsy), the dropsy disappeared, and in 13 cases all the calculi were expelled, and in 21 (50%) cases the calculi were partially expelled, while in 8 cases there were no changes on reexamination. Edema of the walls of pelvis and ureter to different extent was detected in 14 cases.
Features of the calculi
The calculi expelled by some of the patients were brown or brown-yellow fine gravels. Some of the calculi were lump-like in appearance (Figure 1); the size of the larger ones was up to 1.0 cm × 0.5 cm and oval in shape, the surface of the stone was covered by a brown soft shell and the inner part was white, the shape of the stone could be changed on compression. Very few of the stones had a meconium-like appearance.
The calculi expelled from 12 cases were analyzed by using combined liquid phase chromatography-mass spectrum method (Esquire-LC MS analyzer, produced by Bruker Co.) and the main contents of the calculi were identified to be uric acid and melamine. The molar ratio of uric acid to melamine was about 2:1.
Urinary calculus is relatively uncommon in children, and its incidence accounts for 2.0% to 2.7% of all urinary calculus in human being. The rate of hospitalization for renal lithiasis varies greatly among different regions, e.g., the rate is 0.001% to 0.1% in the United States and up to 7.0% in Asia.5 The most common factor that induces childhood urinary calculi is metabolic abnormalities; the urinary calculus caused by metabolic disorders can reach over 40%,5,6 and the next common factors are urinary tract infection and urinary system deformities. In children the most common urinary calculi are those containing calcium, accounting for over 80%,7 which have high density and is radiopaque; stones composed of calcium oxalate account for 45% to 65%, and those composed of calcium phosphate 14% to 30%, and uric acid, struvite and cystine calculi 5% to 10%.6–8 Ceftriaxone may lead to radiopaque renal calculi.9 Calculus consisted of uric acid is very rare, and accounts for approximately 6%.10 None of the 121 cases with urinary calculi summarized by Coward had uric acid calculus.11 Among 1392 cases reported by Pak et al,8 uric acid calculi were found in only 5.8%. Since uric acid calculus does not contain calcium, it can not be visualized by X-ray, and it is one of the most commonly seen radiolucent calculi.10
All the 395 cases with urinary calculi in our series had a history of ingesting melamine-contaminated milk powder, therefore we may term the disease as melamineassociated urinary calculus (MAUC) or lithiasis. The number of patients with this disease accounts for 1.39% of the total number of children who have a history of ingesting the problematic milk powder products. The age of onset of the disease is 6 months to 2 years in 70.9% of all the patients with melamine-associated urinary calculus. It is generally believed that the echogenicity has no specificity in relation to the contents of urinary stones.12 However, the major contents of the melamine-associated urinary calculi are melamine and uric acid, and these stones basically do not contain calcium, therefore the echo intensity properties of the MAUC are similar to those of uric acid stones. The lump-like MAUC had weaker echogenicity than calcium-containing calculi. Most of the larger stones are oval in shape and the whole echogenicity the stones can be shown, i.e., the central part of the stone and its posterior edge (Figure 2). Weak or no echo image is shown behind the image of the stones. Some of the stones show strong shell-like echogenicity for the edges and the central parts are hypoechoic (Figure 3). Up to 40% of the stones are gravel-like and could be shown more clearly with the use of high frequency transducer. The echogenicity for gravel-like stones have an appearance of aggregated fine gravel without particular shape (Figure 4), and there are no or weak shadows posterior to the stone echogenicity. Calculus of single granules was shown as strong point-like echogenicity 0.1 cm-0.3 cm in diameter, there was no acoustic shadows but there was a sign of comet tail (Figure 5).
It was reported that intrarenal calculus accounted for 66% of patients with urinary stones.5 In our series, the stones in most of the cases were in the kidney and ureter, and 321 cases (81.3%) had simple intrarenal stones and there were singular or multiple stones (Figure 6), and coexistence of lump-like and gravel-like stones was also seen. In 40 cases the stones were found in both ureter and the kidney. Urinary bladder stone was found in one case and urethral stone was found in 3 cases (Figure 7).
The internal diameter is smaller in infants and young children than in preschool children, and the three narrow segments are even narrower. Therefore the lump-like stones are often incarcerated in these segments, and the gravel-like stones can also be aggregated at these sites and lead to hydronephrosis and hydroureterosis at the upper parts of the obstruction. In children complicated with obstruction, the anterior-posterior diameter of the pelvis is generally less than 2 cm but the parenchyma of the kidney is not thinned. In this series of patients, 76 ureters were found to be obstructed by the stones and the obstruction was at the junction of the pelvis and ureter (Figure 8) in 44.7% of the 76 ureters, and at the end of the ureter (Figure 9) in 39.5%, and the remaining at the site of ureter crossing over the iliac vessels (Figure 10). In the cases who had bilateral ureteral incarceration of stones at the same time with empty bladder, the sonography could also show significantly enlarged kidneys with markedly increased cortical echogenicity, which suggested postrenal kidney failure. A few seriously ill patients had ascites, mesenteric edema and perirenal fat sac edema.
Among the children who received reexamination, the gravel-like calculus had a higher removal rate (80.4%), while intrarenal lump-like calculi seemed to be difficult to be expelled, none of the 26 outpatients with such stones could expel the calculi. In 57.1% of the 42 hospitalized patients with hydronephrosis, the hydronephrosis disappeared after taking the following approaches: increased water intake, alkalization of the urine, peritoneal dialysis and deoppilation via retrograde ureteral catheterization. However, complete removal of the calculi was seen in only 31% of these cases. Reexamination also showed edema of the pelvis and ureteral walls in 14 cases, which may suggest that the walls might have been injured transiently when the stones were being expelled.
It is known that uric acid calculus does not contain calcium, and it is the most common radiolucent calculus.10 However, 4 of the 13 cases who had abdominal X-ray plain films showed low density images of the lump-like stones (Figure 11), which may be due to increased resolution of the digitalized photographs and relatively shorter anterior-posterior diameter of the abdomen of infants and young children. At the same time, it is also possible that larger stones might also contain a certain amount of calcium at the edges as suggested by the stronger echogenicity around the stones. Filling defect, which may also suggest diagnosis of urinary calculus, was seen in the 5 cases that underwent IVP. Nevertheless, neither X-ray plain film of the abdomen nor IVP can visualize gravel-like calculi, unless such calculi aggregate and form larger lumps.
Ultrasound examination is simple and easy to perform, it may provide accurate and reliable results, and does not apply any radiation. Therefore, ultrasound examination can be used to determine the size and location of calculus, to see if there is complicated urinary tract obstruction, to observe the size of the kidney and echogenicity of the cortex; high frequency transducer can show fine gravel-like calculi 0.1–0.2 cm in size. Studies indicated that all the calculi which could be found by X-ray could also be shown on ultrasound examination.13 Report from our hospital indicated that the detection rate of urinary calculus by ultrasound among infants and young children could be over 90%.14 In our series of 25 children (age 5–22 months) with acute renal failure, the urinary calculus was confirmed by ultrasound examination on the first visit. In contrast to the results of an overseas report that ultrasound examination could only detect 38% of ureteral calculus despite much higher detection rate for renal calculus in children,15 the rate of consistency of ultrasound diagnosis with observations on expelled stones and the results of cystoscopic ureteral catheterization was 100% among the 51 infants and children with ureteral melamine associated calculus complicated with obstruction. Even in patients without hydroureterosis or hydronephrosis, the calculi could be detected when high frequency transducers were used to carefully examine the full length of the ureter (Figure 12). Single small granular calculus should be differentiated from the strong echogenicity of renal sinus to avoid pseudo-positivity. The hydronephrosis caused by congenital PUJO complicated with calculus (7 cases in this series) can be differentiated from that caused by melamine-associated calculi based on the facts that in the former the calculi locate in the pelvis and calices instead of the obstructed site and dropsy is more severe.
In summary, the ultrasonographic findings of urinary calculi caused by melamine have certain characteristics. In infants and young children, attentive ultrasound examination may prevent missed diagnosis of ureteral calculus. Most of the gravel- like calculi can be expelled within a short period, but lump-like calculi can hardly be expelled. Ultrasound examination is at present the method of choice for diagnosis of melamine-associated urinary calculus although a low proportion of larger calculi can also be detected by X-ray plain abdominal film.
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