In 2008, infants in some areas of China suffered from stones of the urinary system which were caused by melamine-contaminated milk formula. Most of the infants were asymptomatic, but a few suffered from acute renal failure induced by urinary obstruction by the stones. Active treatments were given by pediatric nephrologists or pediatric urologists for the recovery of the infants from acute obstructive renal failure.
This study was undertaken to investigate the significance of blood purification in treatment of infants with acute obstructive oligo-anuric renal failure due to urinary multiple obstruction caused by melamine-contaminated milk formula.
Thirteen infants with urinary stones and acute renal failure who were fed with melamine-contaminated Sanlu brand infant formula were admitted to the nephrology wards of Beijing Children's Hospital Affiliated to Capital Medical University between March and October of 2008. All patients (10 boys and 3 girls) with oliguria or anuria and hyperkalemia were treated with dialysis. They were investigated for the epidemiological characteristics, image features and indications of dialysis. The ratio of male to female was 3.3:1.0. Their age ranged from 6 months to 45 months, and the average age was (17.1±12.8) months. The period for consumption of melamine-contaminated milk formula ranged from 0.5 months to 30 months, with an average of (11.7±8.4) months.
The dialysis group was compared with the two control groups to assess the recovery time of renal function. Another 13 patients were treated with cystoscope retrograde catheterization into the ureter to drain and 9 were treated by infusion and urine alkalinization to dispel stones.
Diagnosis of acute renal failure induced by melamine stones
The following criteria were used for the diagnosis: infants fed with melamine-contaminated milk formula; stones resulting in obstruction of the urinary tract; occurrence of oliguria or anuria and rapidly increased levels of serum creatinine and urea nitrogen; ultrasound features including bilateral renal enlargement, hydronephrosis and calicectasis, and blunted renal calyces; ureteral stones seen mostly at the pelviureteral junction where the ureter passes across the iliac artery and the ureter-bladder junction; dilation of the ureter above the obstruction point and stones that could be found at the lowest point of the expanded section.
Indications of dialysis
Without surgical intervention, infants who had one of the following indications were treated with dialysis: serum urea nitrogen >28.5 mmol/L; serum potassium >6.5 mmol/L; severe metabolic acidosis, severe uremia with risk of encephalopathy and/or pericarditis, severe pulmonary edema, oliguria for two days, anuria for one day. After surgical intervention, infants who still suffered from oliguria or anuria, electrolyte imbalance, hyperkalemia, acidosis, heart failure, pulmonary edema, etc were also treated with dialysis. Ischemic renal tubular necrosis (substantial renal failure) may occur due to the extended duration of oliguria or anuria. Dialysis should be done immediately for patients with such problem.
All data were expressed as mean±standard deviation (SD) and analyzed by SPSS 13.0. One-way analysis of variance (ANOVA) was performed to compare the recovery time of renal function in the three groups. P values less than 0.05 were considered statistically significant.
Patients and treatment
In the 13 infants with oliguria or anuria, hyperkalemia and fluid overload who were treated with dialysis, their blood urea nitrogen (BUN) was (30.9±7.9) mmol/L and creatinine (Cr) was (572±173) μmol/L. Of this series, 8 infants were subjected to peritoneal dialysis, 5 to hemodialysis. As a result, in 10 infants the renal function recovered to urinate 24–72 hours later. Three of the 13 infants (peritoneal dialysis in 2 and hemodialysis in 1) were in stable conditions but had persistent urethral obstruction after the dialysis. They were further treated by cystoscopic retrograde intubation into the ureter for drainage, and the renal function was recovered resumed soon after operation. The average time of peritoneal dialysis (PD) and hemodialysis (HD) was (2.1±0.8) days and (1.2±0.4) days respectively. The average time of all dialyses was (1.77±0.83) days (Table). The recovery time of renal function in patients with renal failure after dialysis was (3.08±1.20) days, which was compared with that of the two control groups undergoing cystoscopic retrograde catheterization into the ureter for drainage and medication. There was no significant difference in the recovery time of renal function among the three groups (P >0.05).
Clinical follow-up outcome
The general conditions of the 13 infants were good at discharge from the hospital, with normal urine tests and renal function. Of the 13 infants, 4 still had small kidney stones at discharge, 2 had kidney stones expelled within 1 month during the follow-up and other 2 had kidney stones expelled within 2 months after discharge.
Melamine (C3N6H6, molecular weight 126.12), also known as cyanuramide, is a synthetic product that forms reins with formaldehyde, and is used in a variety of products in which resin-based coatings are found. In experimental murine models, chronic melamine exposure resulted in the production of kidney stones or bladder stones.1 Chemical analysis of the calculi in experimental animals demonstrated equimolar amounts of melamine and uric acid, accounting for 61%—81% of the stone weight.2 Since melamine stone is loose and sand-like, it is likely to be expelled after a considerable amount of fluid is infused. After hyperkalemia and other electrolyte imbalances are corrected by medication and fluid is infused in the early period, some infants with oliguria have more urine for stone discharge while rapid recovery of renal function occured.3 However, the treatment of infants with severe oliguria or anuria should emphasize two aspects. First, urinary obstruction can be relieved surgically and urine drained; second, blood purification therapy is feasible for renal failure associated with severe hyperkalemia, electrolyte imbalances, and uremia.
Blood purification modes include HD, PD, continuous renal replacement therapy (CRRT), blood perfusion, double filtration plasmapheresis (DFPP), hemodialysis etc. In the treatment of renal failure, HD and PD remove toxins by means of diffusion and ultrafiltrtion, and when applicable to small molecular weight solute, medium molecules, the free fraction will be dialysed. Since melamine has a low toxicity, infants with concretion in the urinary system do not require blood purification. If the infant suffers from acute renal failure, melamine could be removed through dialysis as melamine is a kind of small molecule substance. Therefore, if surgical intervention is impossible, blood purification is useful to help the infant pass the critical stage of acute renal failure. In this series of 13 infants treated with dialysis, renal function of 10 cases returned to normal urination 24–72 hours after dialysis; this was correlated with the correction of water imbalance, acidosis and urine alkalinization.
Blood purification modes
Choice of treatment should be made according to infant conditions, medical equipment, and experience of professionals. Most infants suffering from urinary stones caused by powder milk contaminated with melamine were less than two years old and lighter than 20 kg. Their hemodynamics was instable, so PD was the preferential treatment. PD does not require complex equipment. It can also be performed in locations where the expertise for pediatric HD and CRRT is unavailable. If infants have experienced abdominal operation such as lithotomy, doctors could make a selection between hemodialysis and CRRT according to the conditions of the infants.4–6
Different from the adult, the ratio of the surface area of the infant's peritoneum to weight is increasing. It makes the solute reach balance more rapidly and more effectively, and PD has a better effect on infants than on adults. There are two major modes, continuous ambulatory PD (CAPD) and automated PD (APD).7–12
Implanting techniques of catheter guarantee the smooth function of PD. CAPD could be done for very sick patients immediately after intubation, and the initial exchange quantity is about 10–15 ml/kg. PD fluid is retained in the abdominal cavity of the patient for 1–2 hours and it is performed 7–8 times daily. The dose for dialysis could be increased gradually to the level of maintenance PD, which is done 4–6 times daily, and the exchange quantity is 40–50 ml/kg each time. The doctors can select dialysis fluid without potassium if the concentration of blood potassium increases. After 4–6 times of PD, the concentration of blood potassium will decrease. At this time, doctors could use the dialysis fluid with low potassium. Four mmol/l dialysis fluid with potassium is selected in the case of hypokalemia. Generally, 1.5% glucose could be used to maintain the balance between intake and output volume. To control fluid status, the concentration of glucose can be increased to 2.5% or 4.5% in case of edema, hypertension, and hypervolemia. The risk of infection, especially peritonitis, is a major concern associated with PD, its development in the acute setting is relatively infrequent.7–12
Notes for hemodialysis
The clearance of blood urea nitrogen is related to the curve of blood flow. It is important to estimate the clearance of blood urea nitrogen when blood flow is given. Small dialysis machine is adopted for infants. When the blood flow rate is rather low, the clearance curve could be fully flat. As for the infants whose blood flow rate is slower than 100 ml/min, the blood flow rate is an important factor that could be used to determine the ultrafiltration rate. The hemodialysis of infants must adopt the dedicated blood pipeline because the pre-charged volume of the blood pipeline used for the adult is in the range of 75–150 ml, while that for children is in the range of 25–71 ml. If a larger circulation is required, the banked blood is required as pre-charged volume. However, this mode may increase the chance of being infected with blood disseminated diseases. One of our infants on hemodialysis, weighing 13.3 kg, was given pre-charged volume of albumen instead of blood to prevent blood disseminated diseases. As for infants and young children less than two years of age, if there is no suitable hemodialysis machine, hemodialysis is not recommended; however, PD would be an ideal choice.4–7
The duration of hemodialysis for infants can be 2–4 hours each time. The blood flow is maintained at 3–5 ml·min-1·kg-1 and the hemodialysis fluid flow rate 250 ml/min. The ultrafiltration volume should not be more than 3%-5%. The initial dose of heparin is 25–50 U/kg and the maintenance dose is 10–25 U·kg-1·h-1. It is stopped 30 minutes before the end of hemodialysis. In case of hemorrhagic tendency, low-molecular weight heparin should be adopted, whereas in case of severe hemorrhage, the non-heparin dialysis is adopted.4–7
Continuous renal replacement therapy
CRRT strategies are particularly useful in hemodynamically compromised infants with acute renal failure. Infants with hypotension, cardiac dysfunction, sepsis hemodynamic instability are usually preferentially treated with CRRT. Advantages of this technique include continuous nature and patient tolerance, despite frequent necessity for substantial fluid removal. Although there is the potential for complications related to anticoagulation preventing filter clotting, the current continuous arteriovenous/venovenous hemofiltration (CAVH/CVVH) equipment should meet the needs of small children, including the production of small vascular catheters. CRRT has contributed to the more universal use of this technique in an age-independent manner. Increasing clinical experience suggests that critically ill infants with renal failure are more easily managed by CRRT than intermittent dialysis.13–21
In summary, acute renal failure induced by melamine-contaminated milk formula in infants requires immediate diagnosis. Through the corrective therapy of blood purification or/and surgical intervention, renal function of the infant could be restored or relieved. For blood purification, PD is the best choice of treatment.
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