Stones In Infants Research Articles

Feasibility, efficacy, and safety of retrograde intrarenal surgery in <1-year age group: A single-center experience

Purpose: Urolithiasis in infants is uncommon. Percutaneous nephrolithotomy, extracorporeal shockwave lithotripsy, and retrograde intrarenal surgery (RIRS) are the management options. RIRS is the least studied of these options in infants. In our series of 23 cases, we aim to assess the feasibility, efficacy, and safety of RIRS in <1-year age group. Materials and Methods: This was a retrospective analysis of a series of 23 infants who underwent RIRS in our hospital from January 2018 to March 2021. Children who were <12 months of age and had the largest stone size of <20 mm were included in the study. Results: Twenty-three patients (male – 15; female – 8) were included in the study. The mean age was 10 ± 2.31 months (range, 4–12 months). The mean stone size was 11.6 ± 2.96 mm (range, 7.5–19 mm). The mean operative time was 29.44 ± 7.45 min (range, 17–42 min). Six patients (22.2%) had mild hematuria (Clavien I), and seven patients (25.9%) had postoperative fever. Stone size had a significant positive correlation with laser time, operative time, and intraoperative intravasation, but no significant association with stone-free rate. At 2-month follow-up, 4 (three patients) out of 27 renal units had residual stones (stone-free rate [SFR] – 85.1%). No patient had long-term complications like urethral or ureteric stricture or stone recurrence during the given follow-up period. Conclusion: RIRS is a feasible and minimally invasive treatment for renal stones in infants with acceptable SFRs.

Effectiveness of extracorporeal shock wave lithotripsy in urolithiasis patients under 2 years of age.

In this study, we present our extracorporeal shock wave lithotripsy (ESWL) outcomes in urolithiasis patients under the age of two. The procedure was performed with patients < 2 years of age sedated, under anesthesia using ketamine and Dormicum (midazolam), in the supine position. Fragmentation was evaluated by fluoroscopy after the procedure. A total of 74 procedures were performed on 65 kidneys. One patient with bilateral stones had two sessions of ESWL on the right side; three sessions of ESWL were performed in one patient with a unilateral stone, and two sessions were performed in seven patients with unilateral stones. All other patients underwent one session of ESWL. As post-procedural complications, hematuria was observed in 14 patients (12 mild and 2 significant), and vomiting occurred in 1 patient. Ureterorenoscopy was performed in 5 patients, and percutaneous nephrolithotomy in 6 patients due to a failed procedure. As a result, ESWL treatment is effective and has advantages such as a short hospitalization time, good reproducibility, cost-effectiveness, and a low rate of complications. Therefore, we recommend ESWL as the first-line treatment for renal and proximal ureteral stones in infants < 2 years of age.

Safety and efficacy of minimally invasive percutaneous nephrolithotomy for infantile nephrolithiasis. Single centre experience from Pakistan.

To assess the efficacy and safety of mini-percutaneous nephrolithotomy (PCNL) for small renal stones 1-2 cm in size in infants less than one year. This descriptive case series was conducted in the department of pediatric urology Institute of Kidney Diseases Peshawar, Pakistan, from March 2019 to March 2022. All the patients underwent mini-PCNL in prone position under GA with 14 Fr access sheath and 10 Fr nephroscope. Stone clearance was assessed by non-contrast CT KUB at 30th postoperative day. Patients with no residual fragments on the non-contrast CT KUB were defined as stone-free. Patients with residual fragments of any size were defined as procedure failure. Safety was determined in terms of intra and postoperative complications. A total of 51 infants were included in the study. The mean age of patients was 9.6 + 1.8 (5-12 month). The mean stone size was 15.8 + 2.7 (10-21) mm in length and 12.3 + 2.2 (8-17) mm in width. PCNL mean operative time was 51.6 ± 7.1 (40-70) minutes. Complete stone clearance at one month was observed in 46 (90.2%) patients. Residual fragments were seen in 5(9.8%) patients with a mean size of 1.6 + 0.4 (0.9-2.0) mm. None of the patients required any additional procedure for clearance of stones. In 7 (13.7%) patients, some post-operative complications were observe, all were grade I complications, including fever in 5(9.8%) and transient hematuria in 2(3.9%) patients. Mini-PCNL is a safe and effective treatment for renal stones in infants measuring 1-2 cm with high SFR and an acceptable complication rate.

A single centre experience of percutaneous nephrolithotomy in infants and its long-term outcomes

Renal stones in infants requiring Percutaneous nephrolithotomy (PCNL) is rare. There is insufficient literature on the long-term implications of PCNL in growing kidneys of these children. To review our experience of PCNL amongst infants i.e., < 1year of age and to analyse the safety and efficacy of this procedure and assess its long-term renal outcomes. This was a retrospective analysis of a prospectively maintained data base between 2005 and 2020. All infants with unilateral renal stones >12mm underwent PCNL. Changes in the serum creatinine, estimated glomerular filtration rate and renal size prior to the PCNL and at the last follow up were monitored. The demographics, clinical profile, operative details, post-operative complications and follow up data were collated and analyzed. 86 children were diagnosed with renal stones of whom, 24 infants met our inclusion criteria and were included in the review. The average age was 9.75 months with fever being the commonest presenting symptom. Five infants were diagnosed with metabolic abnormalities, hypercalciuria being the commonest. Majority of the infants (22) had single stones and the lower calyx was the commonest site (50%). The mean stone burden was 19.5mm. The stone free rate was 91% during the primary PCNL, which increased to 100% after re-do PCNL. The overall complication rate was 16% which was graded by the modified Clavien Dindo scale for surgical complications. The median follow up period was 144 months and average age at the last follow up was 10.5 years. At the last follow up, a mean serum creatinine of 0.4mg/dl, mean estimated glomerular filtration rate of 98ml/min/1.72m2 and a mean renal size of 8.3cm was recorded, which was comparable to that of a normal child, thus signifying no deterioration of renal functions and renal growth. Three children showed the presence of cortical scars on an isotope scan at follow up. However, all the 24 operated renal units demonstrated preserved renal functions. PCNL performed during infancy does not hinder the growth potential of the kidney. Each of the 24 children achieved the target renal size and estimated glomerular filtration rate corresponding to the duration and body size at the end of the follow-up. Thus, PCNL in infants <1 year of age is safe and effective with no adverse effects at long term follow-up.

Micro-Ureteroscopy as a Treatment of Renal Pelvis Lithiasis in Young Children.

Aim: Miniaturization of endoscopic instruments has allowed to improve the efficacy of kidney stone treatment in young children. Aim of the study is to evaluate the usefulness of microureteroscopy with 4.85F sheath in the treatment of renal stones in children.M&M: We present 4 cases of microureteroscopy in 3 younger than 3 years patients with renal pelvic stones. Lithiasis was unilateral in 2 female patients and bilateral in 1 male patient. Microureteroscopy was performed using a MicroPerc set 4.85F sheath, without placing a safety guide or dilating the meatus in 3 procedures. The lithotripter system used was Ho:YAG Laser with 200-μm fiber in all cases.Results: Mean operating time was 100 ± 16 min. There were no intraoperative complications. In all procedures, complete pulverization of the lithiasis was achieved, except in the coraliform lithiasis in which 5 mm residual lithiasis remained in the lower calyx. All patients were discharged 24 h after the intervention.Conclusion: Microureteroscopy can be considered a new alternative for treatment of selected cases of renal pelvic stones in infants and children.

The Relationship between the Type of Milk Consumed and the Risk of Kidney Stones in Children Under Two Years of Age

Background: Kidney stones are one of several serious health problems in childhood that cause nutritional and growth disorders, and may finally lead to chronic kidney failure in this group. Methods: In this analytical study conducted through a case-control design, 30 children under the age of two with kidney stones, and 125 children of the same age and sex without stones were studied. Patient information including personal profile and the results of some necessary tests were extracted from patient records and listed in a checklist. The data was analyzed using SPSS (Version 17.0). Statistical significance was considered when p-value was &lt;0.05. Results: In terms of duration of breastfeeding, a significant difference was observed between the patients with stones and patients without stones; the duration of breastfeeding was longer in the control group (p=0.003). In addition, the duration of feeding with formula milk and cow milk was longer in the case group (p=0.038 and p=0.012, respectively). Conclusion: Breastfeeding can serve as a nutritional factor that plays a preventive and protective role against the formation of kidney stones in infants.

440 - Comparing micro-percutaneous nephrolithotomy and flexible ureteroscopic lithotripsy in treating 1-2 cm solitary renal stones in infants

440 - Comparing micro-percutaneous nephrolithotomy and flexible ureteroscopic lithotripsy in treating 1-2 cm solitary renal stones in infants

Effect of Delayed versus Early Cord Clamping on Neonatal Outcomes and Iron Status at 4 Months

Background: The optimal timing of umbilical cord clamping has been debated in the scientific literature for over a century. Early clamping of the umbilical cord is widely practised as part of the management of labour. Early clamping of the cord was one of the first routine medical interventions in labour. Its place in modern births was guaranteed by its incorporation into the triad of interventions that make up the active management of the third stage of labour. Babies who have immediate cord clamping have also been shown to be more likely to be anaemic, have decreased fine motor skills, and have decreased social skills during their first few years of age. Delayed umbilical cord clamping appears to have clear benefit for term infants. Delayed umbilical cord clamping increases hemoglobin levels at birth and improves iron stores in the first few months of life, which improve the developmental outcomes. There is growing evidence that delayed cord clamping is beneficial and can improve the infant’s iron status for up to 6 months after birth. For the first few minutes after birth, there is still circulation from the placenta to the infant. Waiting to clamp the umbilical cord for 2 - 3 min, or until cord pulsations cease, allows a physiological transfer of placental blood to the infant (placental transfusion), the majority of which occurs within 3 min. This placental transfusion provides sufficient iron reserves for the first 6 - 8 months of life, preventing or delaying the development of iron deficiency until other interventions. WHO’s findings suggest that late cord clamping (one to three minutes after delivery or longer) is recommended for all births. Aim of the study: 1) To evaluate the benefit of delayed cord clamping on the infant’s health status. 2) To assess hemoglobin, iron and ferritin at birth and at 4 months of age in infants who underwent early cord clamping (at 30 seconds) as compared with infants who underwent delayed cord clamping (at 60 seconds). Methods: A randomized controlled trial was conducted in Benghazi Medical Center and Elmgharif Hospital at Ejdabia. Study population was 256 women. The participants were randomized to delayed cord clamping or early cord clamping study groups. The data were checked manually for completeness, coded and analyzed by using Statistical Package for Social Sciences (SPSS). The incidence, relative risk, risk reduction, frequency percentage, mean, and standard deviation were used. Also t-test and chi sequare test (to test difference between means and proportions respectively) were used to compare between early and late cord clamping groups. Results: Two hundred forty seven participants completed the study (the attrition rate was 3.5%); 121 (49%) were control group (early cord clamping) and 126 (51%) were study group (delayed cord clamping) group. At birth no significant difference between two groups regarding the level of hemoglobin, iron and ferritin. At 4th month of age delayed cord clamping was associated with improved hemoglobin, iron and ferritin and that the incidence of anemia among infants who exposed to delayed cord clamping was 0.07, while the incidence of anemia among the infants who exposed to early cord clamping was 0.5. Conclusion: There was strong association between delayed umbilical cord clamping and improvement of iron indices and developmental mile stones in infants at 4th month of age.

560 - Outcomes of flexible ureteroscopic lithotripsy for treatment of kidney stones in infants

560 - Outcomes of flexible ureteroscopic lithotripsy for treatment of kidney stones in infants

Composition of urinary calculi in infants: a report from an endemic country.

Pediatric urolithiasis remains endemic in low-resource countries where infants constitute 17-40% of all children with urolithiasis. This study reports socio-economic factors, medical history and chemical composition of urinary stones in 976 infants of up to 2years of age. Between 1992 and 2016, 976 infants presented to our institute with 1038 stones. Chemical composition of stones was analyzed by Fourier transformation infrared spectroscopy (FTIR). The mean age of infants was 19.5±5.74months with a M:F ratio of 5.5:1. Half (50%) of the infants were rural dwellers, 90% belonged to low socio-economic class and 70% were malnourished. A history of chronic diarrhoea was reported in 13% and urinary tract infections in 5%. The anatomic location was bladder in 487 (46.9%), kidney in 246 (23.6%), ureter in 142 (13.6%), urethra in 2 (0.2%) and 161 (15.5%) were passed spontaneously. Overall frequency of compounds in stones showed ammonium acid urate (AAU) in 772 (74.37%), calcium oxalate (CaOx) in 410 (39.5%). Uric acid (UA) in 119 (11.46%), calcium phosphate apatite (CaP) in 96 (9.25%), magnesium ammonium phosphate (Struvite) in 45 (4.34%), cystine in 12 (1.16%) and xanthine in 40 (3.85%). Frequency of compounds was similar in genders. Infants of age 0-6months had higher frequency of UA (28%), CaOx (50%) and low AAU (61%) as compared to 11, 39 and 75%, respectively, in 7-24months (p<0.049) (p<0.002) (p<0.001). Nucleus of stones showed pure AAU in 63 and 43% on the surface due to addition of CaOx, struvite and CaP. Our study has shown that AAU is a major component of stones in infants where the main risk factors are poverty, malnutrition, diarrheal diseases and dehydration.

Outcomes of miniaturized percutaneous nephrolitotomy in infants: single centre experience

ABSTRACTObjectives:The present study was aim to evaluate the safety and efficacy of Mini-PNL to treat kidney stones in patients aged <3 years. This is the one of the largest series in the literature in this age group of patients.Material and methods:From May 2012 to April 2016, the medical records of 74 infant patients who underwent mini-PNL for renal stones were reviewed retrospectively. All infants were evaluated with the plain abdominal radiograph, urinary ultrasound, non-contrast computerized tomography and/or intravenous urogram. Pre-operative, intraoperative and post-operative data were analyzed.Results:A total of 74 infant (42 male, 32 female) with a mean age 21.5±8.2 (10-36) months were included in this study. The mean size of the stones was 22.0±5.9 (14-45) mm. A 17 Fr rigid pediatric nephroscope with a pneumatic intracorporeal lithotripsy were used through 20-22 Fr access sheath. The stone-free rate was 84.7% at 1 month after the operation. Mean operative time was 74.0 (40-140) min. Mean fluoroscopy screening time was as 4.3(3.1-8.6) min. Average hospitalization time was 3.8 (2-9) day. Auxiliary procedures were performed to 11(15.3%) patients (7 extracorporeal shock wave lithotripsy, 3 re- percutaneous nephrolitotomy, 1 retrograde intrarenal surgery). No major complication classified as Clavien IV-V observed in study group.Conclusions:Mini-PNL with pneumatic intracorporeal lithotripsy can be performed safely and effectively to manage kidney stones in infants with high stone free rate and low complications.

Postrenal Failure due to Urinary Stones Associated with Acute Viral Gastroenteritis: Three Case Reports.

Acute gastroenteritis with viral infection in infants causes severe diarrhea and often results in acute renal failure due to severe dehydration. However, a viral infection, particularly rotavirus, rarely induces postrenal failure due to bilateral stones in infants. Herein, we report three cases of postrenal failure in infants due to bilateral ureteral stones induced by acute gastroenteritis with rotavirus. Following immediately nephrostomy, chemical dissolution therapy succeeded to treat postrenal failure. Immediate nephrostomy for the release of upper urinary tract obstruction combined with urinary alkalization as a chemical dissolution therapy should be considered in such cases.

Outcome of Mini-percutaneous Nephrolithotomy for Renal Stones in Infants and Preschool Children: A Prospective Study

To assess the safety and efficacy of Miniperc for renal stones in preschool-age patients. To the best of our knowledge, this may be the first prospective study on this subject. Reports on Miniperc are still few and mostly retrospective using a sheath size of ≥ 18Fr, which is still relatively large for young children. From January 2012 to May 2013, Miniperc was performed for 26 children (≤ 6 years old) with renal calculi <5 cm through 14Fr sheath using a 9.5Fr semirigid ureteroscope with Holmium:yttrium-aluminum-garnet laser lithotripsy. Effects of different factors on operative time, complications, and stone-free rate (SFR) were compared using chi-square, Fischer exact, or Mann-Whitney tests as appropriate using SPSS v15.0. Primary SFR, SFR after retreatment, and SFR after auxiliary extracorporeal shock wave lithotripsy (ESWL) were 77%, 85%, and 92%, respectively. Retreatment rate was 8%. Auxiliary ESWL was done in 11%. Complications were bleeding (8%), hematuria and blood transfusion (4%), renal pelvis perforation (4%), leakage (8%), and fever (15%). Operative time was significantly prolonged in multiple (>2) stones (P = .006), calyceal stones (P = .002), or stone size ≥ 30 mm (P = .022). SFR was significantly lower in children with >2 stones (P = .028) and increased stone size ≥ 30 mm (P = .014). Miniperc is a safe and effective minimally invasive procedure for pediatric renal stones using 14Fr access sheath. SFR was significantly lower in children with >2 stones or increased stone size ≥ 30 mm. This was overcome by retreatment and auxiliary ESWL.

Management of stone disease in infants.

Evaluating and treating renal stone disease in infants are technically challenging. In this study, we evaluated the surgical treatment of renal stones in children under 1 year of age. We retrospectively reviewed the records of patients under 1 year old who were treated with ESWL, endourological or open surgical procedures for renal stone disease between January, 2009 and December, 2012. The patients' age, gender, stone size, stone location and number, complications, stone-free status, and postoperative complications were recorded. 19 of 121 infants with a mean age of 10.2 ± 3.07 months were treated with surgical procedures. Six (75%) of eight cystinuria patients required a surgical intervention. Retrograde endoscopic management was performed in thirteen patients (63.4%) as an initial surgical approach. There were three major (15.7%) complications. The rate of open surgical procedures was 31.6% (6 of 19 infants). The cutoff value of stone size for open surgery was 10 mm. There was a significant relationship between the conversion to open procedures and stone size, stone location, and symptom presentation especially the presence of obstruction (p < 0.05). After repeated treatments, the stone clearance rate of RIRS reached 84.6%. Retrograde intrarenal surgery is an effective and safe treatment method for renal stones in infants and can be used as a first-line therapy in most patients under 1 year old. This is especially important if an associated ureteral stone or lower pole stone that requires treatment is present and for patients with cystinuria, which does not respond favorably to ESWL.

Minimally invasive percutaneous nephrolithotomy: an effective treatment for kidney stones in infants under 1year of age. A single-center experience.

We aimed to present the outcomes of PNL surgery performed in infantile patients with small renal stones who were younger than 1 year of age. A single-center prospective trial was initiated and during the period between Jan 2013 and Jan 2015, PNL was applied to 20 renal units of 16 infants (6 girls and 10 boys), including 4 patients with bilateral kidney stones. PNL was performed in patients with renal stones larger than 2 cm, as well as stones resistant to SWL or renal stones that were undetectable during SWL. The mean age of the patients was 9.55 (5-12) months. Of the 20 renal units, 1 had complete staghorn stones, 3 had partial staghorn stones, 13 had renal pelvic stones, and 3 had lower pole stones. The mean stone size was 18.5 mm (range 12-36 mm). Mean operative time for PNL was 88 (25-135 min). Mean fluoroscopy time was estimated as 3.4 min. Mean hemoglobin loss was 0.72 g/L (0.2-3). The mean hospital stay was 4.1 days (2-8 days). On postoperative day 1, a complete stone-free state was achieved in 70% of renal units (14 of 20). At the end of the first postoperative week, the remaining two patients had insignificant residual fragments of 3 mm and were followed conservatively without any specific intervention. Thus, the total SFR was 80% (16 of 20) at discharge. In infants aged less than 1 year, minimal access tract dilation during PNL, the use of smaller caliber pediatric instruments, and the realization of this procedure by surgeons with adequate experience in adults carry utmost importance. In addition, special care should be taken to avoid hypothermia and radiation exposure during PNL.

Urgent percutaneous nephrolithotomy for acute kidney injury secondary to bilateral stones: is it safe and effective in infants?

To evaluate the efficacy and safety of urgent percutaneous nephrolithotomy (PNL) for acute kidney injury secondary to bilateral upper urinary stones in infants. A total of seven infants (five boys and two girls), aged from 5 to 12 months, underwent urgent PNL for calculus anuria from September 2011 to March 2013. The initial blood test revealed acute renal injury in all infants. After correcting electrolyte imbalance and acid-base status through medical treatment in a short time without dialysis, all urgent PNL procedures were performed with 16F percutaneous access and small-diameter nephroscopes designed specifically for pediatric surgery on the side with the more dilated pelvis. Stones were fragmented with a pneumatic lithotripter. Stones were completely removed from the operative side kidneys. The operating time ranged from 35 to 57 min. Blood BUN, serum creatinine, and electrolyte levels returned to normal on postoperative 36 h. There were no major perioperative or postoperative complications and deaths. When performed by experienced endourologists, urgent PNL is a safe and effective procedure in infants for acute kidney injury secondary to bilateral upper urinary stones.

Extracorporeal shockwave lithotripsy under sedoanalgesia for treatment of kidney stones in infants: a single-center experience with 102 cases.

We present the efficacy of shockwave lithotripsy (SWL) therapy administered with sedoanalgesia in infants with kidney stones. We enrolled 102 patients aged 5-24 months who had kidney stones and received SWL therapy under sedoanalgesia using a Siemens Lithostar Modularis device. Patient and stone characteristics, therapy parameters, pain score, complications, discharge time, and follow-ups were registered and evaluated. Pain score was assessed using a Neonatal Infant Pain Score (NIPS). Postanesthetic discharge scoring system (PADSS) was used for the assessments of postprocedural discharge procedure. Mean age of the patients was 17.2 ± 6.3 months (5-24 months). Mean stone size was 7.9 ± 3.3 mm (5-23 mm). The most common concomitant metabolic disorders were hypercalciuria and hypocitraturia. The stone-free rates of the infants were 70.6, 87.3, and 99.1 % after the first, second, and third sessions of SWL therapy, respectively. The mean NIPS scores procedure during, and at 1 h after SWL procedure were determined as 0.24 ± 0.45 and 0.34 ± 0.47, respectively. There was no statistically significant difference between two pain score values (P = 0.114). The mean discharge time of patients after the SWL procedure were 108.6 ± 27.9 min. Forty-two patients (41.1 %) were followed up. The follow-up period varied between 8 and 48 months (mean 19.5 months); none of those patients showed evidence of diabetes mellitus, hypertension, or renal function impairment. SWL therapy under sedoanalgesia is a safe and efficient treatment modality that can be administered with low complication rates and high stone-free rates in the treatment of renal stones in infants.

Efficacy of shock wave lithotripsy in management of kidney stones in infants

Introduction and objectivesDespite being uncommon, infantile kidney stone remains a major health problem due to its higher recurrence rate and morbidity. The parents usually notice that their infants have recurrent fever and failure to thrive of unknown origin. Those patients comprise a big challenge for the urologist in management. Therefore, this study aimed to evaluate the outcome of shockwave lithotripsy (SWL) in management of renal stones in infants. Subjects and methodsA retrospective analysis of prospectively collected data performed between January 2009 and December 2012 for infants underwent SWL for single radio-opaque renal stones ≤15mm at a single stone center. SWL was performed with Dorneir S lithotripter with a maximum of 1500 shocks per session. A single session was indicated for each infant, but a second session was performed when satisfactory disintegration was not achieved. Follow-up based on urinalysis, urine culture and sensitivity, plain X-ray kidney ureter bladder (KUB) and abdominal ultrasonography (US) was carried out 2 weeks post SWL and monthly for 3 successive months. Multislice Computed tomography (MSCT) was performed 3-months post-SWL to confirm the stone-free status. ResultsA total of 87 infants, less than 24 months of age were enrolled in this research. SWL success was defined as absence of any residual fragments on MSCT 3-months after the last session. Stone free rate was 93.1% after the first SWL session and reached 100% after the second session. Rate of retreatment with second session of SWL was 6.9%. Urinary tract infection (UTI) was detected in 10.3%, transient renal obstruction with low grade fever in 4.6% of infants and no major complication had been recorded. ConclusionThe new generation of SWL technology with a precise focal area seems to be safe and effective in management of kidney calculi in infants.

S247 ESWL in the management of renal stones in infants

S247 ESWL in the management of renal stones in infants

Repeat oral dose toxicity studies of melamine in rats and monkeys

Melamine is an important and widely used organic industrial chemical. Recently, clinical findings of renal failure and kidney stones in infants have been associated with ingestion of melamine-contaminated infant formula. To understand the toxicity and clinical outcome of melamine exposure, repeated oral dose studies in rats and monkeys were performed to characterize the subchronic toxicity of melamine. Assessment of toxicity was based on mortality, clinical signs, body weights, ophthalmic findings, clinical pathology, gross pathology, organ weights, and microscopic observations. The first rat study was intended to be a 14-day oral study followed by an 8-day recovery period. The dose levels were 140, 700, and 1,400mg/kg/day (lowered to 1,000mg/kg/day subsequently due to mortality). Oral administration of melamine at 700mg/kg/day for 14 consecutive days in rats produced compound-related clinical signs (red urine), decreased body weights, and changes in clinical pathology (increased serum urea nitrogen and creatinine) and anatomical pathology (renal tubular cell debris, crystal deposition, and hyperactive regeneration of renal tubular epithelium). The kidney was identified as the target organ. Oral administration at 1,400mg/kg/day (subsequently lowered to 1,000mg/kg/day) resulted in animal death and moribundity. There were no treatment-related findings in the 140mg/kg/day group. There were no compound-related findings in the high-dose recovery animals. The second rat study was a 5-day oral toxicity study with genomic biomarkers assayed in the kidney tissues. At the top dose of 1,050mg/kg/day, similar clinical and anatomical pathology findings as described above were observed. The genes measured, Kim-1, Clu, Spp1, A2m, Lcn2, Tcfrsf12a, Gpnmb, and CD44, were significantly up-regulated (fivefold to 550-fold), while Tff3 was significantly down-regulated (fivefold). These results indicated that genomic markers could sensitively diagnose melamine-induced kidney injury. A 3-month oral study with 4-week recovery in monkeys was also conducted. In this monkey study, the animals were treated with melamine at doses of 60, 200, or 700mg/kg/day. The administration of 700mg/kg/day melamine by nasal-gastric gavage to monkeys resulted in test article-related clinical signs including turbid and whitish urine, urine crystals, red blood cell changes, increased serum alanine aminotransferase and kidney and/or liver weights, and microscopic findings including nephrotoxicity, pericarditis, and increased hematopoiesis. Nephrotoxicity was also noted at 200mg/kg/day. It was concluded that the kidney is the primary target organ and the NOAEL was estimated to be 140mg/kg/day in rats following a 14-day oral administration and 60mg/kg/day in the monkey study.