Urinary crystal formation and urothelial effects of pyroxasulfone administered to male rats.

Pyroxasulfone induced a low incidence of urinary bladder tumors in male rats in a 2-year bioassay at 1000 and 2000 ppm, with occasional urinary calculi. No increased incidence of tumors of any tissue occurred in female rats or in mice of either gender. We performed three short-term studies to evaluate early development of pyroxasulfone-induced urinary crystals and urothelial cytotoxicity with consequent regenerative proliferation. First, male rats were treated with dietary 50, 1000 or 2000 ppm pyroxasulfone for 1, 3 or 7 days. The urothelium was examined by light and scanning electron microscopy (LM, SEM) and bromodeoxyuridine labeling index (BrdU LI). In two other studies, male rats were treated with dietary 20 000 ppm pyroxasulfone for 1 week. Urine collected at various times of day was examined by SEM and energy dispersive spectroscopy (EDS) or by LM, SEM, EDS, and infrared spectroscopy (IFS). Urinary crystals were present at various time points. EDS and IFS showed some contained calcium; others contained organic matter. Cytotoxicity was detected by SEM as cellular swelling, craters, and necrosis and by LM as cellular hypertrophy. Increased cell proliferation was detected by LM (hyperplasia), SEM (piling up of round cells), and by increased BrdU LI. There was no evidence of increased apoptosis. These findings support a mode of action for pyroxasulfone-associated bladder tumors in male rats involving formation of urinary crystals leading to urothelial cytotoxicity and regenerative proliferation. This is a high dose phenomenon, therefore, pyroxasulfone is not likely to be carcinogenic to humans at exposure levels that do not cause crystals with subsequent calculi formation in the urinary tract.

[TRANSURETHRAL URETEROLITHOTRIPSY FOR UPPER URINARY TRACT STONE IN SMALL CHILDREN WEIGHNING AROUND 10KG].

Management strategy for upper urinary tract calculi in small children is still a matter controversial. We report successful management of ureteral stone with transurethral ureterolithotripsy (TUL) in 2 boys weighing around 10 kg. Case 1: A 2-year-old boy (78 cm in height, 9.6 kg in weight), who received hydrocortisone and fludrocortisone for the treatment of 21-hydroxylase deficiency, was referred to our hospital with a right 9-mm lower ureteral stone. For TUL, a 7.5 Fr rigid cystoscope was introduced into the ureter directly after dilation of the ureteral orifice. By using Holmium:YAG laser for lithotripsy, complete stone evacuation was achieved. Stone analysis showed the composition of calcium phosphate and calcium oxalate. Case 2: A 1-year-old boy (80 cm in height, 10.5 kg in weight) with neurofibromatosis type 1 was referred to our hospital with a left 7.5-mm ureteral stone at the ureteropelvic junction. TUL was performed using a 4.5 F rigid ureteroscope and Holmium:YAG laser. No residual stone was identified. Stone analysis showed the composition of calcium oxalate. TUL is a safe and feasible option for small children, even in boys weighing approximately 10 kg.

Health risks and benefits from calcium and vitamin D supplementation: Women's Health Initiative clinical trial and cohort study.

SUMMARY: The Women's Health Initiative (WHI) double-blind, placebo-controlled clinical trial randomly assigned 36,282 postmenopausal women in the U.S. to 1,000 mg elemental calcium carbonate plus 400 IU of vitamin D(3) daily or placebo, with average intervention period of 7.0 years. The trial was designed to test whether calcium plus vitamin D supplementation in a population in which the use of these supplements was widespread would reduce hip fracture, and secondarily, total fracture and colorectal cancer. INTRODUCTION: This study further examines the health benefits and risks of calcium and vitamin D supplementation using WHI data, with emphasis on fractures, cardiovascular disease, cancer, and total mortality. METHODS: WHI calcium and vitamin D randomized clinical trial (CT) data through the end of the intervention period were further analyzed with emphasis on treatment effects in relation to duration of supplementation, and these data were contrasted and combined with corresponding data from the WHI prospective observational study (OS). RESULTS: Among women not taking personal calcium or vitamin D supplements at baseline, the hazard ratio [HR] for hip fracture occurrence in the CT following 5 or more years of calcium and vitamin D supplementation versus placebo was 0.62 (95 % confidence interval (CI), 0.38-1.00). In combined analyses of CT and OS data, the corresponding HR was 0.65 (95 % CI, 0.44-0.98). Supplementation effects were not apparent on the risks of myocardial infarction, coronary heart disease, total heart disease, stroke, overall cardiovascular disease, colorectal cancer, or total mortality, while evidence for a reduction in breast cancer risk and total invasive cancer risk among calcium plus vitamin D users was only suggestive. CONCLUSION: Though based primarily on a subset analysis, long-term use of calcium and vitamin D appears to confer a reduction that may be substantial in the risk of hip fracture among postmenopausal women. Other health benefits and risks of supplementation at doses considered, including an elevation in urinary tract stone formation, appear to be modest and approximately balanced.

Melamine-induced urinary calculi in infants--sonographic manifestations and outcomes 1 year after exposure.

BACKGROUND: In 2008, the melamine-tainted-milk incident started with reports of increased incidence of urolithiasis in infants in China. Affected children were screened for urolithiasis. OBJECTIVE: The purpose of this study was to analyze sonographic characterization of infant melamine-induced urolithiasis. MATERIALS AND METHODS: Transabdominal US examination was done in 603 infants with melamine-induced calculi. The imaging characteristics of calculi and hydronephrosis were analyzed. Follow-up US imaging was performed. RESULTS: Comet-tail sign was seen behind the calculus of <4 mm. Calculi of ≥ 4 mm were found in 299 inpatients with clear posterior border and with or without light shadowing. Solitary and multiple stones had similar incidence. Incidence of calculi in the inferior renal calyx was the highest (55.2%) in inpatients. Calculus size in inpatients age 2-3 years was smaller than that of children younger than 2 years old (P < 0.05). Inpatients age 2-3 years had the highest incidence rate (48.0%) of hydronephrosis. CONCLUSION: Calculi of <4 mm manifested as hyperechoic foci near the renal papillae, while calculi of ≥ 4 mm usually manifested as echogenic foci with visible inferior edge in the renal calyx. Hydronephrosis was a common imaging finding in inpatients ages 2-3 years.

[Comparative efficacy of nitrofurans in children and adolescents with pyelonephritis in presence of crystalluria].

AIM: To evaluate the efficacy of nitrofurans in children and adolescents with pyelonephritis in the presence of crystalluria. SUBJECTS AND METHODS: The study included 50 patients aged 4-14 years with chronic pyelonephritis in the presence of dysmetabolism. The patients underwent general blood test, general urinalysis with an urocytogram, bacteriological examination of urine, biochemical test of serum (uric acid, calcium, phosphorus, magnesium, urea, and creatinine) and 24-hour urinary excretion (uric acid, oxalates, calcium, phosphorus, and magnesium) at hospital admission and over time. The treatment regimen for Group 1 patients after antibiotic therapy involved furamag, Group 2 received furagin. The drugs were used in a dosage of 2 mg/kg/day in 2 divided doses for 14 days. Complaints, major clinical manifestations, crystalluria patterns, and a number of laboratory findings were analyzed over time. RESULTS: The urinary sediment showed leukocyturia and bacteriuria in all the patients, oxaluria in 70% of the patients, uraturia in 10%, and mixed crystalluria in 20%. The main etiological agent of pyelonephritis was Escherichia coli (48.4%). Increased serum uric acid concentrations were revealed in 14% of the patients. Daily urine tests revealed hyperoxaluria, hyperuricosuria, and hypercalciuria in 86, 18, and 8% of the patients, respectively; urinary magnesium excretion was reduced in 86%. After treatment, Group 1 patients showed a more marked therapeutic effect in terms of a number of indicators (leukocyturia, crystalluria, uricosuria, magnesuria). CONCLUSION: The results of the study showed that the antibacterial therapy involving antibiotics and nitrofurans for an exacerbation of chronic pyelonephritis in the presence of crystalluria not only provides an anti-inflammatory effect, but also leads to reductions in the level of crystalluria and the urinary content of uric acid and calcium. There was a significantly marked reduction in crystalluria, serum uric acid, and urinary oxalates and calcium in the children taking furamag. Out of nitrofurans, furamag may be recommended as the drug of choice to treat urinary tract infections in the presence of crystalluria.

Risk of urinary stone formation associated to proton pump inhibitors: A systematic review and metanalysis.

OBJECTIVE: Proton pump inhibitors are widely used as treatment of acid-related disorders. They are considered safe although their long-term use has been associated with some adverse effects including an increased propensity for urinary calculi formation. The aim of this study was to systematically review available data from studies evaluating the association of PPIs and nephrolithiasis. MATERIALS AND METHODS: We searched two electronic databases (PubMed and EMBASE) for cohort studies or case-control studies evaluating the relationship between treatment with proton pump inhibitors and the risk of stone formation published up to 31 October 2022. The overall association of PPIs and urinary calculi was analyzed using a random effects model (RevMan5). The quality of the included studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. RESULTS: A total of 550 studies were retrieved; 7 were selected by title and abstract screening; after removal of duplicates, 4 records were evaluated by full-text examination. An additional study was retrieved by handsearching the references included in screened studies. In the unadjusted analysis, the odds of urinary calculi were greater in subjects taking PPIs compared to controls (unadjusted OR = 2.10, 95% CI 1.74-2.52, p < 0.00001). The pooled odds ratio of two case-control studies confirmed that use of PPIs increased the odds of urinary calculi compared with non-use (OR 2.44, 95% CI 2.29 to 2.61). Pooled analysis of three cohort studies evaluating incident nephrolithiasis showed an overall hazard ratio estimate of 1.34 (95% CI = 1.28-1.40). One study found lower urinary citrate and urinary magnesium levels in subjects exposed to PPIs. The Newcastle-Ottawa Quality Assessment Scale scores ranged between 6 and 8. CONCLUSIONS: PPIs showed an association with urinary calculi in patients included in the studies included in this review. If these data will be confirmed in adequately powered randomized trials, clinicians may consider limiting the long-term use of PPIs, to avoid unnecessary prolongation of treatment. Urinary magnesium and citrate should be evaluated in renal stone forming patients taking PPIs to supplement their intake when requested.

Melamine-related urinary stones in 195 infants and young children: clinical features within 2 years of follow-up.

OBJECTIVE: To summarize the clinical features and follow-up, the effects of melamine-tainted milk powder (MMP) consumption on kidney and body growth in children who suffered from melamine-related urinary stones (MUS) 2 years earlier were checked. MEASUREMENTS: Body height and weight, kidney and bladder morphology monitored by ultrasound, urinalysis and renal function were recorded. Plain abdominal radiography was performed for differential diagnosis. The first follow-up was carried out at 15 months and the second 2 years later for patients who showed any abnormality at the first follow-up. Two hundred age- and gender-matched cohorts were included. RESULTS: All cases received conservative treatment in hospital. Fifteen months of follow-up was successfully carried out in 167 cases. 91 children had residual MUS at the time of discharge, 58 MUS disappeared completely, 25 dissolved partially, 1 increased in size, and 7 did not change. At 2 years of follow-up, the residual stones all disappeared except for 1 case; the patient who showed a delayed development with regard to height caught up at 24 months of follow-up. CONCLUSIONS: Conservative treatment shows a high effectiveness in cases with residual MUS. Consumption of MMP with timely treatment did not demonstrate an evident impact on kidney and bladder although body height is slightly affected in a few cases.

Melamine-tainted milk product-associated urinary stones in children.

BACKGROUND: An outbreak of urinary stones related to consumption of melamine-tainted milk products (MTMP) occurred in China in 2008. The aim of the present study was to evaluate such children to identify their clinical features and risk factors. METHODS: Renal ultrasound was performed for 7328 children who presented to a Sichuan teaching hospital between 13 September and 15 October 2008 due to concern of such stones. Clinical data, family information, feeding history and urinary stones were analyzed. RESULTS: Of the 7328 children, 189 (2.58%) had ultrasound findings of urinary stones, and 51 were admitted. Age (mean ± SD) was 27.4 ± 25.5 months, and 101 were male and 88, female. The odds ratio (OR) for urinary stones for infants and young children (1-3 years) as compared to older children (>3 years), was 2.42 (95% confidence interval [CI], 1.64-3.56; P < 0.0001) and 1.95 (95%CI, 1.31-2.89; P < 0.0011), respectively. Independent risk factors associated with urinary stones included consumption of MTMP with melamine at > 5500 mg/kg (OR, 13.3; 95%CI, 6.8-26.1, P < 0.0001) as compared to that with melamine at < 200 mg/kg, and younger father (P = 0.0006). On logistic regression, the only risk factor associated with inpatient care was lower family income per person (OR, 4.4; 95%CI, 1.2-15.9, P = 0.02). Repeat ultrasound for 51 children at mean follow up of 15.3 ± 8.9 days found that 33 passed out all stones, which was associated with a larger number of smaller stones (P = 0.003). Urinary stones contained melamine and uric acid, but no cyanuric acid. CONCLUSIONS: MTMP-associated urinary stones were more frequent in young children and more severe in children from poorer families.

[Clinical strategies for prevention of drug-induced urinary calculi].

Drug-induced urinary calculi, although they account for only 1-2% of urinary calculi, deserve consideration because most of them are preventable. In the drug-containing calculi resulting from the crystallization of a certain drug and its metabolites in the urine, stone analysis can identify the responsible drug. While, in the drug-induced metabolic calculi caused by interference with calcium, oxalate and purine metabolism, careful clinical inquiry is necessary to reveal involvement of a certain drug in stone formation. Better awareness of the possible drugs with lithogenic potential and close surveillance of patients on long-term treatment with these drugs are necessary. Especially, in patients with a history of urolithiaisis, prescription of lithogenic drugs deserve careful consideration.

Melamine-induced infant urinary calculi: a report on 24 cases and a 1-year follow-up.

Melamine has been the main factor leading to infant urinary calculi occurring on a rather wide scale in China in 2008, which were the results of a rapid aggradation of metabolites such as cyanuric acid diamide, cyanuric acid, etc., causing uric acid stone to accumulate. Here, we present a report on 24 infants who were admitted to our department, their ages ranging from 3 to 10 months. All of these infants had a confirmed history of having been fed with the "Sanlu" brand milk powder, which contained excessive levels of melamine, with the highest being 2,563 mg/kg. The diagnosis, medical treatment and follow-up by ultrasonography at 1, 3, 6, 12 months were reported. 22 cases of these infants were rehabilitated after medical treatment and 1 infant underwent pyelolithotomy for relieving an obvious ureter obstruction. No recurrence was found in these babies thereafter. Another infant died from rapidly worsening renal failure. Therefore, this series of cases have demonstrated that melamine contained in the "Sanlu" milk powder was the main cause of these urinary stones. Urine alkalinization and stone liberalization were the most effective treatments. Fast diagnosis and treatment of acute obstructive urolithiasis may prevent the development of acute renal failure, which is associated with high morbidity and mortality rates.

Ultrasound of urinary system and urinary screening in 14 256 asymptomatic children in China.

AIM: The aim of this study is to assess the characteristics of urinary system diseases and the role of the ultrasound screening and urinalysis screening for chronic kidney disease (CKD) in asymptomatic children in China. METHODS: Between September 2008 and November 2008, 14 256 children excluding those with obvious symptoms and signs were enrolled in our study. All the subjects accepted ultrasound and urinary screening. A case-control study was performed to evaluate the relative risk of having stones in those children exposed to melamine formula. RESULTS: Of the enrolled children, 6.10% (869 of 14 256) showed abnormalities, of which 409 (2.87%) were established by ultrasound, 572 (4.01%) by urinalysis and 112 (0.79%) by both ultrasound screening and urinalysis. The abnormalities included congenital anomalies of kidney and urinary tract, urinary stones and/or hydronephrosis, leucocyturia and haematuria and/or proteinuria. Children exposed to melamine formula were 5.17 times as likely to have kidney stones as children exposed to no-melamine formula (95% confidence interval, 3.28-8.14; P < 0.001); the probability of kidney stones in melamine-fed infants were 6.28 times as likely as those no melamine-fed (95% confidence interval, 3.71-10.65; P < 0.001). CONCLUSION: Ultrasonography and urinalysis could complement each other and play important roles in the early diagnosis of anomalies of the urinary system, but urinalysis is a more cost-effective screening tool for CKD in children in China. Exposure to melamine-contaminated formula associated with urinary stones, especially in infants, was significantly higher than the control group.

The characteristics of immune system changes in children who ingested melamine-contaminated powdered formula in China.

Since 2008, the food safety issue of melamine poisoning has again become a health scare for children. The mechanism of how melamine initiates kidney stones and kidney-associated renal complications is still unknown. Some children who ingested melamine-contaminated powdered formula had leukocyturia, but none had typical symptoms of urinary tract infection. We believed that the children's immune systems might have some changes. We followed up 170 children who ingested melamine-contaminated powdered formula and tested their blood and urine and to observe their immune state, and also performed ultrasonography. In the immune responses of children with stones, immunoglobulin M takes a major immune response and the level of CD3(+), CD4(+) decreased compared with children without stones. There was no difference in complete blood count between the children with stones and those without stones. We concluded that leukocyturia had a certain relationship with non-urinary tract infectious renal disease and these children are susceptible to infectious diseases.

Cadmium-exposed population in Mae Sot district, Tak province: 3. Associations between urinary cadmium and renal dysfunction, hypertension, diabetes, and urinary stones.

OBJECTIVE: To study the associations between urinary cadmium and renal dysfunction, hypertension, diabetes, and urinary stones in an adult population living in cadmium-contaminated areas in Mae Sot District, Tak Province, Thailand. MATERIAL AND METHOD: Seven hundred ninety five cadmium-exposed adults were screened for urinary cadmium, renal dysfunction, hypertension, diabetes, and urinary stones in 2005. Six selected markers of renal function in the present study were urinary excretion of beta2-microglobulin (beta2-MG), N-acetyl-beta-D-glucosaminidase (NAG), total protein and calcium, serum creatinine, and glomerular filtration rate (GFR). RESULTS: The mean age of the study persons was 50-years-old. The overall prevalence rates of hypertension, diabetes, and urinary stones were 33.3%, 6.2%, and 8.9% respectively. The prevalence of increased proteinuria was greatest in those with urinary cadmium levels > or = 15 microg/g creatinine. Urinary excretion of beta2-MG, NAG, and total protein significantly increased with increasing urinary cadmium levels, after adjusting for other co-variables by multiple linear regression analysis. However, urinary cadmium was not significantly associated with urinary calcium, serum creatinine, and GFR. The prevalence rates of hypertension, diabetes, and urinary stones did not significantly increase with increasing urinary cadmium levels. Hypertension, diabetes, and urinary stones were also significant predictors of impaired renal function. CONCLUSION: In this population, increasing levels of urinary cadmium are associated with increasing urinary excretion of beta2-MG, NAG, and total protein. Risk for hypertension, diabetes, and urinary stones remains uncertain in relation to cadmium exposure.

[Follow-up study on children with urinary calculi associated with exposure to melamine-contaminated formula].

OBJECTIVE: To understand the prognosis of the children with urinary calculi associated with exposure to melamine-contaminated formula. METHODS: A follow-up study was performed in 47 out-patients from the Third Hospital of Peking University who were diagnosed with urinary calculi associated with exposure to melamine-contaminated formula. Urinary tract B-ultrasound and renal function examinations were done during the 1 to 6-month follow-up. RESULTS: By the 6th month of follow-up, spontaneous stone passage was found in 36 children (77%). The follow-up failed in four children. None of the patients had any complications. Spontaneous stone passage was not associated with the volume and the period exposed to melamine in formula, but was associated with the location of calculi. The time to spontaneous stone passage in boys appeared to be longer than in girls, but there were no statistical differences. CONCLUSIONS: Spontaneous stone passage can be found in most children and the prognosis of children with urinary calculi associated with exposure to melamine-contaminated formula is good.

Childhood urinary stones induced by melamine-tainted formula: how much we know, how much we don't know.

Through screening, diagnosing, and treating childhood urinary stones induced by melamine-tainted formula, Chinese doctors obtained more experience with the clinical as well as the imaging features of the stones, although there still are many questions regarding melamine-associated stones. By reviewing the earlier reports on animals along with our recent experiences with humans, we concluded that there was no evidence either from animal experiments or from humans to support the direct toxicity of melamine on the kidney, although a feasible follow-up and assessment might be needed. It is also speculated that further studies on the mechanism of stone formation may need to take into account human internal metabolism changes and tubular function.

Clinical and imaging features in 16 infants exposed to food contaminated with melamine and cyanuric acid.

OBJECTIVE: The objective of our study was to describe the clinical and imaging features of infants exposed to milk formula contaminated with melamine and cyanuric acid. CONCLUSION: The imaging feature of patients exposed to food contaminated with melamine and cyanuric acid was multiple calculi of the urinary tract that varied greatly in size and shape. Most patients presented with symptoms of urinary obstruction.

Mesalazine: A Novel Etiology For Drug-Induced Urinary Calculi.

We report the case of a 23-year-old woman treated by mesalazine for ulcerative colitis and who subsequently presented recurrent renal colic due to mesalazine urinary stones. This is the second case described in the literature.Mesalazine stones are soft, friable and have an orange-beige color. They are not visible on non-contrast computed tomography (CT). Their diagnosis is based on morpho-constitutional analysis and CT-urography. Patients treatedby mesalazine who present renal colic should undergo CT-urography in order to make the diagnosis.

Urinary stone disease in pediatric and adult metabolic bone clinic patients.

Kidney stones are increasing in the pediatric and adult populations; similarly osteoporosis is increasingly recognized in children. While kidney stone formers are known to suffer from low bone density, metabolic bone patients have not been considered a high risk population for kidney stones. Retrospective chart review of Nationwide Children's Hospital Metabolic Bone Clinic patients from October 2009-2013. Patients were identified by ICD 9 codes for osteoporosis, osteopenia, low bone density and kidney stones. Only patients with radiologic evidence of both diseases were included.Twenty-six of 889 patients met criteria; this is equivalent to an incidence of 30 per 100,000 patients. Osteoporosis was the most frequent bone diagnosis. Males were the majority (68%). Most common secondary diagnoses: seizure (52%) and cerebral palsy (44%). TREATMENT: calcium (48%), vitamin D (40%), bisphosphonates (48%). The majority (75%) were non-ambulatory. Most frequent lithogenic medications: Topiramate (42%) and corticosteroids (27%). This is one of the first studies to consider metabolic bone patients as high risk for urinary stone disease. We found a higher rate of kidney stones in pediatric metabolic bone patients compared to data available for the general pediatric kidney stone population. The most common risk factor for bone and stone disease was nonambulatory status. Males were more frequently affected than females; this is the reverse of general adolescent kidney stone population. The predominance of cerebral palsy and seizure patients can be attributed to their frequency of non-ambulatory status and lithogenic medications such as Topiramate.