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.

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.

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.

The Association of Uric Acid Calculi with Obesity, Prediabetes, Type 2 Diabetes Mellitus, and Hypertension.

OBJECTIVES: To disclose the link between the composition of urolithiasis, especially that of uric acid calculi, and obesity, prediabetes, type 2 diabetes mellitus, and hypertension. MATERIALS AND METHODS: Patients who had urinary calculi and underwent surgical treatment were registered in the study. The composition of urinary calculi was analyzed and correlated with clinical features and biomedical profiles of the patients before surgical intervention. RESULTS: A total of 666 patients with urolithiasis who underwent surgical management were registered and analyzed. In those who had uric acid calculi, there was a significant association with prediabetic (OR: 20.11, 95% CI: 7.40-54.63, P < 0.001) and diabetic states (OR: 11.55, 95% CI: 4.41-29.97, P < 0.001). It also seemed that uric acid calculi were related to obesity but there was no statistical significance (OR: 2.45, 95% CI: 0.91-6.62, P = 0.078). There was no association of uric acid calculi with hypertension (OR: 1.08, 95% CI: 0.54-2.17, P = 0.822) and concurrent urinary tract infection (OR: 0.93, 95% CI: 0.44-1.96, P = 0.841). CONCLUSION: There was a remarkable association of uric acid calculi with prediabetic and diabetic states. The uric acid calculi were also seemingly associated with obesity in patients with urolithiasis undergoing surgical management.

Melamine-associated urinary stone.

The devastating contamination of milk formula with Melamine, which caused havoc in China, happened almost eight years ago. Although most patients with melamine-associated urinary stone were given conservative medical treatment, the impact was not completely eliminated. Extensive studies are needed to assess chronic effects in the affected population. In this review, we describe the pathogenesis, pathology, clinical manifestations, management and epidemiology; and the need for longer term follow-up of melamine-associated urinary stones.

Melamine-contaminated milk formula and its impact on children.

The melamine contaminated milk powder contamination scandal occurred in China in 2008. Its main consequences so far have been urinary stone formation in children with associated renal damage and increased child mortality. Eight years have passed, but food safety issues still remain of concern in the daily lives of millions of Chinese. Vigilance is required to ensure no recurrence of such food safety problems. Ongoing studies focus on the early detection of food industry malpractice, mechanisms whereby these toxic substances induce disease and how its advent may be prevented and better managed. Melamine undergoes renal excretion, but is metabolized slowly and excreted largely unchanged in the urine. Urinary melamine measurement may provide a rapid and inexpensive way to identify exposure to melamine adulterated food items. Although most patients with melaminerelated urinary stones (MUS) have been responsive to conservative treatment, longer time follow-up is needed to assess chronic effects. Aside from MUS, melamine is a recognized carcinogen and can induce urinary tract tumours. Very little is known about the effects of excessive exposure to melamine contaminated milk powder in infants on growth, adolescent and adult health, although short-term effects have become apparent during the scandal.

Assessment of chronic renal injury from melamine-associated pediatric urolithiasis: an eighteen-month prospective cohort study.

BACKGROUND: The illegal use of melamine in powdered baby formula resulted in a widespread outbreak of melamine-associated pediatric urolithiasis and kidney damage in China in 2008. We conducted this study because more needs to be known about the long-term effects of melamine-associated urolithiasis and kidney damage. OBJECTIVES: To determine the prognosis and long-term implications of chronic kidney damage in children with urolithiasis resulting from melamine consumption. DESIGN: Prospective cohort study. SETTING: Children's Hospital of Fudan University. PATIENTS AND METHODS: Children six years of age or older with a history of having consumed melamine-contaminated milk powder were voluntarily screened. We measured urinary microprotein profiles [microalbumin (ALBU), immunoglobulin G (IgG), and n-acetyl-ß-d-glucosidase (NAG)] and creatinine (CR) results at 6 and 18 months in children with melamine-associated urolithiasis. This study was conducted from September 17 to October 15, 2008. MAIN OUTCOME MEASURES: Changes in urinary microprotein profiles. RESULTS: Of 8335 children screened, 102 children (1.22%) were diagnosed with melamine-associated urolithiasis. Follow-up rates at 6 and 18 months were 91.4% (96/105) and 89.2% (91/102), respectively. Eighteen months later, 90.3% patients had spontaneously passed a stone. The incidence rates of proteinuria and microscopic hematuria at 6 months were significantly higher than at 18 months (P=.029 and P=.017, respectively). The proportion of patients with abnormal ALBU/CR, IgG/CR and NAG/CR at 6 months (27.6%, 17.1% and 21.1%, respectively) was significantly higher than at 18 months (6.4%, 5.1% and 12.8%, respectively). The high concentration of melamine consumed was the primary factor correlated with the high microprotein levels. Approximately 90% melamine-associated urolithiasis cases can be resolved within 18 months by non-surgical therapy. CONCLUSION: The long-term presence of stones associated with a previous exposure to melanine can cause chronic kidney glomerular and tubular injuries. Passing these stones as soon as possible can reduce kidney injury and accelerate recovery. LIMITATIONS: We could not control for possible selection bias due to more visits to our hospital or visits to our hospital after diagnosis at other hospitals, which might have increased the rate of diagnosis.

Protective Effect of Propolis in Proteinuria, Crystaluria, Nephrotoxicity and Hepatotoxicity Induced by Ethylene Glycol Ingestion.

BACKGROUND AND AIMS: Propolis is a natural honeybee product with wide biological activities and potential therapeutic properties. The aim of the study is to evaluate the protective effect of propolis extract on nephrotoxicity and hepatotoxicity induced by ethylene glycol in rats. METHODS: Five groups of rats were used. Group 1 received drinking water, group 2 received 0.75% ethylene-glycol in drinking water, group 3 received 0.75% ethylene-glycol in drinking water along with cystone 500 mg/kg/body weight (bw) daily, group 4 received 0.75% ethylene-glycol in drinking water along with propolis extract at a dose of 100 mg/kg/bw daily, and group 5 received 0.75% ethylene-glycol in drinking water along with propolis extract at a dose of 250 mg/kg/bw daily. The treatment continued for a total of 30 d. Urinalyses for pH, crystals, protein, creatinine, uric acid and electrolytes, and renal and liver function tests were performed. RESULTS: Ethylene-glycol increased urinary pH, urinary volume, and urinary calcium, phosphorus, uric acid and protein excretion. It decreased creatinine clearance and magnesium and caused crystaluria. Treatment with propolis extract or cystone normalized the level of magnesium, creatinine, sodium, potassium and chloride. Propolis is more potent than cystone. Propolis extract alleviates urinary protein excretion and ameliorates the deterioration of liver and kidney function caused by ethylene glycol. CONCLUSIONS: Propolis extract has a potential protective effect against ethylene glycol induced hepatotoxicity and nephrotoxicity and has a potential to treat and prevent urinary calculus, crystaluria and proteinuria.

[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.

Short term effects of increasing dietary salt concentrations on urine composition in healthy cats.

High dietary salt (NaCl) concentrations are assumed to be beneficial in preventing the formation of calcium oxalate (CaOx) uroliths in cats, since increased water intake and urine volume have been observed subsequent to intake. In human beings, dietary NaCl restriction is recommended for the prevention of CaOx urolith formation, since high NaCl intake is associated with increased urinary Ca excretion. The aim of the present study was to clarify the role of dietary NaCl in the formation of CaOx uroliths in cats. Eight cats received four diets that differed in Na and Cl concentrations (0.38-1.43% Na and 0.56-2.52% Cl dry matter, DM). Each feeding period consisted of a 21 day adaptation period, followed by a 7 day sampling period for urine collection. Higher dietary NaCl concentrations were associated with increased urine volume and renal Na excretion. Urinary Ca concentration was constant, but renal Ca excretion increased from 0.62 to 1.05 mg/kg bodyweight (BW)/day with higher dietary NaCl concentrations (P ≤ 0.05). Urinary oxalate (Ox), citrate, P and K concentrations decreased when NaCl intake was high (P ≤ 0.05), and urinary pH was low in all groups (6.33-6.45; P > 0.05). Relative supersaturation of CaOx in the urine was unaffected by dietary NaCl concentrations. In conclusion, the present study demonstrated several beneficial effects of high dietary NaCl intake over a relatively short time period. In particular, urinary Ca concentration remained unchanged because of increased urine volume. Decreased urinary Ox concentrations might help to prevent the formation of CaOx uroliths, but this should be verified in future studies in diseased or predisposed cats.

[Pyonephrosis due to xanthine stones in a bitch treated with allopurinol]. / Pyonephrose durch Xanthinsteine bei einer mit Allopurinol behandelten Hündin.

A 2-year-old, neutered, crossbreed bitch was presented as an emergency with painful abdomen, fever and vomiting. The cause of the acute abdomen was a pyonephrosis of the left kidney, caused by four xanthine stones, which had blocked the ureter. After surgical removal of the heavily altered left kidney, the bitch recovered rapidly. Because of a leishmaniasis the bitch had been treated with allopurinol over an extended period, the xanthine stone formation is likely to have resulted from allopurinol usage. Because there were additionally small concrements in the right kidney, the medication was stopped. Subsequently, the dog has received a low purine diet, and the leishmaniasis titer and renal function have been monitored regularly.

[Clinical analysis of 41 children's urinary calculus and acute renal failure].

OBJECTIVE: To analyze the treatment of acute renal failure caused by irrational drug use. METHOD: Data of 41 cases of acute renal failure seen from July 2008 to June 2012 in our hospital were reviewed. Bilateral renal parenchymas diffuse echo was found enhanced by ultrasound in all cases. Calculus image was not found by X-ray. All children had medical history of using cephalosporins or others. Alkalinization of urine and antispasmodic treatment were given to all children immediately, 17 children were treated with hemodialysis and 4 children accepted intraureteral cannula placement. RESULT: In 24 children who accepted alkalinization of urine and antispasmodic treatment micturition could be restored within 24 hours, in 11 children micturition recovered after only one hemodialysis treatment and 2 children gradually restored micturition after hemodialysis twice, 4 children who accepted intraureteral cannula immediately restored micturition. In all children micturition recovered gradually after a week of treatment. Ultrasound examination showed that 39 children's calculus disappeared totally and renal parenchymas echo recovered to normal. The residual calculi with diameter less than 5 mm were found in 2 children, but they had no symptoms. The children received potassium sodium hydrogen citrate granules per os and were discharged from hospital. Ultrasound showed calculus disappeared totally one month later. CONCLUSION: Irrational drug use can cause children urolithiasis combined with acute renal failure, while renal dysfunction can reverse by drug withdrawal and early alkalinization of urine, antispasmodic treatment, intraureteral cannula or hemodialysis when necessary, most calculus can be expelled after micturition recovered to normal.

[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.

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.

Sulphadiazine-induced obstructive renal failure complicating treatment of HIV-associated toxoplasmosis.

A patient with newly-diagnosed HIV infection and biopsy-proven cerebral toxoplasmosis was treated with sulphadiazine and pyrimethamine. Despite adequate hydration and daily examination of urine for sulphadiazine crystals obstructive uropathy due to bilateral ureteric stones with hydronephrosis occurred, resulting in rapid onset renal failure. Sulphadiazine was discontinued and clindamycin was substituted. With intravenous fluid hydration and bilateral nephrostomies the urolithiasis resolved. This case serves to remind clinicians of the need for vigilance when treating cerebral toxoplasmosis with sulphadiazine, in order to avoid this potentially serious complication of treatment.