An Unusual Course of a 2,8-Dihydroxyadeninuria Crystalline Nephropathy Secondary to Adenine Phosphoribosyltransferase Deficiency.

Adenine phosphoribosyltransferase (APRT) deficiency is a rare disorder caused by an autosomal recessive genetic disease leading to the deposition of 2,8-dihydroxyadenine (2,8-DHA) in the kidney. The disease remains under-recognized, oftentimes diagnosed in late stages of renal insufficiency or a failed kidney allograft with biopsy-proven disease recurrence. Here, we present the case of a 59-year-old middle eastern male patient diagnosed with 2,8-DHA nephropathy after a very unusual presentation, and we show how the initiation of an appropriate therapy slowed down his evolution toward kidney replacement therapies. His disease was found to be secondary to a specific APRT gene variant c.188G>A p (Gly63Asp) also described in 4 other patients, all from middle eastern origins.

Antioxidant and Polyphenol-Rich Ethanolic Extract of Rubia tinctorum L. Prevents Urolithiasis in an Ethylene Glycol Experimental Model in Rats.

Treatment of kidney stones is based on symptomatic medications which are associated with side effects such as gastrointestinal symptoms (e.g., nausea, vomiting) and hepatotoxicity. The search for effective plant extracts without the above side effects has demonstrated the involvement of antioxidants in the treatment of kidney stones. A local survey in Morocco has previously revealed the frequent use of Rubia tinctorum L. (RT) for the treatment of kidney stones. In this study, we first explored whether RT ethanolic (E-RT) and ethyl acetate (EA-RT) extracts of Rubia tinctorum L. could prevent the occurrence of urolithiasis in an experimental 0.75% ethylene glycol (EG) and 2% ammonium chloride (AC)-induced rat model. Secondly, we determined the potential antioxidant potency as well as the polyphenol composition of these extracts. An EG/AC regimen for 10 days induced the formation of bipyramid-shaped calcium oxalate crystals in the urine. Concomitantly, serum and urinary creatinine, urea, uric acid, phosphorus, calcium, sodium, potassium, and chloride were altered. The co-administration of both RT extracts prevented alterations in all these parameters. In the EG/AC-induced rat model, the antioxidants- and polyphenols-rich E-RT and EA-RT extracts significantly reduced the presence of calcium oxalate in the urine, and prevented serum and urinary biochemical alterations together with kidney tissue damage associated with urolithiasis. Moreover, we demonstrated that the beneficial preventive effects of E-RT co-administration were more pronounced than those obtained with EA-RT. The superiority of E-RT was associated with its more potent antioxidant effect, due to its high content in polyphenols.

Tea and coffee consumption and the risk of urinary stones-a systematic review of the epidemiological data.

OBJECTIVE: To explore the relationship between the consumption of coffee and tea with urolithiasis. We evaluated large epidemiological and small clinical studies to draw conclusions regarding their lithogenic risk. METHODS: A systematic review was performed using the Medline and Scopus databases, in concordance with the PRISMA statement. English, French, and Spanish language studies regarding the consumption of caffeinated and decaffeinated coffee and tea, and the relationship to urinary stone disease were reviewed. Case reports and letters, unpublished studies, posters, and comments were excluded. RESULTS: As per the inclusion criteria, 13 studies were included in the final review. Most studies, including four large prospective studies and one meta-analysis, reported a reduced risk of stone formation for coffee and tea. Caffeine has a diuretic effect and increases the urinary excretion of calcium, but if these losses are compensated for, moderate caffeine intakes may have little or no deleterious effects. Green and Herbal teas infused for short time had low oxalate content compared to black tea. CONCLUSION: There is no evidence that moderate consumption of coffee raises the risk for stone formation in healthy individuals, provided the recommended daily fluid intake is maintained. The currently available literature supports in general a protective role for tea against the stone formation, mainly for green tea. However, heterogeneity of published data and lack of standardization needs to be addressed before final and clear conclusions can be given to patients and to the public in general.

Consensus of multiple national guidelines: agreed strategies for initial stone management during COVID-19.

PURPOSE: To review the existing available information regarding urolithiasis management and the impact of COVID-19 on this, and propose recommendations for management of emergency urolithiasis presentations in the COVID-19 era. METHODS: Review of published guidelines produced by Urological Governing Bodies, followed by the literature review regarding urolithiasis management during the COVID-19 pandemic. RESULTS: Consistent recommendations across guidelines and literature were that urolithiasis with concurrent sepsis or renal failure remains a urological emergency warranting urgent intervention within the pandemic environment. Ureteric stenting and percutaneous nephrostomy are considered equivalent for decompression in this setting, with both ideally to be performed under local anaesthesia where possible to spare ventilators and reduce aerosol-generating procedures. Greater utilization of medical expulsive therapy and dissolution chemolysis may occur during the pandemic, and longer indwelling stent times may be accepted while definite stone clearance is deferred. CONCLUSIONS: Urolithiasis will continue to be a source of emergency presentations requiring urgent intervention during the COVID-19 pandemic. However, it is possible to limit these interventions to decompression of the collecting system in the setting of concurrent obstruction or infection, performed under local anaesthesia to limit use of resources and minimise aerosol-generating procedures, with deferral of definitive management.

Evaluation of diuretic efficacy and antiurolithiatic potential of ethanolic leaf extract of Annona squamosa Linn. in experimental animal models.

OBJECTIVE: The study is to investigate the diuretic and antiurolithiatic activities of ethanolic leaf extract of Annona squamosa Linn. in experimental animals. MATERIALS AND METHODS: For both studies, Wistar albino rats and two doses of extract (250 and 500 mg/kg) were used. Diuretic activity was evaluated by Lipschitz model. Urine volume and urine pH were noted, the concentration of sodium and potassium was estimated by flame photometry, and diuretic index, natriuretic index, and Lipschitz values were calculated from the results. Furosemide was used as a positive control. Ethylene glycol-induced urolithiasis model was used for antiurolithiatic study. Urine volume, urine pH, body weight, and biochemical parameters such as calcium, urea, uric acid, and creatine both from serum and urine were estimated. Antioxidant parameters and histopathological analysis of the kidney were evaluated. Cystone was used as a positive control in this study. Results were expressed as mean ± standard error of mean. Statistical analysis was carried out using one-way analysis of variance, followed by Dunnett's multiple comparison tests. RESULTS: In both diuretic and antiurolithiatic studies, both doses of the extract showed efficacy, and the dose of 500 mg/kg has shown a significant effect compared to positive control and negative control. CONCLUSION: The dose of 500 mg/kg showed a promising diuretic and antiurolithiatic activity.

A probabilistic approach for benchmark dose of melamine exposure for a marker of early renal dysfunction in patients with calcium urolithiasis.

Environmental exposure to melamine has been associated with early renal injury in urolithiasis patients even when urinary concentrations of melamine are low. The aim of this study was to derive a benchmark dose (BMD) for melamine for urolithiasis patients. To do this, one-spot urine sample from 309 participants was obtained to measure urinary melamine and N-acetyl ß-D-glucosaminidase (NAG), an early renal damage biomarker. The participants were then classified into four exposure groups based on the outcomes of melamine tableware usage questionnaire. A beta distribution of urinary excretion fraction for each group was assumed to estimate their average daily intakes (AvDIs) of melamine. The BMD and the corresponding one-sided 95% lower bound (BMDL) was then derived based on Bayesian model averaging of alternative regression models between the participants' NAG levels and their estimated AvDIs, adjusting for age, gender, and other covariates. Bayesian Markov chain Monte Carlo simulations were used for all the estimates. With a benchmark response of 0.10, the simulated BMDL of 4.89 µg/kg-bw/day for melamine exposure threshold was much lower than the WHO's current recommended tolerable daily intake of 200 µg/kg_bw/day and the US FDA's 63 µg/kg_bw/day. The current regulation level of melamine might not safeguard urolithiasis patients from further deterioration of renal function.

Antiurolithiatic activity of Boldoa purpurascens aqueous extract: An in vitro and in vivo study.

ETHNOPHARMACOLOGICAL RELEVANCE: Boldoa purpurascens Cav. (Nyctaginaceae) is a plant species used in traditional medicine in Cuba as antiurolithiatic. AIM OF THE STUDY: The aim of the present investigation was to evaluate the in vitro and in vivo antiurolothiatic activity of an aqueous extract from the leaves of Boldoa purpurascens. MATERIALS AND METHODS: The aqueous extract from leaves of Boldoa purpurascens was evaluated for antiurolithiatic activity in vitro and in vivo. In vitro crystallization of calcium oxalate (CaOx) was assessed using a nucleation, aggregation and growth assay. The effects of the extract and of Cystone®, used as a positive control, on the slope of nucleation and aggregation, as well as on the growth of CaOx crystals, were evaluated spectrophotometrically. The densities of the formed crystals were compared microscopically. In vivo activity was evaluated in an urolithiasis model in rats, in which kidney stones are induced by ethylene glycol (0.75%) and ammonium chloride (2%) in drinking water for 10 days. Three different experimental doses (100, 200 and 400 mg/kg, p.o.) of the extract and Cystone® were administered for 10 days. After 10 days, various biochemical parameters were measured in urine and serum, and histopathological analysis of the kidneys was carried out. RESULTS: The aqueous extract of Boldoa purpurascens inhibited the slope of nucleation and aggregation of CaOx crystallization, and decreased the crystal density. It also inhibited the growth and caused the dissolution of CaOx crystals. Cystone® exhibited similar effects. At a dose of 400 mg/kg the extract reduced the concentration of uric acid in urine, as well as the serum concentration of uric acid and creatinine. Histopathologic analysis of the kidneys of the same treatment group revealed reduced tissue damage; the results were almost similar to the untreated healthy control group. CONCLUSION: This study indicates that an aqueous leaf extract of Boldoa purpurascens may be effective in the prevention of urinary stone formation, and substantiates the traditional claim.

High-salt diet promotes crystal deposition through hypertension in Dahl salt-sensitive rat model.

OBJECTIVES: To study the promotive effect of salt-induced hypertension on crystal deposition and urolithiasis using a salt-sensitive rat hypertension model. METHODS: Hyperoxaluria and hypercalciuria were induced in male Dahl salt-sensitive rats with administration of ethylene glycol and alfacalcidol. Hypertension was induced by a high-salt diet. Eplerenone, a selective mineralocorticoid receptor antagonist, was given. Blood and urine were collected to evaluate renal function, electrolytes and the blood renin-angiotensin-aldosterone system. Renal calcium content was also evaluated. Histological examination, transcriptome analysis with DNA microarray and semiquantitative reverse transcriptase polymerase chain reaction were carried out. RESULTS: A high-salt diet increased crystal deposition in Dahl salt-sensitive rats with hypertension, and eplerenone administration significantly suppressed it. The mRNA expression profile was associated with crystal formation, growth, adhesion and cellular injury, and it was regulated in the group exposed to a high-salt diet and ethylene glycol. CONCLUSIONS: A high-salt diet has a promotive effect on salt-sensitive hypertension and urolithiasis. This promotive effect can be prevented by eplerenone administration. Hence, salt-sensitive hypertension has promotive effects on crystal deposition in Dahl salt-sensitive rats.

Novel Risk Loci Identified in a Genome-Wide Association Study of Urolithiasis in a Japanese Population.

BACKGROUND: A family history of urolithiasis is associated with a more than doubling of urolithiasis risk, and a twin study estimating 56% heritability of the condition suggests a pivotal role for host genetic factors. However, previous genome-wide association studies (GWAS) have identified only six risk-related loci. METHODS: To identify novel urolithiasis-related loci in the Japanese population, we performed a large-scale GWAS of 11,130 cases and 187,639 controls, followed by a replication analysis of 2289 cases and 3817 controls. Diagnosis of urolithiasis was confirmed either by a clinician or using medical records or self-report. We also assessed the association of urolithiasis loci with 16 quantitative traits, including metabolic, kidney-related, and electrolyte traits (such as body mass index, lipid storage, eGFR, serum uric acid, and serum calcium), using up to 160,000 samples from BioBank Japan. RESULTS: The analysis identified 14 significant loci, including nine novel loci. Ten regions showed a significant association with at least one quantitative trait, including metabolic, kidney-related, and electrolyte traits, suggesting a common genetic basis for urolithiasis and these quantitative traits. Four novel loci were related to metabolic traits, obesity, hypertriglyceridemia, or hyperuricemia. The remaining ten loci were associated with kidney- or electrolyte-related traits; these may affect crystallization. Weighted genetic risk score analysis indicated that the highest risk group (top 20%) showed an odds ratio of 1.71 (95% confidence interval, 1.42 to 2.06) - 2.13 (95% confidence interval, 2.00 to 2.27) compared with the reference group (bottom 20%). CONCLUSIONS: Our findings provide evidence that host genetic factors related to regulation of metabolic and crystallization pathways contribute to the development of urolithiasis.

Urolithiasis in the pediatric population - current opinion on epidemiology, patophysiology, diagnostic evaluation and treatment.

Urolithiasis, a condition in which calculi are found in the urinary tract, has been known for centuries. Although the disease was considered casuistic in the pediatric population, its prevalence is rising among both children and infants. The occurrence of the disease is greater in developed countries, therefore urolithiasis should be considered a lifestyle disease. Its etiopathogenesis has not yet been well understood. Kidney stone formation is influenced by factors such as climate, eating habits, profession, fluid intake, genetic predisposition, urinary tract infections and malformations of the urinary tract. Calculi are usually composed of mixed mineral substances. Only about 30% are made up of one chemical substance, calcium oxalate being the most common. Urolithiasis can be asymptomatic and accidentally diagnosed. Abdominal pain is the most common clinical symptom, however disease presentation among infants is nonspecific. Hematuria is a common clinical finding. Ultrasonography is the most important diagnostic tool in the diagnosis of kidney stone disease. Metabolic evaluation is required in every case of urolithiasis in the pediatric population, as metabolic disorders can be found in the majority of cases in this age group. The spontaneous passage of calculi less than 6mm in diameter is likely. Invasive treatment should be carried out if stones exceed 6mm in diameter or fail to expulse spontaneously. Prophylactic treatment includes adequate fluid intake, healthy eating habits and physical activity to maintain a healthy weight. Urolithiasis is a recurrent disease, therefore long-term treatment, prophylaxis and a lasting change in dietary habits are essential.

Familial Risks Between Urolithiasis and Cancer.

Urolithiasis (UL, urinary tract stone disease) has been reported to increase subsequent cancers in the urinary tract. Recently, we showed data that surveillance bias may be an important confounder in the reported associations. In the present approach we want to address the question of possible cancer risk posed by UL mechanistically. Both UL and cancer have strong genetic components and we hypothesize that familial association between UL and cancer may be plausible. We thus assess familial risks between UL and cancer, hoping to find an explanation why UL may pose a risk of cancer. UL patients were identified from hospital inpatient and outpatient records and they were organized in families based on the Multigeneration Register into which also national cancer data were linked. Standardized incidence ratios were calculated for cancer in the offspring generation when parents were diagnosed with UL, and conversely for UL when parents were diagnosed with cancer. Familial risks between UL and cancer were generally small and inconsistent providing no convincing support of genetic sharing between UL and cancer. However, bladder UL was associated weakly with prostate cancer, and ureter and bladder UL were associated with salivary gland cancer. Potential mechanisms for these findings are proposed.

Risk factors associated with feline urolithiasis.

Urinary tract diseases are among the main reasons for consultation in veterinary clinics and hospitals. It affects animals of any age, breed and gender. Among the diseases that affect this system, urolithiasis is the second largest cause of clinical signs compatible with feline urinary tract disease. The term urolithiasis refers to the presence of uroliths in any region of the urinary tract, but it is more commonly seen in the bladder and urethra. Uroliths are classified based on the type of mineral present in their composition, therefore, quantitative and qualitative analyzes are important for a better therapeutic approach. The animals may suffer from the disease and be asymptomatic, or show nonspecific clinical signs, making the diagnosis difficult. The disease should not be seen as a single problem, but as a consequence of various disorders. As dietary, metabolic, genetic and infectious causes, as well as factors that potentiate the chance of development of uroliths such as breed, age, sex, age range, obesity, sedentary lifestyle, geographic region and climate. Thus, the knowledge of the factors that influence the formation of uroliths, as well as the understanding of the pathophysiology, are key elements for better alternatives of therapy and prevention. The recognition of these factors helps to identify susceptible populations, minimizing exposure and increasing the protection factors, which facilitates the diagnosis and treatment of patients with urolithiasis. The objective of this paper is to present the main risk factors involved in the formation of urinary lithiasis in felines.

The evaluation and management of urolithiasis in the ED: A review of the literature.

BACKGROUND: Urolithiasis is a common condition in the U.S. Patients frequently present to the emergency department (ED) for care, including analgesia and treatments to facilitate stone passage. OBJECTIVE: With the new evidence concerning the evaluation and treatment of urolithiasis, this review summarizes current literature regarding the ED management of urolithiasis. DISCUSSION: Urolithiasis occurs primarily through supersaturation of urine and commonly presents with flank pain, hematuria, and nausea/vomiting. History, examination, and assessment with several laboratory tests are cornerstones of evaluation. Urinalysis is not diagnostic, but it may be used in association with other assessments. Risk assessment tools and advanced imaging can assist with diagnosis. Computed tomography (CT) is often considered the gold standard. Newer low-dose CT imaging may reduce radiation. Recent studies support ultrasound as an alternate diagnostic modality, especially in pediatric and pregnant patients. Nonsteroidal anti-inflammatory drugs remain first-line therapy, with opioids or intravenous lidocaine reserved for refractory pain. Tamsulosin can increase passage in larger stones but has not demonstrated benefit in smaller stones. Nifedipine and intravenous fluids are not recommended to facilitate passage. Surgical intervention is based upon stone size, duration, and modifying factors. Patients who are discharged should be advised on dietary changes. CONCLUSION: Urolithiasis is a common disease increasing in prevalence with the potential for significant morbidity. Focused evaluation with history, examination, and testing is important in diagnosis and management. Understanding the clinical features, risk assessment tools, imaging options, and treatment options can assist emergency physicians in the management of urolithiasis.

Postrenal acute kidney injury in a patient with unilateral ureteral obstruction caused by urolithiasis: A case report.

RATIONALE: In patients with bilateral ureteral obstruction, the serum creatinine levels are often elevated, sometimes causing postrenal acute kidney injury (AKI). In contrast, those with unilateral ureteral obstruction present normal serum creatinine levels, as long as their contralateral kidneys are preserved intact. However, the unilateral obstruction of the ureter could affect the renal function, as it humorally influences the renal hemodynamics. PATIENT CONCERNS: A 66-year-old man with a past medical history of hypertension and diabetes mellitus came to our outpatient clinic because of right abdominal dullness. DIAGNOSES: Unilateral ureteral obstruction caused by a radio-opaque calculus in the right upper ureter and a secondary renal dysfunction. INTERVENTIONS: As oral hydration and the use of calcium antagonists failed to allow the spontaneous stone passage, extracorporeal shock wave lithotripsy (ESWL) was performed. OUTCOMES: Immediately after the passage of the stone, the number of red blood cells in the urine was dramatically decreased and the serum creatinine level almost returned to the normal range with the significant increase in glomerular filtration rate. LESSONS: Unilateral ureteral obstruction by the calculus, which caused reflex vascular constriction and ureteral spasm in the contralateral kidney, was thought to be responsible for the deteriorating renal function.

Urolithiasis - Ten things every general practitioner should know.

BACKGROUND: Upper urinary tract stones are a common problem in Australia, with an incidence of 0.13% per year, and a lifetime prevalence of up to 15% in males and 8% in females. Many of these patients first present to general practitioners (GPs), so a thorough understanding of the diagnosis, treatment and prevention of stone disease is an important part of any GP's arsenal. OBJECTIVE: In this article, we present evidence-based guidelines regarding urolithiasis, from diagnosis, through to conservative and operative management, and prevention, as a reference for GPs and other primary care physicians. DISCUSSION: The majority of urolithiasis cases can be conservatively managed. However, prior to conservative management, adequate imaging must be obtained and emergent conditions must be excluded. Conservative management should not be initiated without a plan in the event the management fails, and adequate analgesia and medical expulsive therapy should be prescribed. Should surgery be necessary, the majority of operations can be performed as minimally invasive day procedures.

Urolithiasis as an extraarticular manifestation of ankylosing spondylitis.

Ankylosing spondylitis (AS) affects sacroiliac and axial joints as well as extraarticular organs, such as the eye, lung, bowel, and heart. Although examples of renal involvement in AS, such as IgA nephropathy, amyloidosis, and glomerulonephritis, have been reported, it has not been emphasized that urolithiasis is frequently formed in the clinical course of AS. Growing evidence indicates that urolithiasis may be observed in AS patients and is more frequent than other extraarticular features. In this review, we will discuss frequency and predictors of AS-related urolithiasis and summarize the possible underlying genetic and biochemical mechanisms. We believe an increased awareness of urolithiasis as a complication of AS will encourage future studies that will shed light on disease mechanisms and preventative therapies.

Urolithiasis secondary to primary obstructive megaureter in an adult: a case report.

BACKGROUND: Primary obstructive megaureter is relatively uncommon in adults. This condition usually regresses spontaneously or is treated during infancy. It can remain asymptomatic for decades until adulthood when symptoms may manifest in the event of complications or during a routine radiologic imaging. Primary obstructive megaureter has been reported to favor stone formation in the upper urinary tract. CASE PRESENTATION: We present the case of a 35-year-old Moroccan man who had a 10-year history of intermittent left flank pain and hematuria. A computed tomography urogram revealed a left megaureter with giant ureteral and renal calculi. CONCLUSIONS: Primary obstructive megaureter should be a differential diagnosis in an adult with hydroureteronephrosis associated with urolithiasis especially when there is kidney impairment. Through this case report we will discuss the diagnosis and management of primary obstructive megaureter associated with urolithiasis in adults.

Influence of bladder lithiasis on lower urinary tract dynamics in patients with spinal cord injury.

STUDY DESIGN: A prospective and a case-matched control study. OBJECTIVES: To study the lower urinary tract dysfunction associated with bladder lithiasis in patients with spinal cord injury (SCI). SETTING: Toledo (Spain). METHODS: We have carried out a urodynamic study in 30 patients with SCI with lithiasis in their bladder before and 3 months after bladder endoscopic lithotripsy. This second study was compared with the urodynamic findings of a different group of 30 patients with SCI, without a history of bladder lithiasis, paired with cases by gender and date of urodynamic study. RESULTS: We have found that the prevalence of neurogenic detrusor overactivity (NDO) was significantly different after bladder lithotripsy, although the cystomanometric capacity was significantly increased. A group of patients with lithiasis showed a maximum flow rate, a voiding maximum detrusor pressure and the detrusor contractility parameter Wmax lower than that in controls. On the other hand, a voiding abdominal straining was found to be significantly greater than that in controls. CONCLUSIONS: Bladder lithiasis affects the presence of NDO in patients with SCI. Patients with SCI who develop bladder lithiasis present a lower detrusor contractility power compared with those who do not.

Clinical relevance of aortic calcification in urolithiasis patients.

BACKGROUND: The aim of the present study is to investigate the clinical relevance of aortic calcification in urolithiasis patients. METHODS: Between January 2010 and September 2014, 1221 patients with urolithiasis were treated in Oyokyo Kidney Research Institute and Hirosaki University Hospital. Among these, 287 patients (Stone group) on whom adequate data were available were included in this retrospective study. We also selected 148 subjects with early stage (pT1N0M0) renal cell carcinoma from 607 renal cell carcinoma patients who underwent radical nephrectomy at Hirosaki University Hospital (Non-stone group) as control subjects. Validity of the Non-stone group was evaluated by comparison with pair-matched 296 volunteers from 1166 subjects who participated in the Iwaki Health Promotion Project in 2014. Thereafter, age, body mass index, aortic calcification index (ACI), renal function, serum uric acid concentrations, and comorbidities (diabetes, hypertension, or cardiovascular disease) were compared between the Non-stone and Stone groups. Independent factors for higher ACI and impaired renal function were assessed using multivariate logistic regression analysis. RESULTS: We confirmed relevance of Non-stone group patients as a control subject by comparing the pair-matched community-dwelling volunteers. Backgrounds of patients between the Non-stone and Stone groups were not significantly different except for the presence of hypertension in the Stone group. ACI was not significantly high in the Stone group compared with the Non-stone group. However, age-adjusted ACI was greater in the Stone group than the Non-stone group. Among urolithiasis patients, ACI was significantly higher in uric acid containing stone patients. The number of patients with stage 3B chronic kidney disease (CKD) was significantly higher in the Stone group than in the Non-stone group (12% vs. 4%, P = 0.008). Multivariate logistic regression analysis showed higher aortic calcification index (>13%), and being a stone former were independent factors for stage 3B CKD at the time of diagnosis. CONCLUSION: Aortic calcification and being a stone former had harmful influence on renal function. This study was registered as a clinical trial: UMIN: UMIN000022962.