Effects of the xanthine oxidase inhibitor, febuxostat, on the expression of monocyte chemoattractant protein-1 and synchronous genes in MDCK cells treated with calcium oxalate monohydrate crystals.

OBJECTIVES: To examine the effects of the selective xanthine oxidase inhibitor febuxostat on the expression of inflammation-related genes involved in stone formation. METHODS: Madin-Darby canine kidney cells were exposed to febuxostat, followed by calcium oxalate monohydrate crystals. Monocyte chemoattractant protein-1 messenger ribonucleic acid expression levels were determined by real-time reverse transcription polymerase chain reaction analysis. Deoxyribonucleic acid microarray analysis was utilized to evaluate gene expression. RESULTS: Calcium oxalate monohydrate crystals activated monocyte chemoattractant protein-1 messenger ribonucleic acid expression in a time- and concentration-dependent manner. Febuxostat suppressed monocyte chemoattractant protein-1 expression. The expression levels of a group of inflammatory genes, including interleukin-8 and chemokine (C-X-C motif) ligand 10, which are downstream of reactive oxygen species, fluctuated similarly to the observed monocyte chemoattractant protein-1 fluctuations and were reduced by febuxostat pretreatment. CONCLUSIONS: Febuxostat exerts preventive effects against reactive oxygen species production and oxidative stress, and might represent a potential treatment for calcium oxalate stones. In the present study, febuxostat downregulated the calcium oxalate monohydrate crystal-induced monocyte chemoattractant protein-1 messenger ribonucleic acid expression.

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.

Chronological changes in epidemiological characteristics of lower urinary tract urolithiasis in Japan.

OBJECTIVES: To determine changes and trends in the annual incidence and epidemiological aspects of lower urinary tract stones in Japan. METHODS: Data about patients who had been diagnosed by urologists in 2015 with first and recurrent lower urinary tract stones were collected from 301 hospitals approved by the Japanese Board of Urology. The estimated annual incidence according to sex, age and stone composition was compared with previous nationwide surveys between 1965 and 2005. RESULTS: The incidence of lower urinary tract stones in Japan has steadily increased from 4.7 per 100 000 in 1965 to 12.0 per 100 000 in 2015. However, the age standardized annual incidence of lower urinary tract stones has remained relatively stable over the same period at 5.5 per 100 000 and 6.0 per 100 000 in 1965 and 2015, respectively. The increase in incidence was most evident among individuals aged ≥80 years. The incidence of calcium oxalate stones has steadily increased among males and females, whereas that of infection-related stones has significantly decreased from 26.2% to 14.3% among men over the past 50 years. CONCLUSIONS: Nationwide surveys suggest a steady increase in the incidence of lower urinary tract stones over a 50-year period in Japan. This trend might reflect changes in the aging population and improved Japanese medical standards.

Chronological changes in the epidemiological characteristics of upper urinary tract urolithiasis in Japan.

OBJECTIVES: To assess epidemiological and chronological trends of upper urinary tract stones in Japan in 2015. METHODS: Patients with a first episode of upper urinary tract stones in 2015 were enrolled in this nationwide survey. The study included all hospitals approved by the Japanese Board of Urology, therefore covering most of the hospitals where urologists practice in Japan. The annual incidence and composition of urolithiasis were evaluated by age and sex. These results were compared with the previous results of the nationwide surveys from 1965 to 2005 to analyze temporal trends. RESULTS: The estimated annual incidence of a first-episode upper urinary tract stone in 2015 was 137.9 (191.9 in men and 86.9 in women) per 100 000. The estimated age-standardized first-episode upper urinary tract stone incidence in 2015 was 107.8 (150.6 in men and 63.3 in women) per 100 000, which did not represent a significant increase since 2005. An equivalent incidence was observed in patients aged >50 years, whereas a reduced incidence was observed in patients aged <50 years in both sexes. The proportion of patients who received percutaneous nephrolithotomy and/or ureteroscopy increased by approximately fivefold in the past 10 years. CONCLUSIONS: The steady increase in the annual incidence of upper urinary tract stones since 1955 leveled off in 2015. The current results show novel trends in the incidence and treatment modalities in the nationwide surveys of urolithiasis in Japan.

Epidemiology of stone disease across the world.

Nephrolithiasis is a highly prevalent disease worldwide with rates ranging from 7 to 13% in North America, 5-9% in Europe, and 1-5% in Asia. Due to high rates of new and recurrent stones, management of stones is expensive and the disease has a high level of acute and chronic morbidity. The goal of this study is to review the epidemiology of stone disease in order to improve patient care. A review of the literature was conducted through a search on Pubmed®, Medline®, and Google Scholar®. This review was presented and peer-reviewed at the 3rd International Consultation on Stone Disease during the 2014 Société Internationale d'Urologie Congress in Glasgow. It represents an update of the 2008 consensus document based on expert opinion of the most relevant studies. There has been a rising incidence in stone disease throughout the world with a narrowing of the gender gap. Increased stone prevalence has been attributed to population growth and increases in obesity and diabetes. General dietary recommendations of increased fluid, decreased salt, and moderate intake of protein have not changed. However, specific recommended values have either changed or are more frequently reported. Geography and environment influenced the likelihood of stone disease and more information is needed regarding stone disease in a large portion of the world including Asia and Africa. Randomized controlled studies are lacking but are necessary to improve recommendations regarding diet and fluid intake. Understanding the impact of associated conditions that are rapidly increasing will improve the prevention of stone disease.

[Clinical Study on the Efficacy and Continuous Docetaxel Based Chemotherapy Treatment for Castration-Resistant Prostate Cancer].

We report a retrospective study on the efficacy, adverse events and the factors for continuous docetaxel (DOC) therapy for patients with castration-resistant prostate cancer (CRPC). Between April 2007 and April 2015, 37 CRPC patients were treated with DOC therapy at Kanazawa Medical University Hospital. DOC was administered every 3 weeks at 70 mg/m2. Prostatic specific antigen (PSA) level, adverse events, cycles of DOC therapy, survival time and clinical passage were examined. Fifteen patients showed a decrease in PSA level of 50% or more, 9 patients showed less than 50% decrease in PSA level and 13 patients showed no decrease in PSA level. Adverse effect of grade 3 consisted of neutropenia in 29.7% and leukocytopenia in 10.8%. The median number of treatment cycles was 11.7 courses. The patients were divided into two groups ; the first group comprised of 26 patients who received short-term DOC therapy (≤10 cycles) and the second group comprised of 11 patients who received long-term DOC therapy (≥11 cycles). The 1-year survival rate was 59 and 100% for the short-term and long-term groups, respectively. Long-term treatment was related to pretreatment PSA nadir, time to progression of CRPC and serum lactate dehydrogenase level.

THE EFFECT OF RADIATION THERAPY FOR BONE METASTASIS IN URINARY ORGAN CANCER.

(Objective) Bone metastasis symptoms are complications that greatly reduce the quality of life (QOL) of cancer patients. We report a retrospective study on the efficacy of radiation therapy for patients with bone metastasis in urinary organ cancer. (Subjects and methods) Subjects are comprised of 17 patients; total irradiated areas consist of 25 sites. There are 5 patients diagnosed with renal cell carcinoma, 1 patient with bladder cancer and 11 patients with prostatic cancer. All of them have undergone radiation therapy for bone metastasis in urinary organ cancer between April 2007 and March 2014 in the Department of Urology, Kanazawa Medical University. The mean age of the patients was 66.7 years old. We looked at irradiated areas, exposure dose and changes of symptom in all patients. (Results) Irradiated areas are thoracolumbar vertebrae (14 sites), cranial base (2 sites), pubic bone (1 site), ilium bone (2 sites), sacral bone (1 site), rib bone (1 site) and hip joint (1 site). The mean exposure dose of one area is 37.5 Gy (13.5-60). 19 irradiated sites which were previously reported to have sharp pain have gained improvement at 16 sites. These 16 sites have comparatively lesser pain or no pain. 8 cases in acknowledgment of walk difficulty, it was with 7 cases walking alone possibility again. (Conclusion) This study showed that radiation therapy have significant improvement in terms of symptoms and QOL for the patients with bone metastasis in urinary organ cancer.

Factors influencing patient satisfaction with antimuscarinic treatment of overactive bladder syndrome: results of a real-life clinical study.

OBJECTIVES: To investigate patient satisfaction with antimuscarinic treatment of overactive bladder syndrome, and to identify factors having a significant influence on satisfaction. METHODS: A cross-sectional questionnaire survey was carried out to assess treatment satisfaction among male and female patients with overactive bladder (age ≥20 years) in the Hokuriku district of Japan. The overactive bladder symptom scores, treatment efficacies, adverse events (dry mouth and constipation), and patient satisfaction scores were investigated and compared among patients using different antimuscarinic therapeutics. RESULTS: In total, 977 survey respondents (52.6% men; mean age 73.6 years) received antimuscarinic treatment. The mean overactive bladder symptom score of these patients was 6.17; in addition, 32.3% patients were satisfied with their treatment, but 33.1% were dissatisfied. Factors having a significant influence on treatment satisfaction were sex (men were less satisfied), efficacy, adverse events and the overactive bladder symptom score. Constipation negatively influenced patient satisfaction to a greater extent than did dry mouth. Patient satisfaction varied according to the drug used. Constipation was less severe with the immediate-release-type agents (imidafenacin and oxybutynin) than with the extended-release-type (propiverine, solifenacin or tolterodine). CONCLUSIONS: Just one-third of Japanese Hokuriku patients with overactive bladder seem to be satisfied with their antimuscarinic treatment. Patient satisfaction is impaired by poor efficacy and the presence of adverse events; furthermore, constipation should be recognized as an adverse event that negatively influences patient satisfaction to a greater extent than dry mouth. Patient satisfaction differs according to the antimuscarinic agent used, with higher patient satisfaction being associated with less severe constipation.

Proteomic analysis of a rare urinary stone composed of calcium carbonate and calcium oxalate dihydrate: a case report.

The objective of the present study was to investigate the matrix protein of a rare urinary stone that contained calcium carbonate. A urinary stone was extracted from a 34-year-old male patient with metabolic alkalosis. After X-ray diffractometry and infrared analysis of the stone, proteomic analysis was carried out. The resulting mass spectra were evaluated with protein search software, and matrix proteins were identified. X-ray diffraction and infrared analysis confirmed that the stone contained calcium carbonate and calcium oxalate dihydrate. Of the identified 53 proteins, 24 have not been previously reported from calcium oxalate- or calcium phosphate-containing stones. The protease inhibitors and several proteins related to cell adhesion or the cytoskeleton were identified for the first time. We analyzed in detail a rare urinary stone composed of calcium carbonate and calcium oxalate dihydrate. Considering the formation of a calcium carbonate stone, the new identified proteins should play an important role on the urolithiasis process in alkaline condition.

Dynamic change and preventive role of stress response via Keap1-Nrf2 during renal crystal formation.

Oxidative stress is a major risk factor for calcium oxalate nephrolithiasis. Reports suggest that oxidative stress response is induced in animals and humans with kidney stones. Keap1, Nrf2, and HO-1 are known as oxidative stress mediators. However, the association between oxidative stress response and stone formation is unclear. In this study, we analyzed oxidative stress response from the acute to the crystal formation phase when crystal formation was applied to renal crystal mice model and bioimaging mice and investigated the effect on crystal formation. In renal tissues, after glyoxylate administration, HO-1 increased for up to 6 h and returned to baseline at 24 h. This was observed following each daily dose until five days after the crystallization phase; however, the range of increase was attenuated. The possibility that Nrf2 activity influenced the number of crystals was considered in the experiment. Crystal formation increased in Nrf2-deficient mice and could be reduced by Nrf2 activators. In conclusion, the oxidative stress response via the Keap1-Nrf2 pathway may contribute to crystal formation. Particularly, this pathway may be a prospective target for drug development to prevent and cure nephrolithiasis.

Practice Variation in the Management of Adult Hydroceles: A Multinational Survey.

Background: Although hydrocele is one of the most common urologic pathologies, it is seldom studied, and the major urologic associations have no guidelines for the management of adult hydroceles. Objective: To characterize international practice variation in the treatment of adult hydroceles. Design setting and participants: An international survey was conducted addressing the management of hydroceles among urologists in Belgium, Denmark, Finland, Iceland, Japan, and the Netherlands from September to December 2020. We invited a random sample of 170 urologists from each country (except Iceland). Outcome measurements and statistical analysis: Urologists' treatment options, factors relevant for decision-making, expected patient satisfaction, and outcomes after aspiration versus surgery were assessed. Results and limitations: Of the 864 urologists contacted, 437 (51%) participated. Of the respondents, 202 (53%) performed both hydrocelectomies and aspiration, 147 (39%) performed hydrocelectomies only, and 30 (8%) performed aspiration only. In Belgium (83%), the Netherlands (75%), and Denmark (55%), urologists primarily performed hydrocelectomies only, whereas in Finland (84%), Japan (61%), and Iceland (91%), urologists performed both hydrocelectomies and aspiration. Urologists favored hydrocelectomy for large hydroceles (78.8% vs 37.5% for small), younger patients (66.0% for patients <50 yr vs 41.2% for ≥70 yr), patients with few or no comorbidities (62.3% vs 23.1% with multiple comorbidities), and patients without antithrombotic agents (53.5% vs 36.5% with antithrombotic agents). Most urologists considered patient satisfaction to be highest after hydrocelectomy (53.8% vs 9.9% after aspiration) despite believing that hydrocelectomy is more likely to cause complications (hematoma 77.8% vs 8.8% after aspiration). Estimates varied between countries. Conclusions: We found a large variation in the treatment of adult hydroceles within and between countries. Optimization of hydrocele management globally will require future studies. Patient summary: Our international survey shows that treatment of adult hydrocele varies considerably within and between countries.

Cyclooxygenase 2 and prostaglandin E2 regulate the attachment of calcium oxalate crystals to renal epithelial cells.

OBJECTIVE: To determine the roles of endogenous cyclooxygenase 2 and prostaglandin E(2) in crystal-cell binding, which is considered to be an important step in the development of intratubular nephrocalcinosis. METHODS: An expression plasmid for human cyclooxygenase 2 was introduced into Madin-Darby canine kidney cells using the lipofection method. Cyclooxygenase activity was measured using thin-layer chromatography, and the prostaglandin E(2) concentration was determined with an enzyme immunoassay. In addition, crystal attachment was evaluated with a liquid scintillation counter using [(14)C] calcium oxalate monohydrate crystals, and immunohistochemistry and an enzyme immunoassay were used to analyze and quantify the expression of hyaluronan, a crystal-binding molecule. RESULTS: Cyclooxygenase 2-overexpressing Madin-Darby canine kidney cells produced about 10-fold more prostaglandin E(2) than wild-type Madin-Darby canine kidney cells, and their hyaluronan production was also upregulated. The attachment of calcium oxalate monohydrate crystals to cyclooxygenase 2-overexpressing Madin-Darby canine kidney cells was significantly reduced compared with their attachment to wild-type and mock-transfected Madin-Darby canine kidney cells. Pre-incubation of the cyclooxygenase 2-overexpressing cells, as well as the mock-transfected and wild-type cells with the cyclooxygenase 2 selective inhibitor etodolac, increased the cellular attachment of calcium oxalate monohydrate crystals in a dose-dependent manner. CONCLUSIONS: These findings suggest that cyclooxygenase 2 expression and the resultant increase in endogenous prostaglandin E(2), leading to increased hyaluronan production, help to prevent nephrocalcinosis by inhibiting the attachment of calcium oxalate monohydrate crystals to the surface of renal epithelial cells.

[Outlook for recurrence prevention from the viewpoint of the guidelines on urolithiasis].

In Japan, the number of patients with urolithiasis has continued to increase at a faster rate, with a lifetime morbidity in 2005 of 15.1% for males and 6.8% for females, possibly due to : 1) westernization of dietary habits and lifestyle, 2) improvement of diagnostic technologies (CT and ultrasound examination), and 3) aging of the population. Additionally, this disease has a higher recurrence rate ; for example, approximately 50% for calcium-containing calculi. The guidelines on urolithiasis consist primarily of the guidelines for treatment and recurrence prevention, and the items concerning recurrence prevention were added in the 2007 updated Guidelines on Urolithiasis by the European Association of Urology (EAU) and the American Urological Association (AUA) (EAU/AUA guidelines). These facts reflect the importance of recurrence prevention. On the other hand, the Japanese guidelines on urolithiasis are now being revised and will adopt the form of "clinical questions". This paper provides an overview of the examination methods for recurrence, lifestyle guidance, and drug therapies based on the current guidelines for diagnosis and treatment of urolithiasis as well as the points for clinical questions to be included in the revised guidelines for a deeper understanding and, consequently, return to routine clinical practice.

Recurrence of renal cell carcinoma after simultaneous radical nephrectomy and cadaver renal transplant.

Introduction: Generally, renal transplantation is contraindicated in cancer patients, and a certain follow-up period is required. We report a case of late recurrence of renal cell carcinoma in a patient who underwent simultaneous radical nephrectomy and cadaver renal transplantation due to renal cell carcinoma observed during renal transplantation after 12 years. Case presentation: Incidental renal cell carcinoma was found in a 48-year-old man during kidney transplantation who subsequently underwent simultaneous cadaver kidney transplantation and radical nephrectomy. Twelve years after transplantation, he developed an anterior mediastinal tumor, a lung tumor which was resected and a right adrenal gland mass which was resected along with the right kidney. Currently, he is being treated with tyrosine kinase inhibitors owing to the metastasis in the left adrenal gland. Conclusion: In patients with metastatic carcinoma undergoing renal transplant, the indications for surgical procedures and choice of immunosuppressants should be carefully considered.

Imaging of acquired cystic disease-associated renal cell carcinoma by contrast-enhanced ultrasonography with perflubutane microbubbles and positron emission tomography-computed tomography.

The preoperative assessment of renal cell carcinoma (RCC) complicated with acquired renal cystic disease in a 63-year-old male patient on long-term hemodialysis (30 years and 8 months) that was difficult because of no or poor contrast enhancement by dynamic CT scan is reported. Contrast-enhanced ultrasonography with perflubutane microbubbles and positron emission tomography-computed tomography (PET-CT) with 18F-fluorodeoxy glucose (FDG) in addition to dynamic CT were effective and useful for preoperative assessment of this patient. The pathological subtype of RCC in this patient was acquired cystic disease-associated RCC (ACD-associated RCC), which has been newly defined by Tickoo et al. (Am J Surg Pathol 30:141-153, 2006).

[Evolution of strategy to measure urinary supersaturation].

Urinary stones have an estimated lifetime morbidity of 15.1% in males and 6.1% in females ; in other words, one out of seven males and one out of fifteen females are affected with this disease at least once in their life. Previously, we reported a simple and easy method using microplates to measure the metastable limit (ML), which indicate the upper limit of supersaturation dissolution. In this study, we examined the usability of this microplate method. We confirmed that ML is correlated with the urinary calcium concentration in healthy subjects, single stone formers (SF), and recurrent stone formers (RSF). There was no significant difference between healthy subjects and RSF in urinary magnesium concentration, and ML was found to be correlated with urinary the concentration of oxalate and citrate acid in healthy subjects only. These results suggest that ML is a simple and easy way to measure the urinary calcium level and that ML could be a useful test item in outpatient settings as a convenient indicator for preventing recurrence of urinary stones in the future.

[Combination chemotherapy of docetaxel and UFT against hormone refractory prostate cancer].

Docetaxel-based chemotherapy has been shown to be effective and well tolerated by Japanese patients with metastatic hormone-refractory prostate cancer (HRPC). This study was undertaken to assess the feasibility of docetaxel in combination with UFT (a combination of tegafur and uracil) in Japanese patients with HRPC. Ten patients aged 60-86 years with HRPC, who were pre-treated with hormonal therapy and expected to have more than 3 month survival and without major organ dysfunction, were included in this study. Treatment consisted of docetaxel 70 mg/m2 every 3 weeks plus UFT 260 mg/m2 /day. The primary end point was prostate-specific antigen (PSA) response, and the secondary end points included progression-free survival and toxicity. Nine patients were evaluable for efficacy and toxicity. The PSA response rate was 50% (1 CR and 4 PR). The most common non-hematological adverse events (of any grade) possibly related to treatment were neutropenia and anorexia. Grade 3/4 neutropenia and anorexia occurred in 50 and 20% of patients, respectively. The combination of docetaxel and UFT was feasible and active in Japanese patients with HRPC, with a manageable adverse-event profile similar to that observed in lung cancer chemotherapy.