Involvement of renin-angiotensin-aldosterone system in calcium oxalate crystal induced activation of NADPH oxidase and renal cell injury.

INTRODUCTION AND OBJECTIVES: Reactive oxygen species (ROS) are produced during the interaction between oxalate/calcium oxalate monohydrate (COM) crystals and renal epithelial cells and are responsible for the various cellular responses through the activation of NADPH oxidase (Nox). Ox and COM also activate the renin-angiotensin-aldosterone system (RAAS). Aldosterone stimulates ROS production through activation of Nox with the involvement of mineralocorticoid receptor (MR), Rac1 and mitogen-activated protein kinases (MAPK). We investigated RAAS pathways in vivo in an animal model of hyperoxaluria and in vitro by exposing renal epithelial cells to COM crystals. METHODS: Hyperoxaluria was induced in male SD rats by administering ethylene glycol. One group of rats was additionally given spironolactone. Total RNA was extracted and subjected to genomic microarrays to obtain global transcriptome data. Normal rat kidney cell line (NRK-52E) was incubated with aldosterone(10(-7) M) and COM(67 µg/cm(2)) with or without spironolactone(10(-5) M), a selective inhibitor of SRC family of kinases; protein phosphatase 2(pp2) (10(-5) M) and Nox inhibitor; diphenylene iodonium (DPI) (10(-5) M). RESULTS: Relative expression of genes encoding for AGT, angiotensin receptors 1b and 2, Renin 1, Cyp11b, HSD11B2, Nr3c2, NOx4 and Rac1 was upregulated in the kidneys of rats with hyperoxaluria. Treatment with spironolactone reversed the effect of hyperoxaluria. Both aldosterone and COM crystals activated Nox and Rac1 expression in NRK52E, while spironolactone inhibited Nox and Rac1 expression. Increased Rac1 expression was significantly attenuated by treatment with PP2 and spironolactone. CONCLUSIONS: Results indicate that hyperoxaluria-induced production of ROS, injury and inflammation are in part associated with the activation of Nox through renin-angiotensin-aldosterone pathway.

[The Effect of Tadalafil on Sexual Function, Urinary Function and Health-Related Quality of Life in Patients Treated with Brachytherapy].

OBJECTIVES: We compared sexual function by the expanded prostate cancer index composite (sexual domains of EPIC), health-related quality of life (SF-8), and International Prostate Symptom Score (I-PSS) inpatients using tadalafil after prostate brachytherapy (PB). Forty-five patients who underwent PB between April 2011 and January 2014 were included in this study. Patients were divided into the tadalafil (20 mg,once/week or once/two weeks) treated and non-treated (NT) groups. Sexual function was assessed prior to PB treatment and followed up to 24 weeks after PB. SF-8, sexual domains of EPIC, IPSS and subjective symptoms were assessed pre-PB and at 4, 8, 16, and 24 weeks post-PB. Patients in the tadalafil group achieved higher sexual function scores compared to NT group at all time points. For SF8, the patients in the tadalafil group significantly improved in mental health by the eighth week, and significantly worsened in the NT group (8 w ; p = 0.04). The voiding domains of EPIC score were found to worsen significantly after 4 weeks from PB in both groups, but the score tended to improve over 24 weeks. There was no significant difference between two groups. The I-PSS total score was found to worsen significantly in both groups post-PB, but the tadalafil group had a tendency to worsen less. PB treatment of localized prostate cancer is preferred for the preservation of sexual function. Management of sexual dysfunction with tadalafil after PB does not worsen sexual functions. We concluded that tadalafil might be applicable to mental health care in the treatment of patients with a high interest in sexual function before PB.

[Cases of Fournier's Gangrene in Kinki University].

The aim of our study was to identify risk factors that may influence outcomes for patients presenting with Fournier gangrene. Twelve patients hospitalized and treated between August 2007 and August 2013 were included in this study. Distinct features were noted after one or two weeks of hospitalization. We did not observe a significant correlation between death risk and the extent of necrosis in this patient set. However, the extent of necrosis tended to correlate with the duration of hospitalization in the survivors. We also compared the results of blood biochemical analyses between the surviving and non-surviving groups. A significant difference was noted in the levels of glucose (Glu) after two weeks. In the non-surviving group, Glu levels were increased. These findings suggest a relationship between glycemic control after the initiation of therapy and death. We also examined the results of blood biochemical analyses according to the duration of hospitalization. The lactate dehydrogenase (LDH) levels at admission and LDH levels after two weeks were significantly higher in the patients with a duration of hospitalization longer than the median duration of 61.5 days. These findings suggest a relationship between the duration of hospitalization and the extent of necrosis at diagnosis.

Add-on anticholinergic therapy for residual nocturia in patients with lower urinary tract symptoms receiving α1-blocker treatment: a multi-centre, prospective, randomised study.

PURPOSE: To evaluate the efficacy and safety of imidafenacin (IM), a novel short half-life anticholinergic, as add-on therapy for male LUTS with nocturia and nocturnal polyuria. MATERIALS AND METHODS: This multicenter, prospective, randomized, open-labelled study was conducted and involved men who had frequency, urgency, and nocturia despite receiving a stable dose of α1-blocker for ≥1 month. Subjects were randomised to control (α1-blocker alone), IM twice/day (α1-blocker +0.1 mg imidafenacin twice daily), or IM nightly (α1-blocker plus 0.1 mg imidafenacin nightly) group; the treatment period was 8 weeks. Primary endpoints included improvements in night-time frequency and Nocturia Quality of Life Questionnaire (N-QOL) scores. Secondary endpoints included changes from the baseline in frequency volume chart variables, and post-void residual volume. RESULTS AND LIMITATIONS: Compared with the controls, IM twice/day and IM nightly patients had a significantly lower night-time frequency (changes from baseline: 0.1 ± 0.8 in control, -0.6 ± 0.9 in IM twice/day, and -0.4 ± 1.0 in IM nightly, p = 0.5227, 0.0006 and 0.0143, respectively). The hours of undisturbed sleep and N-QOL score were significantly improved in IM twice/day group, though not IM nightly group. Nocturnal urine volume was significantly reduced in IM nightly group, although total urine volume remained unchanged. CONCLUSIONS: A short half-life anticholinergic is suggested to be safe and effective as an add-on therapy for residual nocturia in patients with male LUTS receiving α1-blocker treatment. Anticholinergic administration nightly could reduce the nocturnal urine volume.

[Uretero-external iliac artery fistula with longterm indwelling of ureteral stent].

We report a case of a patient with a fistula between the right ureter and external iliac artery. The patient was a 75-year-old woman who had undergone abdominal radical hysterectomy for uterine cancer, and whole pelvis radiotherapy for right external iliac lymph node metastasis. Her post-operative course was complicated by hydronephrosis of the right kidney, which was treated by the insertion of a double-J stent. While removing the frequently obstructed double-J stent after percutaneous nephrostomy, arterial hemorrhage occurred from the external urethral meatus. Computed tomographic scan demonstrated right ureteral external iliac artery fistula formation located adjacent to the pseudoaneurysm. The patient was treated successfully with endovascular stent grafting and has showed no episode of hematuria since then.

Osteopontin knockdown in the kidneys of hyperoxaluric rats leads to reduction in renal calcium oxalate crystal deposition.

Osteopontin (OPN) expression is increased in kidneys of rats with ethylene glycol (EG) induced hyperoxaluria and calcium oxalate (CaOx) nephrolithiasis. The aim of this study is to clarify the effect of OPN knockdown by in vivo transfection of OPN siRNA on deposition of CaOx crystals in the kidneys. Hyperoxaluria was induced in 6-week-old male Sprague-Dawley rats by administering 1.5% EG in drinking water for 2 weeks. Four groups of six rats each were studied: Group A, untreated animals (tap water); Group B, administering 1.5% EG; Group C, 1.5% EG with in vivo transfection of OPN siRNA; Group D, 1.5% EG with in vivo transfection of negative control siRNA. OPN siRNA transfections were performed on day 1 and 8 by renal sub-capsular injection. Rats were killed at day 15 and kidneys were removed. Extent of crystal deposition was determined by measuring renal calcium concentrations and counting renal crystal deposits. OPN siRNA transfection resulted in significant reduction in expression of OPN mRNA as well as protein in group C compared to group B. Reduction in OPN expression was associated with significant decrease in crystal deposition in group C compared to group B. Specific suppression of OPN mRNA expression in kidneys of hyperoxaluric rats leads to a decrease in OPN production and simultaneously inhibits renal crystal deposition.

Efficacy of silodosin in patients undergoing brachytherapy: a randomized trial involving a pressure flow study.

PURPOSE: The purpose of the study is to investigate the efficacy of an alpha-1 adrenergic receptor antagonist (silodosin) for the treatment of lower urinary tract symptoms (LUTS) associated with interstitial (125)I implantation for prostate cancer. METHODS: This randomized single-center study involved 105 patients (53 with and 52 without silodosin). Silodosin was postoperatively administered, daily, for 6 months (8 mg/day). Urinary symptoms and pressure flow were evaluated preoperatively and postoperatively at 1, 3, 6, and 12 months. RESULTS: At 12 months, interstitial (125)I implantation had induced a significant decrease in prostate volume (28.3 ± 11.1-20.5 ± 8.1 g in the silodosin group and 26.1 ± 9.7-17.7 ± 4.9 g in the controls) and the prostate-specific antigen level (7.1 ± 3.6-1.4 ± 1.7 ng/mL in the silodosin group and 8.1 ± 4.3-1.3 ± 1.2 ng/mL in the controls). Significant improvements in the international prostate symptom voiding subscores at 6 months and quality of life at 3 months were observed in those receiving silodosin. The pressure flow studies demonstrated that silodosin had significantly enlarged the bladder capacity when the first non-voiding contraction was seen at 3 and 12 months (3M: 127.1 ± 74.8 vs. 118.2 ± 83.9 mL, p = 0.001; 12M: 123.7 ± 79.3 vs. 100.3 ± 73.4 mL, p = 0.01); however, there were no improvements in the bladder outlet obstruction index (BOOI) or urinary flow. CONCLUSIONS: Silodosin temporarily improved LUTS, but did not improve the BOOI after (125)I implantation in the prostate.

[A case of testicular tumor of ovarian epithelial type].

Testicular tumors of ovarian epithelial types are rare, and their etiology is unknown. Moreover, a clear treatment policy has not become settled. Under the diagnosis of a testicular tumor, this patient underwent a high orchiectomy, and the pathology revealed testicular tumor of ovarian epithelial type. CA125 was elevated for three years post-operatively and a recurrence was discovered in the left inguinal region by positron emission tomography-computed tomography. Therefore, tumor extirpation was performed. The pathology result confirmed the recurrence of testicular tumor of ovarian epithelial type. After the surgery, the patient was given combined therapy with paclitaxel and carboplatin, which is a regimen of ovarian cancer, on a triweekly basis. After five courses of this therapy, the patient remains in remission.

The effects of chlormadinone acetate on lower urinary tract symptoms and erectile functions of patients with benign prostatic hyperplasia: a prospective multicenter clinical study.

Purpose. To evaluate the effects of chlormadinone acetate (CMA), progesterone-derived antiandrogen, on lower urinary tract symptoms (LUTS) and erectile functions of benign prostatic hyperplasia (BPH). Methods. A multicenter, single-cohort prospective study was conducted. A total of 114 patients received CMA for 16 weeks. The endpoints were changes in International Prostate Symptom Scores (IPSS), IPSS-QOL, International Index of Erectile Function-5, Q max prostate volume, and residual urine volume. Results. Significant improvements were observed in IPSS from week 8 to week 48 (32 weeks after treatment). IPSS-QOL improvements were also significant from week 8 to week 48. Q max increased to a maximum at Week 16 and remained elevated throughout the study. Moreover, a decrease of 25% in prostate volume was observed at Week 16. IPSS, QOL, and Qmax changes during the study were not different between the previously treated and untreated patients. IPSS storage subscore changes differed between the age groups. Few severe adverse reactions were observed, except for erectile dysfunction. Conclusions. CMA rapidly and significantly reduced prostate volume and improved voiding and storage symptoms and QOL. Our results suggest that CMA is safe and beneficial, especially for elderly patients with LUTS associated with BPH.

[Penile metastasis from esophageal cancer: a case report].

A 61-year-old man visited our department with the complaint ofa palpable hard mass in the penile shaft which showed a significant uptake on fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT). He had undergone a surgery for local invasive esophageal cancer and had received adjuvant chemotherapy. Open biopsy revealed metastases in the carvenous body and the glans of the penis from esophageal squamous cell carcinoma. He died from the cancer 5 months after the biopsy in spite of additional chemotherapy.

Survey on lower urinary tract symptoms and sleep disorders in patients treated at urology departments.

OBJECTIVES: This study examined the association between sleep disorders and lower urinary tract symptoms in patients who had visited urology departments. METHODS: This was an independent cross-sectional, observational study. Outpatients who had visited the urology departments at the Kinki University School of Medicine or the Sakai Hospital, Kinki University School of Medicine, between August 2011 and January 2012 were assessed using the Athens Insomnia Scale and the International Prostate Symptom Score. RESULTS: In total, 1174 patients (mean age, 65.7 ± 13.7 years), with 895 men (67.1 ± 13.2 years old) and 279 women (61.4 ± 14.6 years old), were included in the study. Approximately half of these patients were suspected of having a sleep disorder. With regard to the International Prostate Symptom Score subscores, a significant increase in the risk for suspected sleep disorders was observed among patients with a post-micturition symptom (the feeling of incomplete emptying) subscore of ≥1 (a 2.3-fold increase), a storage symptom (daytime frequency + urgency + nocturia) subscore of ≥5 (a 2.7-fold increase), a voiding symptom (intermittency + slow stream + hesitancy) subscore of ≥2 (a 2.6-fold increase), and a nocturia subscore of ≥2 (a 1.9-fold increase). CONCLUSION: The results demonstrated that the risk factors for sleep disorders could also include voiding, post-micturition, and storage symptoms, in addition to nocturia.

Sorafenib rechallenge in patients with metastatic renal cell carcinoma.

UNLABELLED: What's known on the subject? and What does the study add? Targeted agents with a similar or different target molecule are often used sequentially in the treatment of metastatic RCC. Two tyrosine kinase inhibitors, sorafenib and sunitinib, have been reported to show little cross-resistance, when used sequentially. In addition, a recent report showed that sunitinib rechallenge could potentially benefit selected patients. This case series shows that patients once refractory to sorafenib could regain disease control on rechallenge with sorafenib during sequential treatment. Outcomes of the sorafenib rechallenge were not significantly affected by the response to the initial sorafenib treatment or by the duration of intervening treatments between first sorafenib and rechallenge. OBJECTIVE: To investigate clinical outcomes of sorafenib rechallenge during sequential therapy for patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients with metastatic RCC who received sorafenib rechallenge after failed treatment first with sorafenib and subsequently with other agents, were retrospectively reviewed for patient characteristics, best response, progression-free survival (PFS), and adverse events (AEs). RESULTS: Of the 14 patients who received sorafenib rechallenge, 12 were evaluable for response. Eleven patients had previously undergone nephrectomy, and 10 had previously received systemic therapy, mostly interferon-α (nine patients) and interleukin-2 (six patients), with a median duration of 9 months. The best responses after the first sorafenib therapy were partial response (PR) in two patients, stable disease (SD) in seven, and progressive disease (PD) in two. The median PFS was 5.7 months. Initial sorafenib therapy was discontinued because of PD in eight patients and AEs in four patients. Rechallenge with sorafenib was undertaken after a 7.6 month median interval from the initial sorafenib challenge. Eight patients achieved SD on sorafenib rechallenge and median PFS was 5.4 (95% confidence interval, 3.8-7.0) months. The outcome of the sorafenib rechallenge was not significantly affected by the response to the initial sorafenib treatment or by the duration of treatments received between first sorafenib and rechallenge. No severe AE was newly observed on the rechallenge. CONCLUSION: In the systemic treatment of advanced RCC, it was suggested that patients once refractory to sorafenib could regain disease control on rechallenge with sorafenib during sequential treatment.

[Prostate cancer in a young adult : a case report].

We report a case of prostate cancer in a 41-year-old male. The patient initially visited another institution with a chief complaint of left breech pain. He was referred to our hospital for further investigation. Serum level of PSA was 267ng/ml and multiple bone metastases were found on bone scintigram. Digital rectal examination revealed a stony-hard prostate. Computed tomography showed multiple lung and lymph node metastases. Transperineal needle biopsy of the prostate revealed moderately differentiated adenocarcinoma (Gleason score 4＋5) frombilateral lobes (the 3th Edition). The patient was diagnosed with cT4N1M1c prostate cancer and maximal androgen blockade therapy was commenced.

[Changes in serum prostate specific antigen and testosterone levels after chlormadinone acetate treatment in patients with benign prostatic hyperplasia : a prospective multicenter clinical study].

In this prospective multicenter study, we investigated the changes in serum prostate-specific antigen (PSA) and testosterone levels after treatment with antiandrogen chlormadinone acetate (CMA) in patients with benign prostatic hyperplasia (BPH). The inclusion criteria for the patients were as follows : PSA value of C10 ng/ml, maximum urine flow rate of ＜15 ml/s, estimated prostate volume of B20 ml, International Prostate System Score (IPSS) of B8, and IPSS-quality of life (QOL) index of B2. Of the 115 patients who registered, 114 qualified for this study. The patients were treated with CMA (50 mg/day) for 16 weeks ; this was followed by a no-CMA phase of 32 weeks. When compared with the baseline PSA level, the levels at 8 and 16 weeks of treatment had decreased by 56.4% (95% confidence interval [CI], 51.1-1.2) and 57.6% (95% CI, 52.3-62.4), respectively. Similarly, when compared with the baseline testosterone level, the levels at 8 and 16 weeks of treatment had decreased by 90.1% (95% CI, 87.8-91.9) and 84.4% (95% CI, 80.7-87.4), respectively. After treatment discontinuation, the PSA levels gradually increased and returned to baseline in 32 weeks. However, the testosterone levels returned to baseline in only 8 weeks. Although patients over 80 years of age showed a gradual decrease in these levels when compared with younger patients, the changes in the levels of PSA and testosterone were not affected by age. Thus, in order to use antiandrogen agents including CMA for treating BPH, we need to determine the PSA value that converted it into double.

[Multifunctional character of osteopontin and strategy for clinical applications].

Osteopontin (OPN) is the major constituent of calcium-containing urinary stones and is involved in the inhibition of nucleation and aggregation of calcium oxalate (CaOx) crystals, promotion of the adherence of CaOx crystals to cultured renal epithelial cells, and regulation of inflammatory cells as chemokine. OPN has different effects (inhibitor and promoter) at each stage of stone formation in vitro and these multifunctional actions of OPN have not been fully elucidated. We developed a modified crystal method using collagen granules (CG) and immobilized OPN. OPN had strong inhibitory activity on the aggregation/growth of CaOx crystals, but the inhibitory activity decreased by use of OPN-immobilized CG. OPN is also a critical promoter of adherence for CaOx crystals to cultured renal epithelial cells in an in vitro experimental system. We examined the effect of OPN in vivo, by OPN siRNA transfection in rats. Hydrodynamic intravenous and renal subcapsular injections with lipofection were performed on days 1 and 8. The calcium concentration in the kidney was significantly lower and the frequency of CaOx crystal deposits in the tubules was lower in the OPN siRNA transfection group (drinking 1.5% ethylene glycol (EG)), than in the EG drinking group (sham operation) at day 15. We examined the effect of candesartan, an angiotensin II (Ang II) type 1 receptor blockers (ARB) in hyperoxaluric rats. ARB reduced crystal formation and calcium concentrations in the whole kidney. Hyperoxaluria leads to CaOx crystallization and the development of tubulointerstitial lesions in the kidney. AngII mediates OPN synthesis, which is involved in both macrophage recruitment and CaOx crystallization. OPN synthesis and production increased with hyperoxaluria but to a lesser extent in ARB-treated hyperoxaluric rats. These results show that oxalate can activate the renal renin-angiotensin system and that oxalate-induced upregulation of OPN is in part mediated via the renal renin-angiotensin system.

Superoxide from NADPH oxidase as second messenger for the expression of osteopontin and monocyte chemoattractant protein-1 in renal epithelial cells exposed to calcium oxalate crystals.

OBJECTIVE To test the hypothesis that exposure of a renal epithelial cell line, NRK52E, to calcium oxalate monohydrate crystals (COM) would up-regulate NADPH oxidase subunit p47(phox), enhance superoxide production and increase monocyte chemoattractant protein-1 (MCP-1) and osteopontin mRNA levels. MATERIALS AND METHODS Confluent cultures of NRK52E cells were exposed to COM (66.7 microg/cm(2)) with or with no pretreatment with diphenileneiodium chloride (DPI, 10 x 10(-6)m) an inhibitor for NADPH oxidase, under serum-free conditions. The conditioned medium was collected and total cellular RNA isolated from the cells, and subjected to enzyme-linked immunosorbent assay and real-time polymerase chain reaction (PCR). Production of reactive oxygen species (ROS) was estimated by dihydroethidium (DHE) staining using a fluorescence microscope. Immunohistochemistry and real-time PCR were used to analyse p47(phox) in NRK52E cells. RESULTS In COM treated NRK52E cells there was enhanced expression of p47(phox) and production of superoxide. COM-induced production of MCP-1 and osteopontin was significantly reduced after treatment with DPI. CONCLUSIONS While the generation of a lot of ROS might play a major role in tissue injury or death, the regulated generation of low concentration of ROS, possibly by NADPH oxidase, may represent a second messenger system for generation of COM-induced MCP-1 and osteopontin production in the renal tubules.

Urinary concentration of osteopontin and association with urinary supersaturation and crystal formation.

OBJECTIVE: In this study, we measured urinary osteopontin (OPN) concentrations in urolithiasis patients as well as in healthy volunteers, and investigated the relationship between urinary excretion of OPN and urinary supersaturation level. METHODS: Supersaturation levels (AP indexes) were determined by using Tiselius's index. Crystals with a maximum diameter of 12 ìm or larger and less than 5 ìm were counted by scanning electron microscopy. A sum of cross-sectional areas of crystals was also calculated as the total crystal volume (VT). RESULTS: Urinary OPN concentrations in the group with no urinary stone were significantly higher than that in the urolithiasis patients with a tendency toward stone enlargement. AP indexes were observed to be significantly higher in patients with stone enlargement, whereas urinary OPN concentrations bore no definite relation to the urinary supersaturation levels. VT and number of large crystals (12 ìm or larger) in patients with a tendency toward stone enlargement were higher than healthy volunteers, but no differences were found between the number of micro-crystal with the diameter of less than 5 ìm. On the basis of the plots of VT and OPN concentrations, regression analysis revealed that VT and log OPN had a significant correlation. CONCLUSION: Urinary OPN tended to be lower in cases with larger crystal volumes and is potentially associated with crystal growth for inhibitory effect.

Analysis of bone mineral density in urolithiasis patients.

BACKGROUND: The association between hypercalciuria and bone mineral density (BMD) has been already recognized. The aim of the present study is to relate BMD to age and sex and to evaluate the calcium metabolism and hypercalciuria-defined dietary or non-dietary category in patients with urolithiasis. METHODS: The BMI of the L2-L4 lumbar vertebrae was measured in 310 renal stone patients (191 men and 119 women). Percent age matched score (%AMS), which is the percent ratio of measured BMD to the mean BMD of age-matched control subjects, was utilized for the appraisal of BMD. Low BMD groups were defined by lower than 90% of %AMS. RESULTS: Low BMD was observed in 27.7% of urinary stone patients, which was not a significant difference to that of control subjects (23.5%) who were measured in the health examination. In male patients with urolithiasis, the frequency of patients in whom BMD had been apt to decrease since youth was high, but there was not a proven significant difference among the three age groups (20-39 years old, 40-59 years old and 60 years old or older). In contrast, for female stone patients, the frequency of low BMD markedly increased in patients aged 40 years or older, when menopause occurs. Furthermore, in female stone patients with hypercalciuria, the frequency of reduced BMD reached more than 40%. When the cause was non-dietary hypercalciuria (classified mainly on the daily amount of urinary calcium excretion after ingestion of calculus test diet), the frequency of reduced BMD reached 65% (P < 0.01). CONCLUSIONS: In case female stone patients with non-dietary hypercalciuria become menopausal, not only the risk of recurrent lithiasis increases, but the possibility of developing osteopenia in the future also increases. Appropriate treatments for prophylactic effects on urolithiasis or osteopenia should be considered, as judged from BMD, diet, sex, urinary calcium excretion and other factors synthetically.