RANKL, but Not R-Spondins, Is Involved in Vascular Smooth Muscle Cell Calcification through LGR4 Interaction.

Vascular calcification has a global health impact that is closely linked to bone loss. The Receptor Activator of Nuclear Factor Kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, fundamental for bone metabolism, also plays an important role in vascular calcification. The Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), a novel receptor for RANKL, regulates bone remodeling, and it appears to be involved in vascular calcification. Besides RANKL, LGR4 interacts with R-spondins (RSPOs), which are known for their roles in bone but are less understood in vascular calcification. Studies were conducted in rats with chronic renal failure fed normal or high phosphorus diets for 18 weeks, with and without control of circulating parathormone (PTH) levels, resulting in different degrees of aortic calcification. Additionally, vascular smooth muscle cells (VSMCs) were cultured under non-calcifying (1 mM phosphate) and calcifying (3 mM phosphate) media with different concentrations of PTH. To explore the role of RANKL in VSMC calcification, increasing concentrations of soluble RANKL were added to non-calcifying and calcifying media. The effects mediated by RANKL binding to its receptor LGR4 were investigated by silencing the LGR4 receptor in VSMCs. Furthermore, the gene expression of the RANK/RANKL/OPG system and the ligands of LGR4 was assessed in human epigastric arteries obtained from kidney transplant recipients with calcification scores (Kauppila Index). Increased aortic calcium in rats coincided with elevated systolic blood pressure, upregulated Lgr4 and Rankl gene expression, downregulated Opg gene expression, and higher serum RANKL/OPG ratio without changes in Rspos gene expression. Elevated phosphate in vitro increased calcium content and expression of Rankl and Lgr4 while reducing Opg. Elevated PTH in the presence of high phosphate exacerbated the increase in calcium content. No changes in Rspos were observed under the conditions employed. The addition of soluble RANKL to VSMCs induced genotypic differentiation and calcification, partly prevented by LGR4 silencing. In the epigastric arteries of individuals presenting vascular calcification, the gene expression of RANKL was higher. While RSPOs show minimal impact on VSMC calcification, RANKL, interacting with LGR4, drives osteogenic differentiation in VSMCs, unveiling a novel mechanism beyond RANKL-RANK binding.

Serum phosphate is associated with increased risk of bone fragility fractures in hemodialysis patients.

BACKGROUND: Bone fragility fractures are associated with high morbidity and mortality. This study analysed the association between the current biochemical parameters of CKD-MBD and bone fragility fractures in the COSMOS project. METHODS: COSMOS is a 3-year, multicentre, open cohort, prospective, observational study carried out in 6797 hemodialysis patients (227 centres from 20 European countries). The association of bone fragility fractures (outcome) with serum calcium, phosphate and PTH (exposure), was assessed using Standard Cox proportional hazards regression and Cox proportional hazards regression for recurrent events. Additional analyses were performed considering all-cause mortality as a competitive event for bone fragility fracture occurrence. Multivariable models were used in all strategies, with the fully adjusted model including a total of 24 variables. RESULTS: During a median follow-up of 24 months 252 (4%) patients experienced at least one bone fragility fracture (incident bone fragility fracture rate 28.5 per 1000 patient-years). In the fractured and non-fractured patients, the percentage of men was 43.7% and 61.4%, mean age 68.1 and 63.8 years and a haemodialysis vintage of 55.9 and 38.3 months respectively. Baseline serum phosphate > 6.1 mg/dL (reference value 4.3-6.1 mg/dL) was significantly associated with a higher bone fragility fracture risk in both regression models (HR: 1.53[95%CI: 1.10-2.13] and HR: 1.44[95%CI: 1.02-2.05]. The significant association persisted after competitive risk analysis (subHR: 1.42[95%CI: 1.02-1.98]) but the finding was not confirmed when serum phosphate was considered as a continuous variable. Baseline serum calcium showed no association with bone fragility fracture risk in any regression model. Baseline serum PTH > 800 pg/mL was significantly associated with a higher bone fragility fracture risk in both regression models, but the association disappeared after a competitive risk analysis. CONCLUSIONS: Hyperphosphatemia was independently and consistently associated with an increased bone fracture risk, suggesting serum phosphate could be a novel risk factor for bone fractures in hemodialysis patients.

Redox Metabolism and Vascular Calcification in Chronic Kidney Disease.

Vascular calcification (VC) is a common complication in patients with chronic kidney disease which increases their mortality. Although oxidative stress is involved in the onset and progression of this disorder, the specific role of some of the main redox regulators, such as catalase, the main scavenger of H2O2, remains unclear. In the present study, epigastric arteries of kidney transplant recipients, a rat model of VC, and an in vitro model of VC exhibiting catalase (Cts) overexpression were analysed. Pericalcified areas of human epigastric arteries had increased levels of catalase and cytoplasmic, rather than nuclear runt-related transcription factor 2 (RUNX2). In the rat model, advanced aortic VC concurred with lower levels of the H2O2-scavenger glutathione peroxidase 3 compared to controls. In an early model of calcification using vascular smooth muscle cells (VSMCs), Cts VSMCs showed the expected increase in total levels of RUNX2. However, Cts VMSCs also exhibited a lower percentage of the nucleus stained for RUNX2 in response to calcifying media. In this early model of VC, we did not observe a dysregulation of the mitochondrial redox state; instead, an increase in the general redox state was observed in the cytoplasm. These results highlight the complex role of antioxidant enzymes as catalase by regulation of RUNX2 subcellular location delaying the onset of VC.

Gene Expression Profile of Stromal Factors in Cancer-Associated Fibroblasts from Prostate Cancer.

Recent investigations point at the stromal microenvironment to assess additional diagnostic information and provide new therapeutic targets in cancer. The aim of the study was to contribute to the characterization of the phenotype of cancer-associated fibroblasts (CAFs) in prostate cancer (PCa) compared with normal prostate-associated fibroblasts (NAFs) and fibroblasts from benign prostatic hyperplasia (BPH). Three patient populations were prospectively recruited: 23 patients with new localized PCa, 14 patients with advanced PCa treated with androgenic deprivation therapy (ADT), and 7 patients with BPH. Gene expression of 20 stroma-derived factors, including the androgen receptor (AR), chaperones (HSPA1A and HSF1), growth factors (FGF2, FGF7, FGF10, HGF, PDGFB, and TGFß), proteins implicated in invasion (MMP2, MMP9, and MMP11), inflammation (IL6, IL17RB, NFκB, and STAT3), and in-stroma/epithelium interaction (CDH11, CXCL12, CXCL14, and FAP), was evaluated. Localized PCa CAFs showed a significant higher expression of FGF7, IL6, MMP2, and MMP11 compared with NAFs or IL17RB compared with BPH fibroblasts, but significantly lower expression of FGF10 and IL17RB compared with NAFs or CXCL14 compared with BPH fibroblasts. In addition, CAFs from ADT-resistant PCa showed significantly higher MMP11 and NFκB but significant lower TGFß expression compared with CAFs from ADT-sensitive tumors. Our results contribute to defining the CAFs phenotypes associated to PCa progression, which may contribute to the diagnosis and design of alternative therapies in PCa.

Review of evidence on handling hazardous drugs and Products in Urology Services; consensus document between the Spanish Urology Association and the Spanish Society of Health-System Pharmacists.

OBJECTIVE: The intravesical administration of hazardous drug products is a  standard practice in the urology setting, which potentially exposing medical  personnel to these drug products. It was deemed necessary to have a consensus document among the scientific societies involved (the Spanish Urological  Association and the Spanish Society of Hospital Pharmacy) that collects the best  available evidence on the safest handling possible of dangerous drug products in the setting of urology departments. METHOD: We reviewed the legislation and recommendations on the handling of  dangerous drug products, both at the national and international level. RESULTS: There is national legislation and regulations for protecting workers who  handle dangerous drugs and products, as well as  recommendations for handling to protect both the product and workers. DISCUSSION: Following the strategic lines of the European Parliament for 2014- 2020 in the chapter on occupational safety and health, the Spanish Urological  Association and the Spanish Society of Hospital Pharmacy proposed a series of  actions that decrease the risks of exposure for practitioners and caregivers  involved in the handling of these products. CONCLUSIONS: After this review, 19 recommendations were established for  handling dangerous drug products, which can be summarised as the need to  train all individuals involved (from management teams to patients and  caregivers), adopt systems that prevent contaminating leaks, implement  exposure surveillance programmes and optimise available resources.

Objetivo: La administración intravesical de medicamentos peligrosos es una  práctica habitual en el ámbito de la urología, con posible exposición del personal  sanitario a dichos medicamentos. Se considera necesario disponer de un  documento de consenso entre las sociedades científicas implicadas ­Asociación  Española de Urología y Sociedad Española de Farmacia Hospitalaria­ que recoja la mejor evidencia disponible para el manejo, de la forma más segura posible,  de medicamentos peligrosos en el ámbito de los servicios de Urología.Método: Se ha realizado una revisión de la legislación y de las recomendaciones sobre el manejo de medicamentos peligrosos tanto a nivel estatal como internacional.Resultados: Se dispone de legislación nacional y de normativas para la  protección de los trabajadores que manipulen medicamentos y productos peligrosos, así como recomendaciones de manipulación para la protección tanto del producto, como de los trabajadores.Discusión: Siguiendo las líneas estratégicas del Parlamento Europeo para el  período 2014-2020 en el capítulo de seguridad y salud laboral, la Asociación Española de Urología y la Sociedad Española de Farmacia Hospitalaria proponen una serie de actuaciones que hagan disminuir los riesgos de exposición de los profesionales y cuidadores implicados en su manejo. Conclusiones: Tras esta revisión se establecen 19 recomendaciones para el  manejo de medicamentos peligrosos que pueden resumirse en la necesidad de  formación de todas las personas implicadas (desde los equipos directivos hasta  los pacientes y cuidadores), la adopción de sistemas que no permitan fugas  contaminantes, programas de vigilancia de las exposiciones y optimización de  los recursos disponibles.

Determinan el pronóstico y la influencia de la terapia endovesical en la recurrencia del cáncer vesical / Predictive factors and influence of intravesical therapy for recurrence of non-muscle invasive bladder cancer

Introducción: Evaluamos, en cuanto a recurrencia, los factores pronósticos en el cáncer vesical no infiltrante de músculo y el efecto de la terapia intravesical. Material y métodos: Estudiamos 419 neoplasias vesicales. Realizamos análisis univariados y multivariados sobre 24 variables de estas neoplasias y valoramos distintos tratamientos. Resultados: Existieron diferencias significativas en el tiempo libre hasta la recurrencia, que fue menor en los tumores que recurrieron en menos de 12 meses, en los tumores múltiples (3 o más tumores) y de cúpula; además existieron diferencias estadísticamente significativas cuando se estudiaron dos grupos homogéneos de cirujanos.El empleo de instilaciones vesicales incrementó de forma independiente el tiempo hasta la recidiva. Se demostró que la recurrencia se produjo significativamente más tarde cuando se habían empleado dosis altas de BCG y terapia de mantenimiento. Conclusiones: Los siguientes factores resultaron independientes para explicar menor tiempo libre hasta la recurrencia superficial: recidiva en el primer año, multiplicidad, técnica quirúrgica, no empleo de lavados intravesicales, tratamiento con dosis bajas de BCG y terapia de inducción frente a mantenimiento. El empleo de instilaciones vesicales, con dosis altas de BCG y terapia de mantenimiento, incrementó de forma independiente el tiempo hasta la recidiva.

[Significance of anemia as an independent prognostic factor in patients with renal cell carcinoma]. / Anemia como factor pronóstico independiente en pacientes con carcinoma renal.

BACKGROUND AND OBJECTIVE: The aim of this study was to analyze the significance of anemia as well as other prognostic factors influencing survival in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: A retrospective review of data of 316 patients who underwent surgery between 1970 and 2003 was performed. Most important known prognostic factors of RCC were investigated. RESULTS: Most of patients had T1b-T2, low nuclear grade and single tumours. In 8.2% and 9% of cases, lymph node and metastatic dissemination were detected at the time of diagnosis, respectively. At the beginning, most frequent symptoms were hematuria and pain, with anemia (Hb >10g/dl) in 69 patients. After a median follow-up of 50 months, 24.1% of patients had a recurrence. From these, more than 50% developed recurrence within one year after nephrectomy. Advanced tumours (T3-4) consisted of high nuclear grade (III-IV) tumours, larger size tumours, with necrosis and vascular infiltration in surgical specimen, as well as lymph node and metastatic dissemination. In multivariate analysis, anemia, time to recurrence, type of treatment for recurrence as well as lymph node dissemination were independent factors of cancer specific survival. CONCLUSION: Anemia seems to be a marker of recurrence and progression in patients with renal cell carcinoma undergoing nephrectomy. From our point of view, anemia could be considered a significantly high mortality rate for renal cancer in these patients.

[Nonspecific sexual cord testicular tumor. Case report]. / Tumor testicular de los cordones sexuales no específico. Presentación de un caso.

OBJECTIVE: We report one case of gonadal stromal testicular tumor and perform a bibliographic review. METHODS/RESULTS: We present the case of a 42 year-old male patient consulting for a painless right testicular mass. Orchiectomy was performed and the patient underwent follow-up. CONCLUSIONS: Nonspecific sexual cord tumors are extremely rare, with slow growing and benign behaviour, presenting positive staining for various markers.

[Renal cell carcinoma: prognostic factors and staging]. / Adenocarcinoma de celulas renales: factores pronosticos y estadificacion.

OBJECTIVES: To evaluate the prognostic significance of the 2002 TNM tumor classification for renal cell carcinoma, as well as other factors intervening in its survival. METHODS: Retrospective chart review of 316 renal carcinomas operated between 1970 and 2003. Twenty-five prognostic variables were analyzed. RESULTS: The histological type was renal cell carcinoma in 90.5% of the patients. Most tumors were T1b or T2, with a Fuhrman nuclear grade I or II. Mean tumor size was 7.17 +/- 3.4 cm. Most cases had a solitary tumor. 8.2% of the patients had lymph node involvement at the time of diagnosis, and 8.6% metastases. The most frequent clinical presentations were hematuria and/or pain. Mean follow-up was 57.8 months. 24.1% of the cases had recurrence, more than 50% of them during the first year. Advanced tumors (T3, T4) had the tendency to have a nuclear grade III-IV, bigger size, necrosis, vascular involvement, lymph node involvement, and metastases. At the end of follow-up, most patients were alive and disease free. The number of months free of disease, the presence of metastatic lymph nodes, the treatment of the first recurrence and the presence of anemia were independent factors for cancer specific mortality. CONCLUSIONS: The modification of the current classification of renal tumors pT3 and pT4 would help to a better decision-making in the therapy of tumors with vascular, perirenal fat or adrenal involvement. Anemia and treatment of the first recurrence are important factors for cancer specific survival.

[Intravesical therapy: Influence on superficial bladder cancer progression]. / Terapia endovesical: influencia sobre la progresión en el cáncer vesical superficial.

OBJECTIVES: To review the influence of various intravesical treatments on superficial bladder cancer progression. METHODS: We retrospectively reviewed 473 superficial bladder neoplasias. Based on diagnosis and transurethral resection of bladder tumor (TUR BT), and depending on pathology, we proposed different treatment and follow-up schemes, with BCG in 139 cases and intravesical chemotherapy, mainly Mytomicin C, in 80. RESULTS: Overall, the use or not of bladder instillations did not show statistically significant differences in time to progression. The use of intravesical therapy and maintenance therapy was an independent risk factor for disease-free time to progression when compared with induction. CONCLUSIONS: The use of maintenance intravesical therapy with BCG resulted in a delayed progression of superficial bladder cancer, so that it seems the most effective treatment, mainly in moderate-high risk tumors.

[Intravesical therapy: Influence on superficial bladder cancer recurrence]. / Terapia endovesical: influencia sobre la recidiva en el cáncer vesical superficial.

OBJECTIVES: To review the influence of various intravesical treatments on superficial bladder cancer recurrence. METHODS: We retrospectively reviewed 473 superficial bladder neoplasias. Based on diagnosis and transurethral resection of bladder tumor (TUR BT), and depending on pathology, we proposed different adjuvant treatment and follow-up schemes. RESULTS: The following factors were independent risk factors for a longer recurrence-free time: intravesical instillations, high dose BCG, and maintenance therapy in comparison to induction. CONCLUSIONS: The use of intravesical instillations independently increases the time to recurrence. It was demonstrated that recurrence was significantly later when high dose BCG and maintenance therapy were employed.

A new form of presentation of renal actinomycosis: renal tumor with retroperitoneal bleeding.

OBJECTIVE: The aim of this case report is to add to the literature a new case of renal actinomycosis, but with a form of presentation that has never been reported: renal tumor with retroperitoneal bleeding. METHODS/RESULTS: We present the case of a 27-year-old woman, with a 5-month history of general syndrome and right flank pain. Radiological findings showed a right renal tumor with suspicious of retroperitoneal bleeding. Right radical nephrectomy was performed and the pathological examination of the specimen found actinomyces colonies. The patient received 8 weeks of Penicillin after surgery and had none sequelae. easily diagnosed because of non-specific clinical and radiological findings. Early diagnosis of renal actinomycosis is important to avoid surgery since actinomyces respond well to high doses of Penicillin.

[Solitary pararenal fibrous tumor]. / Tumor fibroso solitario pararrenal.

OBJECTIVES: To report a rare clinical case of solitary pararenal fibrous tumor, analyzing its pathological characteristics and prognosis by a bibliographic review. METHODS/RESULTS: We present the case of a 36-year-old male consulting for right flank colic pain, which was diagnosed of a solid mass in the lower pole of the right kidney and underwent right radical nephrectomy. Pathological study of the surgical specimen showed the presence of a solitary pararenal fibrous tumor. CONCLUSIONS: Solitary fibrous tumor is a rare neoplasia, being its pararenal localization even rarer. It is a tumor with benign behavior in up to 90% of the cases. The immunohistochemical study is the key to diagnosis.

[Spontaneous regression of venous thrombus in a case of renal carcinoma]. / Regresión espontánea de trombosis venosa en un caso de carcinoma renal.

OBJECTIVES: To report the first case of spontaneous regression of renal vein and inferior vena cava thrombus in a patient with renal clear cell carcinoma. METHODS/RESULTS: We describe the case of a woman with the diagnosis of renal mass with venous thrombus of the renal vein and inferior vena cava. Extension studies before radical nephrectomy showed regression of the thrombus which was confirmed during nephrectomy. CONCLUSIONS: Spontaneous regression of clear cell renal carcinoma metastases is estimated below 1 % of the cases. This is the first case report of regression of a tumoral thrombus of the renal vein and inferior vena cava.

[Relationship between LUTS (lower urinary tract symptoms) and quality of life]. / Relación entre síntomas del tracto urinario inferior y calidad de vida.

OBJECTIVES: To evaluate the impact of the lower urinary tract symptoms (LUTS) included in the IPSS on the quality of life and to determine the relationship between quality of life or total IPSS score and treatment. METHODS: Retrospective review of the IPSS questionnaire in 125 male patients who had consulted for LUTS between January 2001 and December 2003. Results were included in an Access database. Statistical analyses were done with the SPSS 11.0 software. RESULTS: 17% of the patients showed severe symptoms in accordance to the IPSS score. In the quality of life evaluation grouped into two categories, 88% referred good or indifferent quality of life. In the evaluation of the association between IPSS individual questions and quality of life there was a significant association for all questions. Patients reporting worse quality of life had a 6 times higher risk of receiving treatment. With a mean follow-up of two years, 91% of patients who were not on treatment continued without it. CONCLUSIONS: The most severe symptoms are, the worse the quality of life. The independent parameters that most influenced decision to start treatment were quality of life and total IPSS. Frequency, weak stream and hesitation may explain quality of life on each patient.

[Treatment of a cavernous hemangioma of the bladder by endoscopical resection]. / Resección endoscópica como tratamiento del hemangioma cavernoso de vejiga.

OBJECTIVES: We report three cases of bladder hemangioma. METHODS: Three cases of cavernous hemangioma of the bladder with pathologic confirmation treated by endoscopical resection. RESULTS: There is no evidence of recurrence in either patient after resection. CONCLUSIONS: The endoscopical treatment of small bladder hemangiomas is an effective treatment.