Quantitative comparison of the renal pelvic urine and bladder urine to examine modifications of the urine proteome by the lower urinary tract.

PURPOSE: Urine proteome is a valuable reservoir of biomarkers for disease diagnosis and monitoring. Following formation as the plasma filtrate in the kidney, urine is progressively modified by the active reabsorption and secretion of the urinary tract. However, little is known about how the urine proteome changes as it passes along the urinary tract. EXPERIMENTAL DESIGN: To investigate this, we compared the proteome composition of the renal pelvis urine (RPU) and individually self-voided bladder urine (BU) collected from seven unilateral urinary tract obstruction male patients by LC-MS/MS screening. To our knowledge, this is the first proteomic comparison of RPU and BU samples from the same individual. RESULTS: Overall, RPU and BU proteomes did not exhibit proteins that were exclusively present in all samples of one urine type while in none of the other type. Nonetheless, BU had more overrepresented proteins that were observed at a higher frequency than RPU. Label-free quantitative analyses revealed BU-RPU differential proteins that are enriched in exosomes and extracellular proteins. However, the differences were not significant after corrections for multiple testing. Interestingly, we observed a significant increase of collagen peptides with hydroxyproline modifications in the BU samples, suggesting differences in protein modifications. CONCLUSIONS AND CLINICAL RELEVANCE: Our study revealed no substantial differences at the protein level between the BU and RPU samples. Future investigations with expanded cohorts would provide more insights about the urothelial-urinary interactions.

Close Association between Altered Urine-Urothelium Barrier and Tertiary Lymphoid Structure Formation in the Renal Pelvis during Nephritis.

BACKGROUND: Kidneys with chronic inflammation develop tertiary lymphoid structures (TLSs). Infectious pyelonephritis is characterized by renal pelvis (RP) inflammation. However, the pathologic features of TLSs, including their formation and association with non-infectious nephritis, are unclear. METHODS: RPs from humans and mice that were healthy or had non-infectious chronic nephritis were analyzed for TLS development, and the mechanism of TLS formation investigated using urothelium or lymphoid structure cultures. RESULTS: Regardless of infection, TLSs in the RP, termed urinary tract-associated lymphoid structures (UTALSs), formed in humans and mice with chronic nephritis. Moreover, urine played a unique role in UTALS formation. Specifically, we identified urinary IFN-γ as a candidate factor affecting urothelial barrier integrity because it alters occludin expression. In a nephritis mouse model, urine leaked from the lumen of the RP into the parenchyma. In addition, urine immunologically stimulated UTALS-forming cells via cytokine (IFN-γ, TNF-α) and chemokine (CXCL9, CXCL13) production. CXCL9 and CXCL13 were expressed in UTALS stromal cells and urine stimulation specifically induced CXCL13 in cultured fibroblasts. Characteristically, type XVII collagen (BP180), a candidate autoantigen of bullous pemphigoid, was ectopically localized in the urothelium covering UTALSs and associated with UTALS development by stimulating CXCL9 or IL-22 induction via the TNF-α/FOS/JUN pathway. Notably, UTALS development indices were positively correlated with chronic nephritis development. CONCLUSIONS: TLS formation in the RP is possible and altered urine-urothelium barrier-based UTALS formation may represent a novel mechanism underlying the pathogenesis of chronic nephritis, regardless of urinary tract infection.

Use of the Nuclear Matrix Protein 22 BladderChek Test for the Detection of Primary and Recurrent Urothelial Carcinoma.

OBJECTIVE: To evaluate the performance of the nuclear matrix protein 22 (NMP22) BladderChek test in urothelial carcinoma (UC). METHODS: We retrospectively analyzed 1318 patients who performed the NMP22 BladderChek tests. Of them, 103 were primary UC patients, 90 were surgical treatment UC patients, and 1125 were benign disease patients. The performance of the NMP22 BladderChek test for the diagnosis of primary and recurrent UC was evaluated. Moreover, the performance of urine cytology and the NMP22 BladderChek test for the diagnosis of primary UC was compared in 90 available subjects including 48 primary UC patients and 42 benign disease patients. RESULTS: The sensitivity and specificity of the NMP22 BladderChek test were 37.9% and 95.8%, respectively, for the diagnosis of primary UC (n = 1228). The corresponding parameters of the NMP22 BladderChek test were 31.0% and 88.5%, respectively, for the diagnosis of recurrent UC (n = 90). The sensitivity and specificity of urine cytology were 54.2% and 97.6%, respectively, for the diagnosis of primary UC (n = 90); the corresponding parameters of the NMP22 BladderChek test were 41.7% and 83.3%, respectively; the corresponding parameters of the two tests combination were 64.6% and 83.3%, respectively. There was a significant difference in the performance between the NMP22 BladderChek test and urine cytology or the combination of two tests (P = 0.017 and 0.001, respectively). CONCLUSIONS: The NMP22 BladderChek test has a low sensitivity for detecting primary and recurrent UC. Urine cytology is superior to the NMP22 BladderChek test, and combined use of the two tests improves the sensitivity in the detection of primary UC.

iTRAQ-based proteomics and in vitro experiments reveals essential roles of ACE and AP-N in the renin-angiotensin system-mediated congenital ureteropelvic junction obstruction.

OBJECTIVE: Ureteropelvic junction obstruction (UPJO) is a common renal obstructive disorder, but its pathogenic mechanisms remain largely unclear. We aimed to investigate the potential involvement of the renin-angiotensin system in congenital UPJO pathogenesis. METHODS: Differentially expressed proteins in exosomes isolated from amniotic fluid of patients with congenital UPJO were characterized using iTRAQ (isobaric tags for relative and absolute quantification)-based proteomics. The expressions of angiotensin-converting enzyme (ACE) and aminopeptidase N (AP-N) in HK2 cells were inhibited by quinapril and siRNA, respectively. Cell proliferation and reactive oxygen species were measured by EdU staining and flow cytometry, respectively. Gene expression was detected by Western blot or qRT-PCR. The inflammatory factors were measured through ELISA. Mice that underwent unilateral ureteral obstruction were used as the animal model. RESULTS: The identity of exosomes from amniotic fluids was confirmed by the expression of CD9 and CD26. In total, 633 differentially expressed proteins were identified in the amniotic fluid-derived exosomes from patients with UPJO, including 376 up- and 257 down-regulated proteins associated with multiple biological processes. Of them, ACE and AP-N were significantly decreased in the amniotic fluid exosomes. Inhibition of ACE and AP-N resulted in suppressed cell proliferation; repressed IARP, AT1R, and MAS1 expression; elevated ROS production; and increased IL-1ß, TNF-α, and IL-6 levels in HK2 cells. Decreased ACE expression and elevated IL-1ß levels were also observed in the mouse model. CONCLUSION: Suppression of ACE and AP-N expression mediates congenital UPJO pathogenesis by repressing renal tubular epithelial proliferation, promoting ROS production, and enhancing inflammatory factor expression.

HER2 Status in Molecular Subtypes of Urothelial Carcinoma of the Renal Pelvis and Ureter.

INTRODUCTION: Erb-b2 receptor tyrosine kinase 2 (ERBB2, also known as HER2) gene amplification or protein overexpression occurs in certain types of urothelial carcinomas. Molecular pathologic classification of urinary bladder cancer using immunohistochemistry has identified basal and luminal subtypes with differing prognoses, but the HER2 status of these subtypes has not been investigated. In addition, research on urothelial carcinoma of the renal pelvis and ureter (UCRPU) has not progressed because of its rarity, though its prognosis is worse than that of bladder cancer. In this study, we evaluated the clinical significance of HER2 status in molecular subtypes of UCRPU. MATERIALS AND METHODS: HER2 status (protein overexpression and/or gene amplification) and molecular subtyping were determined for 148 cases of UCRPU (83 and 65 cases in the renal pelvis and ureter, respectively), using immunohistochemistry and fluorescent in situ hybridization, and compared with clinicopathologic factors. RESULTS: Subtype analysis revealed that the cases were 46% basal and 54% luminal. HER2 protein overexpression and/or gene amplification was observed in 14% of UCRPU cases and was significantly more frequent in the luminal subtype than in the basal (22% vs. 4%; P = .0030). Univariate analysis showed that the overall survival of patients with HER2-positive UCRPU was significantly shorter than those with HER2-negative tumors. CONCLUSIONS: HER2 protein overexpression and gene amplification were specifically observed in the luminal subtype of UCRPU, suggesting that these cases may respond to HER2-targeted therapies like trastuzumab.

Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction.

Intrinsic ureteropelvic junction obstruction is the most common cause of congenital hydronephrosis, yet the underlying pathogenesis is undefined. Hedgehog proteins control morphogenesis by promoting GLI-dependent transcriptional activation and inhibiting the formation of the GLI3 transcriptional repressor. Hedgehog regulates differentiation and proliferation of ureteric smooth muscle progenitor cells during murine kidney-ureter development. Histopathologic findings of smooth muscle cell hypertrophy and stroma-like cells, consistently observed in obstructing tissue at the time of surgical correction, suggest that Hedgehog signaling is abnormally regulated during the genesis of congenital intrinsic ureteropelvic junction obstruction. Here, we demonstrate that constitutively active Hedgehog signaling in murine intermediate mesoderm-derived renal progenitors results in hydronephrosis and failure to develop a patent pelvic-ureteric junction. Tissue obstructing the ureteropelvic junction was marked as early as E13.5 by an ectopic population of cells expressing Ptch2, a Hedgehog signaling target. Constitutive expression of GLI3 repressor in Ptch1-deficient mice rescued ectopic Ptch2 expression and obstructive hydronephrosis. Whole transcriptome analysis of isolated Ptch2+ cells revealed coexpression of genes characteristic of stromal progenitor cells. Genetic lineage tracing indicated that stromal cells blocking the ureteropelvic junction were derived from intermediate mesoderm-derived renal progenitors and were distinct from the smooth muscle or epithelial lineages. Analysis of obstructive ureteric tissue resected from children with congenital intrinsic ureteropelvic junction obstruction revealed a molecular signature similar to that observed in Ptch1-deficient mice. Together, these results demonstrate a Hedgehog-dependent mechanism underlying mammalian intrinsic ureteropelvic junction obstruction.

Renal sodium handling and blood pressure changes in gestational protein-restricted offspring: Role of renal nerves and ganglia neurokinin expression.

BACKGROUND: Considering long-term changes in renal sodium handling and blood pressure in maternal protein-restricted (LP) offspring, we assumed that the development of LP hypertension results from abnormal dorsal root ganglia (DRG) neurokinin expression associated with impaired responsiveness of renal sensory receptors, promoting a reduced urinary excretion of sodium. The present study investigates whether increased blood pressure in protein-restricted offspring would be associated with changes in the DRG cells and in renal pelvic wall expression of NK1R, SP and CGRP when compared to NP offspring. In addition, we assessed the tubular sodium handling, estimated by creatinine and lithium clearances before and after bilateral renal denervation in conscious LP offspring relative to age-matched NP counterparts. METHODS: Dams received a normal (NP) or low-protein diet (LP) during their entire pregnancy period. Male NP or LP offspring underwent bilateral surgical renal denervation before the 8-week renal functional test and blood pressure measurements. Immunofluorescence staining in DRG cells was assessed in optical sections by confocal laser scanning microscope. RESULTS: The current data demonstrated a sustained rise in blood pressure associated with a decrease in fractional excretion of sodium (FENa) by reducing post-proximal tubule sodium rejection in 16-wk old LP rats relative to age-matched NP counterparts. According to this study, bilateral renal denervation attenuated blood pressure and increased FENa in LP offspring. Furthermore, an immunohistochemical analysis showed a reduced expression of SP and CGRP in DRGs of LP when compared with NP rats. Renal pelvis of LP rats did not show a strong CGRP expression related to NP rats, whereas there was no change in SP immunostaining. CONCLUSIONS: These observations raise the possibility that impaired DRG and pelvic neurokinin expression associated with responsiveness of renal sensory receptors in 16-wk old LP offspring are conducive to excess renal reabsorption of sodium and development of hypertension in this programmed model.

Comparison of renal pelvic pressure and postoperative fever incidence between standard- and mini-tract percutaneous nephrolithotomy.

This study was proposed to compare the clinical effectiveness of mini-tract percutaneous nephrolithotomy (MPCNL) with standard-tract percutaneous nephrolithotomy (SPCNL) and verify whether MPCNL is associated with both higher renal pelvic pressure (RPP) and incidence of postoperative fever. A total of 228 patients with kidney stone were randomly allocated to the MPCNL group (n=114) and SPCNL group (n=114). Both intraoperative and postoperative indexes along with the incidence of complications were compared between the two treatment groups. RPP was measured using a baroreceptor which was connected to an open-ended ureteric catheter during the operation of percutaneous nephrolithotomy. The MPCNL group exhibited significantly longer average operation time, more average amount of flush water, and lesser average amount of bleeding during the operation than the SPCNL group (p<0.05). Moreover, significantly lesser average amount of postoperative serum creatinine, shorter average hospital stay, and more average amount of postoperative hemoglobin were observed in the MPCNL group than in the SPCNL group (p<0.05). MPCNL were more applicable to clear caliceal stones (p<0.05), whereas SPCNL were more effective for the removal of simple pelvic stones. The difference in the incidence of postoperative fever between the two treatment groups also appeared to be significant (p<0.05). Logistic regression provided solid evidence that both RPP and its accumulation time at which RPP≥30 mmHg significantly affected the incidence of postoperative fever. MPCNL was correlated with both higher RPP and increased likelihood of postoperative fever compared with SPCNL.

Primary Carcinoid Tumor of the Renal Pelvis Arising From Intestinal Metaplasia: An Unusual Histogenetic Pathway?

OBJECTIVES: Primary carcinoid tumor of the renal pelvis is a rare neoplasm with few cases reported in the literature. Here we present the clinical and histopathologic findings of a primary carcinoid tumor arising in the left renal pelvis of a horseshoe kidney in a 61-year-old female patient. MATERIALS AND METHODS: Pathologic features were evaluated with standard hematoxylin and eosin sections and immunohistochemical studies. A literature review was performed to place our case in context to previous reports. RESULTS: The tumor was associated with intestinal metaplasia with high-grade dysplasia and neuroendocrine hyperplasia. Molecular testing for microsatellite instability and loss of heterozygosity were negative. CONCLUSIONS: This report portrays a unique presentation of carcinoid tumor arising from intestinal metaplasia of the pelvic urothelium, and supports its histogenesis from urothelial intestinal metaplasia and neuroendocrine hyperplasia.

La sesión científica que no tuvo lugar / The clinical session that never happened

OBJETIVOS: Una enfermedad da a los clínicos signos que nos permiten el diagnóstico por ocultos que puedan estar, incluso en una momia de hace 3.000 años, gracias a los avances de la medicina y la semejanza con los casos ya conocidos de Litiasis ósea. MÉTODOS: Analizamos en el tiempo las facetas de su localización (vesical, ureteral o renal); el conocimiento se ha ido abriendo paso para permitir hoy una respuesta al enigma de un arcano final. RESULTADOS: La identificación del caso investigado. CONCLUSIONES: Hallamos hoy, 3.000 años después en una momia, la causa más probable de su fallecimiento gracias al cuidado exquisito de su preservación y a la decisión de los científicos de aplicar, entre las técnicas actuales de estudio las menos destructivas con esos restos sabiamente embalsamados

OBJECTIVES: Every illness provides signs that enable diagnosis no matter how hidden they may be, even in a 3.000 years old mummy thanks to the advances in medicine and similarity with other known cases of osseous lithiasis. METHODS: We have analyzed the features of its localization (bladder, ureteral or renal); knowledge got its way to allow today the answer to the final arcane enigma. RESULTS: The identification of the case being investigated. CONCLUSION: Today, in a 3.000 years old mummy, we found the most likely cause of his death thanks to the careful preservation and the scientists decision to select, among the current inspection techniques, those which are less destructive of the wisely embalmed rests

Factores predictores de la evolución en la hidronefrosis prenatal / Predictive factors of the outcomes of prenatal hydronephrosis

OBJETIVO: Determinar predictores independientes prenatales y postnatales de una mala evolución de la función renal, de la resolución espontanea o de la necesidad de cirugía en la hidronefrosis prenatal. MÉTODOS: Estudio retrospectivo en pacientes con hidronefrosis prenatal. Analizamos diferentes variables clínicas prenatales y postnatales, así como, el DAP (diámetro anteroposterior) de la pelvis renal en la ecografía prenatal del tercer trimestre, y en la primera y segunda ecografía postnatal. Las analizamos mediante t de Student, chi-cuadrado, análisis de supervivencia, y curvas de COR. RESULTADOS: Se incluyeron 218 pacientes con 293 UR (unidades renales). Operadas 147/293 (50,2%) UR, resolución espontánea 76/293 (25,9%) UR, y 76/293 (25,9%) UR presentaron mala evolución. Encontramos como factores de riesgo para la cirugía el bajo peso al nacer (OR 3,84; IC 95% 1,24-11,84), la prematuridad (OR; 4,17 IC 95% 1,35-12,88), la duplicidad (OR 4,99; IC 95% 2,21-11,23) y la presencia de patología nefrourológica subyacente (OR 53,54; IC 95% 26,23-109,27). Para la no resolución espontánea se encontraron las alteraciones en el volumen del líquido amniótico (RR 1,46; IC 95% 1,33-1,60) así como la patología nefrourológica subyacente y la duplicidad. Para la mala evolución la alteración del volumen del líquido amniótico (OR 11,99; IC 95% 2,70-53,21), la presencia de patología nefrourológica subyacente (OR 4,81 IC 95% 2,60-8,89) y la cirugía (OR 4,23 IC 95% 2,35-7,60). El DAP en las tres ecografías es fiable para la predicción de cirugía (área bajo la curva 0,65; 0,82; 0,71), para resolución espontánea (área bajo la curva 0,80; 0,91; 0,80) y solo el DAP de la primera ecografía postnatal para mala evolución (área bajo la curva 0,73). Los DAP con mayor sensibilidad y especificidad son los de la primera ecografía postnatal; 14,60mm para cirugía; 11,35mm para resolución espontánea; y 15,50 mm para mala evolución. CONCLUSIÓN: A mayor DAP en la pelvis renal en cualquiera de las tres ecografías las probabilidades de cirugía y de no resolución espontanea son mayores. La primera ecografía es la más fiable para predecir la evolución en la hidronefrosis prenatal. Existen otros factores a tomar en cuenta para predecir la evolución de los pacientes con HN prenatal

OBJECTIVES: To determine prenatal and postnatal independent predictors of poor outcome, spontaneous resolution, or the need for surgery in patients with prenatal hydronephrosis. METHODS: We performed a retrospective study of patients with prenatal hydronephrosis. The renal pelvis APD was measured in the third prenatal trimester ultrasound, as well as in the first and second postnatal ultrasound. Other variables were taken into account, both prenatal and postnatal. For statistical analysis we used Student t-test, chi-square test, survival analysis, logrank test, and ROC curves. RESULTS: We included 218 patients with 293 renal units (RU). Of these, 147/293 (50.2%) RU were operated. 76/293 (25.9%) RU had spontaneous resolution and other 76/293 (25.9%) RU had poor outcome. As risk factors for surgery we found low birth weight (OR 3.84; 95% CI 1.24-11.84), prematurity (OR 4.17; 95% CI 1.35-12.88), duplication (OR 4.99; 95% CI 2.21- 11.23) and the presence of nephrourological underlying pathology (OR 53.54; 95% CI 26.23-109.27). For the non-spontaneous resolution, we found as risk factors the alterations of amniotic fluid volume (RR 1.46; 95% CI 1.33-1.60) as well as the underlying nephrourological pathology and duplication. In the poor outcome, we found as risk factors the alterations of amniotic fluid volume (OR 4.54; 95% CI 1.31-15.62), the presence of nephrourological pathology (OR 4.81 95% CI 2.60-8.89) and RU that was operated (OR 4.23, 95% CI 2.35-7.60). The APD of the renal pelvis in all three ultrasounds were reliable for surgery prediction (area under the curve 0.65; 0.82; 0.71) or spontaneous resolution (area under the curve 0.80; 0.91; 0.80), only the first postnatal ultrasound has predictive value in the poor outcome (area under the curve 0.73). The higher sensitivity and specificity of the APD as predictor value was on the first postnatal ultrasound, 14.60 mm for surgery; 11.35 mm for spontaneous resolution and 15.50 mm for poor outcome. CONCLUSION: The higher APD in the renal pelvis in any of the three ultrasounds, the greater the chances of surgery and failure of spontaneous resolution. The first postnatal ultrasound is the most reliable in predicting outcome of prenatal hydronephrosis. There are other factors to take into account to predict the outcomes of these patients

Quiste intrabdominal y retención crónica de orina / Abdominal cyst and chronic urinary retention

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Role of endothelin-1 for the regulation of renal pelvic function.

Endothelin-1 (ET-1) stimulates contractions in isolated rat renal pelves. The signal transduction mechanisms that mediate ET-1-induced renal pelvic contractions and the role of ET-1 for the in vivo regulation of renal pelvic function are not well characterized. We tested if ET-1 stimulates contractions in murine and human renal pelves, if ET-1 activates the renal pelvic RhoA/ROCK pathway, and if low renal ET-1 formation or ET receptor blockade reduce renal pelvic contractile activity. ET-1 increased contraction frequency and force in murine renal pelves. The majority of human renal pelvic tissue samples showed tonic contractions in response to ET-1. Seven out of 20 human tissue samples showed phasic contractions. In four samples, they were elicited by ET-1 at 10-33 nmol/l. ET-1 increased renal pelvic RhoA-GTP content and myosin phosphatase target subunit 1 phosphorylation in isolated rat renal pelves. Renal pelvic contraction frequency (29 ± 2 vs. 29 ± 3 min(-1)) and renal pelvic pressure (7.1 ± 0.9 vs. 5.9 ± 1.7 mmHg) were similar in collecting duct-specific ET-1 knockout mice and in ET-1 floxed controls in vivo. ET-1 sensitivity of isolated renal pelves was similar in both groups. ET receptor blockade did not significantly affect pelvic contraction frequency and pressure in rats. We conclude that ET-1 stimulates phasic contractions in murine, rat, and, to a lesser extent, in human renal pelves. ET-1 activates the RhoA/ROCK pathway in the renal pelvic wall. Endogenous, kidney-derived ET-1 does not play a major role for the regulation of renal pelvic contractions in vivo.

Carcinoid tumor associated with adjacent dysplastic columnar epithelium in the renal pelvis: A case report and literature review.

Carcinoid tumors are well documented in the pulmonary and gastrointestinal systems, but very rare in the urinary tract, especially in the renal pelvis. We report on a 60-year-old female patient who presented with left flank pain and fever. Abdominal computed tomography demonstrated a heterogeneously enhancing mass in the left renal pelvis and a stone at the left proximal ureter. Multiple parenchymal lesions were also observed, which were identified as uneven caliectasis displaying air-fluid levels and renal parenchymal atrophy. The patient underwent simple nephro-ureterectomy. Macroscopically, a polypoid mass was observed in the renal pelvis. Microscopically, the tumor revealed acinar, tubular, and solid pattern and was composed of small, monotonous and hyperchromatic cells. Lining epithelia in renal pelvis and ureter revealed columnar epithelia with dysplastic change. The tumor cells were positive for chromogranin A, synaptophysin, CD56, and focally positive for cytokeratin. Immunohistochemical staining of synaptophysin and chromogranin A highlighted the neuroendocrine cells in the columnar epithelium. Ki-67 (1:50; MIB-1) labeling index was less than 1% in the area with highest uptake. We report here a case of carcinoid tumor of the renal pelvis that was associated with adjacent dysplastic columnar epithelium.

Complexity of FGFR signalling in metastatic urothelial cancer.

BACKGROUND: Urothelial cancers (UC) are the fourth most common tumours worldwide after prostate (or breast), lung and colorectal cancer. Despite recent improvements in their management, UC remain an aggressive disease associated with a poor outcome. Following disease progression on first-line platinum-based chemotherapy, very few effective treatment options are available and none of them have shown significant improvement in overall survival. Alterations of the fibroblast growth factor receptor (FGFR) pathway including amplification, mutations and overexpression are common in UC. Pre-clinical data suggest that the presence of such dysregulations may confer sensitivity to FGFR inhibitors. MATERIALS AND METHODS: We present here the case of a patient with a metastatic UC of the renal pelvis with lymph node metastases treated with the selective FGFR inhibitor AZD4547. RESULTS: To date, the patient has been on a study drug for 32 months with acceptable tolerance and maintained radiological partial response as per RECIST 1.1 criteria. Exploratory biomarker analysis showed FGFR3, FGFR1, FGF-ligand and fibroblast growth factor receptor substrate 2 (FRS2) expression in the patient's tumour, together with the presence of a germ-line mutation in the FGFR3 extracellular binding domain. This is not a known hotspot mutation, and the functional significance remains unclear. CONCLUSIONS: The FGFR inhibitor AZD4547 exhibits antitumour activity in a metastatic urothelial cancer displaying FGFR1, FGFR3, FGF-ligand and FRS2 expression. This lends support to the further exploration of FGFR inhibitors in urothelial cancer. Further studies are required to determinate the most effective way to select those patients most likely to respond.

The Prognostic Role of Ki-67/MIB-1 in Upper Urinary-Tract Urothelial Carcinomas: A Systematic Review and Meta-Analysis.

BACKGROUND: Upper urinary-tract urothelial carcinomas (UTUC) constitute 5% of urothelial malignancies. Prognostic biomarkers would allow lower risk surgical approaches for less aggressive UTUCs. One biomarker-Ki-67/mindbomb E3 ubiquitin protein ligase 1 (Ki-67/MIB-1)-shows promise in UTUC, but there have been conflicting findings regarding its prognostic role. The systematic review and meta-analysis aim to determine the prognostic value of Ki-67/MIB-1 in UTUC in terms of UTUC-specific mortality rate, 5-year disease-free survival, and 5-year overall survival (including disease-specific survival). METHODS: A systematic review of the current literature produced 654 records. A total of 13 studies consisting of 1030 patients were finally included in the meta-analysis. Hazard ratios (HRs) with 95% confidence intervals (CI) were extracted or estimated. The individual HR estimates were combined into a pooled HR using a fixed-effects model that summed homogeneity of the individual true HRs. RESULTS: Patients with Ki-67/MIB-1 overexpression displayed significantly higher UTUC-specific mortality rate (pooled HR: 2.14, 95% CI: 1.73-2.64; p<0.00001), significantly reduced 5-year disease-free survival (pooled HR: 2.27, 95% CI: 1.79-2.92; p<0.00001), and significantly reduced 5-year overall survival (pooled HR=1.77; 95% CI: 1.39-2.23 p<0.00001). There was significant heterogeneity detected in the UTUC-specific mortality rate meta-analysis (I(2)=63%) and the 5-year disease-free survival meta-analysis (I(2)=65%), but there was no significant heterogeneity detected in the 5-year overall survival meta-analysis (I(2)=0%). Egger's testing showed that none of the outcomes were influenced by publication bias (p>0.05). CONCLUSIONS: Ki-67/MIB-1 overexpression shows promise as a prognostic biomarker for UTUC patients and requires further investigation.

Urothelial Defects from Targeted Inactivation of Exocyst Sec10 in Mice Cause Ureteropelvic Junction Obstructions.

Most cases of congenital obstructive nephropathy are the result of ureteropelvic junction obstructions, and despite their high prevalence, we have a poor understanding of their etiology and scarcity of genetic models. The eight-protein exocyst complex regulates polarized exocytosis of intracellular vesicles in a large variety of cell types. Here we report generation of a conditional knockout mouse for Sec10, a central component of the exocyst, which is the first conditional allele for any exocyst gene. Inactivation of Sec10 in ureteric bud-derived cells using Ksp1.3-Cre mice resulted in severe bilateral hydronephrosis and complete anuria in newborns, with death occurring 6-14 hours after birth. Sec10 FL/FL;Ksp-Cre embryos developed ureteropelvic junction obstructions between E17.5 and E18.5 as a result of degeneration of the urothelium and subsequent overgrowth by surrounding mesenchymal cells. The urothelial cell layer that lines the urinary tract must maintain a hydrophobic luminal barrier again urine while remaining highly stretchable. This barrier is largely established by production of uroplakin proteins that are transported to the apical surface to establish large plaques. By E16.5, Sec10 FL/FL;Ksp-Cre ureter and pelvic urothelium showed decreased uroplakin-3 protein at the luminal surface, and complete absence of uroplakin-3 by E17.5. Affected urothelium at the UPJ showed irregular barriers that exposed the smooth muscle layer to urine, suggesting this may trigger the surrounding mesenchymal cells to overgrow the lumen. Findings from this novel mouse model show Sec10 is critical for the development of the urothelium in ureters, and provides experimental evidence that failure of this urothelial barrier may contribute to human congenital urinary tract obstructions.

Uropatía incrustante por Corynebacterium urealiticum: comentarios a partir de tres casos clínicos / Fouling uropathy by Corynebacterium urealyticum: Comments from three clinical cases

La uropatía incrustante es una enfermedad infecciosa del tracto urinario causada por la bacteria urealítica Corynebacterium urealyticum (CU). En nuestra serie (datos no publicados) sólo el 15% de las infecciones por CU produce uropatía incrustante. La formación de incrustaciones de estruvita y apatita en la pared del urotelio puede afectar a pelvis renal (pielitis), uréter, vejiga (cistopatía) y próstata, incluyendo la celda prostática después de resección ("celdopatía"). La pielitis es la más frecuente. La clínica corresponde a la triada orina alcalina, piuria y cristaluria de estruvita. Los pacientes suelen ser inmunodeprimidos o multioperados. El cultivo de orina debe estar dirigido al diagnóstico de CU. La TC es la prueba de imagen de elección. Muestra típicas imágenes de calcificación laminar. El tratamiento de la uropatía incrustante es multimodal. Incluye antibioterapia, acidificación de la orina y cirugía (algunos casos) (AU)

The encrustant uropathy is an infectious disease of the urinary tract caused by urealithic bacteria Corynebacterium urealyticum (CU). In our series (unpublished data) only 15% of CU infections caused encrustant uropathy. Formation of apatite and struvite on the wall of the urothelium can affect renal pelvis (pyelitis), urether, bladder (cystophatie) and prostate, including prostate cell after resection ("cellpathy"). Pyelitis is the most common. Clinical triad corresponds to alkaline urine, pyuria and struvite crystalluria. Patients are usually immunocompromised or or multiple previous surgeries. Urine culture should be directed to the diagnosis of UC. CT is the imaging test of choice. Shows typical images of laminar calcification. Treatment of encrusted uro pathy is multimodal. Includes antibiotics, acidification of urine and surgery (sometimes) (AU)

Metastasis-associated in colon cancer 1 is a novel survival-related biomarker for human patients with renal pelvis carcinoma.

Metastasis-associated in colon cancer 1 (MACC1) has recently been identified as a novel independent prognostic indicator for metastasis occurrence, overall survival and cancer-free survival for patients with colon cancer and other solid tumors. In this study, we investigated the role of MACC1 in the development and progression of renal pelvis carcinoma, a form of upper tract urothelial carcinomas. MACC1 protein has been found in the cytoplasm as well as in the nucleus of the transitional epithelial cells of the normal renal pelvis in immunohistochemical (IHC) assays. Quantitative IHC examinations revealed that MACC1 abnormal abundance in cancerous tissues might represent a biological indicator clinically suggestive of tumor malignancy in the renal pelvis. Furthermore, investigation of the association of MACC1 protein levels with clinicopathological parameters in this study has suggested a correlation of MACC1 expression with tumor-node-metastasis stage and histopathological grade of patients with renal pelvis carcinoma, with elevated MACC1 protein levels frequently associated with higher aggressiveness of the disease. Moreover, both disease-free survival and overall survival for the patients in the high MACC1 expression group were significantly lower than those in the low expression group. Multivariate analysis with a Cox proportional-hazards model suggested that MACC1 is indeed an independent prognostic indicator of overall survival and cancer-free survival for patients with renal pelvis carcinoma. Thus, MACC1 may represent a promising prognostic biomarker candidate, as well as a potential therapeutic target for this disease.

[Changes of the cytokines profile in patients with hydronephrosis and indicated operative treatment].

The pronounced dysbalance of the cytokines profiles in the blood of patients, suffering recurrent hydronephrosis, caused by pelvio-ureteric segment stenosis of various etiology and in different clinical course, in the inborn obstruction especially, was revealed on a 21th postoperative day, witnessing the existence of various ways of the stricture recurrence occurrence. As a prognostic criterion of risk of the recurrence occurrence there were proposed: a ratio of level of a tumor necrosis factor-alpha (TNF-alpha) to interleukin-10 (IL-10) level, and as an additional diagnostic criterion--the IL-17 level, as well as revealing of the inherited genesis of the disorder in a system of fibrillogenesis regulation--the IL-4 level.