Rac-GTPase promotes fibrotic TGF-ß1 signaling and chronic kidney disease via EGFR, p53, and Hippo/YAP/TAZ pathways.

Rac-GTPases are major regulators of cytoskeletal remodeling and their deregulation contributes to numerous pathologies. Whether or how Rac promotes tubulointerstitial fibrosis and chronic kidney disease (CKD) is currently unknown. We showed that the major profibrotic cytokine, TGF-ß1 promoted rapid Rac1-GTP loading in human kidney 2 (HK-2) human renal epithelial cells. A Rac-specific chemical inhibitor, EHT 1864, blocked TGF-ß1-induced fibrotic reprogramming in kidney epithelial cells and fibroblasts. Stable Rac1 depletion in HK-2 cells, moreover, eliminated TGF-ß1-mediated non-SMAD pathway activation [e.g., Src, epidermal growth factor receptor (EGFR), p53] and subsequent plasminogen activator inhibitor-1 (PAI-1), connective tissue growth factor, fibronectin, and p21 induction. Rac1 and p22phox knockdown abrogated free radical generation by TGF-ß1 in HK-2 cells, consistent with the role of Rac1 in NAPD(H). TGF-ß1-induced renal epithelial cytostasis was also completely bypassed by Rac1, p22phox, p47phox, and PAI-1 silencing. Rac1b isoform expression was robustly induced in the fibrotic kidneys of mice and humans. Intraperitoneal administration of EHT 1864 in mice dramatically attenuated ureteral unilateral obstruction-driven EGFR, p53, Rac1b, yes-associated protein/transcriptional coactivator with PDZ-binding motif activation/expression, dedifferentiation, cell cycle arrest, and renal fibrogenesis evident in vehicle-treated obstructed kidneys. Thus, the Rac1-directed redox response is critical for TGF-ß1-driven epithelial dysfunction orchestrated, in part, via PAI-1 up-regulation. Rac pathway inhibition suppressed renal oxidative stress and maladaptive repair, identifying Rac as a novel therapeutic target against progressive CKD.-Patel, S., Tang, J., Overstreet, J. M., Anorga, S., Lian, F., Arnouk, A., Goldschmeding, R., Higgins, P. J., Samarakoon, R. Rac-GTPase promotes fibrotic TGF-ß1 signaling and chronic kidney disease via EGFR, p53, and Hippo/YAP/TAZ pathways.

Preoperative nomogram to predict the likelihood of complications after radical nephroureterectomy.

OBJECTIVES: To construct a nomogram based on preoperative variables to better predict the likelihood of complications occurring within 30 days of radical nephroureterectomy (RNU). PATIENTS AND METHODS: The charts of 731 patients undergoing RNU at eight academic medical centres between 2002 and 2014 were reviewed. Preoperative clinical, demographic and comorbidity indices were collected. Complications occurring within 30 days of surgery were graded using the modified Clavien-Dindo scale. Multivariate logistic regression determined the association between preoperative variables and post-RNU complications. A nomogram was created from the reduced multivariate model with internal validation using the bootstrapping technique with 200 repetitions. RESULTS: A total of 408 men and 323 women with a median age of 70 years and a body mass index of 27 kg/m2 were included. A total of 75% of the cohort was white, 18% had an Eastern Cooperative Oncology Group (ECOG) performance status ≥2, 20% had a Charlson comorbidity index (CCI) score >5 and 50% had baseline chronic kidney disease (CKD) ≥ stage III. Overall, 279 patients (38%) experienced a complication, including 61 events (22%) with Clavien grade ≥ III. A multivariate model identified five variables associated with complications, including patient age, race, ECOG performance status, CKD stage and CCI score. A preoperative nomogram incorporating these risk factors was constructed with an area under curve of 72.2%. CONCLUSIONS: Using standard preoperative variables from this multi-institutional RNU experience, we constructed and validated a nomogram for predicting peri-operative complications after RNU. Such information may permit more accurate risk stratification on an individual cases basis before major surgery.

Physical, Complementary, and Alternative Medicine in the Treatment of Pelvic Floor Disorders.

PURPOSE OF REVIEW: The purpose of the study was to catalog the most recent available literature regarding the use of conservative measures in treatment of pelvic floor disorders. RECENT FINDINGS: Pelvic floor disorders encompass abnormalities of urination, defecation, sexual function, pelvic organ prolapse, and chronic pain, and can have significant quality of life implications for patients. Current guidelines recommend behavioral modifications and conservative treatments as first-line therapy for pelvic floor disorders. We have reviewed the literature for articles published on physical, complementary, and alternative treatments for pelvic floor disorders over the past 5 years. Review of pelvic floor muscle physiotherapy (PFMT) and biofeedback (BF) shows a benefit for patients suffering from bladder dysfunction (incontinence, overactive bladder), bowel dysfunction (constipation, fecal incontinence), pelvic organ prolapse, and sexual dysfunction (pelvic pain). Combination of PFMT and BF has shown improved results compared to PFMT alone, and some studies find that electrical stimulation can augment the benefit of BF and PFMT. Additionally, acupuncture and cognitive behavioral therapy has shown to be an effective treatment for pelvic floor disorders, particularly with respect to pelvic pain. This update highlights beneficial conservative treatments available for pelvic floor dysfunction, and supplements the current literature on treatment options for patients suffering from these disorders.

Pelvic Irradiation: A Rare Cause of Concomitant Radiation Cystitis and Uretero-Iliac Artery Fistula Causing Gross Hematuria and Hemorrhagic Shock.

Uretero-iliac artery fistulas (UIAFs) are a rare cause of gross hematuria. They form as a result of poorly vascularized uretero-iliac adhesions and the resultant fibrosis and chronic inflammatory changes. Causes include previous pelvic surgery, radiotherapy, and chronic ureteral stenting. The presentation is usually intermittent massive gross hematuria with acute anemia and hemorrhagic shock. A high index of suspicion is warranted in patients with predisposing factors for prompt diagnosis and management as it may be associated with life-threatening hemorrhage. Due to the intermittent nature of symptoms, identification is not always apparent. Open surgical repair was the treatment of choice in the past. With advancements in interventional radiology techniques, endovascular stenting of the iliac artery and concomitant ureteral stenting is the current treatment of choice. We report a case of massive gross hematuria leading to hemorrhagic shock with underlying UIAF and predisposing risk factor of pelvic irradiation. Our case report describes the diagnostic challenges with associated comorbid conditions causing delays in successful management.

Metastatic pancreatic adenocarcinoma to the scrotum.

Metastatic cancer to the scrotum is a rare occurrence. We describe the first case of cutaneous scrotal lesions consistent with metastatic pancreatic adenocarcinoma. A brief discussion including epidemiologic factors and clinical presentation is presented.