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‐β1 promoted rapid Rac1‐GTP loading in human kidney 2 (HK‐2) human renal epithelial cells. A Rac‐specific chemical inhibitor, EHT 1864, blocked TGF‐β1‐induced fibrotic reprogramming in kidney epithelial cells and fibroblasts. Stable Rac1 depletion in HK‐2 cells, moreover, eliminated TGF‐β1‐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‐β1 in HK‐2 cells, consistent with the role of Rac1 in NAPD(H). TGF‐β1‐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‐β1‐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‐β1 signaling and chronic kidney disease via EGFR, p53, and Hippo/YAP/TAZ pathways. FASEB J. 33, 9797–9810 (2019). http://www.fasebj.org

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.

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.

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