Indoxyl sulfate (IS), a uremic toxin, causes chronic kidney disease (CKD) progression via its tubulotoxicity. After cellular uptake, IS directly induces apoptotic and necrotic cell death of tubular cells. Additionally, IS increases oxidative stress and decreases antioxidant capacity, which are associated with tubulointerstitial injury. Injured tubular cells are a major source of transforming growth factor-β1 (TGF-β1), which induces myofibroblast transition from residual renal cells in damaged kidney, recruits inflammatory cells and thereby promotes extracellular matrix deposition in renal fibrosis. Moreover, IS upregulates signal transducers and activators of transcription 3 phosphorylation, followed by increases in TGF-β1, monocyte chemotactic protein-1 and α-smooth muscle actin production, which participate in interstitial inflammation, renal fibrosis and, consequently, CKD progression. Clinically, higher serum IS levels are independently associated with renal function decline and predict all-cause mortality in CKD. The poor removal of serum IS in conventional hemodialysis is also significantly associated with all-cause mortality and heart failure incidence in end-stage renal disease patients. Scavenging the IS precursor by AST-120 can markedly reduce tubular IS staining that attenuates renal tubular injury, ameliorates IS-induced oxidative stress and rescues antioxidant glutathione activity in tubular epithelial cells, thereby providing a protective role against tubular injury and ultimately retarding renal function decline.

Intravesical injection of onabotulinumtoxinA is effective for idiopathic detrusor overactivity refractory to antimuscarinics. However, safety is a major concern, especially in elderly individuals. We investigated the efficacy and safety of intravesical onabotulinumtoxinA injection for refractory idiopathic detrusor overactivity in the frail elderly population. A total of 166 patients with urodynamic idiopathic detrusor overactivity refractory to previous antimuscarinics for more than 3 months received 1 intravesical 100 U onabotulinumtoxinA injection from 2004 to 2009. Frail elderly was defined as age greater than 65 years and 3 or more of certain criteria, including unintentional weight loss, self-reported exhaustion, weakness, slow walking speed and/or low physical activity. Treatment results were assessed by the Patient Perception of Bladder Condition, voiding diary, urodynamic parameters and Kaplan-Meier estimates of survival plots. We evaluated 61 frail elderly patients, 63 who were elderly without frailty and 42 younger than 65 years. Large post-void residual urine volume (greater than 150 ml) after onabotulinumtoxinA injection was significantly higher in the frail elderly group than in the other groups (60.7% vs 39.7% and 35.7%, respectively, p = 0.018). Urinary retention developed in 7 frail elderly patients (11.5%), 4 (6.3%) who were elderly without frailty and 1 younger patient (2.4%) (p = 0.203). Recovery duration was significantly longer in frail elderly patients. The cumulative success rate was significantly lower in the frail elderly group than in the other 2 groups (p = 0.009). Although safety and efficacy were similar between elderly patients without frailty and younger patients, an increased risk of large post-void residual urine volume and a lower long-term success rate in frail elderly patients were noted after intravesical onabotulinumtoxinA injection for refractory idiopathic detrusor overactivity.

The d-galactose (d-gal)-injected animal model, which is typically established by administering consecutive subcutaneous d-gal injections to animals for approximately six or eight weeks, has been frequently used for aging research. In addition, this animal model has been demonstrated to accelerate aging in the brain, kidneys, liver and blood cells. However, studies on aging in male reproductive organs that have used this animal model remain few. Therefore, the current study aimed to optimize a model of male reproductive aging by administering d-gal injections to male mice and to determine the possible mechanism expediting senescence processes during spermatogenesis. In this study, C57Bl/6 mice were randomized into five groups (each containing 8–10 mice according to the daily intraperitoneal injection of vehicle control or 100 or 200 mg/kg dosages of d-gal for a period of six or eight weeks). First, mice subjected to d-gal injections for six or eight weeks demonstrated considerably decreased superoxide dismutase activity in the serum and testis lysates compared to those in the control group. The lipid peroxidation in testis also increased in the d-gal-injected groups. Furthermore, the d-gal-injected groups exhibited a decreased ratio of testis weight/body weight and sperm count compared to the control group. The percentages of both immotile sperm and abnormal sperm increased considerably in the d-gal-injected groups compared to those of the control group. To determine the genes influenced by the d-gal injection during murine spermatogenesis, a c-DNA microarray was conducted to compare testicular RNA samples between the treated groups and the control group. The d-gal-injected groups exhibited RNA transcripts of nine spermatogenesis-related genes (Cycl2, Hk1, Pltp, Utp3, Cabyr, Zpbp2, Speer2, Csnka2ip and Katnb1) that were up- or down-regulated by at least two-fold compared to the control group. Several of these genes are critical for forming sperm-head morphologies or maintaining nuclear integration (e.g., cylicin, basic protein of sperm head cytoskeleton 2 (Cylc2), casein kinase 2, alpha prime interacting protein (Csnka2ip) and katanin p80 (WD40-containing) subunit B1 (Katnb1)). These results indicate that d-gal-injected mice are suitable for investigating male reproductive aging.

Intravesical botulinum toxin (BoNT) injection is effective in reducing urgency and urinary incontinence. It temporarily inhibits the detrusor muscle contraction by blocking the release of acetylcholine (Ach) from the preganglionic and postganglionic nerves in the efferent nerves. BoNT-A also blocks ATP release from purinergic efferent nerves in the detrusor muscle. In afferent nerves, BoNT-A injection markedly reduces the urothelial ATP release and increases nitric oxide (NO) release from the urothelium. BoNT-A injection in the urethra or bladder has been developed in the past few decades as the treatment method for detrusor sphincter dyssyndergia, incontinence due to neurogenic or idiopathic detrusor overactivity, sensory disorders, including bladder hypersensitivity, overactive bladder, and interstitial cystitis/chronic pelvic pain syndrome. Although the FDA only approved BoNT-A injection treatment for neurogenic detrusor overactivity and for refractory overactive bladder, emerging clinical trials have demonstrated the benefits of BoNT-A treatment in functional urological disorders. Cautious selection of patients and urodynamic evaluation for confirmation of diagnosis are crucial to maximize the successful outcomes of BoNT-A treatment.

Intravesical injection of onabotulinumtoxinA is an effective treatment for overactive bladder (OAB). Nonetheless, the treatment outcome is unclear in OAB patients with central nervous system (CNS) lesions. This study evaluated the efficacy and safety of intravesical onabotulinumtoxinA treatment in elderly patients with chronic cerebrovascular accidents (CVAs), Parkinson’s disease (PD) and dementia. Patients with CVA, PD, dementia, and OAB refractory to antimuscarinic therapy were consecutively enrolled in the study group. Age-matched OAB patients without CNS lesions were selected to serve as a control group. OnabotulinumtoxinA (100 U) was injected into the bladder suburothelium at 20 sites. The clinical effects, adverse events, and urodynamic parameters were assessed at baseline and 3 months post-treatment. The Kaplan-Meier method was used to compare long-term success rates between groups. A total of 40 patients with OAB due to CVA (23), PD (9), dementia (8) and 160 control patients were included in this retrospetive analysis. Improvement of urgency severity scale, increased bladder capacity and increased post-void residual volume were comparable between the groups at 3 months. Patients with CNS lesions did not experience increased risks of acute urinary retention and urinary tract infection; nonetheless, patients with CVA experienced a higher rate of straining to void. Long-term success rates did not differ between the patients with and without CNS lesions. Intravesical injection of 100 U of onabotulinumtoxinA effectively decreased urgency symptoms in elderly OAB patients with CNS lesions. The adverse events were acceptable, and long-term effects were comparable to OAB patients in general. Nonetheless, the possibility of longstanding urinary retention and chronic catheterization need careful evaluation for this very vulnerable population before choosing intravesical onabotulinumtoxinA treatment.