This Month in Investigative Urology

Article Outline

• Differential Renal Ablation by Histotripsy
• Botulinum a Toxin in Patients With Painful Bladder Syndrome
• Protective Effects of Bilirubin Against Hemorrhagic Cystitis
• Does Oxybutynin Slow Alzheimer’s Disease?
• Early Orchiopexy Improves Subsequent Testicular Development
• Copyright

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Differential Renal Ablation by Histotripsy 

A potential alternative treatment for renal masses is histotripsy. Histotripsy is a noninvasive technology that uses pulsed, focused ultrasound energy to induce nonthermal, mechanical fractionation of tissue through acoustic cavitation. Histotripsy is distinctly different from high intensity focused ultrasound in that it relies on mechanical and not thermal methods for tissue destruction. The cavitational bio-effects that are responsible for this process are isolated by delivering ultrasound energy of high intensity and low duty cycle (percent of treatment time during which energy is delivered), which minimizes thermal bio-effects.

Lake et al (page 1150) from Ann Arbor, Michigan explored the spectrum of histotripsy bio-effects on different tissue types in an in vitro porcine kidney model. Using an 18 element focused annular array ultrasound system, histotripsy treatments were performed in the in vitro porcine kidneys, targeting 7 cortical volumes and 17 tissue volumes bridging the cortex, medulla and/or collecting system. Based on gross pathology and histopathology in this in vitro model, complete mechanical fractionation and cellular destruction are achieved in cortical tissue only. Medullary tissue is vulnerable to histotripsy but it appears to have a higher threshold for damage or destruction. The collecting system appears to have the highest threshold to damage, demonstrating only minimal damage at the cellular level and no gross breach in structural integrity after a histotripsy treatment. A possible explanation for this differential effect is that collecting system and medullary pyramids (containing collecting ducts) contain proportionally higher amounts of fibrous connective tissue, which may be more resistant to the effects of histotripsy. The differential histotripsy treatment effect observed in renal tissue types may provide advantages and disadvantages. The ability to preserve the collecting system with a margin of safety while treating adjacent renal parenchyma may minimize the complications associated with damage to the collecting system (ie urine leaks, hydrocalicosis, fibrosis and obstruction). However, the relatively higher threshold for histotripsy damage as tissues become more fibrous suggests that the therapeutic parameter sets evaluated in this study may not be an adequate treatment for more fibrous tumors. This differential effect is a notable finding that may prove useful in future planning of ablative treatments for renal tissue.

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Botulinum a Toxin in Patients With Painful Bladder Syndrome 

Giannantoni et al (page 1031) from Perugia, Italy evaluated the 1-year efficacy and tolerability of botulinum A toxin intravesically injected in patients with painful bladder symptoms associated with increased urinary frequency, refractory to conventional treatments. Three men and 12 women were prospectively included in the study. Under short general anesthesia the patients were given injections of 200 U commercially available botulinum A toxin. Overall 13 patients (86.6%) reported subjective improvement at the 1 and 3-month followups. Mean visual analog scale score, and daytime and nighttime urinary frequency were significantly decreased. At the 5-month followup the beneficial effects persisted in 26.6% of cases, but increased daytime and nighttime urinary frequency, and an increased visual analog scale score were observed compared to baseline. At 12 months after treatment pain recurred in all patients. Intravesically injected botulinum A toxin is effective for short-term management of refractory painful bladder syndrome. The beneficial effects decreased progressively within a few months after treatment. Thus, repeat injections of the neurotoxin are required for efficacious treatment of patients with the disease.

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Protective Effects of Bilirubin Against Hemorrhagic Cystitis 

The end product of the heme oxygenase pathway, bilirubin, is the most abundant endogenous antioxidant in mammals. Matsuoka et al (page 1160) from Tokyo, Japan reported on the heme oxygenase-1-mediated production of bilirubin and its cytoprotective roles in cyclophosphamide induced hemorrhagic cystitis in rats. Rats received intraperitoneal administration of cyclophosphamide. In the first experiment hemin (an inducer of heme oxygenase-1) with or without zinc protoporphyrin IX (an inhibitor of heme oxygenase activity) was given before cyclophosphamide injection. Endogenous bilirubin production was analyzed in bladder tissues immunohistochemically. In another experiment bilirubin solution was administered before the cyclophosphamide injection. Bilirubin was generated in bladders with cyclophosphamide induced cystitis, especially in the urothelium and suburothelium. Hemin pretreatment provided increased production of endogenous bilirubin, which was decreased by zinc protoporphyrin IX. In an evaluation of the roles of bilirubin, exogenous bilirubin administration ameliorated cyclophosphamide induced inflammatory changes and reduced the increase in bladder weight. The increased expression of inducible nitric oxide synthase and interleukin-1β in cyclophosphamide induced cystitis was significantly down-regulated by exogenously applied bilirubin. These results suggest that bilirubin may have therapeutic potential against bladder inflammatory insults such as cyclophosphamide induced cystitis.

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Does Oxybutynin Slow Alzheimer’s Disease? 

In elderly patients oxybutynin is commonly used to treat overactive bladder despite the increased prevalence of Alzheimer’s disease in this population. Klausner et al (page 1173) from Richmond, Virginia determined whether oxybutynin altered plaque formation, amyloid β peptide expression and behavior in a transgenic mouse model of Alzheimer’s disease. Animals treated with chronic oxybutynin had a decreased plaque burden in the hippocampus and cortex compared to animals treated with vehicle. Oxybutynin treated animals also had decreased expression of amyloid β peptides compared to animals treated with vehicle. Female Alzheimer’s disease mice treated with oxybutynin displayed improved behavior. The study demonstrated that treatment with the nonselective muscarinic receptor antagonist oxybutynin appears to limit the pathogenesis of amyloid plaque deposition. Three separate modalities support this unexpected finding, including histochemistry to directly visualize amyloid plaques, enzyme-linked immunosorbent assay to identify amyloid β proteins, and behavioral testing. Further studies are required to confirm these findings, and may ultimately lead to a more comprehensive understanding of the pathogenesis mediating Alzheimer’s disease and overactive bladder.

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Early Orchiopexy Improves Subsequent Testicular Development 

The most appropriate period for orchiopexy is controversial. Mizuno et al (page 1195) from Nagoya, Japan performed histological analyses of undescended testes to evaluate the influence of orchiopexy timing in an experimental cryptorchid rat model. Experimental cryptorchid rats were induced with androgen blocker by injecting flutamide into the abdomen of pregnant Sprague-Dawley rats for 7 days from days 14 to 20 of gestation. Approximately 90% of male newborns had undescended testes, and orchiopexy was performed at 4, 5 and 7 weeks after birth. The testes were removed 10 weeks after birth in all groups. Nonoperated undescended testes exhibited atrophic and hypospermatogenesis with germ cell apoptosis, whereas treated undescended testes showed the development of early elongated spermatids. In addition, performing orchiopexy 4 weeks after birth decreased the degeneration of undescended testes compared with those in other groups. In terms of testicular development, 4-week-old rats reportedly correspond to 1-year-old humans. While we should be cautious when extrapolating these findings to the clinical setting, this study provides evidence in support of early orchiopexy during the first year of life.