The Effect of Tadalafil on Renal Fibrosis Induced by Ureteral Obstruction / Efecto del Tadalafil en la Fibrosis Renal Inducida por Obstrucción Uretral

ABSTRACT Objective: It has been reported that phosphodiesterase-5 (PDE-5) inhibitors improve kidney function during acute and chronic renal failure. This study aimed to determine the possible therapeutic effects of tadalafil, a specific PDE-5 inhibitor, on renal fibrosis induced by unilateral ureteral obstruction (UUO). Methods: Male Sprague-Dawley rats were used and randomly divided into three groups (n = 6) as sham-operated, UUO and tadalafil-treated (10 mg/72 hours, ig) UUO (UUO+T) groups. Unilateral ureteral obstruction was induced by complete ligation of the left ureter and 14 days after surgery creatinine clearance, urinary cyclic guanosine monophosphate (cGMP), renal alpha-smooth muscle actin (α-sma) and transforming growth factor βeta (TGF-β) levels, as well as histologic changes, were observed in all the animals. Results: Unilateral ureteral obstruction-induced renal fibrosis was confirmed by increased α-sma level, collagen deposition, tubular dilation, inflammatory cell infiltration and necrosis. An increased renal TGF-β level and decreased urinary cGMP level was also observed in obstructed animals in addition to reduced creatinine clearance. Tadalafil treatment, which restored the animals 'urinary cGMP level, significantly attenuated the fibrotic changes and TGF-β increase in their kidneys. Conclusion: This study suggests that tadalafil treatment ameliorates renal fibrosis by reducing TGF-β expression and may have important clinical relevance since tadalafil is currently used clinically to treat erectile dysfunction and pulmonary hypertension.

RESUMEN Objetivo: Se ha reportado que los inhibidores de la fosfodiesterasa-5 (PDE-5) mejoran las funciones renales durante la insuficiencia renal aguda y crónica. Este estudio tuvo por objetivo determinar los posibles efectos terapéuticos del tadalafil - un inhibidor específico de la PDE-5 - sobre la fibrosis renal inducida por una obstrucción ureteral unilateral (OUU). Métodos: Se utilizaron ratas machos Sprague-Dawley, divididas de manera aleatoria en tres grupos (n = 6): operación simulada, OUU y tratamiento con tadalafil (10 mg/72 horas, IG), y OUU (OUU+T). La obstrucción uretral unilateral fue inducida por una ligadura completa del uréter izquierdo y 14 días después de la cirugía, se observaron niveles de monofosfato de guanosina cíclico (GMP) urinario, alfa-actina de músculo liso (α-SMA), y factor de crecimiento transformante βeta (FCT-β), así como cambios histológicos en todos los animales. Resultados: La fibrosis renal inducida por obstrucción uretral unilateral fue confirmada por un aumento del nivel de α-SMA, deposición de colágeno, dilatación tubular, infiltración de células inflamatorias y necrosis. También se observó un aumento del nivel de FCT-β renal y una disminución del nivel de GMP urinario en los animales con obstrucción, además de una reducción del aclaramiento de la creatinina. El tratamiento con tadalafil, que restauró el nivel de GMP urinario de los animales, atenuó significativamente los cambios fibróticos y el aumento de FCT-β en los riñones. Conclusión: Este estudio sugiere que el tratamiento con tadalafil mejora la fibrosis renal al reducir la expresión de FCT-β y puede tener una importante relevancia clínica por cuanto el tadalafil se usa hoy día clínicamente para tratar la disfunción eréctil y la hipertensión pulmonar.

Metastatic penile carcinomas : a study of nine cases and review of the literature

Objective: Primary penile carcinoma is one of the rarest male genital tract tumors in Turkey; because circumcision is performed routinely. In general; metastatic carcinoma of the penis is the second most common penile tumor. Despite the fact that the penis is rarely affected by metastases; there have been 319 cases reported in the literature. This study was carried out to throw light on the main characteristics of the metastatic disease. Patients and Methods: Nine patients aged between 32 and 68 years (median 62.9 years) with metastatic tumors of the penis were the subject of this study. The clinical history of the cases was reviewed; and the patients' data were recorded including location; histology of the primary tumor; presence and location of other metastases; clinical findings; treatment and outcome. The microscopic preparations from both the primary tumor and the penile metastases were reviewed in our pathology department to confirm that the penile lesions showed the same histomorphological characteristics as the primary tumor. Results: The primary tumors were located in the genitourinary system in 7 / 9 patients(transitional cell carcinoma of the bladder); while in the remaining two patients the primary site was the lung (squamous cell carcinoma) and the bone marrow (lymphoblastic leukemia); respectively. Percutaneous needle aspiration cytology was performed in all cases and incisional biopsy in one case for diagnosis. Total penectomy was the treatment of choice in 7 cases and bilateral cavernotomy in the leukemia case. No treatment was given to one patient because of multiple metastases in other organs. Survival after treatment lasted from 4 months to 62 months; the longest survival (5 years) was found in the leukemia case. Conclusion: Metastatic penile carcinomas are relatively rare and present a challenging problem. Total penectomy and local excision of solitary nodules or distal penile involvement still represent the treatment of choice. However; because of the association of a penile metastatic lesion with advanced disease; survival rates are limited; and the majority of the patients die within one year