This study supports the hypothesis that bladder augmentation appears to be an independent risk factor for TCC, with a lag time of less than 20 years. We recommend endoscopic surveillance of all patients with a history of bladder augmentation beginning 10 years after initial surgery.

Obstruction of the upper urinary tract induces a progressive loss in renal mass through apoptotic renal cell death. Although TNF-alpha has been implicated in ischemia-reperfusion-induced apoptotic renal cell death, its role in obstructive renal cell apoptosis remains unknown. To study this, male Sprague-Dawley rats were subjected to left unilateral ureteral obstruction vs. sham operation. Twenty-four hours before surgery and every 84 h thereafter, rats received either vehicle or a pegylated form of soluble TNF receptor type 1 (PEG-sTNFR1). The kidneys were harvested 1, 3, or 7 days postoperatively, and tissue samples were subsequently analyzed for TNF-alpha (ELISA, RT-PCR), Fas ligand (RT-PCR), apoptosis (TUNEL, ELISA), and caspase 8 and 3 activity (Western blot). Renal obstruction induced increased tissue TNF-alpha and Fas ligand mRNA levels, TNF-alpha protein production, apoptotic renal tubular cell death, and elevated caspase 8 and 3 activity, whereas treatment with PEG-sTNFR1 significantly reduced obstruction-induced TNF-alpha production, renal tubular cell apoptosis, and caspase activity. PEG-sTNFR1 did not significantly alter Fas ligand expression. These results demonstrate that TNF-alpha mediates obstruction-induced renal tubular cell apoptosis and proapoptotic signaling and identify TNF-alpha neutralization as a potential therapeutic option for the amelioration of obstruction-induced renal injury.

Bladder augmentation provides immeasurable improvements in quality of life but it requires lifelong dedication from the patient, family and health care providers. While the requirements for additional surgery are not trivial, 66% of our patients have not required any further surgery in the augmented bladder.

Meldrum KK, Misseri R, Metcalfe P, Dinarello CA, Hile KL, Meldrum DR. TNF-␣ neutralization ameliorates obstruction-induced renal fibrosis and dysfunction.

Abstract-Heat shock protein 72 (HSP72) is a stress-inducible protein capable of protecting a variety of cells from toxins, thermal stress, and ischemic injury. The cytoprotective role and mechanism of action of HSP72 in renal cell ischemic injury remain unclear. To study this, HSP72 was introduced (liposomal transfer) or induced (thermal stress, 43°Cϫ1 hour) in renal tubular cells (LLC-PK1) with Western blot confirmation. Cells were subjected to simulated ischemia 24 hours after liposomal HSP72 transfer or thermal stress, and the effect of HSP72 on nuclear factor-B (NF-B) activation (electrophoretic mobility shift assay and immunohistochemistry), IB␣ production (Western blot), postischemic tumor necrosis factor-␣ (TNF-␣) production (RT-PCR), and apoptosis (TUNEL assay) were determined. In separate experiments, the role of TNF-␣ in apoptosis was determined (anti-TNF-␣ neutralizing antibody). Results demonstrated that both liposomal transfer of HSP72 and thermal induction of HSP72 prevented NF-B activation and translocation, TNF-␣ gene transcription, and subsequent ischemia-induced renal tubular cell apoptosis. Furthermore, TNF-␣ neutralization also inhibited ischemia-induced renal tubular cell apoptosis. These results indicate that liposomal delivery of HSP72 inhibits ischemia-induced renal tubular cell apoptosis by preventing NF-B activation and subsequent TNF-␣ production. Further elucidation of the mechanisms of HSP-induced cytoprotection may result in therapeutic strategies that limit or prevent ischemia-induced renal damage.

We believe that this large and comprehensive series gives valuable insight into this serious complication. The delineation of these potential risk factors serves as a guide for further discussion and investigation.

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