Pre-neoplastic changes in rat urothelium following portacaval anastomosis

The development of pre-neoplastic and neoplastic changes has been documented in the urinary tract of the rat after portacaval shunting (PCS) and has been attributed variously to circulating carcinogens, the development of bladder stones, or deficiency of vitamin A. Therefore, an investigation of the pathogenesis of bladder tumors after PCS was undertaken in 120 PCS and 120 sham-operated male Sprague Dawley rats. Ten rats from each group were sacrificed at monthly intervals for 1 year after surgery. The incidence of calculus formation in the bladder increased from 20% at 2 months to 80% at 12 months after PCS. Hyperplastic mucosal changes occurred 3 months after surgery. After 5 months, distinct papillomas developed, and after 7 months, increasingly severe papillary changes and squamous metaplasia were evident. Interestingly, these urothelial changes were seen both in animals with and without bladder stones. Significantly decreased serum vitamin A levels were observed at 6 months (54.0 +/- 8.8 IU/dl, n = 10) (P less than .01), and 12 months (41.0 +/- 7.9 IU/dl, n = 10) (P less than .01), compared to those in sham-operated controls of 126.0 +/- 12.5 IU/dl (n = 10) and 122.7 +/- 19.2 IU/dl (n = 10). In addition, PCS resulted in a significantly increased activity of urothelial ornithine decarboxylase (ODC), a marker of neoplastic changes, at 6 months (3.1 +/- 0.4 nmoles CO2 in 60 min/mg protein, n = 5) (P less than .05) and 12 months (8.1 +/- 0.6 nmoles CO2 in 60 min/mg protein, n = 5) (P less than .05), when compared to ODC activity in controls (0.9 +/- 0.2 nmoles CO2 in 60 min/mg protein, n = 5). These data suggest that the development of urinary bladder tumor after PCS in the rat may be due to vitamin A deficiency rather than to bladder calculi or urinary carcinogens.