Lower-Than-Expected Vitamin A Concentrations in a Commercial Diet Associated with Uroliths and Pyelonephritis in Rats

SIMPLE SUMMARY: Rats are often used to screen new foods or medications to ensure they are safe for human consumption. As the presence of lesions in a rat in such a study could indicate toxicity, it is essential that rats do not develop background lesions due to other diseases. In the present report, around 5% of rats in an oral safety study developed uroliths, with two of the affected rats also developing kidney infections. Histology was suggestive of vitamin A deficiency. Analysis of the food revealed much lower levels of vitamin A than stated on the label, but enough vitamin A to meet the published minimal nutritional requirements of rats. When the study was continued using rats fed food from a different source, no urinary tract lesions were observed. This suggests dietary factors may have caused the development of the uroliths in this case. It is hypothesized that the lower-than-expected concentration of vitamin A in the diet, potentially along with other dietary and environmental factors, resulted in squamous metaplasia of the uroepithelium and subsequent uroliths and pyelonephritis. The observations highlight the need to use high-quality diets for safety studies in rats. ABSTRACT: Five of 95 rats in an oral safety study developed uroliths, with two of these rats also developing pyelonephritis. Histology of the urinary tract revealed squamous metaplasia suggestive of vitamin A deficiency. Analysis of the diet showed around half the expected concentration of vitamin A, although the concentrations were close to the published nutritional requirements for rats. Due to the presence of squamous metaplasia of the transitional epithelium and the low vitamin A concentration in the diet, a presumptive diagnosis of vitamin A deficiency was made, although an interaction between the low vitamin A concentrations and other dietary components appears possible. Although the uroliths did not cause clinical signs of disease, the lesions observed during this study could have been misinterpreted as being due to the test substance. Observations from this study highlight the need for high-quality food to ensure background lesions do not develop when performing safety studies in rats.