Are urea and creatinine uremic toxins in the rat?

Urea and creatinine are not generally considered to be important uremic toxins despite evidence from dialysis experiments to the contrary, and despite striking elevations of these nitrogenous waste products in uremia. In order to study this problem in acute uremia, we used a new dietary method for prolonging the survival of bilaterally nephrectomized rats. Urea or creatinine were injected on three successive days starting one day after the inception of uremia. Urea or creatinine injections shortened the survival time of acutely uremic rats, and increased the involution of thymus and spleen. The extra urea, but not creatinine, increased the serum osmolality. These data indicate that urea and creatinine are toxic in the acutely uremic rat. Hypertonicity of the serum may contribute to the toxicity of urea. Additional mechanisms of toxicity and additional toxins are not excluded.