The present study permits the following conclusions.
1. Uranium nitrate in the dog has a high degree of selective affinity as a nephrotoxic for the epithelium of the proximal convoluted tubules. The glomeruli participate in the injury and develop obliterative connective tissue changes as evidence of a preexisting acute injury followed by repair.
2. The repair to the degenerated tubular epithelium is accomplished by two processes. First, by a regeneration of convoluted tubule cells from such cells not too severely injured in this location. This type of regenerated epithelium has no resistance to uranium. Second, the regeneration may occur as an ingrowth of cells or as syncytial buds from cells in the terminal portion of the proximal convoluted tubule or from the upper end of the descending limb of Henle's loop. This type of regenerated epithelium which is entirely different cytologically from normal convoluted tubule epithelium is resistant to a second injury from uranium even when the amount of this nephrotoxic agent has been increased to double the amount of the initial injection.
3. The kidney does not develop a local tissue immunity or resistance to uranium in the sense that cells of the same type once injured by it acquire as a result of the injury a resistance. The resistance and apparent but not real immunity is due to another type of cell with resistance having been substituted for a cell with but little resistance. This fact may be looked upon as constituting part of a defense mechanism in the kidney and may in part explain the long duration of certain types of chronic nephritic processes.
4. The functional studies which have been made during the initial injury from uranium to the tubules and during the secondary injury in animals which have either shown a resistance or a lack of resistance, emphasize the importance of the tubular epithelium as a part of a secretory mechanism in urine formation. During periods when the proximal convoluted tubule epithelium is in a state of acute degeneration there is a disturbance in the acid-base equilibrium of the blood, a reduction in the elimination of phenolsulphonephthalein and a retention of urea nitrogen, non-protein nitrogen and creatinine. When this epithelium is regenerated by the formation of a tubular epithelium normal in character for this location of the tubule, regardless of structural changes in the glomeruli, the above evidence of renal dysfunction returns to the normal. If at such a period this type of regenerated epithelium be injured by a secondary injection of uranium a state of acute renal dysfunction is induced in an intensified form. In those animals in which the repair to the tubules was accomplished by the formation of an atypical type of epithelium in the convoluted tubules as well as by the formation of cells normal in histological appearance for this part of the tubule there was an improvement in the degree of depletion of the reserve alkali of the blood, in the elimination of phenolsulphonephthalein and in the retention of urea nitrogen, non-protein nitrogen and creatinine. Certain of these values did not reach the normal. In such a state of renal repair when a second injection of uranium was given the kidney was found to have developed a marked resistance to it. There was but slight evidence of a depression in renal function. Associated with this acquired functional resistance there was no evidence of injury to the atypical, flattened regenerated epithelium of the proximal convoluted tubules.