Prevention of Renal Failure in Experimental Renal Disease

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THE EXTREME EXPENSE and high morbidity and mortality associated with the treatment of endstage renal disease encourage the search for an effective way of preventing or interrupting the progression of renal failure to this stage . Previous attempts have focused on specific treatment modalities such as immunosuppression therapy for immunologically mediated renal disease and surgical correction of genitourinary disorders such as reflux or obstructive uropathies . Another approach to eradicating endstage renal failure by prevention involves reducing exposure to certain nephrotoxic agents such as the removal of phenacetin from analgesics and more aggressive management of hypertensive states. Although these approaches have resulted in some success such forms of management are either not applicable or ineffective in the management of the great majority of renal diseases . Irrespective of the cause of renal failure, it has been reasonably well established that once a critical level of renal functional deterioration is achieved invariable progression to endstage disease occurs even if the initiating disease or condition has resolved or been eradicated. It has been assumed that this phase of progressive functional deterioration is inevitable irrespective of intervention . However , recent studies provide encouragement that this late functional deterioration may be slowed or prevented. Because of the frequency that calcification is found in human end stage kidneys, it was speculated that renal parenchymal calcium deposition could be a late common pathogenetic mechanism which promotes and accelerates the rate of functional deterioration. To test this possibility, studies have been carried out in experimental models of chronic renal failure in rats. It has been known for years that after a critical mass of renal tissue is removed in a variety of species of animals , subsequent deterioration of the remaining renal parenchyma ensues and the animals ultimately die of uremia. In order to test the hypothesis that renal parenchymal calcification, resulting from either hyperparathyroidism or altered phosphorus metabolism present in the uremic state, was responsible for the destruction of the renal remnant, animals were provided a phosphate deficient diet prior to the establishment of a remnant kidney. In this model of renal failure, phosphate restriction was totally protective of functional deterioration , renal parenchymal calcification and histologic damage . l These studies were extended to determine if phosphate restriction would be equally protective after the disease in the remnant kidney was well established . Thirty days following the establishment of the remnant kidney , at a time of significant functional deterioration, histologic damage and proteinuria, animals were switched to a phosphate restricted diet. Even at this stage of renal disease, phosphate restriction was associated with functional improvement, and the reversal of histologic changes and proteinuria. 2 Thus, in this model of renal failure, phosphate restriction was shown to be totally protective suggesting that phosphorus was somehow important in mediating this disease. These studies were extended to determine if phosphorus restriction would be equally as effective in an experimental renal disease more closely akin to human renal disease. The animal model employed involved rats with experimental glomerulonephritis , nephrotoxic serum nephritis (NSN) . This disease is induced by preimmunizing the rats with rabbit IgG and subsequently injecting them with rabbit antirat glomerular basement membrane antibodies. It has been thought that this type of disease has two phases . The first phase is the heterologous phase directly caused by the antiglomerular basement membrane antibody which results in the early induction of proteinuria. The second phase has been termed the autologous phase which results from the formation of antibodies to the rabbit gamma globulin fixed