The Effect of Cyclosporin A on Disease Progression in Proliferative Immune Complex Glomerulonephritis

Abstract

In rats with the proliferative immune complex glomerulonephritis of chronic serum sickness, kidney function deteriorates in three discrete and readily distinguishable stages: Mild, Moderate, and Severe. The mononuclear cell composition of glomerular inflammation is also different in each stage. The immunosuppressive drug, cyclosporin A, was administered to rats with chronic serum sickness in order to investigate the relationship between glomerular immunopathology and pathophysiology in proliferative immune complex nephritis. When introduced after the onset of proteinuria, daily treatment with cyclosporin A failed to prevent the progression from Moderate to Severe nephritis, which is characterized by the abnormal differentiation and local proliferation of glomerular macrophages, as well as grave deterioration in kidney function. In contrast, when cyclosporin A therapy started before the onset of proteinuria, the course of proliferative glomerulonephritis was altered significantly. Although the levels of proteinuria and macrophage accumulation that are characteristic of the Moderate stage of nephritis were not reduced, progression to Severe nephritis did not occur. The number of glomerular macrophages appeared to increase in two separate phases in this chronic serum sickness model of proliferative immune complex glomerulonephritis. The first phase, which coincided with the onset of proteinuria, did not require T cells and culminated only in moderate hypercellularity and proteinuria. The second increase in the number of glomerular macrophages, which was accompanied by the expression of abnormal macrophage phenotypes, was closely linked to the development of severe kidney insufficiency. The protective effect of cyclosporin A therapy was consistent with, although not conclusive proof for, the hypothesis that local T cell activation may contribute to the progression of proliferative immune complex glomerulonephritis. Since cyclosporin A can also directly influence the responses of macrophages and mesangial cells, the effect of the drug on the course of nephritis in this model might not be related to its immunosuppressive action.