Nephrol Dial Transplant (2001) 16: 518-524
© 2001 European Renal Association-European Dialysis and Transplant Association
Prevention and treatment of experimental crescentic glomerulonephritis by blocking tumour necrosis factor-
Renal Section, Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, UK
Background. The mechanisms controlling progression of glomerulonephritis are poorly understood, but there is increasing evidence that tumour necrosis factor-
(TNF-) plays a central role in many aspects of glomerular inflammation and scarring. We investigated the role of TNF- in an experimental model of crescentic glomerulonephritis in Wistar Kyoto (WKY) rats by continuously blocking endogenous TNF-, using its soluble receptor sTNFr p55, both before and after establishment of nephritis.
Methods. Glomerulonephritis was induced by a single intravenous injection of 0.1 ml nephrotoxic serum. In the first experiment, rats were pre-treated with sTNFr p55 2 mg/kg intraperitoneally 1 hour before induction of nephritis and on a daily basis thereafter until day 4. In the second experiment, a similar protocol was followed, but treatment with sTNFr p55 was continued until day 10. In the third experiment, treatment with sTNFr p55 was delayed until 4 days after induction of nephritis and continued until day 10. The effects of treatment on renal function, renal histology, cellular infiltration, activation and proliferation, and IL-1ß expression were assessed by standard methods.
Results. In the first experiment, short-term treatment with sTNFr p55 caused a marked reduction in albuminuria and fibrinoid necrosis. It also reduced glomerular cell infiltration, activation and proliferation. In the second experiment, prolonged treatment with sTNFr p55 caused a sustained reduction in albuminuria and all histological and cellular parameters of glomerular inflammation; in particular it completely prevented the development of crescents. In the third experiment, delayed therapy of established nephritis with sTNFr p55 significantly reduced albuminuria and glomerular inflammation, including the prevalence of crescent formation. In both long-term experiments, there was less glomerular expression of IL-1ß and lower serum concentrations of IL-ß in sTNFr p55-treated rats.
Conclusions. This study shows that neutralization of endogenous TNF- is effective in preventing acute glomerular inflammation and crescent formation, and in treating established disease, in a rat model of crescentic nephritis. These results may have therapeutic implications for human glomerulonephritis.
Keywords: crescentic glomerulonephritis; glomerular basement membrane; nephrotoxic serum; tumour necrosis factor-; Wistar Kyoto (WKY) rat
Correspondence and offprint requests to: Professor Charles Pusey, Renal Section, Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, UK.
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