Antibody blockade of TNF-alpha reduces inflammation and scarring in experimental crescentic glomerulonephritis

Kidney Int. 2005 May;67(5):1812-20. doi: 10.1111/j.1523-1755.2005.00279.x.


Background: Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine produced by macrophages, and by renal mesangial and tubular epithelial cells. It stimulates the release of interleukin (IL)-1beta, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta (TGF-beta). Blockade of TNF-alpha is currently used clinically in several autoimmune inflammatory diseases. We hypothesised that blocking TNF-alpha with a monoclonal antibody would prevent inflammation and renal fibrosis in crescentic glomerulonephritis.

Methods: Nephrotoxic nephritis was induced in Wistar Kyoto (WKY) rats by intravenous injection of rabbit antirat glomerular basement membrane (GBM) nephrotoxic serum (NTS). Anti-TNF-alpha monoclonal antibody or saline was given intraperitoneally three times per week in four protocols: experiment 1, days 0 to 7; experiment 2, days 0 to 14 and days 4 to 14; experiment 3, days 4 to 28; and experiment 4, days 14 to 28.

Results: In experiment 1, rats treated from disease induction had less glomerular fibrinoid necrosis and fewer glomerular macrophages at day 7. In experiment 2, rats treated from day 0 or day 4 showed improved renal function, as judged by serum creatinine, with a significant reduction in crescents. In experiment 3, anti-TNF-alpha treatment significantly reduced urine protein to creatinine ratio and urinary MCP-1 levels. Serum creatinine was preserved at both day 14 and day 28. Tubulointerstitial inflammation, glomerular and tubulointerstitial scarring, and markers of fibrosis [alpha-smooth muscle actin (alpha-SMA) and type IV collagen] were significantly less in treated rats at day 28. In experiment 4, serum creatinine was higher and tubulointerstitial scarring was less in delayed-treated animals.

Conclusion: Neutralization of endogenous TNF-alpha reduces glomerular inflammation, crescent formation, and tubulointerstitial scarring, with preservation of renal function, in experimental crescentic glomerulonephritis. TNF-alpha blockade is effective even when introduced at the time of maximum glomerular inflammation.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Basement Membrane / immunology
  • Creatinine / blood
  • Glomerulonephritis / etiology
  • Glomerulonephritis / immunology
  • Glomerulonephritis / pathology
  • Glomerulonephritis / therapy*
  • Kidney Glomerulus / immunology
  • Male
  • Rabbits
  • Rats
  • Rats, Inbred WKY
  • Time Factors
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*


  • Antibodies, Monoclonal
  • Tumor Necrosis Factor-alpha
  • Creatinine