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Effective methylprednisolone dose in experimental crescentic glomerulonephritis
1Research Institute, International Medical Center of Japan, Tokyo, Japan.
Abstract:
Pulse methylprednisolone (MP) therapy improves the prognosis of crescentic glomerulonephritis, but the optimal dose is uncertain. We reported previously that treatment with MP at a dose of 30 mg/kg reduces glomerular crescents and infiltrating mononuclear cells and ameliorates the clinical abnormalities in an animal model of crescentic glomerulonephritis. In the present study, we assessed MP dose requirement for these beneficial effects in correlation with the effect on gene expression of chemokines, potential molecules responsible for recruitment and activation of leukocytes. Animals were treated with MP, 5 to 30 mg/kg/d, for 4 consecutive days after cellular crescents had been formed diffusely. The level of crescents and numbers of glomerular and interstitial monocytes/macrophages and T lymphocytes were reduced significantly by 5 mg/kg of MP, but maximal effect was obtained by 30 mg/kg of MP. Urinary protein was reduced significantly in a 30-mg/kg group but not in other groups. The gene expression of chemokines, MCP-1, MCP-3, TCA3, MIP-1alpha, MIP-1ss, RANTES, and lymphotactin, was enhanced in this model and was inhibited strongly by 5 mg/kg of MP. These results indicate that MP reduces the number of infiltrating mononuclear cells and crescents in the rat model in a dose-dependent fashion and that, despite the strong inhibition of chemokine expression at a lower dose, the beneficial effect of MP is maximal at a dose of 30 mg/kg.
Insights
Pulse methylprednisolone (MP) therapy for crescentic glomerulonephritis shows dose-dependent benefits. While lower MP doses inhibit inflammatory gene expression, maximal therapeutic effects on reducing crescents and improving kidney function require higher doses.
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Crescentic glomerulonephritis (CGN) is a severe kidney disease.
- Pulse methylprednisolone (MP) therapy is used for CGN, but optimal dosing is unclear.
- Previous studies showed MP at 30 mg/kg benefits an animal model of CGN.
Purpose of the Study:
- To determine the optimal dose of MP for treating CGN in an animal model.
- To correlate MP's therapeutic effects with its impact on chemokine gene expression.
Main Methods:
- Rats with CGN received MP (5-30 mg/kg/day) for 4 days.
- Glomerular crescents, infiltrating immune cells, and urinary protein were assessed.
- Gene expression of various chemokines was analyzed.
Main Results:
- MP significantly reduced crescents and immune cells even at 5 mg/kg.
- Maximal reduction in crescents and urinary protein occurred at 30 mg/kg MP.
- MP strongly inhibited chemokine gene expression at 5 mg/kg, but higher doses were needed for maximal clinical benefit.
Conclusions:
- MP's beneficial effects in CGN are dose-dependent.
- Maximal therapeutic efficacy of MP in this model is achieved at 30 mg/kg.
- Higher MP doses are required for optimal outcomes despite potent chemokine inhibition at lower doses.