INTERLEUKIN-1 RECEPTOR ANTAGONIST HALTS THE PROGRESSION OF ESTABLISHED CRESCENTIC GLOMERULONEPHRITIS IN THE RAT

The pathogenic role of interleukin-1 (IL-1) in the progression of esta blished rat crescentic glomerulonephritis was investigated by administ ration of the interleukin-1 receptor antagonist (IL-1ra). Passive acce lerated antiglomerular basement membrane (GEM) disease was induced in three groups of six rats. One group was killed on day 7 with no treatm ent. The other groups received a constant infusion of IL-1ra or saline from day 7 until being killed on day 21. All animals developed modera te glomerular injury, a significant loss of renal function and marked histological damage including crescent formation by day 7. Saline trea ted animals showed a significant deterioration in these parameters ove r days 7 to 21. In contrast, animals treated with the IL-1ra over this period showed stabilization of glomerular injury (proteinuria; P < 0. 001) and a recovery of normal renal function (creatinine clearance; P < 0.05). Histologically, IL-1ra treatment suppressed glomerular cell p roliferation (PCNA expression; P < 0.001) and significantly inhibited crescent formation (P < 0.005), glomerular sclerosis (P < 0.005), tubu lar atrophy (P < 0.05) and interstitial fibrosis (P < 0.05). A key fin ding was that IL-1ra treatment not only stopped renal leukocyte accumu lation over days 7 to 21 (P < 0.01), but that treatment also suppresse d immune activation of the infiltrate (P < 0.01). In conclusion, this study provides direct evidence that IL-1 plays a key role in the progr essive/chronic phase of renal injury in experimental crescentic glomer ulonephritis and indicates that IL-1ra treatment may be of therapeutic benefit in human rapidly progressive crescentic glomerulonephritis.