INFECTIONS AND REDUCED FUNCTIONING KIDNEY MASS INDUCE CHRONIC REJECTION IN RAT-KIDNEY ALLOGRAFTS

The etiology of chronic rejection of kidney allografts is unknown, alt hough hyperfiltration, acute rejection, viral infection and initial gr aft ischemia have been implicated. To test whether endothelial activat ion may be the link between these factors and chronic rejection, the e ndotoxin (lipopolysaccharide - LPS), a potent activator of endothelial cells, was evaluated in an established chronic rejection model. Bilat erally nephrectomized Lewis recipients of orthotopically transplanted Fisher 344 kidneys were treated briefly with low dose cyclosporine (1. 5 mg/kg/day x 10). Recipients were given a non-lethal dose of LPS (2 m g) i. p. at 8 weeks and compared to allografted controls treated with vehicle. Urine protein was measured every 4 weeks. Rats in the treated group were sacrificed at 12 and 16 weeks, control animals at 12, 16 a nd 24 weeks (20/group) and examined histologically. In the chronically rejecting control allografts, progressive interstitial and glomerular sclerosis and vascular intimal proliferation had become apparent by 1 2 weeks. Infiltration of glomeruli, particularly by macrophages (M phi ), and the coincident presence of cytokines were prominent, peaking at 16 weeks. LPS treatment accelerated and intensified these changes; pr oteinuria was more pronounced (16 weeks: 79 mg/24 h vs. 49 mg/24 h, p< 0.05). Numbers of infiltrating M phi peaked at 12 weeks in LPS treated hosts (69 c/FV vs. 27 c/FV in untreated controls, p<0.01), accompanie d by an increased upregulation of MHC class II and cytokine expression , particularly TNF alpha and PDGF around arteries and areas of infiltr ation. By 16 weeks, 35 +/- 3% of glomeruli in LPS treated recipients h ad become sclerotic vs. 15 +/- 6% (p<0.05) in controls, again associat ed with increased expression of cytokines (PDGF, TNF alpha, TGF beta), adhesion molecules (ICAM-1) and extracellular matrix proteins. Overal l, the extent of chronic rejection of grafts in LPS treated rats at 16 weeks was similar to that developing in non-treated rats at 24 weeks. Activation of graft endothelium and/or host leucocytes increased the pace of graft infiltration and the expression of cytokines and other m olecules. These events accelerate the process of chronic rejection.