Late graft dysfunction after prolonged cold ischemia of the donor kidney -Inhibition by cyclosporine

Background. The present study was devised to elucidate the influence of pro longed cold ischemia on the development of chronic transplant dysfunction ( CTD) in kidney isografts (Brown Norway-->Brown Norway; BN-->BN) and in kidn ey allografts (BN-->Wistar Agouti/Rij [WAG]) under temporary cyclosporine ( CsA) therapy, Methods. To induce ischemic injury, BN donor kidneys were preserved for 24 hr in 4 degrees C University of Wisconsin solution before transplantation. Renal function (proteinuria), histomorphology according to the BANFF criter ia for CTD, and infiltrating cells were assessed. Grafts were examined both early at days 2, 3, 6, and 10, and late at week 26 (allografts) or at week 52 (isografts), Results. Nonischemic isografts preserved a normal function and morphology, Ischemic isografts developed a progressive proteinuria over time and demons trated significantly more glomerulopathy with macrophage (M Phi) infiltrati on and intimal hyperplasia than nonischemic controls at week 52, During the initial 10 days, there was an increased infiltration of MHC class II+ cell s, predominantly CD4(+) cells and M Phi, coinciding with up-regulated inter cellular adhesion molecule-1 expression. CsA treatment in ischemic isograft s inhibited infiltration of MHC II+ cells in the early stage, which was acc ompanied by significantly less renal damage at week 52 compared with untrea ted controls (proteinuria: 59+/-8 vs. 134+/-19 mg/24 hr; BANFF score: 2.8+/ -0.4 vs. 4.3+/-1.0), Under CsA therapy, 24-hr cold ischemia of the allograf t affected neither the onset or progress of proteinuria, nor the histomorph ology (BANFF score: 7.8+/-2.4 vs. 7.3+/-1.9). In both ischemic and nonische mic allografts, intercellular adhesion molecule-1 expression and mononuclea r cell infiltration (CD4, CD8, M Phi,) was abundantly present during the fi rst 10 days and function deteriorated rapidly. Conclusions, Prolonged cold ischemia plays a role in the induction of CTD, but its deleterious effect can be successfully inhibited by CsA Therefore, the alloantigeneic stimulus is the overriding component in the multifactori al pathogenesis of CTD.