PREVENTION OF LATE RENAL CHANGES AFTER INITIAL ISCHEMIA REPERFUSION INJURY BY BLOCKING EARLY SELECTIN BINDING/

Background. Increasing clinical evidence suggests that delayed initial function secondary to ischemia/reperfusion injury alone, and particul arly in combination with early episodes of acute rejection, reduces ki dney allograft survival over time, Methods, We investigated changes de veloping over the long term following a standardized ischemia/ reperfu sion insult in a Lewis rat model, The left kidney was isolated in a un inephrectomized host and cooled, and the pedicle was clamped for 45 mi n, Animals were followed for 48 weeks after initial renal injury, Orga ns were removed serially (4, 8, 16, 24, 32, 40, and 48 weeks) for immu nohistology and reverse transcriptase polymerase chain reaction, Resul ts, Progressive proteinuria developed after 8 weeks, By immunohistolog y, CD4(+) leukocytes and ED-1(+) macrophages infiltrated the ischemic organs in parallel with up-regulation of major histocompatibility comp lex class II antigen expression, Because macrophages have been shown t o be critical in chronic changes in other models, they were examined p rimarily in these studies, By reverse transcriptase polymerase chain r eaction, macrophage-derived, fibrosis-inducing factors (transforming g rowth factor-beta, interleukin 6, and tumor necrosis factor-alpha) rem ained highly and constantly expressed throughout the follow-up period, The long-term influence of initial treatment with the soluble form of P-selectin glycoprotein ligand-1, a soluble ligand for P-and E-select in, was then examined, All functional and structural changes remained at relative baseline, similar to uninephrectomized controls, Conclusio ns, These data suggest that blocking the initial selectin-mediated ste p after ischemia/reperfusion injury, which triggers significant early cellular and molecular events, also reduces later renal dysfunction an d tissue damage over time, In part, the findings may be explained by t he sparing of functioning nephron units, which if destroyed or comprom ised by the original insult, may contribute to long-term graft failure , This approach may be important clinically in the transplantation of kidneys from non-heart-beating or marginal donors or organs experienci ng prolonged ischemic times.