A clinical research consortium sponsored by NIAID and JDRF
Farris AB, Taheri D, Iafrate AJ, Smith RN, Tolkoff-Rubin N, Spitzer TR, Kawai T, Cosimi AB, Sachs DH, Colvin RB, Collins AB
Massachusetts General Hospital (MGH), Boston, MA Emory U, Atlanta, GA Harvard Medical School, Boston, MA
Background: Renal transplantation without maintenance immunosuppression has been described in recipients of combined bone marrow (BM) and kidneys from single-haplotype mismatched living related donors. Most patients developed a capillary leak syndrome about 10 days post-transplant when donor chimerism is first becoming detectable associated with spontaneously reversible renal dysfunction. A similar phenomenon occurs in autologous and allogeneic BM transplants and has been called the “engraftment syndrome” (ES). Here we present the novel renal pathologic findings in this syndrome.
Design: Indication renal biopsies were obtained from all patients who developed graft dysfunction on day 10-12 (7/9 recipients) and examined by light, immuno- and electron microscopy (EM), and with a panel of immunohistochemical markers for cell types, proliferation (Ki67) and XY FISH to identify cell origin in gender mismatched cases. Controls included transplant biopsies from patients on standard therapy with acute tubular injury (ATI) (n = 5) or normal findings (n = 3) at the same time post-transplant.
Result: Biopsies from patients with ES had prominent ATI, commonly with interstitial edema, hemorrhage and congestion of capillaries. Diffuse C4d was present in one case and focal endothelialitis in another. EM showed marked endothelial injury and loss in glomeruli and peritubular capillaries (PTC). Loss of PTC endothelial cells was evident on CD34 and CD31 stains. The most striking finding was a prominent and significant increase in the number of intracapillary Ki67 cells, both in glomeruli and in PTC compared with transplant biopsies with ATI. Control cases with ATI had mostly tubular cell Ki67+ and had a similar density of CD68 cells. XY FISH demonstrated that CD45+ cell in the peritubular capillaries were of recipient origin with a smaller number of CD34+ circulating cells of recipient origin.
Conclusion: The engraftment syndrome is manifested by widespread renal allograft endothelial injury and proliferation of intracapillary cells, the latter readily detected with Ki67 and quite different from ordinary ATI. It remains to be defined whether the mechanism involves a cytokine storm, drug toxicity, and/or allo- or auto-reactivity.
