Several controversies regarding desensitization strategies for successful ABO-incompatible (ABOi) kidney transplantation still exist. This study aimed to investigate whether pretransplant anti-A/B antibody removal is mandatory in an ABOi kidney transplant recipient with low baseline isoagglutinin titers.We adopted a modified desensitization protocol with two doses of rituximab (RTX, 100 mg/body) without pretransplant antibody removal for ABOi kidney transplant recipients with a titer of ≤1:64 (group A; n = 35) and investigated the feasibility of this protocol by comparing it with the clinical outcomes of patients undergoing standard pretransplant plasmapheresis (group B; n = 21).There was no significant difference in the rate of antibody-mediated rejection within the first month after transplantation between the two groups (11.4% in group A vs. 2% in group B, p = 0.6019). Moreover, no differences were observed in the short- and long-term graft outcomes between the groups. However, two major critical acute antibody-mediated events occurred in group A; one patient lost the graft due to hyperacute rejection, and the other patient developed thrombotic microangiopathy after surgery. Risk factors predicting these perioperative complications were not identified.We conclude that not only B-cell depletion using RTX but also pretransplant antibody removal is still recommended even for patients with low isoagglutinin titers. In addition, a new diagnostic tool is needed for accurate risk stratification.
An in vivo model system to understand the mechanism of xenograft rejection was established using human peripheral blood leukocyte-reconstituted SCID (hu-PBL-SCID) mice. Human xenoreactive natural antibodies (XNA), of IgM and IgG subtypes, capable of binding to pig aortic endothelial cells (PAEC) were detected in the sera of hu-PBL-SCID by ELISA and flowcytometric methods. Western blot analysis of PAEC lysates showed that IgM and IgG XNA from hu-PBL-SCID recognized xenoantigens with similar molecular mass as those recognized by XNA from normal human serum (NHS). This result demonstrated that hu-PBL-SCID contained XNA representing the same repertoire as that of the NHS. XNA from NHS and hu-PBL-SCID were also able to induce intracellular Ca2+ signals in cultured PAEC several fold above the basal level. This result revealed their functional similarity and demonstrated for the first time that XNA in the absence of C can activate PAEC, which may lead to the pathology of xenograft rejection. In vivo, PAEC transplanted under the kidney capsule of hu-PBL-SCID mice showed deposition of human IgM and mouse C. In summary, the present study demonstrates that hu-PBL-SCID can serve as a useful model to characterize innate immunity against xenograft.
We conducted a multi-center prospective study to evaluate the safety and efficacy of steroid withdrawal after renal transplantation in children. In 52 children (51 living-related donor transplants and 1 cadaver donor transplant), immunosuppressive therapy was started with cyclosporine (CyA), mizoribine (MZ), methylprednisolone (MPL) and anti-lymphocyte globulin. Administration of MPL was reduced to alternate days more than 6 months after transplantation, and attempts were made to withdraw it. Acute rejection was noted in 19 patients (36.5%) by 1 month after transplantation. The whole-blood CyA trough level using monoclonal antibody was 175.0+/-17.0 ng/ml in patients who developed acute rejection and 282.0+/-25.3 ng/ml in those who did not show acute rejection (p<0.01). During the 37 attempts at alternate-day MPL administration, clinical acute rejection was observed in only 1 patient and chronic rejection in 3. During 10 attempts to withdraw MPL, acute rejection was noted in 3 patients, but graft function recovered to the pre-rejection level after treatment of the acute rejection. At the last observation, graft function was lost in 3 patients, 22 were receiving MPL on alternate days, and MPL had been withdrawn from 7 for a mean period of 16.7 months. The survival rate of the patients and the grafts was 100% and 94% after an average follow-up period of 4 years. Evaluation of growth showed catch-up growth in all patients during the withdrawal period.
Abstract Background Although recently strengthened immunosuppression protocols have decreased the incidence of clinical acute rejection of renal transplants, subclinical acute rejection and borderline changes remain problematic. This study was performed to evaluate the effects of antirejection therapies for early subclinical acute rejection and borderline changes. Methods In total, 269 renal transplant patients who received 3-month and 1-year protocol biopsies after renal transplantation were enrolled this study and divided into those with normal findings (Group A) and those with ≥ borderline changes (Group B) according to the 3-month pathological results. Pathological changes, graft function, and graft survival were evaluated at 1 year. Results The 3-month protocol biopsy revealed normal findings in 166 patients (Group A) and borderline changes and subclinical acute rejection in 103 patients (Group B). In Group A, 65.1% ( n = 108) of the patients maintained normal findings at 1 year, while 30.1% ( n = 50) deteriorated to ≥ borderline changes. In Group B, 52.4% ( n = 54) of patients improved to normal. Among patients with subclinical acute rejection, 25.0% ( n = 5) maintained subclinical acute rejection at 1 year despite antirejection therapy. The mean estimated glomerular filtration rate decreased from 60.4 ± 24.5 to 58.3 ± 19.0 mL/min/1.73 m 2 in Group A and from 57.2 ± 28.2 to 53.7 ± 20.3 mL/min/1.73 m 2 in Group B ( p = 0.417). The 3-, 5-, and 7-year graft survival rates were 99.4%, 99.4%, and 97.6% in Group A and 100.0%, 98.6%, and 98.6% in Group B, respectively ( p = 0.709). Conclusions Subclinical acute rejection is likely to recur. However, intervention for subclinical acute rejection in the early period after transplantation may help to prevent subsequent histological changes.
