Shoichi Iida

Acute antibody-mediated rejection in living ABO-incompatible kidney transplantation: long-term impact and risk factors.

The impact of acute antibody‐mediated rejection (AAMR) on the long‐term outcome on ABO‐incompatible (ABOI) kidney transplantation is not well understood. We retrospectively analyzed the long‐term impact of AAMR and risk factors for AAMR in 57 consecutive recipients performed between 1999 and 2004. Nineteen patients (33%) who developed AAMR within 3 months posttransplantation constituted of the AMR group. The graft survival rate was significantly lower in the AMR group (AMR vs. non‐AMR, respectively; 5 years: 84% vs. 95%; 8 years: 45% vs. 95%; p = 0.009). The prevalence of transplant glomerulopathy at 1 year posttransplantation was significantly higher in the AMR group (AMR 64% vs. non‐AMR 3%, p < 0.001). Multivariate analysis demonstrated that anti‐blood group IgG antibody titers of 1:32 at the time of transplantation (OR, 9.52; p = 0.041) and donor‐specific anti‐HLA antibodies (DSHA) detected by Luminex single bead method (OR, 5.68; p = 0.015) were independent risk factors for AAMR regardless of baseline anti‐blood group IgG antibody titers. Our results indicate that AAMR has a heavy impact on the long‐term outcome and preoperative DSHA appears to have a more significant association with poor graft outcomes than anti‐blood group antibodies, even in ABOI kidney transplantation.

Evaluation of immunosuppressive regimens in ABO-incompatible living kidney transplantation- : Single center analysis

Several protocols allow the successful ABO incompatible living‐related kidney transplantation (ABO‐ILKT), yet no single method has emerged as the best. We have made several substantial changes to our ABO‐ILKT protocol over the past decade and a half and have attempted to determine whether the changes in immunosuppressive agents have resulted in a better outcome. We used methylprednisolone (MP), cyclosporine (CsA), azathioprine (AZ), antilymphocyte globulin (ALG) and deoxyspergualine (DSG) in the 105 cases of ABO‐ILKT (group 1) between 1989 and 1999, and MP, tacrolimus (FK506), mycophenolate mofetil (MMF) in the 117 cases of ABO‐ILKT (group 2) between 2000 and 2004. We compared the patient and graft survival rates as well as the incidence rate of acute rejection in these two eras, when different regimens were used. There were significant differences in the 1‐ and 5‐year graft survival rates between groups 1 and 2 (1‐year: 78% in group 1 vs. 94% in group 2; 5‐year: 73% in group 1 vs. 90% in group 2, p = 0.008). Also, a higher incidence rate of acute rejection was significantly observed in group 1 (50/105, 48%) than in group 2 (18/117, 15%) (p < 0.001). We conclude that the FK/MMF combination regimen provides excellent graft survival results in ABO‐ILKT.

Analysis of Renal Transplant Protocol Biopsies in ABO-Incompatible Kidney Transplantation

Numerous studies have shown that protocol biopsies have predictive power. We retrospectively examined the histologic findings and C4d staining in 89 protocol biopsies from 48 ABO‐incompatible (ABO‐I) transplant recipients, and compared the results with those of 250 controls from 133 ABO‐compatible (ABO‐C) transplant recipients given equivalent maintenance immunosuppression. Others have shown that subclinical rejection (borderline and grade I) in ABO‐C grafts decreased gradually after transplantation. In our study, however, subclinical rejection in the ABO‐I grafts was detected in 10%, 14% and 28% at 1, 3 and 6–12 months, respectively. At 6–12 months, mild tubular atrophy was more common in the ABO‐C grafts whereas the incidence of transplant glomerulopathy did not differ between the two groups (ABO‐C: 7%; ABO‐I: 15%; p = 0.57). In the ABO‐I transplants, risk factors for transplant glomerulopathy in univariate analysis were positive panel reactivity (relative risk, 45.0; p < 0.01) and a prior history of antibody‐mediated rejection (relative risk, 17.9; p = 0.01). Furthermore, C4d deposition in the peritubular capillaries was detected in 94%, with diffuse staining in 66%. This deposition, however, was not linked to antibody‐mediated rejection. We conclude that, in the ABO‐I kidney transplantation setting, detection of C4d alone in protocol biopsies might not have any diagnostic or therapeutic relevance.

The low dose of rituximab in ABO-incompatible kidney transplantation without a splenectomy: a single-center experience.

Shirakawa H, Ishida H, Shimizu T, Omoto K, Iida S, Toki D, Tanabe K. The low dose of rituximab in ABO‐incompatible kidney transplantation without a splenectomy: a single‐center experience. 
Clin Transplant 2011: 25: 878–884.

Retroperitoneoscopic Living Donor Nephrectomy: Experience of 425 Cases at a Single Center

BACKGROUND AND PURPOSE Laparoscopic living donor nephrectomy (LLDN) is a standard method of donor nephrectomy. Most cases of LLDN are transperitoneal. Retroperitoneal access, however, implies a direct approach to the retroperitoneal organs without interfering with any of them. Since 2001, we have been trying to establish the technique of retroperitoneoscopic live donor nephrectomy (RPLDN). To assess the safety, feasibility, and usefulness of RPLDN, we reviewed the experience with this technique at our institution. PATIENTS AND METHODS From July 2001 to March 2009, 425 patients underwent live donor renal transplantation at our institution with allografts procured by RPLDN. Study variables included operative time, time to retrieval of the kidney, blood loss, warm ischemia time, length of hospital stay, number and length of renal vessels, graft function, and complications. RESULTS Mean follow-up was 53 months. Donor nephrectomy was performed successfully in all patients. The complication rate was 4.9%. In one case, the procedure was changed to open donor nephrectomy because of severe adhesion in the renal hilum from previous surgery. Ureteral complications occurred in four patients, who were successfully treated with retrograde ureteral stent placement. None of the donors needed readmission. Mean warm ischemia time was 4.8 minutes. Creatinine levels returned to normal in all patients, and long-term allograft function was good. Serum creatinine levels at postoperative days 1, 7, and 14 were 3.7 mg/dL, 1.4 mg/dL, and 1.4 mg/dL on average, respectively. Slow graft function was noted in four (1.1%) cases but returned to the normal level within 2 weeks after surgery. One-year donor survival was 99%, and 1-year graft survival was 98.2%. CONCLUSIONS Excellent donor safety and allograft function were obtained with RPLDN. These results suggest that RPLDN could be an option for LLDN.

New-onset diabetes after transplantation in tacrolimus-treated, living kidney transplantation: long-term impact and utility of the pre-transplant OGTT

BackgroundTo evaluate the role of the oral glucose tolerance test (OGTT) before transplantation and to examine the risk factors for new-onset diabetes after transplantation (NODAT) during long-term follow-up of renal transplant recipients receiving FK-based therapy.MethodsThe study evaluated 378 patients pre-transplantation using the OGTT and assigned them to one of three groups: Group 1, normal pattern; Group 2, impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) pattern (IFG/IGT); and Group 3, DM pattern.ResultsAlthough the incidence of NODAT was higher in Group 3 than in groups 1 and 2, no significant difference was found between the three groups with regard to graft survival during long-term follow-up. Multivariate analysis showed that only a family history of diabetes was a significant factor determining NODAT progression.ConclusionsImpaired glucose tolerance appears to be a threshold influencing NODAT; however, it was not a significant factor in graft survival. Careful monitoring and management based on the result of the pre-transplantation OGTT appear to prevent the deterioration of impaired glucose tolerance in renal transplant recipients receiving FK-based therapy, even when a pre-operative OGTT shows impaired glycemic control.

Cytomegalovirus infection following renal transplantation in patients administered low‐dose rituximab induction therapy

Anti‐CD20 antibody (rituximab) is recently being used as a B cell‐depleting agent in renal transplantation (RTx). However, the incidence of infectious complications associated with rituximab therapy remains uncertain. We evaluated the incidence of cytomegalovirus (CMV) infection associated with rituximab therapy in RTx. A total of 83 patients were enrolled. The immunosuppressive regimen consisted of tacrolimus or cyclosporin, mycophenolate mofetil, methylprednisolone and basiliximab. In 54 patients, only one dose of rituximab (200 or 500 mg/kg body weight) was given before RTx. A total of 25 of 43 (58.1%) recipients who were CMV seropositive prior to RTx and who received rituximab induction therapy developed CMV infection, compared to 18 of 24 (75%) CMV seropositive recipients who did not receive rituximab therapy (P = 0.1676). A total of 8 of 11 patients who were CMV seronegative prior to RTx and who received rituximab developed CMV infection. However, CMV seroconversion was seen in all 8 of these infected patients. Low‐dose rituximab induction therapy in renal transplant recipients appears to have no influence on the incidence of CMV infection and CMV seroconversion. However, we have to consider anti‐CMV prophylaxis therapy, because of high incidents of CMV infection, especially for CMV seronegative recipients who received rituximab.

Minimal effect of cold ischemia time on progression to late-stage chronic kidney disease observed long term after partial nephrectomy.

OBJECTIVES To assess the influence of cold ischemia on postoperative renal function and the new onset of late-stage chronic kidney disease during long-term follow-up after partial nephrectomy. METHODS A total of 131 patients with renal tumors who underwent partial nephrectomy and were followed up for >or=12 months were included in the present study. Renal function was analyzed using the estimated glomerular filtration rate (e-GFR). RESULTS We classified the subjects into 3 groups according to the length of cold ischemia time: group 1, 1-30 minutes; group 2, 31-60 minutes; and group 3, >60 minutes. Although the postoperative e-GFR was lower in group 3 than in groups 1 and 2, no significant difference was found among the 3 groups during long-term follow-up when preoperative CKD was absent. A cold ischemia time of >or=44 minutes significantly increased the probability of freedom from the new onset of an e-GFR of <45 mL/min/1.73 m(2), but this difference was minimal. Multivariate analysis showed that the preoperative e-GFR and the relative decrease of e-GFR at 1 year after surgery were the significant factors determining postoperative renal function. CONCLUSIONS A cold ischemia time of >44 minutes appears to be a threshold influencing the new onset of late-stage CKD; however, it was not a significant factor on multivariate analysis. Thus, renal hypothermia appears to prevent the deterioration of renal function long term after surgery for patients undergoing a longer ischemia time.

Transient Lymphopenia Breaks Costimulatory Blockade-Based Peripheral Tolerance and Initiates Cardiac Allograft Rejection

Lymphopenia is induced by lymphoablative therapies and chronic viral infections. We assessed the impact of lymphopenia on cardiac allograft survival in recipients conditioned with peritransplant costimulatory blockade (CB) to promote long‐term graft acceptance. After vascularized MHC‐mismatched heterotopic heart grafts were stably accepted through CB, lymphopenia was induced on day 60 posttransplant by 6.5 Gy irradiation or by administration of anti‐CD4 plus anti‐CD8 mAb. Long‐term surviving allografts were gradually rejected after lymphodepletion (MST = 74 ± 5 days postirradiation). Histological analyses indicated signs of severe rejection in allografts following lymphodepletion, including mononuclear cell infiltration and obliterative vasculopathy. Lymphodepletion of CB conditioned recipients induced increases in CD44high effector/memory T cells in lymphatic organs and strong recovery of donor‐reactive T cell responses, indicating lymphopenia‐induced proliferation (LIP) and donor alloimmune responses occurring in the host. T regulatory (CD4+ Foxp3+) cell and B cell numbers as well as donor‐specific antibody titers also increased during allograft rejection in CB conditioned recipients given lymphodepletion. These observations suggest that allograft rejection following partial lymphocyte depletion is mediated by LIP of donor‐reactive memory T cells. As lymphopenia may cause unexpected rejection of stable allografts, adequate strategies must be developed to control T cell proliferation and differentiation during lymphopenia.

Endogenous Memory CD8 T Cells Are Activated Within Cardiac Allografts Without Mediating Rejection

Endogenous memory CD8 T cells infiltrate MHC‐mismatched cardiac allografts within 12–24 h posttransplant in mice and are activated to proliferate and produce IFN‐γ. To more accurately assess the graft injury directly imposed by these endogenous memory CD8 T cells, we took advantage of the ability of anti‐LFA‐1 mAb given to allograft recipients on days 3 and 4 posttransplant to inhibit the generation of primary effector T cells. When compared to grafts from IgG‐treated recipients on day 7 posttransplant, allografts from anti‐LFA‐1 mAb‐treated recipients had increased numbers of CD8 T cells but these grafts had marked decreases in expression levels of mRNA encoding effector mediators associated with graft injury and decreases in donor‐reactive CD8 T cells producing IFN‐γ. Despite this decreased activity within the allograft, CD8 T cells in allografts from recipients treated with anti‐LFA‐1 mAb continued to proliferate up to day 7 posttransplant and did not upregulate expression of the exhaustion marker LAG‐3 but did have decreased expression of ICOS. These results indicate that endogenous memory CD8 T cells infiltrate and proliferate in cardiac allografts in mice but do not express sufficient levels of functions to mediate overt graft injury and acute rejection.