Kazuya Omoto

Chronic Antibody-Mediated Rejection Is Reduced by Targeting B-Cell Immunity During an Introductory Period

Transplantation across blood group antigen and human leukocyte antigen (HLA) barriers are immunologically high risk. Both splenectomy and rituximab injection were developed to overcome those immunological barriers. The idea behind these treatments is to control B‐cell immunity before and after renal transplantation and antibody production. Between January 2001 and December 2004, recipients underwent pretransplant double‐filtration plasmapheresis (DFPP) and splenectomy at the time of transplantation in the ABO‐incompatible group (ABO‐I‐SPX; n= 45). From January 2005 to June 2009, a low dose of rituximab was given as an alternative to splenectomy (ABO‐I‐RIT; n = 57). As a control group, we selected 83 cases of ABO‐C living‐donor kidney transplantation between January 2001 and December 2007 (ABO‐C). We compared the graft survival rate and chronic antibody‐mediated rejection (C‐AMR) rate between ABO‐C and ABO‐I kidney transplantation with induction treatment. C‐AMR rates 2 years after the operation were 8.8, 3.5 and 28.9%, and de novo donor‐specific anti‐HLA antibody (DSHA) positive rates were 2.2, 1.7 and 18.1% in the ABO‐I‐SPX, ABO‐I‐RIT and ABO‐C groups, respectively. The ABO‐C group showed the highest rate of C‐AMR and de novo DSHA. B‐cell depletion protocols, such as splenectomy or rituximab administration, reduced C‐AMR after kidney transplantation.

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.

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.

Evaluation of Two Different Preconditioning Regimens for ABO-Incompatible Living Kidney Donor Transplantation

INTRODUCTION Although splenectomy has been employed in most documented protocols for ABO-incompatible kidney transplantation (ABO-ILKT), its utility is not yet determined. The aim of this study was to evaluate the long-term results of ABO-ILKT with splenectomy, and also compare the outcome of ABO-ILKT with splenectomy versus non-splenectomy. METHODS We did a retrospective study of ABO-incompatible living donor kidney transplants at our institution and affiliated hospital between January 2001 and December 2006 (n = 70). All patients were treated with a combination of immunosuppressive drugs, including tacrolimus (FK), mycophenolate mofetil (MMF) and methylprednisolone (MP). Between January 2001 and December 2004, all patients underwent pretransplant double filtration plasmapheresis (DFPP) and splenectomy at the time of transplant (n = 46) (ABO-I-SPX group). Between January 2005 and December 2006, splenectomy was not performed and a protocol that involved pretransplant low-dose injection of rituximab was employed (ABO-I-RIT group). ABO-compatible living kidney transplants (n = 55) performed between January 2001 and December 2004 were employed as a control group (ABO-C group). RESULTS Patient survival was 100% in all groups. Three-year graft survival was 98.2, 93.5 and 95.8% in the ABO-C, ABO-I-SPX and ABO-I-RIT groups, respectively. Five-year graft survival was 93 and 91.3% in the ABO-C and ABO-I-SPX groups, respectively. Renal allograft function was comparable among the three groups. However, compared to the ABO-I-RIT group, the incidence of acute antibody-mediated rejection (acute AMR) or chronic AMR was significantly higher in the ABO-C and ABO-I-SPX groups. CONCLUSIONS Although long-term outcome of the ABO-I-SPX group was excellent and showed no significant difference compared to the ABO-C group, splenectomy is not essential for successful ABO-ILKT. The rituximab-treated patients showed excellent short-term graft survival and renal function, and the incidence of AMR in the ABO-I-RIT group was significantly reduced compared to the ABO-I-SPX group.

Successful renovascular reconstruction for renal allografts with multiple renal arteries.

Background. Kidney grafts with multiple renal arteries have been considered a relative contraindication because of the increased risk of complications. In the present study, we retrospectively reviewed multiple renal artery reconstruction in kidney transplantation to elucidate the usefulness of these grafts. Methods. From January 1997 until August 2001, 431 recipients underwent kidney transplantation at our institution; 393 patients are reviewed. The surgical techniques of vascular reconstruction and short-term outcome are reported. The living kidney transplant recipients were divided into vascular reconstructed and nonreconstructed groups, and mean serum creatine levels, warm and total ischemic times, and incidences of acute rejection and posttransplantation hypertension were compared. Results. We noted multiple renal arteries in 96 (24.4%) of the 393 grafts. Arterial reconstruction was performed on 53 (13.5%) grafts, whereas 43 (10.9%) small polar arteries were simply ligated. Surgical management of the multiple arteries was variable. The most common reconstruction was conjoined anastomosis (17 cases) between two arteries of equal size and end-to-side anastomosis (14 cases) of smaller arteries to larger arteries. In nine cases, autogenous hypogastric or epigastric artery grafts were used to reconstruct multiple renal arteries. Multiple anastomosis was performed in six cases. In seven cases, complicated surgical vascular reconstruction was performed. The mean total ischemic times in the reconstructed and nonreconstructed groups were 102.6 and 71.0 min, respectively (P <0.01). The incidences of posttransplantation hypertension in the reconstructed and nonreconstructed groups were 68.2% (30/44) and 48.6% (141/290), respectively (P <0.05). There was no significant difference between the reconstructed and nonreconstructed groups in mean warm ischemic times, mean creatinine levels, and incidences of acute rejection. Conclusions. Allografts with multiple renal arteries can be used successfully in kidney transplantation.

Use of candesartan cilexetil decreases proteinuria in renal transplant patients with chronic allograft dysfunction.

Background. Posttransplant proteinuria and hypertension are difficult to treat after renal transplantation. Therefore, we examined whether candesartan cilexetil is effective in reducing urinary protein excretion or in controlling hypertension in patients with renal allograft dysfunction. Methods. Sixty-two renal transplant recipients with proteinuria were enrolled in this study. They underwent kidney transplantation under cyclosporine or tacrolimus immunosuppression between February 1983 and December 1998. Causes of proteinuria were chronic rejection in 28, glomerulonephritis in 16, cyclosporine or tacrolimus nephrotoxicity in 9, and unknown in 9 recipients. The dose of candesartan cilexetil ranged from 4 to 12 mg/day. Eleven patients with proteinuria who had not been treated with candesartan cilexetil constituted a matched control population. Results. Hypertension was well controlled by administration of candesartan cilexetil. Both systolic blood pressure and diastolic blood pressure significantly decreased from 141.7±14.8 mm Hg to 118.7±11.9 mm Hg and 121.2±11.6 mm Hg, and from 89.0±13.0 mm Hg to 72.0±10.4 mm Hg and 74.9±9.4 mm Hg, at 2 months and 1 year after administration, respectively. Urinary protein excretion was reduced from 0.93±1.2 g/day to 0.34±0.7 g/day and 0.43±1.2 g/day at 2 months and 1 year after administration, respectively. The levels of creatinine clearance were 55.7±28.9 mL/min before treatment, 50.9±24.8 mL/min at 2 months, and 52.6±24.8 mL/min at 1 year after treatment, respectively. There was no clinically significant difference between them. Regarding the calcineurin inhibitor levels, there was no significant difference between the levels before and 1 year after treatment. There was a significant difference in all examinations (systolic blood pressure, diastolic blood pressure, proteinuria, and renal function) between the patients with and without candesartan at 1 year after treatment. No significant adverse effects occurred. Conclusions. Candesartan cilexetil can effectively control hypertension and proteinuria without deterioration in renal allograft function. These data suggest that treatment with candesartan cilexetil may be useful for maintaining long-term renal allograft function.

Analysis of predictive and preventive factors for de novo DSA in kidney transplant recipients.

Background Development of de novo donor-specific anti-HLA antibodies (dnDSA) has been associated with poor graft outcome, although the preventive factor for its production is still elusive. We analyzed the incidence of dnDSA within 5 years posttransplant in 562 living-kidney transplant recipients to evaluate predicting and preventive factors for dnDSA development. Materials and Methods All patients were considered to be non-HLA sensitized, as determined by the preoperative single-antigen bead assay (SABA), although they included various ABO blood type compatibilities. Preoperative administration of rituximab was indicated for 48% of patients, mainly for ABO incompatible transplantation. We retrospectively compared the patients with dnDSA and those without. Results Development of dnDSA was observed in 27 of the total 562 patients (5%). Chronic rejection was more frequently observed in patients with dnDSA than in those without (41% vs. 6%, P<0.001). The dnDSA-positive patients showed decreased graft function and poorer graft survival rates than those who tested negative. In multivariate analysis, higher likelihood of dnDSA production was observed in male recipients (odds ratio 6.57, P=0.012) and patients with a higher number of HLA-DR mismatches (odds ratio 2.41, P=0.008), whereas lower likelihood was observed in patients treated with rituximab induction (odds ratio 0.33, P=0.040). Conclusion Results suggest that rituximab induction as a standard immunosuppression protocol may have a preventive effect for dnDSA production in the non-HLA sensitized low immunologic risk patients.

Significance of low‐level DSA detected by solid‐phase assay in association with acute and chronic antibody‐mediated rejection

We sought to clarify the controversial issue of whether detecting low‐level anti‐donor‐specific HLA antibody (HLA‐DSA) by single‐antigen flow‐bead assay (SAFB) may have a potential role in reducing acute and chronic antibody‐mediated rejection (AMR). We retrospectively studied the preoperative serum of ABO‐compatible living kidney transplantation recipients transplanted between 2001 and 2004 by SAFB using a Luminex platform. HLA‐DSA was detected only by SAFB in 24 patients, although all of them showed negative T‐cell and B‐cell complement‐dependent cytotoxicity (CDC) crossmatches. The HLA‐DSA patients went on to have surprisingly high levels of acute and chronic AMR despite being only weakly sensitized (acute AMR, 33.3%; chronic AMR, 41.7%). After 2005, we implemented SAFB routinely and any patient having a positive HLA‐DSA was considered to be a desensitization candidate. The 52 patients found to have HLA‐DSA underwent kidney transplantation after prior treatment with a single dose of rituximab (RIT) and three or four sessions of double‐filtration plasmapheresis (DFPP) in addition to regimens commonly used between 2001 and 2004. After 2005, there was a significant reduction in the occurrence of acute and chronic AMR (acute AMR, 4.7%, P < 0.001; chronic AMR, 4.7%, P < 0.001). The 5‐year graft survival rate also improved after implementing SAFB (83.3–98.1%, P = 0.032). The RIT/DFPP‐induction protocol may improve graft survival even in patients with low‐level DSA.

ABO-Incompatible Living Kidney Transplants: Evolution of Outcomes and Immunosuppressive Management.

ABO‐incompatible living kidney transplantation (ABO‐ILKT) has steadily become more widespread. However, the optimal immunosuppressive regimen for ABO‐ILKT remains uncertain. We aimed to determine the longitudinal changes in the outcomes from ABO‐ILKT compared with those from ABO‐compatible living kidney transplantation (ABO‐CLKT) over the last 25 years. Of 1195 patients who underwent living kidney transplantations (LKT) at our institute between 1989 and 2013, 1032—including 247 ABO‐ILKT and 785 ABO‐CLKT cases—were evaluated for graft survival, patient survival, infectious adverse events, and renal function. The patients were divided into four groups according to the transplantation era and ABO‐compatibility. In the past decade, ABO‐ILKT and ABO‐CLKT recipients yielded almost equivalent outcomes with respect to the 9‐year graft survival rates, which were 86.9% and 92.0%, respectively (hazard ratio [HR] 1.38, 95% confidence interval [CI] 0.59–3.22, p = 0.455). The graft survival rate for ABO‐ILKT conducted between 2005 and 2013 was better than that for ABO‐ILKT conducted between 1998 and 2004 (HR 0.30, 95% CI 0.13–0.72, p = 0.007). ABO‐ILKT recipients showed substantial improvements in the graft survival rate over time. Graft survival was almost identical over the past decade, regardless of ABO‐incompatibility. Currently, ABO‐ILKT is an acceptable treatment for patients with end‐stage renal disease.