Tadahiko Tokumoto

Long-term results of ABO-incompatible living kidney transplantation: a single-center experience.

Background. Despite great efforts to promote the donation of cadaveric organs, the number of organ transplantations in Japan is not increasing and a serious shortage of cadaveric organs exists. These circumstances have forced a widening of indications for kidney transplantation. For this purpose, ABO-incompatible living kidney transplantations (LKTs) have been performed. Although we have already reported the short-term results of ABO-incompatible LKT, there is no report of long-term results in such cases; anti-A and anti-B antibodies could cause antibody-induced chronic rejection and result in poor long-term graft survival. In this study, we have reviewed the long-term results of ABO-incompatible LKT and tried to identify the most important factors for long-term renal function in ABO-incompatible LKT. Methods. Sixty-seven patients with end-stage renal failure underwent ABO-incompatible living kidney transplantation at our institute between January, 1989, and December, 1995. The mean age was 34.9 years (range, 8-58 years), with 38 males and 29 females. Incompatibility in ABO blood group antigens was as follows: A1<O, 23 patients; B→O, 19 patients; A1B→A1, 7 patients; B→A1, 8 patients; A1→B; 4 patients; A1B<B, 4 patients; A1B→O, 2 patients. The number of HLA-AB, and -DR mismatches were 1.6±1.1 and 0.76±0.6, respectively. Plasmapheresis and immunoadsorption were carried out to remove the anti-AB antibodies before the kidney transplantation. In the induction phase, methylprednisolone, cyclosporine, azathioprine, antilymphocyte globulin, and deoxyspergualin were used for immunosuppression. Local irradiation of the graft was performed at a dose of 150 rad, on the first, third, and fifth days after transplantation. Splenectomy was done at the time of kidney transplantation in all cases. Results. Patient survival was 93% at 1 year and 91% at 8 years. Graft survival was 79% at 1, 2, 3, and 4 years, 75% at 5 and 6 years, and 73% at 7 and 8 years. Patient survival was not significantly different from that of ABO-compatible patients. However, graft survival was significantly different between ABO-incompatible grafts and ABO-compatible grafts. Specifically, ABO-incompatible transplant recipients experienced a significantly higher rate of early graft loss up to 3 years but showed an equivalent graft loss by year 4. Among 67 patients, 16 grafts were lost during the observation period. Loss was due to acute rejection in 5 patients, followed by chronic rejection in 5 patients and death with function in 3 patients, whereas immunosuppression was withdrawn in 3 patients due to nonimmunological reasons. Of 16 grafts lost, 15 were lost within 1 year after transplantation. Of the 67 patients, 5 died during observation. Three patients with functioning grafts died of uncontrolled bleeding due to duodenal ulcer, malignant lymphoma, and cerebral hemorrhage (one patient each). One patient died of ischemic colitis due to secondary amyloidosis and one patient of cerebral hemorrhage after graft loss due to humoral rejection. There was no fatal infectious complication, whereas 10 patients had non-tissue-invasive cytomegalovirus infection. The stepwise logistic regression model was employed to identify the most important factors for long-term renal function.

Role of anti-A/B antibody titers in results of ABO-incompatible kidney transplantation.

Background. Our previous studies showed that the incidence of humoral rejection was extremely high in ABO-incompatible living kidney transplantation. This result suggests that anti-A/B antibody titers directly influence the graft survival of ABO-incompatible kidney transplantation. In this study, we examined the impact of preoperative anti-A/B antibody titers on the results of ABO-incompatible living kidney transplantation. Methods. Sixty-seven patients underwent ABO-incompatible living kidney transplantation at our institution between January 1989 and December 1995. The mean age was 34.9 years with 38 males and 29 females. Sixty-one of the 67 recipients were included in an analysis of the impact of anti-A/B antibody titer in long-term graft survival. The remaining six patients were excluded because of death with a functioning graft (three patients) and withdrawal of immunosuppression due to nonimmunological reasons (three patients) within 1 year after renal transplantation. Results. The graft survival rate for the level of less than 1:16 in maximum IgG antibody before transplantation (n=21) at 1, 5, and 8 years was 81.0, 66.8, and 66.8%, respectively. The corresponding values for the level of 1:32–1:64 (n=33) and higher than 1:128 (n=7) were 93.9, 90.5, and 79.7%, and 42.9, 28.6, and 28.6%, respectively (log-rank test, P =0.0007). There was no significant association between maximum anti-A/B IgM titers, minimum anti-A/B IgM titers, minimum anti-A/B IgG titers, and graft survival. Conclusions. Preoperative maximum anti-A/B IgG titers correlated with the long-term graft survival in ABO-incompatible living kidney transplantation. Thus, preoperative maximum levels of anti-A/B IgG titers are one of the good predictors of the results of ABO-incompatible living 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.

Time-dependent risk factors influencing the long-term outcome in living renal allografts: donor age is a crucial risk factor for long-term graft survival more than 5 years after transplantation.

BACKGROUND Most investigations have revealed that the improvement in early graft survival has not resulted in a corresponding improvement in long-term graft survival. The risk factors for long-term graft survival should be clarified. METHODS A single-center experience of 1100 consecutive renal transplant recipients who received kidneys from living donors from 1983 to 1998 was reviewed to clarify the time dependency of risk factors for long-term graft survival. We examined various possible risk factors, including HLA-AB and -DR mismatches, ABO-blood group incompatibility, graft weight, donor age and sex, recipient age and sex, and the presence or absence of acute rejection by using the time-dependent, nonproportional Coxs hazards model. RESULTS Acute rejection episode, donor age, HLA-AB 4-antigen mismatches, ABO-incompatible transplantation, smaller kidney weight compared with the patients body weight (Kw/Bw ratio less than 2.67), and transplantation from an unrelated living donor were risk factors for long-term graft outcome. Multivariate analysis for time-dependent risk factors showed that donor age of more than 60 years was the most important risk factor for long-term graft failure after 5 years posttransplantation (hazard ratio: 2.57). In contrast, acute rejection, ABO incompatibility, and nonrelated donors were significant risk factors for short-term graft failure within 5 years after kidney transplantation (hazard ratios: 2.68, 1.57, and 1.69, respectively). CONCLUSIONS Donor age of more than 60 years was a crucial risk factor affecting long-term graft survival. In contrast, acute rejection, ABO incompatibility, and nonrelated donors were significant risk factors for short-term graft failure.

Association of the Outcome of Renal Transplantation with Antibody Response to Cytomegalovirus Strain—Specific Glycoprotein H Epitopes

BACKGROUND Cytomegalovirus (CMV) is the most important pathogen affecting the outcome of renal transplantation. The combination of CMV-seronegative transplant recipients with CMV-seropositive transplant donors places recipients at the highest risk of CMV disease. In cases of congenital CMV infection, existing immunity only partially protected mothers from reinfection with a different genotypic strain. The effect of differences in infected CMV strains between CMV-seropositive transplant donors and CMV seropositive transplant recipients on the outcome of transplantation remains unclear. METHODS In this prospective multicenter study, the presence of antibodies against strain-specific glycoprotein H epitopes in 84 CMV-seropositive transplant donor/CMV-seropositive transplant recipient renal transplantation cases were determined, and their relationships to acute transplant rejection, CMV infection, degree of antigenemia, and CMV disease were evaluated. RESULTS Among the 84 donor/recipient pairs, 45 and 32 had matched and mismatched strain-specific glycoprotein H antibodies, respectively. Acute transplant rejection in the mismatched group was more frequent than it was in the matched group (63% vs. 22%; P=.005). CMV disease was also more frequently observed in the mismatched group (28% vs. 9%; P=.026). The mismatched group had a higher level of antigenemia (P=.019). CONCLUSIONS Our results illustrate more adverse events in the cases with a CMV-seropositive transplant donor and a CMV-seropositive transplant recipient in which the glycoprotein H antibodies are mismatched, suggesting that reinfection with a different CMV strain results in more complications.

ETHANOL INJECTION THERAPY OF THE PROSTATE FOR BENIGN PROSTATIC HYPERPLASIA: PRELIMINARY REPORT ON APPLICATION OF A NEW TECHNIQUE

PURPOSE We evaluate the efficacy of a new technique of minimally invasive treatment for benign prostatic hyperplasia involving direct injection of dehydrated ethanol. MATERIALS AND METHODS Dehydrated ethanol was injected transurethrally with lumbar or sacral and urethral anesthesia in 10 patients with prostatic hyperplasia. Endoscopic injection was performed at 4 to 8 sites in the prostate and 3.5 to 12.0 ml. ethanol were used. RESULTS There were no intraoperative complications but postoperative urinary retention occurred transiently in all patients which required catheterization for a mean of 8.8 days. Mean symptom score plus or minus standard deviation was 12.2+/-5.8 at 3 months postoperatively, which was significantly improved from 23.1+/-7.0 preoperatively (p<0.01). Mean quality of life score also improved significantly from 5.1+/-0.6 preoperatively to 3.2+/-1.5 at 3 months postoperatively (p<0.01), mean peak urinary flow rate increased from 8.0+/-2.2 (9 patients) to 13.1+/-3.6 ml. per second (p<0.05) and mean residual urine volume decreased from 129.1+/-55.3 (9 patients) to 49.3+/-34.7 ml. (p<0.05). There was no significant change in prostate volume. Acute epididymitis and chronic prostatitis occurred in 1 patient each. CONCLUSIONS This technique can be performed as an outpatient procedure and appears to be safe and cost-effective. Retrograde ejaculation can be avoided.

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.

Long-term outcome of abo-incompatible renal transplantation

Based on the long-term experience with ABO-incompatible kidney transplantation, the following can be concluded: 1. Renal transplantation across ABO incompatibility is an acceptable treatment for patients with end-stage renal failure. [table: see text] 2. Long-term patient and graft survival in ABO-incompatible kidney transplantation is influenced primarily by acute rejection episodes occurring within 1 year. 3. Despite the removal of anti-ABO natural antibodies before transplantation, hyperacute rejection crises may occur in some cases. 4. Humoral rejection is the most prominent type of rejection in ABO-incompatible renal transplantation. Even though most of this rejection is controllable with anti-rejection therapy, the prognosis for a graft that undergoes humoral rejection is significantly poor. 5. The maximum IgG titers of anti-A/B antibody before transplantation may have a harmful effect on graft acceptance in ABO-incompatible kidney transplantation. 6. Renal transplantation across ABO incompatibility is principally the most significant risk factor to affect long-term allograft function in ABO-incompatible living kidney transplantation.