Kota Takahashi

Excellent Long‐term Outcome of ABO‐Incompatible Living Donor Kidney Transplantation in Japan

Owing to the severe shortage of cadaveric grafts in Japan, we have performed ABO‐incompatible living donor kidney transplantation since 1989. This study assessed short‐ and long‐term outcomes in 441 patients who received ABO‐incompatible living donor kidney transplants between January 1989 and December 2001. We compared our results with historical data from 1055 recipients of living kidney transplantation. Overall patient survival rates 1, 3, 5, 7, and 9 years after ABO‐incompatible transplantation were 93%, 89%, 87%, 85%, and 84%, respectively. Corresponding overall graft survival rates were 84%, 80%, 71%, 65%, and 59%. After ABO‐incompatible transplantation, graft survival rates were significantly higher in patients 29 years or younger than in those 30 years or older and in patients who received anticoagulation therapy than in those who did not receive such therapy. There were no significant differences between A‐incompatible and B‐incompatible recipients with respect to clinical outcomes. The graft survival rate at 1 year in the historical controls was slightly but not significantly higher than that in our recipients of ABO‐incompatible transplants. We conclude that long‐term outcome in recipients of ABO‐incompatible living kidneys is excellent. Transplantation of ABO‐incompatible kidneys from living donors is a radical, but effective treatment for end‐stage renal disease.

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.

The Influence of Androgen Deprivation Therapy on Dihydrotestosterone Levels in the Prostatic Tissue of Patients with Prostate Cancer

Purpose: The influence of androgen deprivation therapy on dihydrotestosterone levels in the prostatic tissue is not clearly known. Changes in dihydrotestosterone levels in the prostatic tissue during androgen deprivation therapy in the same patients have not been reported. We analyzed dihydrotestosterone levels in prostatic tissue before and after androgen deprivation therapy. Experimental Design: A total of 103 patients who were suspected of having prostate cancer underwent prostatic biopsy. Sixty-nine patients were diagnosed as having prostate cancer whereas the remaining 34 were negative. Serum samples were collected before biopsy or prostatectomy. Dihydrotestosterone levels in prostatic tissue and serum were analyzed using liquid chromatography/electrospray ionization-mass spectrometry after polar derivatization. In 30 of the patients with prostate cancer, dihydrotestosterone levels in prostatic tissue were determined by performing rebiopsy or with prostate tissues excised after 6 months on androgen deprivation therapy with castration and flutamide. Results: Dihydrotestosterone levels in prostate tissue after androgen deprivation therapy remained at ∼25% of the amount measured before androgen deprivation therapy. Dihydrotestosterone levels in serum decreased to ∼7.5% after androgen deprivation therapy. The level of dihydrotestosterone in prostatic tissue before androgen deprivation therapy was not correlated with the serum level of testosterone. Serum levels of adrenal androgens were reduced to ∼60% after androgen deprivation therapy. Conclusions: The source of dihydrotestosterone in prostatic tissue after androgen deprivation therapy involves intracrine production within the prostate, converting adrenal androgens to dihydrotestosterone. Dihydrotestosterone still remaining in prostate tissue after androgen deprivation therapy may require new therapies such as treatment with a combination of 5α-reductase inhibitors and antiandrogens, as well as castration.

Role of XIAP in the malignant phenotype of transitional cell cancer (TCC) and therapeutic activity of XIAP antisense oligonucleotides against multidrug-resistant TCC in vitro.

XIAP directly inhibits executor caspases, making it the most downstream antiapoptotic molecule. Here, we examined the expression and function of XIAP in normal urothelium and TCC. We also examined the therapeutic effect of xiap AS PODN on the cell cycle and apoptosis of multidrug‐resistant T24 bladder cancer cells. XIAP was moderately expressed in normal transitional epithelium with prominent expression on the superficial layer cells. Seventy‐nine of 108 (73.15%) tumor samples were positive for XIAP protein, but XIAP positivity was not correlated with tumor stage or grade. Moreover, 4 bladder cancer cell lines (SCaBER, HT1376, T24 and RT4) expressed similar levels of XIAP. xiap AS PODN dose‐dependently reduced the XIAP protein level and induced apoptosis, leading to decreased cell viability by 87%. Combined administration with doxorubicin resulted in marked cytotoxicity due to escalation of apoptosis. Overexpression of XIAP in T24 cells resulted in a modest but statistically significant (p < 0.01) survival advantage compared to parental cells. Thus, XIAP expression may be critical for maintaining the viability and drug resistance of TCC, and endogenous XIAP levels are sufficient to protect cells from apoptosis. Our results suggest that XIAP may play an important role early in human TCC carcinogenesis. xiap AS may be a candidate for use as a cancer therapy for overcoming drug resistance in highly malignant TCC.

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.

Anti-AB titer changes in patients with ABO incompatibility after living related kidney transplantations: survey of 101 cases to determine whether splenectomies are necessary for successful transplantation.

Background. A shortage of organ donors for transplantation has become a serious problem throughout the world. To overcome this problem, transplantations across ABO blood barriers have been performed with some success. In general, however, the graft survival rate for transplantation with ABO incompatibility is lower than that of transplantation with ABO compatibility. Unfortunately, the mechanism by which isohemagglutinins might injure an ABO-incompatible graft remains uncertain. Here, the pre- and posttransplantation anti-AB titers in patients who received transplants from ABO-incompatible living donors are reviewed and the pathological findings are compared. Methods One hundred and one patients underwent ABO-incompatible living related kidney transplantation (i-LKT) between January 1989 and October 1999 at our hospital. Plasmapheresis and immunoadsorption were performed in all of the i-LKT patients before the transplantation to remove anti-AB antibodies. A splenectomy was also performed during the operation, followed by the local irradiation of the graft with a dose of 150 rad. The anti-AB titers and pathological findings for 93 i-LKT patients, excluding 8 patients who died, were then examined. Results Immediately after the i-LKT, the anti-AB titer dropped rapidly to below 1:4 in all 93 cases. Seventy of patients (70/93, 75%) showed no elevation in their anti-AB titer during their follow-up. However, the remaining 23 patients (23/93, 25%) showed a significant elevation of their anti-AB titer to over 1:16. Sixteen of these patients (16/93, 17%) exhibited an anti-AB titer of over 1:32. Out of these 16 patients, 11 patients (11/16, 69%) lost their grafts. The anti-AB titer in the remaining five patients (5/16, 31%) spontaneously decreased without any special treatment. Seven patients (7/93, 8%) exhibited an elevated titer of 1:16. Out of these patients, only one patient (1/7, 14%) lost his graft. The elevated titers in the remaining six patients (6/7, 86%) eventually decreased. The graft function improved in patients whose elevated anti-AB titers eventually decreased. Control patients (ABO-compatible kidney transplant patients) showed a normal elevation of their titer values compared with preoperative titers. Pathological findings showed severe humoral rejections in all cases with high anti-AB titers that lost grafts. Humoral rejection was also detected in most of the patients whose anti-AB titer was elevated to over 1:16 after the transplantation, but excellent renal function was resumed once the titers decreased to below 1:4. Conclusions In 23 out of 93 i-LKT patients (25%), the anti-AB titers were significantly elevated after the splenectomy. In view of other reports of i-LKT without splenectomy, we feel that a splenectomy in i-LKT patients might be unnecessary. Pathological evidence suggests that the decrease in the anti-AB titer after transplantation might be the net result of plasmapheresis before the operation and the adsorption of antibodies to the endothelium of the transplanted organ after the operation, neither of which is influenced by a splenectomy.

EFFECT OF PRE- AND POSTOPERATIVE PLASMAPHERESIS ON POSTTRANSPLANT RECURRENCE OF FOCAL SEGMENTAL GLOMERULOSCLEROSIS IN CHILDREN

Background. Posttransplant recurrence is frequent in patients who received renal transplantation for focal segmental glomerulosclerosis (FSGS). The recurrence has been ascribed to a circulating permeability factor or factors. We have used plasmapheresis (PP) to treat recurrent FSGS and also studied whether preoperative PP is effective in preventing recurrence of FSGS. Methods. We retrospectively analyzed 21 allografts of 20 patients with nephrotic syndrome and biopsy-proven FSGS. They were divided into two groups depending on whether they had prophylactic PP; a prophylactic (n=15) and a nonprophylactic group (n=6). PP was performed two to three times prophylactically and therapeutically until proteinuria was markedly reduced. In each session, 50–75 ml/kg of the patient’s plasma was exchanged with 5–8% albumin. Results. FSGS recurred in 9 of 21 allografts, 4 of 6 in the nonprophylactic group, and 5 of 15 in the prophylactic group. Therapeutic PP was performed in seven of nine recurrent patients without definite adverse effect, with satisfactory results except in one patient. Children lost proteinuria after 6 to >100 sessions of PP and the number correlated with the pretreatment level of proteinuria. The mean follow-up periods were 62.7 and 41.6 months for the prophylactic and nonprophylactic groups, respectively. At the last follow-up, 66.7% of relapsing and 81.8% of nonrelapsing patients had a functioning graft. Conclusion. PP appears to be effective for the prevention and treatment of posttransplant recurrence of FSGS, although further consideration of cost/benefit and risks is required before a conclusive judgement can be made.

A novel rescue drug, 15-deoxyspergualin: first clinical trials for recurrent graft rejection in renal recipients

The present multicentral clinical study performed in 6 institutes demonstrated that the novel immunosuppressive agent, 15-deoxyspergualin (DSG), is very effective on rejection. In 34 cases of rejection, 30 were treated with DSG at 40 mg/m2 (1 case), 80 mg/m2 (7 cases), 120 mg/m2 (9 cases), 180 mg/m2 (9 cases), and 220 mg/m2 (8 cases). The overall remission rate was 79% in 34 cases of rejection including accelerated, acute, and chronic rejection in different periods after transplantation. Analyzing the remission rates of early phase acute rejection occurring within 3 months after transplantation according to treatment pattern, the remission rate was 100% in 3 cases treated with DSG alone (using DSG 1 week or longer after other agents), 88% in 8 cases treated by rescue use of DSG (using DSG within 1 week after other agents), and 86% in 7 cases treated by combined use of DSG with other agents. Adverse reactions included reductions in WBC and platelets, anemia, perioral numbness, gastrointestinal troubles, and others. However all these symptoms were so mild that DSG treatment was not discontinued. Further studies are necessary on the effect of DSG, especially in acute rejection under conditions that reduce the many influences of other agents as much as possible.

Retroperitoneal Laparoscopic Adrenalectomy for Functioning Adrenal Tumors: Comparison With Conventional Transperitoneal Laparoscopic Adrenalectomy

PURPOSE We attempted to confirm the possibility and feasibility of laparoscopic adrenalectomy via the retroperitoneal approach, and to compare results of the transperitoneal and retroperitoneal approaches. MATERIALS AND METHODS Three men and 8 women (mean age 39.6 years) with functioning adrenocortical tumors (primary aldosteronism in 5 and Cushings syndrome in 6) underwent laparoscopic adrenalectomy via the retroperitoneal approach using a balloon dissection technique and a newly developed ultrasonic aspirator. Results were compared to those of 27 cases of transperitoneal laparoscopic adrenalectomy. RESULTS Although the retroperitoneal approach was successful in all 5 patients with primary aldosteronism, it succeeded in only 2 of the 6 cases of Cushings syndrome. In 3 Cushings syndrome cases the retroperitoneal approach was changed to the transperitoneal laparoscopic approach due to difficulty in exploration. Open laparotomy was required in 1 case of left Cushings syndrome because of an inadvertent pancreatic injury. Subcutaneous emphysema developed in 6 patients without hypercapnia or prolonged postoperative symptoms. Mean operative time and blood loss, and time to oral intake and ambulation were 248.3 minutes, 151.4 ml., and 1.55 and 2 days, respectively. There was no difference between retroperitoneal and conventional transperitoneal laparoscopic adrenalectomy in regard to these factors or to convalescence. CONCLUSIONS Retroperitoneal laparoscopic adrenalectomy is feasible for primary aldosteronism. However, Cushings syndrome is presently a much more difficult indication than primary aldosteronism for this new operative technique.

Enhancement of gene therapy specificity for diffuse colon carcinoma liver metastases with recombinant herpes simplex virus.

OBJECTIVE The authors determined whether a recombinant herpes simplex virus (HSV) vector could destroy human colon carcinoma cells in vitro and whether the vector would selectively replicate in colon carcinoma liver metastases but not surrounding hepatocytes in vivo. BACKGROUND The HSV vector hrR3 is defective in the gene encoding ribonucleotide reductase and contains the lacZ reporter gene. Ribonucleotide reductase is expressed in actively dividing cells and generates deoxyribonucleotides for DNA synthesis. hrR3 replicates only in actively dividing cells that can provide ribonucleotide reductase in complementation, but not in quiescent cells such as normal hepatocytes. METHODS hrR3-mediated lysis of HT29 human colon carcinoma cells was first determined in vitro. For in vivo studies, athymic BALB/c nude mice underwent intrasplenic injection of HT29 and intrasplenic injection of hrR3 7 days later, and were killed 7 days after viral injection. Their livers were examined histochemically for lacZ expression. RESULTS All the HT29 cells were destroyed in vitro when hrR3 was added at a titer of 1 plaque-forming unit per 10 tumor cells. One hundred one of 105 tumor nodules examined in liver sections from mice treated by intrasplenic injection of hrR3 demonstrated lacZ expression. Minimal beta-galactosidase activity was present in normal liver. CONCLUSIONS The hrR3 HSV vector effectively destroys HT29 human colon carcinoma cells at very low multiplicities of infection. Differential expression of ribonucleotide reductase between liver metastases and normal liver allows hrR3 to selectively replicate in tumor cells with minimal replication in surrounding normal liver. Further investigation of HSV-based vectors as oncolytic agents for liver metastases is warranted.