Hidetaka Ushigome

Short- and long-term donor outcomes after kidney donation: analysis of 601 cases over a 35-year period at Japanese single center.

Background. The lack of deceased donors in Japan means that living-donor kidney transplantation is necessary in as many as 80% of cases. However, there are few data on perioperative complications and long-term outcome for live kidney donors. Methods. To determine associated perioperative morbidity and long-term mortality among live kidney donors, we reviewed 601 donor nephrectomies performed at our institution between 1970 and 2006 and attempted to contact all of the donors (or their families) to ascertain their present physical status. The survival rate and causes of death were compared with an age- and gender-matched cohort from the general population. Results. Although three donors (0.5%) experienced major perioperative complications, that is, femoral nerve compression, pulmonary thrombosis, and acute renal failure, all of the donors recovered and left hospital without complications. Among 481 donors (80%) for whom details were available at the time of inspection, 426 (88.5%) were still surviving. Donor survival rates at 5, 10, 20, and 30 years were 98.3%, 94.7%, 86.4%, and 66.2%, respectively. The mean interval between kidney donation and death was 183±102 (7–375) months, and the mean age at death was 70±11 years. The survival rate of kidney donors was better than the age- and gender-matched cohort from the general population, and the patterns and causes of death were similar. Conclusions. Our data suggest that continuation of living-donor kidney transplantation programs is justified in short- and long-term donor safety.

Tissue factor antisense oligonucleotides prevent renal ischemia-reperfusion injury.

Background. Tissue factor (TF) expression is induced on macrophages and endothelial cells during the immune response. We designed an antisense (AS) phosphorothioate oligodeoxynucleotide (ODN) to specifically inhibit the expression of rat TF to study the effects of the AS ODN on renal ischemia-reperfusion injury in the rat. Method. AS-1 ODN for TF was delivered intravenously to inhibit the expression of TF in endothelial cells. After 8 hr, the right kidney was harvested and the left renal artery and vein were clamped. The kidney was reperfused after 90 min of ischemia, and rats were killed at 0, 1.5, 5, 12, and 24 hr after reperfusion. TF expression was analyzed by immunohistochemical staining using monoclonal antibody. Results. In the untreated ischemic group, 0 of 20 rats survived beyond day 3. However, treatment with AS-1/TF led to 12 of 20 rats surviving beyond day 4. TF was detected on distal tubular epithelial cells, endothelial cells, and blood vessels but not on necrotic and proximal tubular epithelial cells. The necrotic area extended and encompassed nearly all of the ischemic kidney within 12 hr after reperfusion. The necrotic area and the grade of TF staining were more significantly reduced in the AS-1/TF-treated group than in the control group. Furthermore, fluorescein isothiocyanate-labeled AS-1/TF was significantly intense in tubular epithelial cells 8 hr after intravenous administration. Conclusions. The results indicate that AS-1/TF inhibited the ischemia-reperfusion injury of the kidney. Microcirculatory incompetence resulting from microthrombus may cause the formation and development of necrosis.

Management and outcome of living kidney grafts with multiple arteries.

PurposeKidney allografts with multiple renal arteries (MRAs) have been used with increasing frequency since the advent of laparoscopic live donor nephrectomy. To determine if MRA grafts affect the short- and long-term outcomes of grafts and patients, we analyzed 340 grafts procured by open nephrectomy.MethodsWe divided the graft recipients into five groups according to the methods used for vascular reconstruction. We compared patient and graft survival, serum creatinine levels, total (rewarm) ischemic times (TIT), incidence of acute tubular necrosis (ATN), need for antihypertensive drugs, incidence of acute rejection episodes, and vascular and urologic complications, between the MRA group and a control group of patients with single-artery renal grafts.ResultsIn patients who underwent multiple anastomoses in situ, prolonged TIT resulted in an increased incidence of ATN, but there was no significant difference between the MRA groups and the control group (P = 0.45). The incidence of vascular complications was higher in the MRA groups (P < 0.01), but there were no significant differences in the other variables among the groups.ConclusionMultiple renal artery grafts procured by open nephrectomy can be transplanted as successfully as those with single arteries, by using meticulous suturing techniques.

Expression of Cyclooxygenase-1 and -2 in Human Breast Cancer

AbstractPurpose. We investigated the expression of cyclooxygenase (Cox-1 and Cox-2) in mammary tissues from patients with breast cancer. Methods. We used reverse transcriptase–polymerase chain reaction (RT-PCR) and immunohistochemistry. Results. The cancer cells showed very weak expression of Cox-1, but strong expression of immunoreactive Cox-2. In contrast, immunoreactive Cox-2 was very weak in all of the benign mammary tumors examined, including fibroadenoma (FA) and mastopathy (MP). Immunoreactive Cox-1 was also very weak in these benign tumors. The extent and intensity of immunoreactive Cox-2 polypeptides was significantly greater in the cancer cells than in the FA cells or MP cells. RT-PCR analysis showed enhanced expression of Cox-2, but not Cox-1 in breast cancer tissue, and faint expression of Cox-2 in benign tissue. Conclusions. These results demonstrated that human breast cancer cells generated Cox-2, indicating that Cox-2 might play an important role in the proliferation of breast cancer cells.

The Consequences for Live Kidney Donors With Preexisting Glucose Intolerance Without Diabetic Complication: Analysis at a Single Japanese Center

Background. Because of lack of deceased donors in Japan, there has been a need to expand the eligibility criteria for live kidney donation. To assess the indications for live kidney donation in glucose intolerance (GI), we analyzed perioperative complications associated with donor nephrectomies performed at our institution and followed up the long-term consequences. Methods. The 444 live kidney donors were divided into two groups based on the results of the 75-g oral glucose tolerance test: a GI group (n=71) who showed a diabetic (n=27) or impaired glucose tolerance (n=44) pattern, and a non-GI group (n=373) who showed a normal oral glucose tolerance test pattern. Perioperative complications, long-term survival rate, and frequencies of hypertension, diabetes, hyperlipidemia, and renal dysfunction in long term were compared in each group. Results. The incidence of perioperative complications was not higher in the GI group than in the non-GI group (4.3% vs. 5.4%, respectively; NS). Survival rates in the GI group at 5, 10, and 20 years were 98.3%, 95.1%, and 89.2%, respectively, whereas those in the non-GI group were 98.0%, 96.1%, and 91.5%, thus showing equivalent mortality. None of the patients in the diabetes mellitus group had developed severe diabetic complications or end-stage renal disease at a mean follow-up point of 88±71 (range, 14–225) months. Conclusions. Our results suggest that individuals who have GI without diabetic complication may be able to donate their kidney safely with little surgical complication and little major morbidity if strict evaluation is performed before transplant.

Current status of organ transplantation in Japan and worldwide

Recent advances in immunosuppressant therapy have dramatically reduced the frequency of acute rejection of organ transplants. Subsequently, the short-term graft survival rate has been improved, and ABO blood type-incompatible and existing anti-HLA antibody-positive kidney transplantation has been enabled, which has increased the availability of living kidney donors. Japan has a unique history and strategies of liver transplantation (LT) for various liver diseases. The outcomes of living donor liver transplantation (LDLT) in Japan is comparable to that of deceased donor liver transplantation (DDLT) in Western countries despite the relatively short history of LT. The main disadvantage of LT in Japan is donor shortage mainly due to the small number of available deceased donors. There are some disadvantages with LDLT in autoimmune liver diseases because of the dependence on blood relative donors. The first brain-dead pancreas transplantation (PTx) was performed in 2000. Since that time, 42 brain-dead PTx, 2 non-heart beating PTx, and 14 living donor PTx had been performed by the end of 2007. One of the 44 recipients of deceased donor PTx died of unknown causes 11 months after transplantation. Although most of the deceased donors in Japan were marginal and their condition was not favorable, the results of these cases were comparable to those of Western countries. Fourteen intestinal transplantations (ITx) had been performed by the end of 2007 in four transplant centers. There were 3 deceased donor and 11 live donor transplants. The original diseases included short bowel syndrome (n = 6), intestinal function disorder (n = 6), and retransplantation (n = 2). The graft and patient survival rate are 60% and 69%, respectively. Eight recipients survived and stopped parenteral nutrition with full-functioning grafts. Amendment of the Japanese law for the utilization of deceased donors should increase the number available donors in the future.

Efficacy of tonsillectomy for patients with recurrence of IgA nephropathy after kidney transplantation

Abstract:  From January 2007, we started to perform the tonsillectomy for every patient with recurrent IgA nephropathy (IgAN) after kidney transplantation. Up to September 2008, four recipients with primary IgAN had biopsy‐proven recurrent IgAN. They had also progressive hematuria or proteinuria from on the average 14.3 months after transplantation. Then their specimens diagnosed as recurrent IgAN were collected and they underwent tonsillectomies on the average 52.3 months after transplantation. Abnormal urinary findings of all patients favorably improved after tonsillectomy. All cases but one had mild renal injury, where the severity of glomerular lesions, glomerular hypercellularity, segmental lesions, and sclerosis was mild, and no deteriorated serum creatinine (SCr) before their tonsillectomies. Even the case with exacerbated SCr and severe renal injury, where the severity of glomerular lesions was severe, had her urinary findings ameliorated promptly after tonsillectomy likely as others. At present, they have almost no symptoms after tonsillectomy and no remarkable change of SCr level compared with before and after tonsillectomy and maintain ameliorated urinary findings continuously. Tonsillectomy had possibility to be a favorable treatment of hematuria or proteinuria in recurrent IgAN recipients.

The Efficacy and Safety of High-Dose Mizoribine in ABO-Incompatible Kidney Transplantation Using Anti-CD20 and Anti-CD25 Antibody Without Splenectomy Treatment

BACKGROUND Mizoribine (MZR) has been developed as an immunosuppressive agent in Japan, but it shows less potent immunosuppressive effects at doses up to 3 mg/kg/d. In this study, we investigated whether high-dose MZR (6 mg/kg/d) was effective for ABO-incompatible (ABO-i) living donor kidney transplantation (LKT) using treatment with anti-CD25 and anti-CD20 monoclonal antibodies without splenectomy. METHODS Since 2007, we encountered 24 cases of ABO-i LKT using anti-CD20 and anti-CD25 monoclonal antibody without splenectomy. The pretransplant immunosuppressive regimen consisted of two doses of anti-CD20 antibody, mycophenolate mofetil (MMF), prednisolone, a calcineurin inhibitor (cyclosporine [7 mg/kg] or tacrolimus [0.2 mg/kg] and two doses of anti-CD25 antibody. Antibody removal by plasmapheresis was performed before LKT up to several times according to the antibody titer. The posttransplant regimen consisted of high-dose mizoribine (6 mg/kg/d) instead of MMF (MZR group, n = 12). RESULTS The 1-year graft survival rates for the MZR and MMF groups were both 100%. The rejection rate in the MZR group (eight %) was not significantly higher than that in the MMF group (seventeen %) Serum creatinine level was not significantly different between the two groups. In the MZR group 6 (50%) patients developed CMV antigenemia-positivity versus 11 (92%) in the MMF group (P < .05). The number of patients who developed CMV disease was 0 in the MZR group and 1 (8%) in the MMF group. The number of patients treated with ganciclovir was 0% and 8%, respectively (not significant). CONCLUSIONS We obtain good clinical results with high-dose MZR in ABO-i LKT using anti-CD20 and anti-CD25 antibody treatment without splenectomy.

Antisense oligonucleotide for tissue factor inhibits hepatic ischemic reperfusion injury

Tissue factor (TF) is an initiation factor for blood coagulation and its expression is induced on endothelial cells during inflammatory or immune responses. We designed an antisense oligodeoxynucleotide (AS-1/TF) for rat TF and studied its effect on hepatic ischemic reperfusion injury. AS-1/TF was delivered intravenously to Lewis rats. After 10 h, hepatic artery and portal vein were partially clamped. Livers were reperfused after 180 min and harvested. TF expression was studied using immunohistochemical staining. One of 10 rats survived in a 5-day survival rate and TF was strongly stained on endothelial cells in non-treatment group. However, by treatment with AS-1/TF, six of seven survived and TF staining was significantly reduced. Furthermore, we observed that fluorescein-labeled AS-1/TF was absorbed into endothelial cells. These results suggest that AS-1/TF can strongly suppress the expression of TF and thereby inhibit ischemic reperfusion injury to the rat liver.

Evaluation of renal allograft fibrosis by transient elastography (Fibro Scan).

BACKGROUND Chronic allograft injury (CAI) is one of the most important factors for graft failure after renal transplantation. Protocol biopsy is the most valuable tool for revealing subclinical renal allograft failure. Transient elastography (TE) is a noninvasive technique that has shown utility for the assessment of hepatic and renal fibrosis. This study sought to evaluate whether TE was a viable and effective method for the assessment of renal allograft failure. PATIENTS AND METHODS Thirty-five patients underwent TE by Fibro Scan (Echosense, Paris, France). Biopsies were performed in 27 patients, allowing classification according to Banff chronic changes in the interstitium grade 0, grade 1 or grade 2. RESULTS Measurement of parenchymal stiffness was successful in 31 of 35 patients (91%). Stiffness was significantly correlated with interstitial fibrosis (P < .05) and inversely related with estimated glomerular filtration rate (eGFR; P < .05). Stiffness values of patients with eGFR > 50 mL/min were lower than those of patients with eGFR < 50 mL/min (P < .05). Patients classed as CAI Banff grade 0 had significantly less parenchymal stiffness than patients with Banff grade 1 or grade 2 CAI (P < .05). Parenchymal stiffness measured by TE reflected interstitial fibrosis in renal allograft. CONCLUSION Assessment of parenchymal renal allograft stiffness by TE was effective for identifying patients with CAI who may subsequently benefit from biopsy and modification of the immunosuppressive regimen. Assessment of parenchymal renal allograft stiffness can be effective for identifying patients with CAI. TE has the potential to reduce the number of renal allograft biopsies required for accurate assessment of CAI.