Kazuya Kabei

Conversion of stable ABO-incompatible kidney transplant recipients from mycophenolate mofetil with standard exposure calcineurin inhibitors (CNIs) to everolimus with very low exposure CNIs–a short-term pilot study

A recent report has demonstrated that as with mycophenolate mofetil (MMF), everolimus is capable of inhibiting human B‐lymphocyte function and activation including B‐lymphocyte proliferation, apoptosis, and immunoglobulin production in vitro. Everolimus may therefore be used as an immunosuppressant in ABO‐incompatible kidney transplantation.

Effects of Conversion From a Twice-Daily Tacrolimus to a Once-Daily Tacrolimus on Glucose Metabolism in Stable Kidney Transplant Recipients

INTRODUCTION The adverse effects of tacrolimus are known to play major roles in new-onset diabetes after transplantation. The purpose of this study was to investigate the effects of conversion from a twice-daily tacrolimus (Tac-BID) to a once-daily tacrolimus (Tac-OD) on glucose metabolism in stable kidney transplant recipients. PATIENTS AND METHODS Twenty-six patients were converted from Tac-BID to Tac-OD on a 1:1 mg basis and examined for its effects on glucose metabolism. Unless rejection or tacrolimus toxicity was suspected, we did not perform dose adjustments of Tac-OD or reconversion to Tac-BID until 4 weeks after conversion. Subsequent dose adjustments were allowed to maintain tacrolimus target trough concentration within the. Changes in clinical parameters were compared between baseline and 24 weeks after conversion. RESULTS Conversion from Tac-BID to Tac-OD on a 1:1 mg basis resulted in a significant decrease in tacrolimus trough level at 4 weeks after conversion. Because dose adjustments were performed, the trough level did not differ significantly between baseline and 24 weeks after conversion. At 4 and 24 weeks after conversion, the homeostasis model assessment of pancreas β-cell function (HOMA-β) increased significantly. CONCLUSIONS Although there was no change in tacrolimus trough level between baseline and 24 weeks after transplantation, HOMA-β at 24 weeks after conversion was significantly higher than that at baseline. These results indicated that conversion from Tac-BID to Tac-OD may improve pancreas β-cell function in kidney transplant recipients.

Late-onset neutropenia and acute rejection in ABO-incompatible kidney transplant recipients receiving rituximab and mycophenolate mofetil

INTRODUCTION Using rituximab, we have performed successful ABO-incompatible kidney transplantations in recipients without splenectomy as well as in those with high pretransplant anti-A/B antibody titers. A common and increasingly recognized toxicity of rituximab is late-onset neutropenia (LON), defined as unexplained grades III to IV neutropenia occurring at least 4weeks after the last dose of rituximab in the absence of an alternative explanation. PATIENTS AND METHODS Between May 2006 and December 2011, 25 patients who received rituximab underwent successful ABO-incompatible kidney transplantation and were enrolled as the subjects in this study. The incidence rate and clinical features of LON as well as the relationship between LON and acute rejection in these patients were studied. RESULTS Twelve recipients (48%) experienced LON 2 to 12months after transplantation. Five of the 12 patients (41.6%) who developed LON had an episode of biopsy-confirmed acute cellular rejection, as compared with one of the 13 patients (7.7%) who did not develop LON. Moreover, 3 patients who experienced LON developed steroid and deoxyspergualin-resistant acute cellular rejection requiring OKT-3 administration. CONCLUSIONS The frequency of acute cellular rejection was higher in ABO-incompatible kidney transplant recipients with LON than in those without LON. Our findings suggested that these recipients who developed LON after rituximab administration may be at an increased risk for acute cellular rejection.

Clinical Outcome of Elderly Kidney Transplant Recipients from Spousal Donors

Introduction: Patients aged 60 years and older stand for the fastest growing group of patients with end-stage renal disease worldwide, and the need for kidney transplants among this population is rising. In Japan, living donor kidney transplantation is mainly performed to deal with the severe shortage of deceased donors, and the number of spousal transplants is currently increasing. Patients and Methods: A total of 164 patients with ESRD underwent living donor kidney transplantation at our institution, of whom 21 patients aged 60 years and older had spousal kidney transplantation. ABO-incompatible kidney transplantation was performed in 5 of the 21 cases. We analyzed these recipients. Results: Patient and graft survival rates were 100%. The incidence of acute rejection was 23.8%. Eight patients experienced cytomegalovirus viremia, two patients experienced Pneumocystis jiroveci infection, and one experienced bacterial pneumonia. Two patients developed cancers and underwent curative operation after transplantation. Conclusions: Elderly kidney transplantation from spousal donors is associated with age-related immune dysfunction, which may develop infections and malignancies and could be immunologically high risk due to the high rate of ABO-incompatibility and poor histocompatibility. An effort to minimize the adverse effect of immunosuppression and to reduce the risk of acute rejection may be needed for an excellent long-term outcome.

Passenger Lymphocyte Syndrome in the ABO-Incompatible Kidney Transplant Recipient Receiving Rituximab

Passenger lymphocyte syndrome is a rare but important disease in which the donor lymphocytes produce antibodies to the red blood cell antigens of the recipient, causing alloimmune hemolysis. It occurs in ABO blood group-mismatched solid-organ and/or bone marrow transplant. We report a case of passenger lymphocyte syndrome occurring after ABO-incompatible kidney transplant. The recipient received rituximab as a desensitization protocol. On posttransplant day 18, the recipient showed a fall in her hemoglobin levels without identifiable bleeding source and an elevation of total bilirubin. Although hemolytic anemia was suspected, schizocytes on the peripheral smear were not observed. Anti-B-type antibodies were detected, and a diagnosis of passenger lymphocyte syndrome was confirmed. The patient was successfully treated with steroid pulse therapy, an increase of mycophenolate mofetil to 2 g/day, and conversion from cyclosporine to tacrolimus. To our knowledge, this is the first demonstration of passenger lymphocyte syndrome in an ABO-incompatible kidney recipients receiving rituximab.

Insulin Resistance and Insulin Secretion in Renal Transplant Recipients With Hepatitis C

BACKGROUND Several reports have suggested an association between hepatitis C virus (HCV) infection and new-onset diabetes after transplantation (NODAT). NODAT is a common complication after renal transplantation, and it has been associated with increased long-term morbidity and mortality. HCV-positive recipients may have abnormal glucose metabolism, even though NODAT has never been previously diagnosed. The aim of this study was to analyze the pathogenic factors responsible for glucose metabolism in a series of HCV-positive renal transplant recipients. METHODS The study population comprised 16 renal transplant patients who received their grafts from deceased or living donors with anti-HCV antibodies. HCV-negative transplant recipients were individually matched with these HCV-positive recipients by year of transplantation, sex, age, serum creatinine levels, and type of calcineurin inhibitors. None of the patients had been diagnosed with diabetes. Insulin secretion and insulin resistance were determined by a 75-g oral glucose tolerance test (OGTT) and compared between the 2 groups. Categories of glucose tolerance were defined according to World Health Organization criteria. RESULTS Glucose intolerance (impaired fasting glucose, impaired glucose tolerance, diabetes mellitus) as assessed by OGTT was detected in 7 of the HCV-positive recipients (43.8%) and 3 of the HCV-negative recipients. The homeostasis model assessment of insulin resistance was greater in the HCV-positive recipients than in the HCV-negative recipients. The homeostasis model assessment of β-cell function was higher in the HCV-positive recipients than in the HCV-negative recipients. CONCLUSIONS The frequency of glucose intolerance tended to be higher in HCV-positive recipients. Furthermore, insulin resistance was greater and insulin secretion higher in HCV-positive recipients, which indicated that the increase in insulin secretion compensated for insulin resistance observed in these patients. However, HCV-positive renal transplant recipients may ultimately develop NODAT as this compensation diminishes with time.

ABO-Incompatible Living Kidney Transplant Recipients from Spousal Donors Receiving Rituximab

Introduction: We summarized our experience with ABO-incompatible living kidney transplant recipients from spousal donors receiving rituximab. Patients and Methods: Between June 2006 and December 2014, 82 patients with end-stage renal disease underwent living donor kidney transplantation at Osaka City University Hospital, of which 23 cases were ABO-incompatible transplantation between spouses with rituximab induction. We analyzed these recipients, focusing on their immunosuppressive protocols, frequency of acute rejections, and patient/graft survivals. Results: Patient and graft survival rates were 100%. The incidence of acute cellular rejection (ACR) was 30.4%. One patient experienced antibody-mediated rejection (AMR) and intractable ACR, 2 had AMR, and 2 had intractable ACR episodes that were treated using thymoglobulin. Conclusions: This study demonstrated that ABO-incompatible kidney transplantation between spouses using rituximab is a radical but effective treatment for end-stage renal disease. However, this procedure could be immunologically high risk due to ABO-incompatibility and poor histocompatibility.

Glucose Intolerance Is Associated With Increased Intimal-Medial Thickness of the Carotid Artery and Increased Pulse-Wave Velocity in Renal Transplant Recipients

BACKGROUND Although new-onset diabetes after transplantation has been demonstrated to have a significant negative impact on allograft and patient survival, the role of glucose intolerance (impaired fasting glucose [IFG] and/or impaired glucose tolerance [IGT], as asymptomatic hyperglycemia and borderline diabetes, has not been identified in renal transplant recipients. METHODS We enrolled 32 renal transplant recipients (at least 1 year after transplantation) without prior evidence of diabetes at our institution in this study. Transplant recipients were divided into 2 groups (normal glucose tolerance group and glucose intolerance group) according to the results of their oral glucose tolerance test with 75 g of glucose. Glucose intolerance included IFG, IGT, and IFG/IGT. Normal glucose tolerance was detected in 19 patients, and glucose intolerance in 13: had 6 IGT, 2 IFG, and 5 IGT/IFG. Bilateral brachial-ankle pulse-wave velocity (baPWV) and intimal-media thickness (IMT) measured as markers of atherosclerosis were compared between the 2 groups. Insulin resistance was estimated with the homeostasis model assessment of insulin resistance (HOMA-R), and pancreatic β-cell function evaluated by the homeostasis model assessment of β-cell function and insulinogenic index. RESULTS The patients in the glucose intolerance group showed significantly greater baPWV and IMT than those in the normal glucose tolerance group. HOMA-R in the glucose intolerance patients was significantly higher than in the normal glucose tolerance patients. Linear regression analysis showed the increased IMT in the renal transplant recipients to be significantly correlated with HOMA-R. CONCLUSIONS Renal transplant recipients with glucose intolerance had increased IMT and baPWV, suggesting that glucose intolerance in renal transplant recipients may induce atherosclerosis and that the rise in insulin resistance may contribute to the increased IMT in renal transplant recipients.

Effect of Age on Conversion to Everolimus with Calcineurin Inhibitor Minimization at A Late Post-Transplant Stage

PURPOSE The purpose of this study was to identify the risk factors for everolimus discontinuation in kidney transplant recipients converted to everolimus with calcineurin inhibitor (CNI) minimization at a late post-transplant stage. MATERIALS AND METHODS An observational retrospective cohort study was conducted on a total of 38 recipients of kidney transplantation at our institution from June 2012 to March 2015 who were converted from antimetabolites to everolimus at a late post-transplant stage and followed for 1 year. We divided the patients into two groups to evaluate the factors affecting everolimus discontinuation after conversion: everolimus continuation group (n = 23), patients in whom everolimus maintained, and everolimus discontinuation group (n = 15), patients in whom everolimus were stopped within 1 year after conversion. RESULTS Age at conversion was significantly older in the everolimus discontinuation group compared to the everolimus continuation group (57.9 ± 12.0 years in the everolimus discontinuation group vs 45.7 ± 11.2 years in the everolimus continuous group; P = .0062). Multivariate cox proportional hazard regression analysis revealed that age at conversion significantly correlated with everolimus discontinuation (P = .012). Receiver operating characteristic curve of age at conversion showed that the cut-off value was 55 years old for the everolimus discontinuation group [area under curve 0.804, 95% confidence interval (0.654-0.954), sensitivity 86.7%, specificity 65.2%]. CONCLUSION Our results indicated that late conversion to everolimus with CNI minimization in elderly recipients older than 55 years of age may be associated with more frequent adverse events and discontinuations.

Favorable Outcomes of Elderly ABO-Incompatible Kidney Transplantation-Pilot Single Center Experience

Background: The growth in the end-stage kidney disease (ESKD) population has been predominantly in the older adult population. In Japan, ABO-incompatible kidney transplantation has become an acceptable treatment option. However, few studies have been conducted on elderly ABO-incompatible kidney transplantation. Patients and Methods: Seventeen patients aged 60 years and older who received their grafts from ABO-incompatible living donors at our institution between December 2006 and September 2016 were enrolled in this study, and the outcome of these recipients was evaluated. Results: All 17 patients underwent successful kidney transplantation. Both overall patient and graft survival rates were 100, 100, and 83.3% at posttransplant 1, 3, and 5 years respectively. Six of the 17 patients (35.3%) had an episode of biopsy-proven acute cellular rejection. Two patients who developed steroid- and deoxyspergualin-resistant acute rejection required anti-human thymocyte immunoglobulin. Conclusion: ABO-incompatible kidney transplantation may be an effective radical renal replacement therapy for elderly patients with ESKD, although it could be a high-risk procedure.