Bok Jin Hyoung

Chronic cyclosporine nephropathy is characterized by excessive autophagosome formation and decreased autophagic clearance.

Background The study was performed to investigate the influence of cyclosporine A (CsA)–induced renal injury on autophagy in an experimental model of chronic CsA nephropathy. Methods Three dosages of CsA (7.5, 15, and 30 mg/kg/day) were administered to mice for 4 weeks. The formation of autophagosomes was measured with microtubule-associated protein 1 light chain 3 phospholipid-conjugated form (LC3-II) and beclin-1, and the ability of autophagic clearance was examined with sequestosome-1 (p62). Autophagic vacuoles were visualized and counted using electron microscopy. Double immunolabeling of LC3-II and active caspase-3 was performed to evaluate the association between autophagy and apoptosis. Oxidative stress was evaluated by measuring urinary 8-hydroxy-2′-deoxyguanosine excretion, demonstrating oxidative DNA damage. Antioxidative drugs, pravastatin and N-acetylcysteine, were used to evaluate the role of CsA-induced oxidative stress on autophagy. Results CsA treatment increased the expressions of LC3-II and beclin-1 in the kidney in a dose-dependent manner. The number of p62-positive cells was also significantly increased in a CsA dose–dependent manner. Electron microscopy revealed excessive autophagic vacuoles in the CsA group compared with the vehicle group. Expression of active caspase-3 was increased in a CsA dose–dependent manner and was colocalized with LC3-II in the injured area of CsA-treated kidneys. Concurrent pravastatin or N-acetylcysteine treatment reduced urinary excretion of 8-hydroxy-2′-deoxyguanosine and subsequently decreased LC3-II expression and the number of p62-positive cells compared with the CsA group. Conclusions Chronic CsA nephropathy is a state of excessive autophagic vacuoles and decreased autophagic clearance. Oxidative stress may play an importation role in the induction of autophagy.

Successful Renal Transplantation with Desensitization in Highly Sensitized Patients: A Single Center Experience

Intravenous immunoglobulin (IVIG) and/or plasmapheresis (PP) are effective in preventing antibody-mediated rejection (AMR) of kidney allografts, but AMR is still a problem. This study reports our experience in living donor renal transplantation in highly sensitized patients. Ten patients with positive crossmatch tests or high levels of panel-reactive antibody (PRA) were included. Eight patients were desensitized with pretransplant PP and low dose IVIG, and two were additionally treated with rituximab. Allograft function, number of acute rejection (AR) episodes, protocol biopsy findings, and the presence of donor-specific antibody (DSA) were evaluated. With PP/IVIG, six out of eight patients showed good graft function without AR episodes. Protocol biopsies revealed no evidence of tissue injury or C4d deposits. Of two patients with AR, one was successfully treated with PP/IVIG, but the other lost graft function due to de novo production of DSA. Thereafter, rituximab was added to PP/IVIG in two cases. Rituximab gradually decreased PRA levels and the percentage of peripheral CD20+ cells. DSA was undetectable and protocol biopsy showed no C4d deposits. The graft function was stable and there were no AR episodes. Conclusively, desensitization using PP/IVIG with or without rituximab increases the likelihood of successful living donor renal transplantation in sensitized recipients.

Changing Donor Source Pattern for Kidney Transplantation over 40 Years: A Single-Center Experience

Background/Aims Kidney transplantations at our center rely mainly on living donors. The purpose of this study was to suggest future donor supply directions by reviewing changing trends in donor type. Methods During the past 40 years, 1,690 kidney transplantations were performed at our center. We divided the follow-up period into four decades and the donor population into three groups: living related, living unrelated, and deceased. We analyzed changing trends in donors from each group for each decade. Patients receiving overseas transplantation were also included. Results The proportion of living related donors decreased from 84% (54/64) in the 1970s to 61% (281/458) in the 2000s. Living unrelated donors showed a sustained proportion of around 20% after 1990. However, among living unrelated donors, the proportion of spouse donors increased from 4.6% (17/369) in the 1980s to 8.5% (39/458) in the 2000s. Transplants from deceased donors were only 3.3% (12/369) in the 1980s. However the proportion of deceased donors increased gradually, reaching 13.2% (105/799) in the 1990s and 19.9% (91/458) after 2000. Overseas transplantations increased after 2000 and reached 20% of all cases treated in our center during the 2000s. Such transplantations peaked in 2006 and decreased markedly thereafter. Conclusions The proportion of each donor type has continuously changed, and the changes were associated with changes in the social structure and system. We expect that this study could be an important reference for other countries to estimate future changes of donor type.

Clinical Impacts of CD38+ B Cells on Acute Cellular Rejection With CD20+ B Cells in Renal Allograft

Background. There is an increasing evidence that the presence of CD20+ B cells is associated with poor clinical outcomes in acute cellular rejection (ACR), but clinical significance of CD38+ B cells is undetermined. We attempted to examine the clinical significance of the CD38+ B cells alone or in combination with CD20+ B cells in renal transplant recipients with ACR. Methods. Fifty-four patients with ACR were included. Biopsy specimens were stained for CD20 and CD38. The clinical outcomes of CD20 or CD38+ B cells were evaluated with late-onset and repeated ACR, steroid resistance, incomplete recovery after rejection treatment, and allograft survival. Results. Twenty-three patients (42.6%) had CD20+ and 25 (46.3%) patients had CD38+ B cells. Of these, 15 patients (27.8%) were positive for both CD20 and CD38 (CD20+CD38+). CD38+ patients had higher rates of late-onset or repeated ACR and incomplete recovery compared with CD38− patients (P<0.05). The patients with CD20+CD38+ had a higher incomplete recovery rate than did patients with only CD20+ or CD38+ (P<0.05). The 5-year allograft survival was lower in CD20+ and CD38+ patients than in CD20− or CD38− patients (P<0.05 for each). CD20+CD38+ patients had lower graft survival than did patients with CD20+ or CD38+ alone (P<0.05). Conclusion. Infiltration of CD38+ B cells alone or in combination with CD20+ B cells is a predictor for poor clinical outcomes of ACR in renal allograft.

Clinical significance of slow recovery of graft function in living donor kidney transplantation.

Background. The clinical significance of slow recovery of graft function (SGF) in living donor kidney transplantation is unclear. We evaluated the incidence, risk factors, and clinical outcome of SGF in living donor transplantation. Methods. Three hundred ten living donor kidney recipients were included and categorized into immediate recovery of graft function (IGF; n=239) and SGF (n=71), according to estimated glomerular filtration rate (60 mL/min/1.73 m2) at posttransplant day 14. We compared the clinical parameters, protocol biopsy findings, acute rejection (AR), and 10-year graft survival between the two groups. Results. The SGF group had an older recipient age, lower ratio of donor to recipient body mass index, and higher incidence of AR than IGF group, as shown by protocol biopsies. The SGF group had significantly more AR episodes than IGF group within 12 months (21.1% vs. 13.4%, P<0.05) and during follow-up period (32.4% vs. 20.1%, P<0.05). The 10-year graft survival rate did not differ between groups, but AR presence was significantly associated with a lower graft survival in the SGF group than the IGF group (64.9% vs. 78.9%, P<0.05). Conclusions. SGF in the early posttransplant period is immunologically active and should be considered as one of the risk factors for determining long-term graft survival in living donor kidney transplantation.

The efficacy and safety of ezetimibe and low-dose simvastatin as a primary treatment for dyslipidemia in renal transplant recipients.

Background/Aims The efficacy and safety of a combination of ezetimibe and low-dose statin as primary treatment for dyslipidemia in renal transplant patients were evaluated prospectively. Methods The study enrolled 77 renal transplant recipients with dyslipidemia. They were given ezetimibe (10 mg) and simvastatin (10 mg) for 6 months as the initial treatment for dyslipidemia. Efficacy and safety were evaluated using lipid profiles, trough calcineurin inhibitor levels, allograft function, and adverse effects. The effects on proteinuria and high sensitivity C-reactive protein (hsCRP) levels were also evaluated. Results Ezetimibe and low-dose simvastatin significantly decreased the levels of total cholesterol (34.6%), triglyceride (16.0%), and low-density lipoprotein cholesterol (LDL-C) (47.6%), and 82.5% of the patients reached the target LDL-C level of <100 mg/dL. No significant change in the trough calcineurin inhibitor levels or allograft function occurred, and no serious adverse effects were observed. Fourteen patients (18.2%) discontinued treatment; eight patients (11.7%) developed muscle pain or weakness without an increase in creatinine kinase levels, and two patients (2.6%) developed elevated liver transaminase levels. The proteinuria and hsCRP levels did not change significantly. Conclusions Ezetimibe and low-dose statin treatment is safe and effective as a primary treatment for dyslipidemia in renal transplant patients.

Improved gastrointestinal symptoms and quality of life after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in renal transplant patients receiving tacrolimus.

It is reported that a conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) relieves gastrointestinal (GI) symptom burden and improves health-related quality of life (HRQoL). However, it is unclear whether renal transplant recipients using tacrolimus receive the same benefit from the conversion. In this prospective, multi-center, open-label trial, patients were categorized into two groups by their GI symptom screening. Equimolar EC-MPS (n=175) was prescribed for patients with GI burdens; those with no complaints remained on MMF (n=83). Gastrointestinal Symptom Rating Scale (GSRS) and Gastrointestinal Quality of Life Index (GIQLI) were evaluated at baseline and after one month. Patients and physicians completed Overall Treatment Effect (OTE) at one month. EC-MPS-converted patients had worse GSRS and GIQLI scores at baseline than MMF-continued patients (all P<0.001). Significant improvements in GSRS and GIQLI scores were observed for EC-MPS-converted patients at one month, but MMF-continued patients showed worsened GSRS scores (all P<0.05). OTE scale indicated that EC-MPS patients improved in overall GI symptoms and HRQoL more than MMF patients did (P<0.001). In tacrolimus-treated renal transplant recipients with GI burdens, a conversion from MMF to EC-MPS improves GI-related symptoms and HRQoL.

Comparison of Long-Term Outcomes between Spousal Transplants and Other Living Unrelated Donor Transplants: Single-Center Experience

Background/Aims: The greater use of living unrelated donors (LUDs) as kidney donors is a worldwide trend in the current era of organ shortage, and spouses are an important source of LUDs. This study was to compare the long-term outcomes of spousal donor grafts with other LUD grafts. Methods: Among 445 LUD grafts, 77 were spouses and 368 were other LUDs. The clinical characteristics and long-term survival rates for spousal transplants were compared with those for other LUD transplants, and risk factors affecting graft survival were assessed. Results: Spousal donors had a significantly higher average number of human leukocyte antigen (HLA) mismatches (4.2 vs. 3.4, p < 0.001) and were older (41 vs. 33 years, p < 0.001) than LUDs. The 10-year survival rates for spousal donor grafts were 60.6%, similar to those for LUD grafts (58.5%, p = 0.61). The 10-year biopsy-proven acute rejection-free survival rates (85.5 vs. 89.6%, p = 0.45) and patient survival rates were also similar (84.3 vs. 79.6%, p = 0.35). The degree of HLA mismatching, the spousal donor type or donor age did not affect the graft survival. Conclusion: Renal transplants from spousal donors show similar long-term outcomes to those from better HLA-matched and younger LUDs.

Comparison of antibody monitoring system with flow cytometric crossmatch test in renal transplant recipients with high panel-reactive antibody.

Background/Aims: The antibody monitoring system (AMS) is a recently developed enzyme-linked immunosorbent assay (ELISA) crossmatch assay to detect donor-specific anti-HLA immunoglobulin G antibodies (DS-HLA Abs). This study was conducted to compare the AMS with the flow cytometric crossmatch (FCXM) test in renal transplant recipients with high panel-reactive antibody (PRA). Methods: Thirty-two sera were obtained from 10 patients with panel reactivity above 50%. When anti-HLA Ab was detected by ELISA PRA and the matched donor had the corresponding HLA antigen, it was considered to indicate DS-HLA Ab. The results of the AMS assay and FCXM were compared with the DS-HLA Abs. Results: Twenty-three (71.9%) sera were positive for DS-HLA Abs by ELISA PRA. The AMS assay showed that the number of compatible sera with DS-HLA Abs was 27 (84.4%), and it was significantly concordant (κ = 0.649, p < 0.0001). For FCXM, the number of compatible sera with DS-HLA Abs was 26 (81.3%), and it was also significantly concordant (κ = 0.614, p < 0.0001). There was a significant degree of concordance between the AMS assay and FCXM in detection of DS-HLA Abs (κ = 0.452, p = 0.010). Conclusion: The AMS assay is comparable to FCXM in detecting DS-HLA Abs in high PRA recipients.