Effects of Inosine Monophosphate Dehydrogenase Inhibition on Platelet-derived Growth Factor- Induced Fibronectin Secretion and Cellular Reactive Oxygen Species in Mouse Mesangial Cells

Purpose: Mesangial cell extracellular matrix (ECM) synthesis plays an important role in various renal diseases. Mycophenolic acid (MPA), which is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), inhibits mesangial cell proliferation and ECM synthesis. However, the exact mechanism of MPA has not been clearly elucidated in mesangial cells. To examine the relative importance of IMPDH on the inhibitory action of MPA, we compared the effects of MPA or IMPDH2 siRNA on platelet-derived growth factor (PDGF)-induced fibronectin secretion and cellular reactive oxygen species (ROS) in mouse mesangial cells (MMC). Methods: MMC were stimulated with PDGF 10 ng/ml with or without MPA 0.1∼10μM, IMPDH2 siRNA 10∼50 nM, or N-acetylcystein (NAC). IMPDH2 siRNA was transiently transfected by lipofectamine for 24 hours. MPA 0.1∼10μM, ribavirin 10∼100μM, and NAC 5 mM were administered 1 hour before the stimulation. Cell viability was measured by methylthiazoletetrazolium (MTT) assay, fibronectin secretion by Western blot analysis, and dichlorofluorescein (DCF)-sensitive cellular ROS by flow cytometry. Results: PDGF 10 ng/ml effectively increased fibronectin secretion and cellular ROS in MMC. MPA and NAC at concentration without affecting basal level of fibronectin and cellular ROS ameliorated PDGF-induced fibronectin secretion and cellular ROS. However, IMPDH2 siRNA only partially reduced PDGF- induced fibronectin secretion and cellular ROS in MMC. Conclusion: These results suggest that MPA may inhibit PDGF-induced fibronectin secretion partly through IMPDH2 or cellular ROS in MMC, and there may be other mechanisms on the inhibitory action of MPA in mesenchymal cells.ope

The Efficacy of the Affinity Column-mediated Immunoassay Method in Cyclosporine Concentration Assay Compared with the Microparticle Enzyme Immunoassay Method

Purpose: Cyclosporine is a potent immunosuppressive drug used in organ transplantation. Because of its substantial toxic effect, narrow therapeutic index, and the inter-individual variability of pharmacokinetics, therapeutic drug monitoring of the whole blood cyclosporine concentration has been recommended. We have investigated the comparability of the results of two immunoassay systems, the affinity column- mediated immunoassay (ACMIA) and the microparticle enzyme immunoassay (MEIA), and compared the differences in the cyclosporine concentrations between the two methods in relation to the hematologic and biochemical values. Methods: One hundred twenty-one blood samples from kidney recipients were used. We used Dimension(R) RxL HM with a CSA Flex(R) reagent cartilage for the ACMIA method and AXSYM(R) Cyclosporine for the MEIA method. Results: Cyclosporine concentrations measured by the ACMIA method (n=121) were closely correlated with those measured by the MEIA method (r=0.948, P＜0.0001). The Bland-Altman plot using concentration differences between the two methods and the average of the two methods also showed no specific trends (R2=0.02, P=0.125). Except hematocrit, other hematologic and biochemical value (albumin, total bilirubin) didn``t affect to both cyclosporine level by MEIA and ACMIC method. Both cyclosporine levels determined by the MEIA method and the ACMIA method were positively correlated with hematocrit (P＜0.05). Conclusion: The ACMIA method used for a cyclosporine assay is precise and has advantages, including the lack of a required pretreatment procedure, and shows same influence by hematocrit compared with the MEIA.ope

Clinical Outcomes of Spousal Donor Kidney Transplantation: Single Center Experience

The supply of deceased donors is limited in Korea and most of kidney transplantations are performed using living related or unrelated donors. In this study, we investigated the clinical characteristics and outcomes of spousal donor kidney transplantation at our center. Methods: From January 2000 to August 2008, we performed 909 cases of kidney transplantations. In this study, 475 one-haplomatch living-related donor (LRD) and 50 spousal donor kidney transplantations were retrospectively analyzed. We compared the outcomes of spousal donor group with those of one-haplomatch LRD group. We also compared the outcomes of husband-to wife with those of wife-to-husband subgroup. Results: The number of Human leukocyte antigen (HLA) mismatch was significantly larger in spousal group (3.3±1.2) than in LRD group (2.7±0.7). The proportion of tacrolimus use was higher in spousal group (72.0%) than in LRD group (26.6%). The incidence rate of delayed graft function was higher in spousal group (4.0%) than in LRD group (0.4%). There was no significant difference in the incidence of acute rejection between the two groups. Graft survival rates in spousal group (98.0% at 1 year and 91.5% at 5 year) were comparable to those in LRD group (99.6% at 1year and 98.7% at 5 year) (P=0.321). There were no significant differences in the incidence of acute rejection and graft survival rates between the subgroups (husband-to-wife vs. wife-to- husband). Conclusions: We achieved excellent outcomes by using spousal donor as an option to reduce the donor organ shortageope

Whole Body Bone Scan for Detecting Missed Bone Injuries in Multiple Trauma Patients

Purpose: Patients with multiple traumas often experience multiple fractures that are missed or overlooked, despite the use of imaging, careful history taking, and physical examinations. This study aimed to evaluate the usefulness of whole body bone scan (WBBS) for detecting missed bone injuries in patients with multiple traumas. Methods: We evaluated 30 patients with multiple traumas who underwent WBBS at single tertiary referral center between March 2008 and February 2016. We assessed the association of patient demographics with WBBS uptake as a binomial outcome variable. Results: There were no significant differences in patient demographics by WBBS. The mean injury severity score did not differ by WBBS (18.1 in the WBBS-negative group vs. 18.4 in the WBBS-positive group), and duration from admission to the evaluation of the WBBS was similar (5.4 days in both groups). The most common uptake site in the WBBS was the ribs (n=7), followed by the tibia (n=3), skull (n=2), ankle (n=1), and sternum (n=1). None of the missed injuries required further treatment, such as manual reduction or surgery. Conclusion: WBBS was useful for detecting missed bone injuries in patients with multiple trauma.ope

Safety and metabolic advantages of steroid withdrawal after 6 months posttransplant in de novo kidney transplantation: A 1-year prospective cohort study

Introduction: This prospective multicenter study aimed at investigating the safety and metabolic advantages of steroid withdrawal (SW) therapy in kidney transplant recipients with tacrolimus-mycophenolate mofetil-based immunosuppression. Methods: We analyzed 179 recipients who received kidney transplantation from March 2016 and September 2018. In 179 recipients, 114 patients maintained an immunosuppressive regimen including steroids (steroid continuation [SC] group). The remaining 65 patients were determined to withdraw steroid therapy after 6 months posttransplant (SW group). Metabolic parameters and graft functions of the two groups were evaluated. Results: The estimated glomerular filtration rates at 12 months posttransplant were 67.29 ± 20.29 ml/min/1.73 m2 in SC group and 73.72 ± 17.57 ml/min/1.73 m2 in SW group (p < .001). The acute rejection occurred to four recipients in the SC group (3.5%) and no acute rejection occurred to SW group recipients during the 6-2 months posttransplant period. Oral glucose tolerance tests revealed that recipients in the SW group were more improved in glucose metabolism than the SC group during 6-12 months posttransplant. In addition, cholesterol levels and blood pressure decreased after the withdrawal of steroids in the SW group. Conclusion: In conclusion, a 6-month withdrawal of steroids in recipients with low immunological risk and stable graft function can be safely conducted and result in improvement of metabolic profiles. Stable recipients without biopsy-proven acute rejection and proteinuria can safely withdraw from steroids out of a maintenance immunosuppressive regimen 6-months posttransplant. A long-term follow-up study is needed to verify our results.ope

Factors influencing the self-management of kidney transplant patients based on self-determination theory: a cross-sectional study

Background: Self-determination theory is useful for explaining how kidney transplant recipients self-manage their postoperative health, including drug regimens, but few studies have applied this theory to transplant recipients. This study aimed to examine the influence of health professionals' autonomy support, autonomous motivation and competence on kidney transplant patients' self-management based on the self-determination theory. Methods: This study included 79 kidney transplant patients from one outpatient clinic in a general hospital in Seoul, Korea. Data on the health professionals' support of patient autonomy and the kidney transplant patients' autonomous motivation, competence, and self-management were collected from self-report questionnaires. Results: The factors that influenced self-management behavior in kidney transplant patients were competence (β=0.377, P=0.001) and autonomous motivation (β=0.293, P=0.006). The explanatory power of these variables was 30.1%. Conclusions: This study found that autonomous motivation and competence in kidney transplant patients affected their self-management, indicating that if healthcare professionals enhance patients' competence and autonomous motivation, their self-management can be improved. The development of intervention programs that assist healthcare professionals in strengthening patients' autonomous motivation and competence is recommended.ope

Long-term Change of Renal Function after Donor Nephrectomy for Kidney Transplantation

Purpose: Occurrence of renal failure and its related complications such as hypertension are long-term problems after donor nephrectomy for living donor kidney transplantation. We retrospectively reviewed renal function of unilateral kidney donor. Methods: From 669 living donors for kidney transplantation from December 1998 to October 2006, laboratory data related to renal function are collected from hospital medical record retrospectively in 251 (37.5%) donors who were followed-up after discharge. The selection criteria of donors were: 1) pre-nephrectomy serum creatinine level below 1.5 mg/dL, 2) no radiologic abnormality in bilateral kidney. The donor nephrectomy was performed by conventional open nephrectomy or video assisted minilaparotomy surgery. The estimated glomerular filtration rate (e-GFR) by Modification of Diet in Renal Disease (MDRD) study was used as renal function monitoring parameter. Results: In immediate post-nephrectomy period, e-GFR was decreased to 67.8±14.6% of pre-nephrectomy level (93.8±19.9 mL/min/1.73 m2). The urinary protein excretion for 24 hours was increased to 255% of pre-nephrectomy level (76.4±44.6 mg/day), but cases with proteinuria more than 300 mg per day were only 4 cases (1.7%, 4/251). After 14.0±15.2 months follow-up (range: 1~80 months), two cases (0.8%, 2/251) of renal failure (chronic kidney disease stage 5) were found. Relative renal function (post-nephrectomy e-GFR ratio versus pre-nephrectomy e-GFR, %) was increased by post-nephrectomy duration. The mean scores of e-GFR ratio within post-nephrectomy 2 months, 3~11 months, 12~23 months and after 24 months were 64.8±10.4%, 66.4±9.7%, 69.5±10.9% and 75.8±17.6% respectively. The relative e-GFR ratio after 24 months was significantly different from those of within 24 months (P＜0.0001 by ANOVA). In linear regression analysis, mean increment of e-GFR ratio per post-nephrectomy year was 2.88%. Conclusion: In spite of possibility of renal failure, our study shows the long-term compensation of residual renal function after nephrectomy.ope

Insulin Secretion and Insulin Resistance Trajectories over 1 Year after Kidney Transplantation: A Multicenter Prospective Cohort Study

Background: We investigated the changing patterns of insulin secretion and resistance and risk factors contributing to the development of post-transplant diabetes mellitus (PTDM) in kidney recipients under tacrolimus-based immunosuppression regimen during 1 year after transplantation. Methods: This was a multicenter prospective cohort study. Of the 168 subjects enrolled in this study, we analyzed a total 87 kidney transplant recipients without diabetes which was assessed by oral glucose tolerance test before transplantation. We evaluated the incidence of PTDM and followed up the index of insulin secretion (insulinogenic index [IGI]) and resistance (homeostatic model assessment for insulin resistance [HOMA-IR]) at 3, 6, 9 months, and 1 year after transplantation by oral glucose tolerance test and diabetes treatment. We also assessed the risk factors for incident PTDM. Results: PTDM developed in 23 of 87 subjects (26.4%) during 1 year after transplantation. More than half of total PTDM (56.5%) occurred in the first 3 months after transplantation. During 1 year after transplantation, insulin resistance (HOMA-IR) was increased in both PTDM and no PTDM group. In no PTDM group, the increase in insulin secretory function to overcome insulin resistance was also observed. However, PTDM group showed no increase in insulin secretion function (IGI). Old age, status of prediabetes and episode of acute rejection were significantly associated with the development of PTDM. Conclusion: In tacrolimus-based immunosuppressive drugs regimen, impaired insulin secretory function for reduced insulin sensitivity contributed to the development of PTDM than insulin resistance during 1 year after transplantation.ope

Delta Neutrophil Index as a New Early Mortality Predictor after Liver Transplantation

Background: Patients with liver disease display numerous defects of the immune system, so infection is a frequent complication of both acute and chronic liver disease. These infections are independently associated with poor outcomes after liver transplantation. Our objective was to evaluate the delta neutrophil index (DNI), a new inflammation marker, as a predictor of survival after liver transplantation (LT). Methods: This observational study retrospectively evaluated the records of 712 patients who underwent LT from January 2010 to February 2018. DNI was evaluated at pre-transplantation and 1, 7, 14, and 30 days after operation. Statistical analysis was performed using the T-test or chi-square test, and logistic regression analysis. Results: The mean MELD score was 16.7 ± 9.4 (0-48). There were 125 mortality cases (17.8%) after liver transplantation. Mean DNI was 1.61 at pre-transplantation, 3.94 one day after operation, 2.67 seven days after operation, 1.61 fourteen days after operation, and 1.64 thirty days after operation, respectively. In multivariate analysis, DNI seven and fourteen days after operation was revealed as an independent prognostic factor for mortality after liver transplantation (p = 0.040 and p < 0.0001). Conclusions: The DNI is a simple and reliable predictor of patient mortality after liver transplantation.ope

Changes in glucose metabolism among recipients with diabetes 1 year after kidney transplant: a multicenter 1-year prospective study

Background: Diabetes mellitus is a common and crucial metabolic complication in kidney transplantation. It is necessary to analyze the course of glucose metabolism in patients who already have diabetes after receiving a transplant. In this study, we investigated the changes in glucose metabolism after transplantation, and a detailed analysis was performed on some patients whose glycemic status improved. Methods: The multicenter prospective cohort study was conducted between 1 April 2016 and 31 September 2018. Adult patients (aged 20 to 65 years) who received kidney allografts from living or deceased donors were included. Seventy-four subjects with pre-transplant diabetes were followed up for 1 year after kidney transplantation. Diabetes remission was defined as the results of the oral glucose tolerance test performed one year after transplantation and the presence or absence of diabetes medications. After 1-year post-transplant, 74 recipients were divided into the persistent diabetes group (n = 58) and the remission group (n = 16). Multivariable logistic regression was performed to identify clinical factors associated with diabetes remission. Results: Of 74 recipients, 16 (21.6%) showed diabetes remission after 1-year post-transplant. The homeostatic model assessment for insulin resistance numerically increased in both groups throughout the first year after transplantation and significantly increased in the persistent diabetes group. The insulinogenic index (IGI30) value significantly increased only in the remission group, and the IGI30 value remained low in the persistent diabetes group. In univariate analysis, younger age, newly diagnosed diabetes before transplantation, low baseline hemoglobin A1c, and high baseline IGI30 were significantly associated with remission of diabetes. After multivariate analysis, only newly diagnosed diabetes before transplantation and IGI30 at baseline were associated with remission of diabetes (34.00 [1.192-969.84], P = 0.039, and 17.625 [1.412-220.001], P = 0.026, respectively). Conclusion: In conclusion, some kidney recipients with pre-transplant diabetes have diabetes remission 1 year after transplantation. Our prospective study revealed that preserved insulin secretory function and newly diagnosed diabetes at the time of kidney transplantation were favorable factors for which glucose metabolism did not worsen or improve 1 year after kidney transplantation.ope