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Recent studies have shown that high levels of serum alkaline phosphatase (ALP) are associated with all-cause and cardiovascular death among patients undergoing hemodialysis. However, there is limited knowledge on the effect of ALP level in kidney transplant recipients (KTRs). The aim of this study was to evaluate if serum ALP levels before and after transplant and the changes in ALP levels are associated with graft failure and mortality.Between January 1997 and December 2012, 3029 KTRs were enrolled in a multicenter cohort. We examined the association of pre- and posttransplant serum ALP levels and long-term outcomes in KTRs.Pretransplant serum ALP level80 IU/L was associated with a hazard ratio (HR) for graft failure of 1.571 in a fully adjusted model. The graft failure rate gradually increased with ALP level increments of 20 IU/L in KTRs with ALP levels60 IU/L. An increase in serum ALP level by 40 IU/L during the first 3 months after kidney transplant was associated with higher rates of graft failure (HR, 2.353) and higher rates of mortality (HR, 2.733).Elevated pre-and posttransplant serum ALP levels and increases in the serum ALP levels after kidney transplant increase the risk of graft failure and mortality among KTRs.

Purpose There are increased therapeutic usages of rituximab in kidney transplantation (KT). However, few studies have evaluated the effect of rituximab on cancer development following KT. This study aimed to evaluate the effect of rituximab on the cancer occurrence and mortality rate according to each type of cancer. Methods Five thousand consecutive recipients who underwent KT at our center were divided into era1 (1990–2007) and era2-rit– (2008–2018), and era2-rit+ (2008–2018) groups. The era2-rit+ group included patients who received single-dose rituximab (200–500 mg) as a desensitization treatment 1–2 weeks before KT. Results The 5-year incidence rates of malignant tumors after KT were 3.1%, 4.3%, and 3.5% in the era1, era2-rit–, and era2-rit+ group, respectively. The overall incidence rate of cancer after transplantation among the 3 study groups showed no significant difference (P = 0.340). The overall cancer-related mortality rate was 17.1% (53 of 310). Hepatocellular carcinoma (HCC) had the highest mortality rate (61.5%) and relative risk of cancer-related death (hazard ratio, 8.29; 95% confidence interval, 2.40–28.69; P = 0.001). However, we found no significant association between rituximab and the incidence of any malignancy. Conclusion Our results suggest that single-dose rituximab for desensitization may not increase the risk of malignant disease or cancer-related mortality in KT recipients. HCC was associated with the highest risk of cancer-related mortality in an endemic area of HBV infection.

Background Recurrent focal segmental glomerulosclerosis (FSGS) after kidney transplantation (KT) is a serious complication and a significant risk factor for graft failure. However, there is no clear evidence of the effectiveness of pre-transplant treatment using plasmapheresis (PP) or rituximab in preventing post-operative FSGS recurrence after KT. Methods This single-center retrospective study included 99 adult patients with biopsy-proven primary FSGS who underwent KT between 2007 and 2018. The patients were divided into the pre-treatment group (N = 53, 53.5%) and no pre-treatment group (N = 46, 46.5%). In the pre-transplant group, prophylactic PP was administered before KT in patients undergoing living donor transplantation and the day after KT in those undergoing deceased donor transplantation. Results The rate of immediate post-operative recurrence was significantly higher in the no pre-treatment group (16 [34.8%]) than in the pre-treatment group (5 [9.4%]; P = 0.002). There were three cases of graft failure due to recurrent FSGS, all of which were in the no pre-treatment group. After adjusting for possible confounding factors, age (per 10-year increase; OR = 0.61, CI, 0.42–0.90; P = 0.012) and pre-transplant treatment (vs. no pre-transplant treatment; OR = 0.17, CI, 0.05–0.54; P = 0.003) were identified as significant factors associated with FSGS recurrence. The rate of death-censored graft survival was significantly superior in the pretransplant treatment group (P = 0.042). Conclusion Pre-transplant treatment with PP was associated with beneficial effects on preventing FSGS recurrence after KT.

Background We aimed to describe the characteristics of immunoglobulin A nephropathy (IgAN) in Korea with assessment for time trends. Methods We performed a multicenter retrospective observational cohort study including biopsy-confirmed native IgAN cases from four tertiary hospitals in Korea. Time eras of diagnosis were stratified into 1979–2003, 2004–9 and 2010–17. The prognostic variable was progression to end-stage kidney disease (ESKD) analyzed by multivariable Cox regression analysis. Results We included 1366 (from 1979 to 2003), 1636 (from 2004 to 2009) and 1442 (from 2010 to 2017) IgAN patients in this study. In the recent periods, IgAN had relatively better clinical characteristics, as patients had higher estimated glomerular filtration rates and lower baseline blood pressures than before. The use of renin–angiotensin–aldosterone system (RAAS) blockers increased from 57.7% in 1979–2003 to 80.0% in 2010–17. During a median follow-up duration of 11.3 years, 722 patients progressed to ESKD with an incidence rate of 12.5 per 1000 person-years. The 10-year risk of progression to ESKD was lower in 2010–17 compared with that of 1979–2003 [adjusted hazard ratio 0.692 (95% confidence interval 0.523–0.915)], even after adjustment for multiple clinicopathologic characteristics. The use of RAAS blockers was a significant mediator (P < 0.001) for the association between time trends and lower 10-year ESKD risk. Conclusions Clinicopathologic characteristics of IgAN in Korea have changed over time. Although the limitation of a retrospective observational study remains, the result showed that the prognosis of IgAN has improved over the study period, possibly related to increased prescription of RAAS blockers.

We evaluated the effectiveness of IGRA-based isoniazid (INH) treatment with the diagnostic value of quantitative IGRA titer for post-transplant tuberculosis (TB) in kidney transplant (KT) recipients.All adult KT recipients were enrolled from January 2014 to December 2017. The development of TB after KT was observed, stratified by quantitative IGRA results as well as by IGRA results with/without INH treatment.Of 1150 KT recipients, 322 (28%) revealed positive IGRA results (≥0.35 IU/mL) and 12 (1.0%) developed TB. Seven (3.2%) of 217 patients with positive IGRA without INH developed TB, whereas none of 105 patients with positive IGRA with INH developed TB (rate difference -1616 per 100,000 person-years, P = 0.016) and 5 (0.6%) of 828 patients with negative or indeterminate IGRA developed TB (rate difference -1388 per 100,000 person-years, P0.001). Among the 217 positive IGRA patients without INH, 6 (6.4%) of 94 patients who had positive IGRA titer2.96 IU/mL developed TB, whereas one (0.8%) of 123 patients who had positive IGRA titer≤2.96 IU/mL developed TB (rate difference 2964 per 100,000 person-years, P = 0.017).IGRA-based INH treatment with risk stratification by quantitative IGRA results appears to be effective to prevent the development of TB in KT recipients.

Background Recent advances in desensitization techniques and immunosuppressive therapy have led to improved outcomes after ABO-incompatible (ABO-i) kidney transplantation (KT). However, questions remain unanswered, particularly regarding which type of ABO isoagglutinin-immunoglobulin M (IgM) or immunoglobulin M (IgG)-is significantly involved in antibody-mediated rejection (AMR). Study design and methods We retrospectively analyzed data from 120 patients who underwent ABO-i KT between 2012 and 2014. Preoperative plasma exchange was performed until the IgM isoagglutinin titer was 4 or less, regardless of the IgG titer. Clinical data were compared between patient groups with pre-KT IgG isoagglutinin titer 16 or greater (high IgG; titer range, 16-256; n = 39) and 8 or less (low IgG; titer range, -8; n = 81). Results The median follow-up periods were 59 (high IgG) and 55 (low IgG) months. Patient survival at 5 years (p = 0.314) was 100% (high IgG) and 97.4% (low IgG). Graft survival at 5 years (p = 0.480) was 100% (high IgG) and 98.7% (low IgG). AMR by anti-ABO antibody occurred in only one patient in the low-IgG group. Conclusion Patients with high pre-KT IgG isoagglutinin titers had equally successful outcomes as those with low IgG titers. ABO-i KT can be successfully performed by reducing the pre-KT IgM isoagglutinin titer to 4 or less, as determined by the immediate spin tube method.

Background : Previous studies have recommended a 2- to 5-year waiting time prior to kidney transplantation (KT) in patients with end-stage renal disease (ESRD) and symptomatic renal cell carcinoma (RCC) and no delay for incidental early-stage RCC. Data on Asian KT recipients are unavailable.Methods : This is a Korean single-center retrospective study on 35 KT recipients with ESRD and RCC. Patients were classified into two groups: early KT (KT performed within 1 year after nephrectomy for RCC, including KT with simultaneous nephrectomy) and delayed KT (KT performed over than 1 year after nephrectomy for RCC). Patient survival, graft survival, and cancer recurrence were compared between both groups.Results : There were no statistically significant differences in patient survival (P = 0.388), graft survival (P = 0.317), or graft rejection rate (P = 0.207) between the early and delayed KT groups. Additionally, there were no differences in pathological characteristics or RCC stage other than cancer histology: acquired cystic disease-associated RCC (47.4%) was the most common RCC type in the early KT group, whereas clear cell type (62.5%) was the most common RCC type in the delayed KT group. No RCC recurrence was observed.Conclusion : Patients with early-stage and asymptomatic RCC do not require a mandatory observational period prior to KT after curative nephrectomy.

Background: Hyperparathyroidism is common in patients with chronic kidney disease with reduced renal function and has been observed after kidney transplantation. The optimal treatment for cases in which hyperparathyroidism persists after kidney transplantation has not been determined. Methods: This retrospective study included 83 patients with tertiary hyperparathyroidism who underwent kidney transplantation between 2000 and 2018 at a single tertiary center in Korea. Sixty-four patients underwent parathyroidectomy and 19 patients were treated with cinacalcet following renal transplantation. Biochemical parameters and clinical outcomes were compared between the two groups. Results: Serum calcium and parathyroid hormone (PTH) levels improved in both the parathyroidectomy and cinacalcet groups. One year after treatment, parathyroidectomy resulted in a lower mean serum calcium level than cinacalcet (9.7 ± 0.7 mg/dL vs. 10.5 ± 0.7 mg/dL, p = 0.001). Regarding serum PTH, the parathyroidectomy group showed a significantly lower PTH level than the cinacalcet group at 6 months (129.1 ± 80.3 pg/mL vs. 219.2 ± 92.5 pg/mL, p = 0.002) and 1 year (118.8 ± 75.5 pg/mL vs. 250.6 ± 94.5 pg/ mL, p < 0.001). There was no statistically significant difference in the incidence of kidney transplant rejection, graft failure, cardiovascular events, fracture risk, or bone mineral density changes between the two groups. Conclusion: Parathyroidectomy appears to reduce PTH and calcium levels effectively in tertiary hyperparathyroidism. However, creatinine level and allograft rejection should be monitored closely.

With the recent update to the Oxford classification for allograft IgA nephropathy (IgAN), additional investigations on the clinical significance of the updated components are warranted. We performed a retrospective cohort study at two tertiary hospitals. Kidney transplant recipients diagnosed with allograft IgAN were included in the study after additional review by specialized pathologists. We applied the updated Oxford classification and determined the MEST-C scores of the patients. The main study outcome was death-censored graft failure within 10 years after the establishment of allograft IgAN diagnosis and was assessed using the Cox regression analysis. Three hundred thirty-three allograft IgAN patients were reviewed: 100 patients with confirmed native IgAN and 233 patients with other, clinical, or unknown primary causes for end-stage renal disease (ESRD). The updated Oxford classification for allograft IgAN demonstrated prognostic value for graft failure, and patients with multiple MEST-C components had worse outcomes. M, E, S, and C were significantly associated with the prognosis of recurred IgAN and T was the only independent prognostic parameter for allograft IgAN without confirmed native IgAN. Therefore, we suggest reporting MEST-C scores in allograft biopsies and careful interpretation of the results according to the primary cause of ESRD.

Background Short-term hemoglobin (Hb) variability related to volume status is observed in chronic kidney disease (CKD) patients receiving hemodialysis (HD). Given the lack of studies regarding outcomes according to the day of Hb sampling, the existing guidelines do not strongly recommend regarding measurement timing. Pre-dialysis mid-week sampling (Wednesday and Thursday) is preferable to minimize short-term Hb variability, although numerous HD centers perform early-week sampling (Monday and Tuesday). The different measurement days may influence the prescribed dose of erythropoiesis-stimulating agent (ESA) and related patient outcomes. We investigated changes in Hb levels and ESA doses according to the Hb measurement day among HD patients. Methods Starting September 2013, the day for pre-dialysis Hb measurement at the Asan Medical Center was changed from early-week days to mid-week days. This single-center retrospective study evaluated medical records of 92 patients who received maintenance HD between September 2012 and August 2014. Results There was no significant difference in the mean Hb levels between early-week days and mid-week days (10.71 ± 0.06 g/dL vs. 10.78 ± 0.47 g/dL, p = 0.105). However, the mean doses of darbepoetin-α on early-week days were higher than those on mid-week days (175.4 ± 72.5 μg/month vs. 163.7 ± 83.6 μg/month, p = 0.022). The mean doses of intravenous iron hydroxide sucrose for early-week measurements were also higher than those for mid-week measurements (623.0 ± 489.0 mg/year vs. 447.0 ± 505.2 mg/year, p = 0.001). The mean interdialytic weight gains were 2.81 ± 0.82 kg on early-week days and 1.99 ± 0.61 kg on mid-week days (p

AIM ABO-incompatible (ABOi) kidney transplantation (KT) has become a routine procedure with graft survival rates comparable to those of ABO-compatible KT. However, the clinical significance of the isoagglutinin titre in ABOi KT remains uncertain. Therefore, in this study, we analysed the clinical outcomes of ABOi KT according to the baseline and post-operative isoagglutinin titre. METHODS All patients who received ABOi KT between 2009 and 2013 were reviewed and followed up until December 2016. The patients were classified according to baseline (

BACKGROUND The permissible extent of pretransplant dialysis for patient and allograft survival is unclear. We assumed that a short period of dialysis before living donor kidney transplantation (LDKT) will show the similar results as preemptive kidney transplantation (PKT). MATERIAL AND METHODS We retrospectively evaluated the outcomes of LDKT according to pretransplant dialysis duration in both unmatched cohorts (n=1984) and propensity-score-matched cohorts (n=986) cohorts. The primary study endpoint was post-transplantation patient survival and death-censored graft survival (DCGS) according to the duration of pretransplant dialysis by 19 months which was the best cutoff value to differentiate clinical outcomes with the use of the time-dependent area under the curve. RESULTS Of 1984 patients with LDKT at our center between January 2005 and September 2016, PKT was performed in 429 patients. The durations of pretransplant dialysis were

To evaluate the efficacy and safety of CKD-11101 (biosimilar darbepoetin-alfa, Chong Kun Dang Pharm.) compared with NESP® in treatment of anaemia in patients with chronic kidney disease not on dialysis.NCT03431623.In this multi-centre, randomized, double-blind study, patients were treated with CKD-11101 and NESP. The efficacy evaluation period (EEP) was 24 weeks, during which patients were treated every 2 weeks. All patients who completed the EEP were treated with CKD-11101 every 2 weeks for the first 4 weeks and every 4 weeks for the safety evaluation period (SEP), which was from 24 weeks to 52 weeks. The primary efficacy endpoint was the change in mean haemoglobin (Hb) level from baseline to end of EEP and mean dose needed to achieve the target Hb.The mean Hb level was increased in both groups during the EEP (both p 0.001). The difference in mean Hb level change between the two groups was 0.01 g/dL (95% CI = -0.213-0.242), indicating that CKD-11101 was equivalent to NESP. The difference in mean administration dose between groups was -1.40 mcg (95% CI = -6.859-4.059) included in the equivalent range. The incidence of AEs and ADRs was not different between the two groups, and the frequency of ADRs was favourable in both groups (1.2% in CKD-11101 vs 7.7% in the NESP to CKD-11101 conversion group).CKD-11101 has an equivalent therapeutic effect as NESP in chronic kidney disease patients with renal anaemia. CKD-11101 can be safely used for long-term treatment and in patients converted from NESP.

Purpose: To investigate the characteristics of lymphedema in patients treated with mammalian target of rapamycin (mTOR) inhibitors and delineate complex decongestive therapy (CDT) outcomes. Methods and Results: We retrospectively analyzed 24 patients with mTOR inhibitor-induced lymphedema and 7 lymphedema patients (control) not treated with mTOR inhibitors, who visited the lymphedema clinic of the department of rehabilitation medicine from March 2016 to December 2019. We comprehensively reviewed clinical features, medication history, associated diseases, lymphoscintigraphy, lower extremity computed tomography venography (LE CTV), and the effect of CDT. By using ImageJ program, we measured the cross-sectional area (CSA) of muscle and subcutaneous fat of mid-thigh image in LE CTV and compared them to a control group not treated with mTOR inhibitors. Seventeen patients on sirolimus and seven patients on everolimus were included, with an approximately equal distribution of stages 2 and 3 lymphedema, and most with pitting edema. Ten patients had breast or gynecological cancer and underwent lymph node dissection. Lymphedema developed after mTOR inhibitor initiation, not postoperatively. Lymphoscintigraphy revealed decreased lymph node uptake and dermal backflow. LE CTV revealed subcutaneous honeycomb-shaped trabecular areas in the affected limbs of seven patients. Patients treated with mTOR inhibitors had a larger mean subcutaneous fat CSA and a smaller mean muscular CSA than controls. Lymphedema improved or remained unchanged after initial CDT. Daily CDT adequately controlled 11 cases, but exacerbation occurred in 5 of 7 poorly compliant patients, and cellulitis occurred in 6 patients. Conclusion: Physicians should identify mTOR inhibitor-related lymphedema early and discuss medication alternatives and CDT with patients.

BACKGROUND Kidney donors may be at increased risk for end-stage renal disease (ESRD) as well as cardiovascular and all-cause mortality. In particular, data on long-term safety after kidney donation in Asian populations are lacking. We aimed to assess the safety of live kidney donation in Korean donors by using a matched control group. MATERIAL AND METHODS We conducted a retrospective cohort study using a hospital-based database (Asan Medical Center, Seoul, Korea) and a control group from the national health insurance claims database in South Korea. We analyzed the health status of 1608 kidney donors who underwent donation between September 1990 and December 2015, and we compared their characteristics with those of matched 6426 non-donors (1: 4 ratio). We also measured the glomerular filtration rate (GFR) with ⁵¹Cr EDTA and urinary albumin excretion and assessed the prevalence of hypertension, diabetes, and general health status in 200 volunteer donors. RESULTS Mortality was significantly lower in kidney donors compared with the matched controls (130.2 vs. 185.4 per 100,000 person-years, P=0.02). There was no significant difference in mortality if a donor had hypertension or was a current smoker at the time of donation. There was also no significant difference in ESRD (43.1 vs. 35.2 per 100,000 person-years, P=0.07) between the 2 groups regardless of hypertension and smoking status. Among the 200 donors with measured GFR, 11.5% had GFR values

Background Pneumocystis pneumonia (PCP) is a life-threatening fungal infection that can occur in kidney transplantation (KT) recipients. A growing number of KT recipients are receiving perioperative treatment with rituximab, which is associated with prolonged B-cell depletion and possible risk of PCP occurrence; however, the optimal prophylaxis duration according to rituximab treatment is yet unknown. We compared the occurrence of PCP and the duration of prophylaxis in KT recipients according to rituximab treatment. Methods We retrospectively analyzed 2110 patients who underwent KT between January 2009 and December 2016, who were divided into non-Rituximab group (n = 1588, 75.3%) and rituximab group (n = 522, 24.7%). Results In the rituximab group, the estimated number needed to treat (NNT) for prophylaxis prolongation from 6 to 12 months was 29.0 with a relative risk reduction of 90.0%. In the non-rituximab group, the estimated NNT value was 133.3 and the relative risk reduction was 66.4%. Rituximab treatment (hazard ratio (HR) = 3.09; P P = 0.03) were significant risk factors for PCP in multivariate analysis. Conclusions Our results suggest that maintaining PCP prophylaxis for 12 months may be beneficial in KT recipients treated with rituximab for desensitization or acute rejection treatment.

Background Pneumocystis pneumonia (PCP) is a life-threatening fungal infection that can occur in kidney transplantation (KT) recipients. A growing number of KT recipients are receiving perioperative treatment with rituximab, which is associated with prolonged B-cell depletion and possible risk of PCP occurrence; however, the optimal prophylaxis duration according to rituximab treatment is yet unknown. We compared the occurrence of PCP and the duration of prophylaxis in KT recipients according to rituximab treatment. Method We retrospectively analyzed 2110 patients who underwent KT between January 2009 and December 2016. The study cohort was divided into non-rituximab group (n = 1588, 75.3%) and rituximab group (n = 522, 24.7%), the latter of which was defined as recipients who had been treated with rituximab due to pre-operative desensitization or rejection treatment within 6 months after transplant. Results In the rituximab group, the estimated number needed to treat (NNT) for prophylaxis prolongation from 6 to 12 months was 29.0 with a relative risk reduction of 90.0%. In the non-rituximab group, the estimated NNT value was 133.3 and the relative risk reduction was 66.4%. Rituximab treatment (hazard ratio (HR) = 3.09; P < 0.01) and acute rejection (HR = 2.19; P = 0.03) were significant risk factors for PCP in multivariate analysis. Conclusion Our results suggest that maintaining PCP prophylaxis for 12 months may be beneficial in KT recipients treated with rituximab for desensitization or acute rejection treatment.

BACKGROUND BK nephropathy (BKN) affects graft function and increases the risk of graft failure. The reduction of immunosuppression is the main treatment for BKN. However, acute rejection may develop following immunosuppression reduction, and data regarding the risk factors of acute rejection during the post-reduction period are insufficient. MATERIAL AND METHODS Of 758 patients who received a kidney transplantation (KT) between 2008 and 2011, 79 who underwent immunosuppression reduction as BKN treatment were enrolled. The risk factors of acute rejection after immunosuppression reduction were identified using multivariate logistic regression analysis. RESULTS During the median follow-up period (75 months), acute rejection developed in 21.5% of study group patients and in 22.5% of KT recipients without BKN. The rejection group showed a trend of higher body mass index (24.13±3.92 vs. 22.40±3.31 kg/m², P=0.070) and lower tacrolimus levels than the no rejection group, although mycophenolate mofetil (MMF) doses were not lower in the rejection group. The rejection group showed worse graft survival than the no rejection group (P=0.001 by the log rank test). A greater number of patients in the rejection group exhibited reduced calcineurin inhibitor (CNI) level by >20% at 1 month after initial BKV detection (34.2% vs. 7.9%, P=0.008). Multivariate analysis indicated that the peak BKV PCR level (odds ratio [OR], 0.136; 95% confidence interval [CI], 0.025-0.732; P=0.020), MMF discontinuation (vs. MMF reduction; OR, 0.112; 95% CI, 0.020-0.618; P=0.012) and CNI level reduction >20% (OR, 33.752; 95% CI, 4.263-267.251; P=0.001) were significantly associated with acute rejection. CONCLUSIONS Acute rejection after immunosuppression reduction for BKN showed worse allograft survival than the patients without acute rejection. In addition, a CNI dose reduction >20% at 1 month after the initial BKV detection can increase the risk of acute rejection.

BACKGROUND Minimizing the tacrolimus dosage in patients with stable allograft function needs further investigation. MATERIAL AND METHODS We performed an open-label, randomized, controlled study from 2010 to 2016 in 7 tertiary teaching hospitals in Korea and enrolled 345 kidney transplant recipients with a stable graft status. The study group received reduced-dose tacrolimus, 1080-1440 mg/day of enteric-coated mycophenolate sodium (EC-MPS), and corticosteroids. The control group received the standard tacrolimus dosage and 540-720 mg/day of EC-MPS with steroids. The primary endpoint was the mean estimated glomerular filtration rate (eGFR) and change in the eGFR at 12 months after randomization. RESULTS The mean tacrolimus trough level of the study group was 4.51±1.62 ng/mL, which was lower than that of the control group, at 6.75±2.82 ng/mL (P

Background/Aims: Lipopolysaccharide (LPS)-activated monocytes/macrophages develop endotoxin tolerance in part by reducing cell surface toll-like receptor 4 (TLR4) through cluster of differentiation 14 (CD14)-dependent endocytosis. In case of endothelial cells, CD14 is expressed in low copy numbers as compared with monocytes/macrophages. Thus, we explored how endothelial cells regulate TLR4 expression after LPS stimulation. Methods: Cultured human aortic endothelial cells (HAECs) were treated with LPS. TLR4 expression was analyzed by Western blot analysis and immunofluorescence staining. A disintegrin and metalloprotease 17 (ADAM17) activity was measured using a fluorescent substrate. Results: TLR4 in cell lysate began to decrease within 30 min of LPS treatment with a maximal reduction at 2 h, and it was accompanied by an increase of N-terminal fragment of TLR4 in culture supernatant, indicating ectodomain shedding of the receptor. LPS activated p38 mitogen-activated protein kinase (p38 MAPK) and ADAM17, while LPS-induced ADAM17 activation was inhibited by SB203580, a p38 MAPK inhibitor. LPS-induced ectodomain shedding of TLR4 was attenuated by siRNA depletion of ADAM17 as well as TAPI-2 (an inhibitor of ADAM family) and SB203580. LPS pretreatment resulted in a blunted response of p38 MAPK activation to further LPS stimulation. In the cells depleted of ADAM17, LPS-induced p38 MAPK activation was prolonged and LPS-induced intercellular adhesion molecule-1 expression was potentiated. Conclusion: HAECs respond to LPS by rapid shedding of the ectodomain of TLR4 and thereby reduce the responsiveness to subsequent LPS exposure. ADAM17, downstream of p38 MAPK, is implicated in the ectodomain cleavage of TLR4.

Background/Aims: High-mobility group box 1 (HMGB1) elicits inflammatory responses through interactions with the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). We investigated how RAGE and TLR4 expressions are regulated after HMGB1 stimulation in cultured human aortic endothelial cells (HAECs). Methods: RAGE and TLR4 expressions were analyzed by Western blot analysis and immunofluorescence staining. A disintegrin and metalloprotease 17 (ADAM17) activity was measured using a fluorogenic substrate. Results: Upon treatment with HMGB1, both RAGE and TLR4 began to decrease in cell lysate and remained decreased up to 24 h. The decrease in cellular RAGE and TLR4 was accompanied by an increase of N-terminal fragment of RAGE and TLR4 in culture supernatant, indicating ectodomain shedding of the receptors. HMGB1 activated p38 mitogen-activated protein kinase (p38 MAPK) and ADAM17, while HMGB1-induced ADAM17 activation was inhibited by SB203580, a p38 MAPK inhibitor. HMGB1-induced ectodomain shedding of RAGE and TLR4 was prevented by siRNA depletion of ADAM17 as well as TAPI-2, an inhibitor of ADAM family, and SB203580. HMGB1 pretreatment abolished p38 MAPK activation in response to 2nd HMGB1 stimulation. In the cells depleted of ADAM17, HMGB1-induced p38 MAPK activation was prolonged. siRNA depletion of RAGE, but not TLR4, suppressed HMGB1-induced p38 MAPK activation. Conclusion: In response to HMGB1 stimulation, HAECs rapidly undergo ectodomain shedding of RAGE and TLR4, and thereby become insensitive to further HMGB1 stimulation. ADAM17, activated through RAGE-p38 MAPK pathway, is implicated in the ectodomain cleavage of the receptors.

Introduction ABO-incompatible transplantation has expanded the limited donor pool for kidney transplantation. Despite the successful desensitization protocols and immunosuppression, undesirable cases of hyperacute rejection occurs. Objective Flow cytometry was used to measure isoagglutinin titer and its IgG subclasses in assessment of the cause of hyperacute rejection in ABO-incompatible kidney transplantation. Materials and methods The recipient was admitted for kidney transplantation due to end-stage renal disease. Pre-transplantation work-up for ABO-incompatible kidney transplantation included blood group typing, HLA DNA typing and HLA antibody analyses. HLA crossmatch analysis was conducted using donor lymphocytes and anti-HLA antibody assay using Luminex panel reactive antibody test (One Lambda, Inc., Canoga Park, CA). Desensitization protocol was composed of therapeutic plasma exchange sessions and rituximab. Results Despite negative HLA crossmatch results, a case of hyperacute rejection occurred after living donor kidney transplantation. Rejection resulted in immediate removal of graft, and the patient later received a second kidney transplantation. Retrospective evaluation of isoagglutinin titer and its subclasses using flow cytometry identified the cause of rejection to increased IgG1 subclass. Desensitization protocol for ABO-incompatible kidney transplantation now implements further caution for blood group O recipients. Discussion Hyperacute rejection resulting from increased IgG1 isoagglutinin subclass has not been previously confirmed using flow cytometry. Unfortunate outcome of this rejection case provides insight to how we should approach and ensure successful ABO-incompatible kidney transplantation.

The focus of studies on kidney transplantation (KT) has largely shifted from T-cell mediated rejection (TCMR) to antibody-mediated rejection (ABMR). However, there are still cases of pure acute TCMR in histological reports, even after a long time following transplant. We thus evaluated the impact of pure TCMR on graft survival (GS) according to treatment response. We also performed molecular diagnosis using a molecular microscope diagnostic system on a separate group of 23 patients. A total of 63 patients were divided into non-responders (N = 22) and responders (N = 44). Non-response to rejection treatment was significantly associated with the following factors: glomerular filtration rate (GFR) at biopsy, ΔGFR, TCMR within one year, t score, and IF/TA score. We also found that non-responder vs. responder (OR = 3.31;P =0.036) and lower GFR at biopsy (OR = 0.56;P =0.026) were independent risk factors of graft failure. The responders had a significantly superior overall GS rate compared with the non-responders (P= 0.004). Molecular assessment showed a good correlation with histologic diagnosis in ABMR, but not in TCMR. Solitary TCMR was a significant risk factor of graft failure in patients who did not respond to rejection treatment.

BACKGROUND/AIMS Kidney transplantation (KT) reportedly provides a significant survival advantage over dialysis in diabetic patients. However, KT outcome in diabetic patients compared with that in non-diabetic patients remains controversial. In addition, owing to recent improvements in the outcomes of KT and management of cardiovascular diseases, it is necessary to analyze outcomes of recently performed KT in diabetic patients. METHODS We reviewed all diabetic patients who received living donor KT between January 2008 and December 2011. Each patient was age- and sex-matched with two non-diabetic patients who received living donor KT during the same period. The outcomes of living donor KT were compared between diabetic and non-diabetic patients. RESULTS Among 887 patients, 89 diabetic patients were compared with 178 non-diabetic patients. The incidence of acute rejection was not different between the diabetic and non-diabetic patients. Urinary tract infection and other infections as well as cardiovascular events occurred more frequently in diabetic patients. However, diabetes, cardiovascular disease, and infection were not significant risk factors of graft failure. Late rejection (acute rejection after 1 year of transplantation) was the most important risk factor for graft failure after adjusting for diabetes mellitus (DM), human leukocyte antigen mismatch, rejection and infection (hazard ratio, 56.082; 95% confidence interval, 7.169 to 438.702; p < 0.001). Mortality was not significantly different between diabetic and non-diabetic patients (0 vs. 2, p = 0.344 by log-rank test). CONCLUSIONS End-stage renal disease patients with DM had favorable outcomes with living donor kidney transplantation.