Evaluating anti-thymocyte globulin induction doses for better allograft and patient survival in Asian kidney transplant recipients.

Anti-thymocyte globulin (ATG) is currently the most widely prescribed induction regimen for preventing acute rejection after solid organ transplantation. However, the optimal dose of ATG induction regimen in Asian kidney recipients is unclear. Using the Korean Organ Transplantation Registry, we performed a retrospective cohort study of 4579 adult patients who received renal transplantation in South Korea and divided them into three groups according to the induction regimen: basiliximab group (n = 3655), low-dose ATG group (≤ 4.5 mg/kg; n = 467), and high-dose ATG group (> 4.5 mg/kg; n = 457). We applied the Toolkit for Weighting and Analysis of Nonequivalent Groups (TWANG) package to generate high-quality propensity score weights for intergroup comparisons. During four-year follow-ups, the high-dose ATG group had the highest biopsy-proven acute rejection rate (basiliximab 20.8% vs. low-dose ATG 22.4% vs. high-dose ATG 25.6%; P < 0.001). However, the rates of overall graft failure (4.0% vs. 5.0% vs. 2.6%; P < 0.001) and mortality (1.7% vs. 2.8% vs. 1.0%; P < 0.001) were the lowest in the high-dose ATG group. Our results show that high-dose ATG induction (> 4.5 mg/kg) was superior to basiliximab and low-dose ATG induction in terms of graft and patient survival in Asian patients undergoing kidney transplant.

A prospective, randomized, non-blinded, non-inferiority pilot study to assess the effect of low-dose anti-thymocyte globulin with low-dose tacrolimus and early steroid withdrawal on clinical outcomes in non-sensitized living-donor kidney recipients.

BACKGROUND: The optimal dose of anti-thymocyte globulin (ATG) as an induction regimen in Asian living-donor kidney recipients is unclear. METHODS: This is a pilot study in which 36 consecutive patients undergoing living-donor kidney transplantation were randomly assigned to receive either 4.5 mg/kg (n = 19) or 6.0 mg/kg (n = 17) of ATG; all patients had corticosteroid withdrawal within 7 days. The primary end point was a composite of biopsy-proven acute rejection, de novo donor-specific antibody formation, and graft failure. RESULTS: At 12 months post-transplant, biopsy-proven acute rejection was more common in the ATG4.5 group (21.1%) than in the ATG6.0 group (0%)(P = .048). Importantly, the rate of the composite end point was significantly higher in the ATG4.5 group (36.8% vs 0%)(P = .006). There were significant differences in neither the renal function nor adverse events between the two groups. One case of death-censored graft failure occurred in the ATG4.5 group and no mortality was observed overall. Compared with pre-transplantation, T cells, natural killer (NK) cells, and natural killer T (NKT) cells were significantly decreased in the first week post-transplantation except for B cells. Although T and NKT cells in both groups and NK cells in the ATG4.5 group had recovered to the pre-transplant levels, NK cells in the ATG6.0 group remained suppressed until six months post-transplant. CONCLUSIONS: Compared with ATG 6.0 mg/kg, ATG 4.5 mg/kg with early corticosteroid withdrawal and low dose maintenance regimen was associated with higher rates of acute rejection in non-sensitized Asian living-donor kidney recipients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02447822.

Urinary Exosomal Cystatin C and Lipopolysaccharide Binding Protein as Biomarkers for Antibody-Mediated Rejection after Kidney Transplantation.

We aimed to discover and validate urinary exosomal proteins as biomarkers for antibody-mediated rejection (ABMR) after kidney transplantation. Urine and for-cause biopsy samples from kidney transplant recipients were collected and categorized into the discovery cohort (n = 36) and a validation cohort (n = 65). Exosomes were isolated by stepwise ultra-centrifugation for proteomic analysis to discover biomarker candidates for ABMR (n = 12). Of 1820 exosomal proteins in the discovery cohort, four proteins were specifically associated with ABMR: cystatin C (CST3), serum paraoxonase/arylesterase 1, retinol-binding protein 4, and lipopolysaccharide-binding protein (LBP). In the validation cohort, the level of urinary exosomal LBP was significantly higher in the ABMR group (n = 25) compared with the T-cell-mediated rejection (TCMR) group and the no major abnormality (NOMOA) group. Urinary exosomal CST3 level was significantly higher in the ABMR group compared with the control and NOMOA groups. Immunohistochemical staining showed that LBP and CST3 in the glomerulus were more abundant in the ABMR group compared with other groups. The combined prediction probability of urinary exosomal LBP and CST3 was significantly correlated with summed LBP and CST3 intensity scores in the glomerulus and peritubular capillary as well as Banff g + ptc scores. Urinary exosomal CST3 and LBP could be potent biomarkers for ABMR after kidney transplantation.

Hepatocellular carcinoma and cancer-related mortality after kidney transplantation with rituximab treatment.

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.

Beneficial effects of posttransplant dipeptidyl peptidase-4 inhibitor administration after pancreas transplantation to improve ß cell function.

PURPOSE: Dipeptidyl peptidase-4 (DPP-4) inhibitors lower blood glucose levels and enhance the function of pancreatic ß cells. Yet, it is unknown whether posttransplant administration of DPP4 inhibitors is beneficial for pancreas transplant recipients. METHODS: We thus retrospectively analyzed the records of 312 patients who underwent pancreas transplantation between 2000 and 2018 at Asan Medical Center (Seoul, Korea) and compared the metabolic and survival outcomes according to DPP-4 inhibitor treatment. RESULTS: The patients were divided into the no DPP-4 inhibitor group (n = 165; no treatment with DPP-4 inhibitors or treated for <1 month) and the DPP-4 inhibitor group (n = 147; treated with DPP-4 inhibitors for ≥1 month). There were no significant differences in levels of glucose, hemoglobin A1c, and insulin between the 2 groups during 36 months of follow-up. However, the level of C-peptide was significantly higher in the DPP-4 inhibitor group at 1, 6, and 24 months posttransplant (all P < 0.05). Moreover, the DPP-4 inhibitor group had significantly higher rates of overall (log-rank test, P = 0.009) and death-censored (log-rank test, P = 0.036) graft survival during a 15-year follow-up. CONCLUSION: Posttransplant DPP-4 inhibitor administration may help improve the clinical outcomes including ß cell function after pancreas transplantation.

Pure T-cell mediated rejection following kidney transplant according to response to treatment.

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.

Robot-assisted Kidney Transplantation.

This paper describes robot-assisted kidney transplantation (RAKT) from a living donor. The robot is docked between the parted legs of the patient, placed in the supine Trendelenburg position. Kidney allografts are provided by a living donor. Before vascular anastomosis, the kidney allograft is prepared by inserting a double-J stent in the ureter, and the temperature for the anastomosis is lowered by wrapping it in an ice-packed gauze. A 12 mm or 8 mm port for the robotic camera and three 8 mm ports for robotic arms are placed. A peritoneal pouch is created for the kidney allograft by raising the peritoneal flaps on both sides over the psoas muscle before dissecting the iliac vessels and bladder. A 6 cm Pfannenstiel incision is made to insert the kidney into the peritoneal pouch, lateral to the right iliac vessels. After clamping the external iliac vein with Bulldogs clamps, a venotomy is performed, and the graft renal vein is anastomosed to the external iliac vein in an end-to-side continuous manner with a 6/0 polytetrafluoroethylene suture. After clamping the graft renal vein, the iliac vein is declamped. This is followed by clamping of the external iliac artery, arteriotomy, arterial anastomosis with a 6/0 polytetrafluoroethylene suture, clamping of the graft renal artery, and declamping of the external iliac artery. Reperfusion is then carried out, and ureteroneocystostomy is performed using the Lich-Gregoir technique. The peritoneum is closed at a few locations with polymer locking clips, and a closed-suction drain is placed through one of the working ports. After deflating the pneumoperitoneum, all incisions are closed.

Lack of Improvement in Insulin Sensitivity After Pancreas Transplantation in Recipients With a High Level of Calcineurin Inhibitors.

OBJECTIVES: This study aimed to assess posttransplant changes in insulin sensitivity and ß-cell function of pancreas transplant recipients according to the type of diabetes mellitus (DM) and the pretransplant insulin sensitivity measured by the Matsuda Index (MI). METHODS: We analyzed 60 patients who underwent pancreas transplantation and oral glucose tolerance test pretransplant and at 1 month posttransplant. RESULTS: At 1 month posttransplant, insulin sensitivity did not show significant improvement; particularly, the MI was significantly lower after transplant in recipients with type 1 DM (T1DM) and those with pretransplant MI of 5 or greater. ß-cell function was significantly improved after transplant in all recipients regardless of the type of DM and pretransplant MI values. Glucose control was significantly improved in recipients with T1DM and in all recipients regardless of the pretransplant MI values. Additional oral glucose tolerance test at 1 year posttransplant revealed that insulin sensitivity remained unimproved and ß-cell function was higher compared with pretransplant. Glucose control had partially reverted to pretransplant levels in recipients with T1DM and those with pretransplant MI of 5 or greater. CONCLUSIONS: Unlike ß-cell function and glucose control, insulin sensitivity did not significantly improve until posttransplant 1 year after pancreas transplantation regardless of the type of DM or the degree of pretransplant insulin sensitivity.

Islet isograft transplantation improves insulin sensitivity in a murine model of type 2 diabetes.

PURPOSE: Type 2 diabetes develops in the presence of chronic overnutrition and genetic susceptibility, and causes insulin resistance and relative insulin deficiency. We hypothesized that islet transplantation can improve insulin sensitivity by modifying the mediators of insulin sensitivity in the pancreas, liver, muscle, and adipose tissues. METHODS: Eight-week-old male mice were used as both recipients and donors in this study. To induce type 2 diabetes with partial ß-cell failure, the mice were fed a high-fat diet for 4 weeks and then injected with low-dose streptozotocin. Approximately 400 islet cells from a donor mouse were injected into the renal capsule of a recipient mouse for islet transplantation. After 6 weeks following transplantation, the mediators of insulin sensitivity in the pancreas, liver, muscle, and adipose tissues were quantitatively compared between islet-transplanted and non-transplanted groups. RESULTS: Intravenous glucose tolerance test showed that whereas the non-transplanted mice failed to show notable reductions in the glucose level, the islet-transplanted mice showed significant reductions in the serum glucose level to ~200 mg/dL at 6 weeks after islet transplantation. The islet-transplanted mice showed significantly higher Matsuda index and significantly lower HOMA-IR than did the non-transplanted mice, thus signifying improved insulin sensitivity. CONCLUSIONS: Islet transplantation resulted in improvements in multiple indices of insulin sensitivity in a murine model of type 2 diabetes. Islet transplantation may be utilized to improve insulin sensitivity in patients with type 2 diabetes.

Serum procalcitonin as a biomarker for differentiating between infectious and non-infectious fever after pancreas transplantation.

Laboratory biomarkers that can differentiate non-infectious fever from infectious fever after pancreas transplantation have yet to be discovered. Non-infectious fever was defined as the presence of fever (>38.3°C) in the absence of a documented clinical diagnosis of infection or a positive culture. Among 184 consecutive recipients, a total of 91 recipients developed fever within 1-month post-transplant, of whom 46 had infectious fever and 45 had non-infectious fever at our center between August 2014 and July 2019. The onset of fever was earlier in the non-infectious fever group (14.4 ± 3.7 post-transplant days) compared with the infectious fever group (16.5 ± 5.8 post-transplant days; p = .033). Multivariate analysis showed that serum procalcitonin at the peak of fever could significantly differentiate infectious fever from non-infectious fever (OR 53.378, 95% CI: 6.819-417.802, p < .001). The area under the curve for differentiating between the two groups was 0.853 (95% CI, 0.780-0.926) for procalcitonin and 0.667 (95% CI, 0.549-0.785) for CRP. The best cutoff values of serum procalcitonin and CRP were 0.405 ng/ml (sensitivity, 77.1%; specificity, 80.8%) and 7.355 mg/dl (sensitivity, 66.7%; specificity, 67.3%), respectively. Serum procalcitonin may be useful for differentiating non-infectious fever from infectious fever after pancreas transplantation.

Acute T cell-mediated rejection after administration of the BNT162b2 mRNA COVID-19 vaccine in a kidney transplant recipient: a case report.

The impact of the coronavirus disease 2019 (COVID-19) vaccination on humoral and cellular immunity in transplant recipients remains unknown. We report the case of a 78-year-old kidney transplant recipient who experienced acute T cell-mediated rejection after receiving the second dose of the BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech). She had no history of acute rejection throughout the 13 years after deceased donor kidney transplantation. Fifteen days after receiving the second dose of the BNT162b2 vaccine, the recipient visited our center with a mild headache and fever. Her serum creatinine level had increased from 0.61 to 4.95 mg/dL. Kidney allograft biopsy indicated acute T cell-mediated rejection (grade IB) with no pathologic evidence of antibody-mediated rejection. Anti-severe acute respiratory syndrome coronavirus 2 spike-immunoglobulin G and -immunoglobulin M measurements were weak positive and negative, respectively. Careful monitoring of kidney allograft function is vital for transplant recipients undergoing COVID-19 vaccination.

Outcomes of Living-Donor Kidney Transplantation in Female Recipients with Possible Pregnancy-Related Pre-Sensitization According to Donor Relationship.

BACKGROUND Given that pregnancy is an immune-sensitizing event, female kidney transplant recipients who receive allografts from their offspring or husbands may have a higher risk of rejection and graft failure due to pre-sensitization acquired during pregnancy or childbirth. We investigated the association between donor relatedness (i.e., offspring, husband, unrelated) and graft survival among female living-donor kidney transplant (LDKT) recipients with pregnancy histories. MATERIAL AND METHODS From January 2009 to January 2018, a total of 2060 LDKTs were performed at Asan Medical Center, Seoul, Korea. After excluding HLA-incompatible transplantation, re-transplantation, and those without a clear history of childbirth, 390 female recipients were included and categorized into group I (offspring-to-mother, n=175), group II (husband-to-wife, n=159), and group III (unrelated, n=56). The primary endpoint was biopsy-proven acute rejection (BPAR) and graft survival. We also evaluated delayed graft function (DGF), death-censored graft failure, and mortality. RESULTS Group I had the lowest number of HLA mismatches (p<0.001), and group II had the highest number of ABO-incompatible transplantations (p=0.005). At 5 years after transplant, graft survival and death-censored graft survival did not significantly differ among the 3 groups (graft survival: 96.0% vs. 95.5% vs. 93.3%, p=0.685; death-censored graft survival: 98.3% vs. 97.5% vs. 100%, p=0.732). Five-year BPAR-free survival showed no significant differences among the 3 groups (88.6 vs. 88.7 vs. 88.6%, p=0.842). Group II had the highest rate of clinical rejection (p=0.103) and DGF (p=0.174), but the difference was not statistically significant. CONCLUSIONS Female LDKT recipients with possible pregnancy-related pre-sensitization who received grafts from offspring or husbands did not show significantly worse clinical outcomes than those who received grafts from unrelated donors.

Acute Rejection and Infectious Complications in ABO- and HLA-Incompatible Kidney Transplantations.

BACKGROUND Patients receiving ABO-incompatible (ABOi) or human leukocyte antigen (HLA)-incompatible (HLAi) kidney transplantation (KT) require potent immunosuppression and are thus at a higher risk of infectious complications. We evaluated the clinical outcomes of KT stratified by ABO and HLA incompatibilities and identified the factors associated with the clinical outcomes. MATERIAL AND METHODS Recipients who underwent living-related KT between 2012 and 2017 were included and classified into 4 groups: ABO-compatible and HLA-compatible (ABOc/HLAc), HLA-incompatible (ABOc/HLAi), ABO-incompatible (ABOi/HLAc), and ABO-incompatible and HLA-incompatible (ABOi/HLAi). Cox proportional hazards regression analyses were carried out to evaluate the risk factors of acute rejection. Out of the 1732 patients who underwent KT, 1190, 131, 358, and 53 were in the ABOc/HLAc, ABOi/HLAc, ABOc/HLAi, and ABOi/HLAi groups, respectively. RESULTS The ABO/HLAi group showed the lowest 5-year graft survival rate (91.7%). Death-censored graft survival was not significantly different among the groups. The mortality rate from infections was significantly higher in the ABOi/HLAi group (7.5%) than the other groups. Antibody-mediated rejection-free graft survival was the lowest in the ABOi/HLAi group, with significant differences compared with the ABOi/HLAc group (P=0.02) and the ABOc/HLAi group (P=0.03). ABOi/HLAi (hazard ratio [HR], 2.63; 95% confidence interval [CI], 1.04-6.65; P<0.01) and combined infection (HR, 1.91; 95% CI, 1.45-2.51; P<0.01) were significant risk factors for acute rejection. CONCLUSIONS Patients with both ABO and HLA incompatibilities showed inferior rates of overall patient and graft survival due to infectious complications. Infection was a prominent risk factor of acute rejection following KT after adjusting for possible confounders including ABO and HLA incompatibility.

The multiple brain abscesses associated with congenital pulmonary arteriovenous malformations: a case report.

In this report, we describe a case of multiple brain abscesses associated with diffuse congenital pulmonary arteriovenous malformations (PAVM). Although the cases of brain abscesses associated with congenital PAVM are very rare, the brain abscess could be an initial clinical manifestation in asymptomatic PAVM as in the case presented in this report. PAVM may contribute to the development of a brain abscess by allowing easy bacterial access to systemic circulation through the right-to-left pulmonary vascular shunt, bypassing the filtering effect of the pulmonary capillaries. Hence, this association should be considered in cases with brain abscesses of undetermined etiologic factors.

Expression of TNF-alpha and TGF-beta 1 in the rat brain after a single high-dose irradiation.

Cytokines and growth factors are important regulatory proteins controlling the growth and differentiation of normal and malignant glial cells. In this study, we investigated the expression and origin of tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta 1 (TGF-beta 1) in the subacute brain injury after a single high-dose irradiation using 60 Sprague-Dawley rats. The right cerebral hemispheres of rats were exposed to a single 10 Gy dose of gamma rays using Ir-192. The radiation effect was assessed at 1 week, 2 weeks, 4 weeks, 6 weeks, and 8 weeks after irradiation, and the results were compared with those in sham operation group. Histological changes characteristic of radiation injury were correlated with the duration after the single dose irradiation. The loss of cortical thickness also increased with the lapse of time after irradiation. The TNF-alpha expression in the irradiated cerebral hemispheres was significantly increased compared with that in the sham operation group. TGF-beta 1 expression was also increased in the irradiated hemispheres. Immunohistochemical study revealed that TGF-beta 1 was expressed predominantly by infiltrating macrophages and astrocytes around the necrotic areas. These findings indicate that TNF-alpha and TGF-beta 1 may play prominent roles in the radiation injuries after a single high-dose irradiation.