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Objectives: This study was designed to investigate the frequency of computed tomography features indicating progression of portal hypertension and their clinical relevance in patients who experienced acute cellular rejection after liver transplantation., Materials and Methods: This retrospective study included 141 patients with pathologically diagnosed acute cellular rejection following liver transplant. Patients were divided into early and late rejection groups according to the time of diagnosis. Two radiologists analyzed the interval changes in spleen size and variceal engorgement on computed tomography images obtained at the times of surgery and biopsy. Aggravation of splenomegaly and variceal engorgement were considered computed tomography features associated with the progression of portal hypertension. Clinical outcomes, including responses to treatment and graft survival, were compared between patients with and without these features., Results: The frequency of progression of portal hypertension was 31.9% and did not differ significantly in patients who experienced early (30.8% [28/91]) and late (34.0% [17/50]) rejection (P = .694). In the late rejection group, computed tomography features indicating progression of portal hypertension were significantly associated with poor response to treatment (P = .033). Graft survival in both the early and late rejection groups did not differ significantly in patients with and without progression of portal hypertension., Conclusions: Computed tomography features suggesting the progression of portal hypertension were encountered in about one-third of patients who experienced acute cellular rejection after liver transplant. Progression of portal hypertension was significantly related to poor response to treatment in the late rejection group.

Background: Obesity and dyslipidemia afflict children of all ages. We explored the prevalence of obesity and dyslipidemia in pediatric heart transplant (HT) recipients and its effects on cardiac allograft vasculopathy (CAV) and survival., Methods: This study included primary HT recipients (≤18 years) transplanted between 01/1996 and 12/2018 included in the Pediatric Heart Transplant Society database. Obesity was categorized according to WHO/CDC guidelines and dyslipidemia according to the National Cholesterol Education Program. Kaplan-Meier analyses for CAV and graft loss stratified for BMI and lipid panels were generated and risk factors identified using multivariate analyses., Results: Among 6291 HT patients (median age [range] at HT = 4.3 [0.6-12.8] years; 45% Female; 68% White), 56% had a normal BMI at HT. Obese patients at HT had an increased risk for graft loss (HR 1.19, 95% CI 1.01-1.4, p = .04). Poor total cholesterol (TC), LDL-C, and TG were associated with the risk of both CAV (HR 1.79, p < .0001; HR 1.65, p = .0015; HR 1.53, p < .0001, respectively) and graft loss (HR 1.58, p = .0008; HR 1.22, p = .04; HR 1.43, p = .0007, respectively)., Conclusions: Pediatric patients who are obese at the time of HT and dyslipidemic at 1 year post-HT are at an increased risk for CAV and graft loss. Preventative interventions may reduce morbidity and mortality among this cohort., (© 2022 Wiley Periodicals LLC.)

Chronic allograft dysfunction (CAD) is the major cause of late graft loss in long-term renal transplantation. In our previous study, we found that epithelial-mesenchymal transition (EMT) is a significant event in the progression of renal allograft tubulointerstitial fibrosis, and impaired autophagic flux plays a critical role in renal allograft fibrosis. Everolimus (EVR) has been reported to be widely used to prevent the progression of organ fibrosis and graft rejection. However, the pharmacological mechanism of EVR in kidney transplantation remains to be determined. We used CAD rat model and the human kidney 2 (HK2) cell line treated with tumor necrosis factor-α (TNF-α) and EVR to examine the role of EVR on TNF-α-induced EMT and transplanted renal interstitial fibrosis. Here, we found that EVR could attenuate the progression of EMT and renal allograft interstitial fibrosis, and also activate autophagy in vivo . To explore the mechanism behind it, we detected the relationship among EVR, autophagy level, and TNF-α-induced EMT in HK2 cells. Our results showed that autophagy was upregulated upon mTOR pathway inhibition by EVR, which could significantly reduce expression of TNF-α-induced EMT. However, the inhibition of EVR on TNF-α-induced EMT was partly reversed following the addition of autophagy inhibitor chloroquine. In addition, we found that TNF-α activated EMT through protein kinase B (Akt) as well as nuclear factor kappa B (NF-κB) pathway according to the RNA sequencing, and EVR's effect on the EMT was only associated with IκB-α stabilization instead of the Akt pathway. Together, our findings suggest that EVR may retard impaired autophagic flux and block NF-κB pathway activation, and thereby prevent progression of TNF-α-induced EMT and renal allograft interstitial fibrosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gui, Suo, Tao, Wang, Zheng, Fei, Chen, Sun, Han, Ju, Zhang, Gu and Tan.)

Background: Atypical Hemolytic Uremic Syndrome (aHUS) is an ultra-rare disease that potentially leads to kidney graft failure due to ongoing Thrombotic Microangiopathy (TMA). The aim was evaluating the frequency of TMA after kidney transplantation in patients with aHUS in a Brazilian cohort stratified by the use of the specific complement-inhibitor eculizumab., Methods: This was a multicenter retrospective cohort study including kidney transplant patients diagnosed with aHUS. We collected data from 118 transplant centers in Brazil concerning aHUS transplanted patients between 01/01/2007 and 12/31/2019. Patients were stratified into three groups: no use of eculizumab (No Eculizumab Group), use of eculizumab for treatment of after transplantation TMA (Therapeutic Group), and use of eculizumab for prophylaxis of aHUS recurrence (Prophylactic Group)., Results: Thirty-eight patients with aHUS who received kidney transplantation were enrolled in the study. Patients' mean age was 30 years (24-40), and the majority of participants was women (63% of cases). In the No Eculizumab Group (n = 11), there was a 91% graft loss due to the TMA. The hazard ratio of TMA graft loss was 0.07 [0.01-0.55], p = 0.012 in the eculizumab Prophylactic Group and 0.04 [0.00-0.28], p = 0.002 in the eculizumab Therapeutic Group., Conclusion: The TMA graft loss in the absence of a specific complement-inhibitor was higher among the Brazilian cohort of kidney transplant patients. This finding reinforces the need of eculizumab use for treatment of aHUS kidney transplant patients. Cost optimization analysis and the early access to C5 inhibitors are suggested, especially in low-medium income countries., Competing Interests: I declared that the authors Modelli de Andrade LG, Palma LM, and Miranda SMC received fees from Alexion pharmaceutical to Travel grants and honoraria for speaking and participation at meetings. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The present COVID-19 pandemic is a cause for concern among solid-organ transplant recipients, who are generally at high risk for infection and for whom infection with COVID-19 carries additional risks for complications and mortality that are higher than the COVID-19-associated risks for the general population. We report the case of a liver transplant recipient who presented with COVID-19 and multiple complications. A 39-year-old woman with a liver transplant was diagnosed with COVID-19 within the first week after transplant surgery. Mycophenolate was withheld, and interferon β was administered for management of COVID-19. She developed thrombotic thrombocytopenic purpura, acute antibody-mediated rejection, and posterior reversible leukoencephalopathy syndrome during hospitalization. All of these complications may be related to COVID-19 or its management modalities. We considered 3 possible causes for thrombotic thrombocytopenic purpura in this patient: the COVID-19 infection itself, immunosuppression treatment with cyclosporine, and treatment with interferon β. Immunosuppression reduction and interferon treatment may result in antibody-mediated rejection. COVID-19, thrombotic thrombocytopenic purpura, and cyclosporine may play a combined role in the development of posterior reversible leukoencephalopathy syndrome. In conclusion, thrombotic thrombocytopenic purpura, antibody-mediated rejection, and posterior reversible leukoencephalopathy syndrome may represent a continuum of 3 thrombotic microangiopathy conditions fostered by interplay between the COVID-19 infection and the treatment modalities for COVID-19 management in this patient.

Background: Hyponatremia is one of the most common electrolyte disorders observed in hospitalized and ambulatory patients. Hyponatremia is associated with increased falls, fractures, prolonged hospitalisation and mortality. The clinical importance of hyponatremia in the renal transplant field is not well established, so the aim of this study was to determine the relationships between hyponatremia and mortality as main outcome and renal function decline and graft loss as secondary outcome among a prospective cohort of renal transplant recipients., Methods: This prospective cohort study included 1315 patients between 1 May 2008 and 31 December 2014. Hyponatremia was defined as sodium concentration below 136 mmol/L at 6 months after transplantation. The main endpoint was mortality. A secondary composite endpoint was also defined as: rapid decline in renal function (≥5 mL/min/1.73 m 2 drop of the eGFR/year), graft loss or mortality., Results: Mean sodium was 140 ± 3.08 mmol/L. 97 patients displayed hyponatremia with a mean of 132.9 ± 3.05 mmol/L. Hyponatremia at 6 months after transplantation was associated neither with mortality (HR: 1.02; p = 0.97, 95% CI: 0.47-2.19), nor with the composite outcome defined as rapid decline in renal function, graft loss or mortality (logrank test p = 0.9)., Conclusions: Hyponatremia 6 months after transplantation is not associated with mortality in kidney allograft patients.

Competing Interests: The authors report no conflicts of interest.

Breakthrough cytomegalovirus (CMV) disease during valganciclovir prophylaxis is rare but may cause significant morbidity and even mortality. In order to identify patients at increased risk the incidence of CMV disease was studied in a large population of renal transplant recipients who underwent a kidney transplantation in the Radboud University Medical Center between 2004 and 2015 (n = 1300). CMV disease occurred in 31/1300 patients. Multivariate binary linear regression analysis showed that delayed graft function (DGF) (p = 0.018) and rejection (p = 0.001) significantly and independently increased the risk of CMV disease, whereas CMV status did not. Valganciclovir prophylaxis was prescribed to 281/1300 (21.6%) high-risk patients (defined as CMV IgG-seronegative recipients receiving a kidney from a CMV IgG-seropositive donor (D+/R-)). Of these 281 patients, 51 suffered from DGF (18%). The incidence of breakthrough CMV disease in D + /R- patients with DGF was much higher than in those with immediate function (6/51 (11.8%) vs 2/230, (0.9%), p = 0.0006 Fisher's exact test), despite valganciclovir prophylaxis. This higher incidence of CMV disease could not be explained by a higher incidence of rejection (and associated anti-rejection treatment) in patients with DGF. D + /R- patients with DGF are at increased risk of developing CMV disease despite valganciclovir prophylaxis. These findings suggest that underexposure to ganciclovir occurs in patients with DGF. Prospective studies evaluating the added value of therapeutic drug monitoring to achieve target ganciclovir concentrations in patients with DGF are needed., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Central airway stenosis (CAS) is a severe airway complication after lung transplantation associated with bronchial ischemia and necrosis. We sought to determine whether hyperbaric oxygen therapy (HBOT), an established treatment for tissue ischemia, attenuates post-transplant bronchial injury., Methods: We performed a randomized, controlled trial comparing usual care with HBOT (2 atm absolute for 2 hours × 20 sessions) in subjects with extensive airway necrosis 4 weeks after transplantation. Endobronchial biopsies were collected at 4, 7, and 10 weeks after transplantation for a quantitative polymerase chain reaction. Coprimary outcomes were incidence of airway stenting and acute cellular rejection (ACR) at 1 year., Results: The trial was stopped after enrolling 20 subjects (n = 10 per group) after a pre-planned interim analysis showed no difference between usual care and HBOT groups in stenting (both 40%), ACR (70% and 40%, respectively), or CAS (40% and 60%, respectively). Time to first stent placement (median [interquartile range]) was significantly shorter in the HBOT group (150 [73-150] vs 186 [167-206] days, p < 0.05). HIF gene expression was significantly increased in donor tissues at 4, 7, and 10 weeks after transplantation but was not altered by HBOT. Subjects who developed CAS or required stenting had significantly higher HMOX1 and VEGFA expression at 4 weeks (both p < 0.05). Subjects who developed ACR had significant FLT1, TIE2, and KDR expression at 4 weeks (all p < 0.05)., Conclusions: Incidence of CAS is high after severe, established airway necrosis after transplantation. HBOT does not reduce CAS severity or stenting. Elevated HMOX1 and VEGFA expressions appear to associate with airway complications., (Published by Elsevier Inc.)

Foxp3 stability of vitamin C-treated induced-regulatory T cells (V-iTregs) is superior to that of conventional iTregs (C-iTregs). However, the role of V-iTregs in allograft rejection under vitamin C-deficient conditions, such as those seen in humans, remains unclear. We aimed to elucidate the role of vitamin C treatment on generation and maintenance of iTregs from gulo knockout (Gulo-KO) mice as well as wild type (WT) mice, and in vitro and in vivo suppressive effects of V-iTregs on heart allograft rejection in either Gulo-KO or WT recipient mice. Conversion efficiency of iTregs was similar between C- and V-iTregs in both WT and Gulo-KO mice. V-iTregs from WT or Gulo-KO mice showed better in vitro Foxp3 stability than C-iTregs, although there was no difference between WT V-iTregs and Gulo-KO V-iTregs. Furthermore, V-iTregs from WT or Gulo-KO mice suppressed in vitro T cell proliferation better than C-iTregs. Heterotrophic heart transplantation from BALB/c mice to WT or vitamin C-deficient Gulo-KO C57BL/6J mice was performed following adoptive transfer of C- or V-iTregs. V-iTregs as well as C-iTregs prolonged heart allograft survival in WT and Gulo-KO mice. However, there was no difference between the C- and V-iTreg groups. Supplementation of low- or high-dose vitamin C did not induce significant changes in heart allograft survival in Gulo-KO recipients that had received V-iTregs. In conclusion, V-iTregs do not exert better suppressive effects on heart allograft survival than C-iTregs in either WT or vitamin C-deficient recipients., Competing Interests: The authors have declared that no competing interests exist.

Background: This study aimed to determine the risk factors associated with cardiac events 1 year after transplant in kidney transplant recipients (KTRs)., Material and Methods: We analyzed the incidence of cardiac events in all KTRs transplanted at our center between 01/2000 and 12/2016, who had non-obstructive cardiac catheterization findings at their pre-transplant evaluation., Results: We identified 141 patients with non-obstructive pre-transplant cardiac catheterization. 83 patients (59%) had cardiac events 1 year after the kidney transplant during a mean follow-up of 7.3 ± 5.3 years. Multivariate Cox regression analysis determined dialysis ≥ 1 year (HR = 2.27, 95% Cl 1.41 - 3.67, p = 0.001), body mass index (BMI) ≥ 35 kg/m 2 at time of transplant (HR = 2.24, 95% Cl 1.43 - 3.52, p = 0.0004), tacrolimus trough ≥ 7 ng/mL at 1 year post-transplant (HR = 4.24, 95% Cl 1.95 - 9.22, p = 0.0003), and HBA1-c ≥ 7% at 1 year post-transplant (HR = 1.71, 95% Cl 1.09 - 2.70, p = 0.02) as significant predictors of cardiac events 1 year post-transplant. In unadjusted Kaplan-Meier analysis, any cardiac event post-transplant was associated with a significant risk of death or graft loss (p = 0.02)., Conclusion: Dialysis duration, morbid obesity, diabetes control, and tacrolimus levels may represent modifiable risk factors to reduce cardiac events in kidney transplant recipients with non-obstructive cardiac catheterization findings at the time of transplant.

Background: Kidney graft recipients receiving immunosuppressive therapy may be at heightened risk for coronavirus disease 2019 (Covid-19) and adverse outcomes. It is therefore important to characterize the clinical course and outcome of Covid-19 in this population and identify safe therapeutic strategies., Methods: We performed a retrospective chart review of 73 adult kidney graft recipients evaluated for Covid-19 from 13 March to 20 April 2020. Primary outcomes included recovery from symptoms, acute kidney injury, graft failure and case fatality rate., Results: Of the 73 patients screened, 54 tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-39 with moderate to severe symptoms requiring hospital admission and 15 with mild symptoms managed in the ambulatory setting. Hospitalized patients were more likely to be male, of Hispanic ethnicity and to have cardiovascular disease. In the hospitalized group, tacrolimus dosage was reduced in 46% of patients and mycophenolate mofetil (MMF) therapy was stopped in 61% of patients. None of the ambulatory patients had tacrolimus reduction or discontinuation of MMF. Azithromycin or doxycycline was prescribed at a similar rate among hospitalized and ambulatory patients (38% versus 40%). Hydroxychloroquine was prescribed in 79% of hospitalized patients. Graft failure requiring hemodialysis occurred in 3 of 39 hospitalized patients (8%) and 7 patients died, resulting in a case fatality rate of 13% among Covid-19-positive patients and 18% among hospitalized Covid-19-positive patients., Conclusions: Data from our study suggest that a strategy of systematic triage to outpatient or inpatient care, early management of concurrent bacterial infections and judicious adjustment of immunosuppressive drugs rather than cessation is feasible in kidney transplant recipients with Covid-19., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Chronic renal disease (CKD) jeopardizes the long-term outcomes of liver transplant recipients. In patients with end-stage liver graft disease and CKD, liver retransplantation associated with kidney transplantation (ReLT-KT) might be necessary. Yet, this specific subset of patients remains poorly described., Methods: Indications, perioperative characteristics, and short- and long-term outcomes of patients undergoing ReLT-KT at 2 transplantation units from 1994 to 2012 were analyzed. Risk factors for postoperative mortality and long-term survivals were evaluated., Results: Among 3060 patients undergoing liver transplantation (LT), 45 (1.5%) underwent ReLT-KT. The proportion of ReLT-KT among LT recipients continuously grew throughout the study period from 0.3% to 2.4% (P < 0.001). Median time from primary LT to ReLT-KT was 151.3 (7.5-282.9) months. The most frequent indications for liver retransplantation were recurrence of the primary liver disease and cholangitis in 15 (33.3%) cases each. CKD was related to calcineurin inhibitors toxicity in 38 (84.4%) cases. Twelve (26.7%) patients died postoperatively. D-MELD (donor age × recipients' MELD) was associated with postoperative mortality (HR: 8.027; 95% CI: 2.387-18.223; P = 0.026) and optimal cut-off value was 1039 (AUC: 0.801; P = 0.002). Overall 1, 3, and 5 years survivals were 68.8%, 65.9%, and 59.5%, respectively. D-MELD > 1039 was the only factor associated with poor survival (P = 0.021)., Conclusions: ReLT-KT is a highly morbid increasingly performed procedure. Refinements in the selection of grafts and transplant candidates are required to limit the postoperative mortality of these patients.

Background: Autoimmune liver disease (ALD) is a chronic liver disease caused by immune dysfunction in the body. However, no causative or curative medical treatment with proven efficacy exists to cure ALDs, and liver transplantation (LT) remains the only effective treatment available. However, the problem of recurrence of ALDs (rALDs) still remains after LT, which seriously affects the survival rate of the patients. Therefore, clinicians need to be aware of the risk factors affecting rALDs after LT. Therefore, this meta-analysis aims to define the risk factors for rALDs, which include the recurrence of primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis., Methods: A systematic search in Pubmed, Embase, Cochrane library and Web of Science databases was performed from 1980 to 2019. The inclusion criteria were risk factors for developing rALDs after LT. However, case series, case reports, reviews, meta-analysis and studies only including human immunodeficiency virus cases, children, and pregnant patients were excluded., Results: The electronic database search yielded 1728 results. Sixty-three retrospective cohort studies met the inclusion criteria and 13 were included in the meta-analysis. The final cohort included 5077 patients, and among them, 21.96% developed rALDs. Colectomy before LT, HR 0.59 (95% confidence interval [CI]: 0.37-0.96), cholangiocarcinoma, HR 3.42 (95% CI: 1.88-6.21), multiple episodes of acute cellular rejection, HR 2.07 (95% CI: 1.27-3.37), model for end-stage liver disease score, HR 1.05 (95% CI: 1.02-1.08), use of mycophenolate mofetil, HR 1.46 (95% CI: 1.00-2.12) and the use of cyclosporin A, HR 0.69 (95% CI: 0.49-0.97) were associated with the risk of rprimary sclerosing cholangitis. In addition, the use of tacrolimus, HR 1.73 (95% CI: 1.00-2.99) and cyclosporin A, HR 0.59 (95% CI: 0.39-0.88) were associated with the risk of rALD., Conclusions: Multiple risk factors for rALDs were identified, such as colectomy before LT, cholangiocacinoma, multiple episodes of acute cellular rejection, model for end-stage liver disease score, and especially the use of mycophenolate mofetil, cyclosporin A and tacrolimus.

Background: Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by systemic thrombotic microangiopathy (TMA) reflected by hemolysis, anemia, thrombocytopenia and systemic organ injury. The optimal management of aHUS-patients when undergoing kidney transplantation to prevent recurrence in the allograft is eculizumab, an approved recombinant antibody targeting human complement component C5., Case Presentation: A 39 year-old woman presented with severe abdominal pain, diarrhea and emesis for 3 days. In her past medical history she had experienced an episode of aHUS leading to end stage renal disease (ESRD) in 2007 and a genetic workup revealed a heterozygous mutation in the membrane cofactor protein gene. In 2014 she underwent cadaveric kidney transplantation. Four years later she had to go back on hemodialysis due to allograft failure following a severe systemic cytomegalovirus infection resulting in transplant failure. At presentation she still received calcineurin-inhibitor therapy and reported subfebrile temperatures and pain projecting over the transplant prior to the current symptoms. A contrast enhanced CT-scan of the abdomen revealed inflammatory wall thickening of the small intestine. Diagnostic endoscopy discovered fresh blood in the small intestine without a clear source of bleeding. Histopathology of the small intestine biopsies showed severe thrombotic microangiopathy. Of note, the patient persistently had no signs of systemic hemolysis. Since the TMA of the small intestine was most likely due to aHUS, eculizumab treatment was initiated which abolished the symptoms., Conclusion: Here we report a patient with thrombotic microangiopathy with predominant manifestation in a single organ, the small intestine, due to aHUS with absence of systemic signs and symptoms. aHUS patients usually require a secondary trigger for the disease to manifest. In this case, the trigger may be attributed to the dysfunctional renal transplant, which was subsequently explanted. Histology of the explanted kidney showed severe inflammation due to purulent nephritis and signs of cellular rejection. After nephrectomy, we continued eculizumab therapy until the patient completely recovered. No signs of TMA recurred after discontinuation of eculizumab, further supporting the concept of the renal transplant as the main trigger of TMA of the small intestine in our patient.

Background: Information on the risk factors, particularly kidney function, and impact of long-term cardiovascular events (CVE) after liver transplantation (LT) remains scarce., Methods: This is a retrospective, single-center study that included consecutive LT recipients between 2007 and 2017. The incidence of CVE, their risk factors, and their impact on patient survival were investigated., Results: We included 627 LT recipients. The incidence of CVE was 8% and 20% at 12 and 60 months after LT, respectively. The independent risk factors of long-term (beyond 12 mo) CVE were age at LT (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.01-1.07), male gender (HR, 2.48; 95% CI, 1.21-5.05), history of pre-LT cardiovascular disease (HR, 2.19; 95% CI, 1.2-3.98), and immunosuppression with cyclosporine A (HR, 1.93; 95% CI, 1.14-3.3). In patients with pre-LT cardiovascular disease, creatinine levels 12 months after LT significantly impacted the risk of long-term CVE. Long-term CVE (HR, 2.12; 95% CI, 1.24-3.61), hepatitis C as the etiology of liver disease (HR, 2.18; 95% CI, 1.29-3.67), cytomegalovirus infection (HR, 1.89; 95% CI, 1.08-3.3), and donor age (HR, 1.02; 95% CI, 1.01-1.04) were independent factors associated with post-LT patient death., Conclusions: Age, male gender, cardiovascular disease before LT, and cyclosporine A were associated with the risk of long-term CVE. The impact of serum creatinine was restricted to patients with pre-LT cardiovascular disease. In these patients, preservation of kidney function early after LT may lessen the incidence of CVE, which are an independent predictor of post-LT death.

This retrospective study analyzed glycemic trends, incidence of post-transplant diabetes mellitus (PTDM) incidence and associated risk factors in a cohort of patients who underwent first-time heart transplantation (HT). Univariate analyses compared patient with and without pretransplant diabetes mellitus (DM). Multivariate regression analyses were conducted to determine association between PTDM and different risk factors. Finally, trends in glucometrics and other outcomes are described across follow-up time points. There were 152 patients who underwent HT between 2010 and 2015, 109 of whom had no pretransplant history of DM. PTDM incidence was 38% by the 1-year follow-up. Pretransplant body mass index (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.01 to 1.23, p = 0.03), insulin use during the final 24 hours of inpatient stay (OR 4.26, 95% CI 1.72 to 10.56, p <0.01), mean inpatient glucose (OR 2.21, 95% CI 1.33 to 3.69, p <0.01), and mean glucose in the final 24 hours before discharge (OR 1.29, 95% CI 1.03 to 1.60, p = 0.03) were associated with increased odds of PTDM at 1 year. In patients on insulin before discharge, blood glucose values were significantly higher compared with those who were not (136 mg/dl vs 114 mg/dl at 1 to 3 months, 112 vs 100 at 4 to 6 months, 109 vs 98 at 8 to 12 months, all p <0.01). This analysis improves understanding of PTDM incidence, glucometric trends, and risk differences by DM status in the HT population. Similar to liver and kidney patients, inpatient glucometrics may be informative of PTDM risk in HT patients. Guidelines for this population should be developed to account for risk heterogeneity and need for differential management., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Brazil ranks second in the absolute number of transplantations in the world. Despite improvements in graft survival, many patients will progress to graft loss and return to dialysis. Concerns exist regarding adverse clinical outcomes in this population when undergone peritoneal dialysis (PD)., Objective: To compare the occurrence of mortality, technique failure, and peritonitis among incident patients in PD coming from either Tx or pre-dialysis treatment., Methodology: A retrospective study in which 47 adult patients with Tx failure (Tx group) were matched for age, gender, diabetes mellitus (DM), modality and start year of PD, with 1:1 predialysis patient (nTx group). The Fine-Gray competing risk model was used to analyze mortality and technique failure., Results: Compared to nTx, the Tx group had a lower body mass index, serum potassium, and albumin concentrations. A higher ferritin level, transferrin saturation and the number of patients with positive serology for viral hepatitis were also observed in the Tx group. In the multivariate analysis, patients of the Tx group had 4.4-times higher risk of death (p = 0.007), with infection as the main cause. Technique failure and peritonitis were similar in both groups., Conclusion: Previous Tx is a risk factor for mortality but not for technique failure or peritonitis in incident patients on a PD program., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Thrombotic microangiopathy (TMA) in post-transplant setting has heterogeneous clinical manifestations., Methods: We retrospectively studied data of 89 patients with post-transplant TMA, which was characterized by thrombi in at least one glomerulus and/or arteriole. Systemic TMA was defined by thrombocytopenia and microangiopathic anemia and early onset TMA, when occurred less than 90 days post transplant., Results: The cumulative incidence was 0.93%. The majority of the recipients were young (mean age 39 years), female (52%) and Caucasian (48%) with primary kidney disease of unknown etiology (37%). Early TMA occurred in 51% of the patients and systemic TMA, in 25%. Underlying precipitating factors were: infection (54%), acute rejection (34%), calcineurin inhibitor toxicity (13%) and pregnancy (3%). 18% of the patients had several triggers. Glomerular TMA was observed in 50% of the biopsies and endothelial cell activation, in 61%. The 1-year patient survival was 97% and corresponding graft survival, 66%. Allograft survival was inferior when acute antibody mediated rejection (ABMR) occurred (with 41%; without 70%, p = 0.01), however no differences were determined by hemolysis, time of onset, thrombi location or endothelial cell activation., Conclusions: Our results suggest that post-transplant TMA is a rare but severe condition, regardless of its clinical and histological presentation, mainly when associated to ABMR., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Dr. HTS reports grants and personal fees from NOVARTIS, grants and personal fees from PFIZER, grants and personal fees from SANOFI and grants from QUARK, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All the other authors declared no relevant competing interests.

Background: Two or more early rejections (<1 y) or any late acute rejection (>1 y) have been associated with coronary artery vasculopathy (CAV) in pediatric heart transplant (HT) recipients. We hypothesized that clinical rejection defined by concurrent new-onset heart failure or left ventricular systolic dysfunction is more strongly associated with future CAV than rejection diagnosed on protocol biopsy., Methods: We identified all subjects <21 years old who received first HT at Boston Children's Hospital during 1986-2015 with at least 1 post-HT coronary angiogram. CAV was diagnosed using 2010 International Society for Heart and Lung Transplantation guidelines. Time to CAV diagnosis was assessed using a Cox model with occurrence of clinical rejection analyzed as a time-varying covariate., Results: Of 228 study subjects, 106 remained rejection-free, 77 had rejection diagnosed only on protocol biopsy (≥2R cellular or antibody-mediated), and 45 had a clinical rejection. Subjects with rejection diagnosed only on protocol biopsy were not at higher risk of CAV (hazard ratio [HR] 1.09, 95% confidence interval [CI]: 0.54-2.09). In contrast, clinical rejection was significantly associated with risk of CAV (HR 4.84, 95% CI: 2.99-7.83). Late rejection was associated with a higher risk of CAV (HR 4.27, 95% CI: 2.42-7.51) if it was clinical rejection but not if it was diagnosed on protocol biopsy (HR 0.83, 95% CI: 0.51-1.37)., Conclusions: Clinical rejection poses a far greater risk for future CAV than rejection on protocol biopsy in pediatric HT recipients. Preventing CAV should therefore become the focus of medical management after initial treatment and resolution of clinical rejection.

Background: Diabetes mellitus (DM) is said to adversely affect transplant outcomes. The aim of this study was to investigate the impact of pre-existing and new-onset DM on liver transplantation (LT) recipients., Methods: A single-center retrospective analysis of prospectively collected data of LT recipients (1990-2015) was undertaken., Results: Of the 2209 patients, 13% (n = 298) had Pre-DM, 16% (n = 362) developed post-transplant diabetes mellitus (PTDM), 5% (n = 118) developed transient hyperglycemia (t-HG) post-LT, and 65% (n = 1431) never developed DM (no DM). Baseline clinical characteristics of patients with PTDM were similar to that of patients with Pre-DM. Incidence of PTDM peaked during the first year (87%) and plateaued thereafter. On multivariate analysis (Bonferroni-corrected), nonalcoholic fatty liver disease and the use of tacrolimus and sirolimus were independently associated with PTDM development. Both Pre-DM and PTDM patients had satisfactory and comparable glycemic control throughout the follow-up period. Those who developed t-HG seem to have a unique characteristic compared with others. Overall, 9%, 5%, and 8% of patients developed end-stage renal disease (ESRD), major cardiovascular event (mCVE), and de novo cancer, respectively. Both Pre-DM and PTDM did not adversely affect patient survival, retransplantation, or de novo cancer. The risks of ESRD and mCVE were significantly higher in patients with Pre-DM followed by PTDM and no DM., Conclusions: In this largest nonregistry study, patients with Pre-DM and PTDM share similar baseline clinical characteristics. Pre-DM increases the risk of ESRD and mCVE; however, patient survival was comparable to those with PTDM and without diabetes. Understanding the impact of PTDM would need prolonged follow-up.

The 2017 Banff meeting provided specific criteria for the diagnosis of tubulointerstitial changes in chronic active T cell-mediated rejection (CATCR), with an emphasis on inflammation in areas of interstitial fibrosis and tubular atrophy, which was thought to reflect an ongoing T cell-mediated alloimmunity. CATCR is considered to occur as a consequence of persistent or recurrent acute T cell-mediated rejection. Acute T cell-mediated rejection is an acute cytotoxic T-cell reaction to HLA antigens on the donor kidneys and causes tubulitis, interstitial inflammation, and intimal arteries. However, unlike early T-cell transplant damage, CATCR can sometimes be difficult to diagnose because the subsequent chronic T-cell damage can become more complex from the accumulation of previous immune and nonimmune injuries. Furthermore, scoring inflammation in areas of interstitial fibrosis and tubular atrophy has potential problems because other diseases and not even native kidneys can have scattered inflammatory cells. Therefore, detailed insights on the pathogenesis of CATCR are indispensable for appropriate diagnosis and further treatment. In this study, the pathologic characteristics and possible factors involved in the interstitial lesions in both typical and complex cases of CATCR are discussed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To describe a case of stromal rejection in a 46-year-old man after small incision lenticule extraction (SMILE) for the correction of residual astigmatism following deep anterior lamellar keratoplasty (DALK)., Methods: Case report., Results: Nine years after an uneventful DALK in the left eye, the patient (uncorrected distance visual acuity [UDVA] = 20/200, corrected distance visual acuity [CDVA] = 20/32, and refraction = -3.25 -4.25 × 165°) underwent SMILE using the VisuMax femtosecond laser platform (Carl Zeiss Meditec, Jena, Germany). The next day, the UDVA, CDVA, and refraction were 20/40, 20/32, and -1.25 -0.50 × 15°, respectively. One week later, the patient presented complaining of pain, photophobia, and blurred vision; at this time, there was a reduction in UDVA to 20/400 and CDVA to 20/63. With a diagnosis of stromal rejection, the patient was treated with corticosteroids (sub-Tenon injection and oral). Five months later, UDVA was 20/40, CDVA was 20/25, and refraction was -1.25 -0.75 × 90°. The graft had completely cleared., Conclusions: SMILE can be an effective alternative for the correction of astigmatism after DALK, but the risks of inflammatory responses and graft rejection call for caution. [J Refract Surg. 2019;35(11):737-739.]., (Copyright 2019, SLACK Incorporated.)

Background: Chronic rejection is the single biggest cause of premature kidney graft failure. HLA antibodies (Ab) are an established prognostic biomarker for premature graft failure so there is a need to test whether treatment decisions based on the presence of the biomarker can alter prognosis. The Optimised TacrolimuS and MMF for HLA Antibodies after Renal Transplantation (OuTSMART) trial combines two elements. Firstly, testing whether a routine screening programme for HLA Ab in all kidney transplant recipients is useful by comparing blinding versus unblinding of HLA Ab status. Secondly, for those found to be HLA Ab+, testing whether the introduction of a standard optimisation treatment protocol can reduce graft failure rates., Methods: OuTSMART is a prospective, open-labelled, randomised biomarker-based strategy (hybrid) trial, with two arms stratified by biomarker (HLA Ab) status. The primary outcome was amended from graft failure rates at 3 years to time to graft failure to increase power and require fewer participants to be recruited. Length of follow-up subsequently is variable, with all participants followed up for at least 43 months up to a maximum of 89 months. The primary outcome will be analysed using Cox regression adjusting for stratification factors. Analyses will be according to the intention-to-treat using all participants as randomised. Outcomes will be analysed comparing standard care versus biomarker-led care groups within the HLA Ab+ participants (including those who become HLA Ab+ through re-screening) as well as between HLA-Ab-unblinded and HLA-Ab-blinded groups using all participants., Discussion: Changes to the primary outcome permit recruitment of fewer participants to achieve the same statistical power. Pre-stating the statistical analysis plan guards against changes to the analysis methods at the point of analysis that might otherwise introduce bias through knowledge of the data. Any deviations from the analysis plan will be justified in the final report., Trial Registration: ISRCTN registry, ID: ISRCTN46157828 . Registered on 26 March 2013; EudraCT 2012-004308-36 . Registered on 10 December 2012.

Aims: Post-transplant thrombotic microangiopathy (TMA) is a rare and clinically challenging finding in renal transplant biopsies. In addition to recurrent atypical haemolytic uraemic syndrome, TMA in renal transplants is associated with various conditions, such as calcineurin inhibitor (CNI) treatment, antibody-mediated rejection (ABMR), viral infections, sepsis, pregnancy, malignancies, and surgery. The therapeutic implications of this diagnosis are considerable. In order to better understand post-transplant TMA and to identify histological or clinical differences between associated causes, we conducted a multicentre retrospective study., Methods and Results: Clinical parameters and transplant renal biopsy findings from 81 patients with TMA were analysed. Biopsies from 38 patients were also analysed with electron microscopy. On the basis of clinical-pathological correlation, TMA was attributed to a main aetiology, whenever possible. TMA occurred at a median of 30 days post-transplantation. Systemic features of TMA were present in only 18% of cases. Twenty-two per cent of cases were attributed to CNI and 11% to ABMR. Although other potentially contributing factors were found in 56% of patients, in most cases (63%) no clearly attributable cause of TMA was identified. Histological differences between groups were minimal. The detection of ultrastructural features that are usually associated with ABMR may help to establish ABMR as the cause of TMA., Conclusions: Although CNI and ABMR appear to be the main contributors to post-transplant TMA, the aetiology of most cases is probably multifactorial, and TMA cannot be unequivocally attributed to a single underlying aetiology. Morphological features of TMA are not discriminating, but electron microscopy may help to identify ABMR-associated TMA., (© 2019 John Wiley & Sons Ltd.)

Toxic epidermal necrolysis (TEN) is a rare condition, causing life-threatening adverse cutaneous reactions. TEN occurrence after bone marrow transplantation (BMT) is a well-known phenomenon; however, to date, only a few cases have been reported in the published work. Here, we describe the case of a 53-year-old woman who experienced TEN after undergoing allogenic BMT for malignant lymphoma. Skin erosion spread across a maximum of 70% of the body surface area and severe mucosal lesions developed. Steroid pulse therapy, plasma apheresis and immunoglobulin therapy were administrated, which resulted in the complete resolution of TEN. However, she developed hemophagocytic lymphohistiocytosis and died 38 days after BMT, owing to rupture of the lower digestive tract complicated by multi-organ failure. In our case, engraftment failure occurred, and the peripheral white blood cell count was less than 100/μL during the TEN course, suggesting that the presence of only a few immune cells could cause TEN. Our findings showed that high mortality rates and widespread skin erosion could be regarded as the most important characteristics of TEN occurring after BMT., (© 2019 Japanese Dermatological Association.)

Background: The incidence of cutaneous squamous cell carcinoma (cSCC) is markedly increased in renal transplant recipients compared with that of the nontransplant population., Aim: To investigate whether there is a relationship between transplant rejection and cSCC., Methods: The Duke Enterprise Data Unified Content Explorer historical database was used to identify patients who had undergone a renal transplant at Duke University Hospital during a 20-year period. Data on patient demographics, transplant dates, first rejection episodes, first cSCC development, medication, laboratory results and survival were recorded., Results: In total, 1684 patients were identified, of whom 126 (7.5%) experienced an episode of rejection and 46 (4.0%) developed a cSCC after transplant. The incidence of cSCC was significantly greater in the rejection group, with 8.7% of patients developing cSCC compared with 2.2% in the no-rejection group (P < 0.001). Median lag time to cSCC was shorter in the rejection group (2.5 years; age 0.4-9.0 years) than the no-rejection group (4.2 years; range 1.3-20.4 years) (P < 0.03)., Conclusions: Transplant rejection is associated with both a higher incidence and an accelerated time course for development of cSCC following renal transplantation. Close dermatological surveillance should be considered following an episode of rejection in this patient population., (© 2018 British Association of Dermatologists.)

Annual vaccination is routinely used in organ transplant recipients for immunization against seasonal influenza. However, detailed analysis of the kinetics of vaccine-induced immune responses in this population is lacking. In this study, we investigated the kinetics of vaccine strains-specific antibody responses to trivalent influenza vaccine in a group of renal transplant recipients and a control group. First, we found that the geometric mean hemagglutination inhibition titer against all 3 vaccine strains in the transplant cohort was significantly low when compared to control subjects. Next, whereas the control group sera showed significantly higher HA-specific IgG and isotype IgG1 antibodies at all four time points, a similar increase in the transplant group was delayed until day 28. Interestingly, within the transplant group, subjects receiving belatacept/MMF/prednisone-based regimen had significantly lower levels of total IgG and HA-specific IgG when compared to tacrolimus/MMF/prednisone-based regimen. Even though IgG-ASC response in both cohorts peaked at day 7 post-vaccination, the frequency of IgG-ASC was significantly low in the transplant group. Taken together, our studies show delayed kinetics and lower levels of influenza vaccine-specific antibody responses in renal transplant recipients and, more importantly, indicate the need to probe and improve current vaccination strategies in renal transplant recipients., (Published by Elsevier B.V.)

Background: Rejection with severe hemodynamic compromise (RSHC) carries a mortality risk approaching 50%. We aimed to identify current risk factors for RSHC and predictors of graft failure after RSHC., Methods: Data from 3,259 heart transplant (HT) recipients between January 2005 and December 2015 in the Pediatric Heart Transplant Study (PHTS) were analyzed. Predictors for RSHC and outcome after RSHC were sought. Time to RSHC was analyzed using the Cox proportional hazards regression model. Cardiac allograft vasculopathy (CAV) after HT and CAV after RSHC were analyzed as time-dependent covariates. Timing of RSHC was analyzed as occurring before and after 4 years after RSHC., Results: There were 309 patients (9.5%) with ≥ 1 RSHC episodes. In 143 patients with RSHC, the first episode was within 1 year after HT. Independent risk factors for RSHC were age 1 to 5 years at HT (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.04-2.18), age > 10 years at HT (HR, 1.83; 95% CI, 1.29-2.60), black race (HR, 1.64; 95% CI, 1.25-2.15), prior cardiac surgery (HR, 1.55; 95% CI, 1.03-2.31), ventricular assist device support at HT (HR, 1.65; 95% CI, 1.18-2.29), maintenance steroids (HR, 1.39; 95% CI, 1.06-1.82), and recipient on inotropes, pressors, or thyroid hormones (HR, 1.45; 95% CI, 1.09-1.94). Graft survival at 5 years after RSHC was 45.7%. RSHC was a greater risk factor for earlier CAV (HR, 7.78; 95% CI, 5.82-10.40) than other rejection types (HR, 2.31; 95% CI, 1.79-3.00). Patients with late RSHC, after 1 year after RSHC had increased risk of graft loss 4 years after RSHC (HR, 7.12; 95% CI, 2.18-23.22). The 5-year graft survival after RSHC was 50.5% for early RSHC and 39.0% for late RSHC., Conclusions: Mortality after RSHC is high in the current treatment era. Many patient risk factors for RSHC cannot be modified, including age, race, prior cardiac surgery, and ventricular assist device support. After RSHC, CAV is the only predictor of graft failure. Patients who have late RSHC fare worse than those who have RSHC within the first year after HT., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We report a rare complication of the use of an intrarectal catheter. An 18-year-old female with T-cell acute lymphoblastic leukemia post-matched unrelated donor allogeneic stem cell transplantation (auto-SCT) developed hepatic encephalopathy secondary to hepatic sinusoidal obstructive disease. A fecal management system was used to contain and divert fecal matter in this immobilized patient. Approximately 1 month after placement of an intrarectal catheter, stool was noted in the vaginal vault. Speculum examination confirmed development of a rectovaginal fistula.

Background and Objectives: AKI is associated with progression of CKD. Little is known about AKI after kidney transplantation in pediatric recipients. We aim to describe the epidemiology, risk factors, consequences, and outcomes of AKI in this population., Design, Setting, Participants, & Measurements: We performed a retrospective longitudinal analysis of pediatric kidney transplant recipients followed at The Hospital for Sick Children (Toronto, Canada) from 2001 to 2012. AKI was defined as an increase in serum creatinine ≥1.5 times baseline, and a rise of serum creatinine ≥1.25 but <1.5 times baseline defined subacute AKI., Results: Of 179 children, 122 were eligible for analysis. At baseline (3 months post-transplant), median age of the children was 13 years old (interquartile range, 9-16 years old), and 53% had CKD stage 2. Congenital anomalies of the kidney and urinary tract accounted for 46% of children. Over the study period (12 years), the incidence of AKI was 37% ( n =45 children), and 65% (79 children) experienced subacute AKI. Twenty-seven percent (33 children) did not develop AKI or subacute AKI. The main causes of AKI were infections other than urinary tract infections, rejection, and urinary tract infections. In a multivariable Poisson regression analysis, independent risk factors for AKI included younger age, girls, grafts from deceased donors, and lower baseline eGFR. AKI was significantly associated with lower long-term GFR and graft loss independent of rejection episodes. Moreover, subacute AKI was associated with progression of CKD., Conclusions: AKI and subacute AKI were common after pediatric kidney transplantation, and they were associated with graft loss, lower eGFR, and more rapid progression of CKD., (Copyright © 2018 by the American Society of Nephrology.)

Introduction: Arterial stiffness depends on both genetic and environmental factors. The aim of this study was to assess arterial stiffness in patients after heart transplant., Methods: The study was conducted between May and June 2017. Fifty patients from the Transplantology Clinic of the Institute of Cardiology in Anin, Warsaw, Poland, were enrolled in the study. Pulse wave velocity (PWV), central systolic blood pressure (CSBP), and central diastolic blood pressure (CDBP) were measured and patients' medical records were also analyzed., Results: In the study, 50 patients aged 57.9 years on average were evaluated, of whom 88% were male patients, with average PWV of 8.94 m/s and an average time after transplant of 9.7 years. The study has shown that age (R = 0.77), total cholesterol concentration (R = 0.22, P = .017) and creatinine concentration (R = 0.34; P = .15) show positive correlation with PWV., Conclusions: Our data indicates that age has significant impact on arterial stiffness and the type of immunosuppressive drugs and transplant rejection episodes do not impact an increase in arterial stiffness., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We aimed to determine the epidemiology, risk factors, and impact of bacterial infection on pancreatic function after pancreas transplantation. Data for pancreas transplant recipients were retrospectively reviewed between 2000 and 2014 for at least 1 year. We collected and analyzed post-transplant data for bacterial infection, morbidity, and mortality. During the study period, 312 pancreas transplants were performed. In total, 509 episodes of bacterial infection were diagnosed in 191 patients (61%). Multidrug-resistant (MDR) organisms were present in 173 of the 513 isolated microorganisms (33%). Risk factors independently associated with bacterial infection were acute allograft rejection (OR 1.7, 95%CI 1.1-3), the need for post-transplant hemodialysis, (OR 5.3, 95%CI 1.8-15.7) and surgical re-intervention (OR 2.8, 95%CI 1.5-5.1), which was also considered a risk factor for infections caused by MDR bacteria. Graft survival was associated with the occurrence of one or more episodes of bacterial infection (log-rank test = 0.009). Surgical re-intervention was independently associated with graft loss (OR 2.5, 95%CI 1.3-4.7). To conclude, pancreas recipients frequently experienced bacterial infections associated with the need for hemodialysis or surgical re-intervention. Infection by MDR organisms is a growing concern in these patients and was related to graft survival. Graft loss was independently associated with surgical re-intervention., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: The association of delayed graft function (DGF) and biopsy proven acute rejection (BPAR) of renal allografts is controversial. Borderline rejections comprise a major portion of biopsy results but the significance of such histologic changes is debated. The present study explores the impact of DGF on BPAR with a special emphasis on discriminating the effects of borderline rejection., Methods: Single center analysis of 417 deceased donor kidney recipients (age>18; transplantation date 1/2008-2/2015). Patients with primary non-function were excluded. DGF was defined as the need for dialysis within the first week after transplantation. Acute rejection was defined according to Banff criteria. Cox proportional hazards models were used to examine the relationship of DGF with BPAR within the first year., Results: No graft loss was observed during the first year after transplantation. DGF significantly associated with BPAR in the first year, irrespective of whether borderline rejections were included (HR 1.71, 95%CI 1.16,2.53) or excluded (HR 1.79, 95%CI 1.13,2.84)., Conclusion: DGF is significantly associated with rejection-with or without borderline changes-within the first year., Competing Interests: The authors have declared that no competing interests exist.

Background and Objectives: Diabetic Kidney Disease is associated with excessive mortality and morbidity. Simultaneous pancreas kidney transplantation (SPK) significantly improves quality of life and increases life expectancy of uremic diabetic patients. It is not known whether pancreas and kidney rejections in these transplant patients is concordant or discordant., Design, Setting, Participants, and Measurements: We analyzed clinical data on all SPK transplants performed between 2003 and 2014 at Indiana University to assess the impact of isolated or combined pancreas and kidney rejections on patient and allograft outcomes. The primary outcome of interest was kidney graft rejection within 1 year of pancreatic rejection and kidney survival in SPK patients with and without pancreatic rejection., Results: Mean age of patients was 44 ± 9 years; 61.9% were males; 88% were Caucasians. A total of 23.8% of cases had rejection [8.7% pancreatic rejection alone (PA), 4.4% had concordant pancreas and kidney (PK) rejection, and 10.7% had kidney rejection alone(KA)]. PK had a worse effect on kidney graft survival than PA (p = 0.019). Neither pancreas rejection nor kidney rejection had an adverse effect on patient survival. However, both pancreas graft failure and kidney graft failure adversely affected patient survival. Tacrolimus levels were not significantly different in all groups over a 10 year period (p = 0.4584)., Conclusions: Concordant pancreas kidney rejection is synergistically deleterious to kidney graft survival. Graft failure, not graft rejection, is adversely associated with patient survival.

Tacrolimus is prescribed to the majority of transplant recipients to prevent graft rejection, and although patients are maintained on oral administration, nonoral routes of administration are frequently used in the initial post-transplant period. CYP3A5 genotype is an established predictor of oral tacrolimus dose requirements, and clinical guideline recommendations exist for CYP3A5-guided dose selection. However, the association between CYP3A5 and nonoral tacrolimus administration is currently poorly understood, and differs from the oral tacrolimus relationship. In addition to CYP3A5, other pharmacogenes associated with CYP3A activity, including CYP3A4, CYP3A7 and POR have also been identified as predictors of tacrolimus exposure. This review will describe the current understanding of the relationship between these pharmacogenes and tacrolimus pharmacokinetics after oral and nonoral administration.

Late antibody-mediated rejection (ABMR) is a leading cause of kidney allograft failure. Uncontrolled studies have suggested efficacy of the proteasome inhibitor bortezomib, but no systematic trial has been undertaken to support its use in ABMR. In this randomized, placebo-controlled trial (the Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection [BORTEJECT] Trial), we investigated whether two cycles of bortezomib (each cycle: 1.3 mg/m 2 intravenously on days 1, 4, 8, and 11) prevent GFR decline by halting the progression of late donor-specific antibody (DSA)-positive ABMR. Forty-four DSA-positive kidney transplant recipients with characteristic ABMR morphology (median time after transplant, 5.0 years; pretransplant DSA documented in 19 recipients), who were identified on cross-sectional screening of 741 patients, were randomly assigned to receive bortezomib ( n =21) or placebo ( n =23). The 0.5-ml/min per 1.73 m 2 per year (95% confidence interval, -4.8 to 5.8) difference detected between bortezomib and placebo in eGFR slope (primary end point) was not significant ( P =0.86). We detected no significant differences between bortezomib- and placebo-treated groups in median measured GFR at 24 months (33 versus 42 ml/min per 1.73 m 2 ; P =0.31), 2-year graft survival (81% versus 96%; P =0.12), urinary protein concentration, DSA levels, or morphologic or molecular rejection phenotypes in 24-month follow-up biopsy specimens. Bortezomib, however, associated with gastrointestinal and hematologic toxicity. In conclusion, our trial failed to show that bortezomib prevents GFR loss, improves histologic or molecular disease features, or reduces DSA, despite significant toxicity. Our results reinforce the need for systematic trials to dissect the efficiency and safety of new treatments for late ABMR., (Copyright © 2018 by the American Society of Nephrology.)