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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.

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.

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: 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: 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.

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: 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.

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: 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.

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.)

Cardiac allograft vasculopathy (CAV) affects approximately 30% of cardiac transplant patients at 5 years post-transplantation. To date, there are few CAV treatment or prevention options, none of which are highly effective. The aim of the study was to investigate the effect of thalidomide on the development of CAV. The effect of thalidomide treatment on chronic rejection was assessed in rat orthotopic aortic transplants in allogeneic F344 or syngeneic Lew rats (n = 6 per group). Animals were left untreated or received thalidomide for 30 days post-transplant, and evidence of graft CAV was determined by histology (trichrome and immunohistochemistry) and intragraft cytokine measurements. Animals that received thalidomide treatment post-transplant showed markedly reduced luminal obliteration, with concomitant rescue of smooth muscle cells (SMCs) in the aortic media of grafts. Thalidomide counteracted neointimal hyperplasia by preventing dedifferentiation of vascular SMCs. Measurement of intragraft cytokine levels after thalidomide treatment revealed downregulation of matrix metalloproteinase 8 and monocyte chemotactic protein 1, cytokines involved in tissue remodelling and inflammation, respectively. Importantly, no negative side effects of thalidomide were observed. Thalidomide treatment prevents CAV development in a rodent model and is therefore potentially useful in clinical applications to prevent post-transplant heart rejection., (© 2017 Steunstichting ESOT.)

A 44-year-old woman presented to the emergency department with central crushing chest pain and dynamic anterior ST elevation on a background of a known left bundle-branch block on her electrocardiogram. Past medical history included insulin-dependent diabetes, asthma, fibromyalgia, and a gradually failing kidney transplant. This case demonstrates the rarely utilized niche role for intracoronary thrombolysis in STEMI treatment in the modern angioplasty era.

BACKGROUND Rituximab induces long-lasting B cell depletion in the peripheral blood and increases the levels of proinflammatory cytokines associated with regulatory B cell depletion. Previous reports showed that B cell-related cytokine release after administration of rituximab may induce acute cellular rejection (ACR) and delayed-onset neutropenia. The present study was conducted to investigate the correlation between acute rejection and delayed-onset neutropenia in ABO-incompatible renal transplant recipients who underwent administration of rituximab for 1 year after transplantation. MATERIAL AND METHODS From June 2006 to July 2015, 47 patients with chronic renal failure received ABO-incompatible renal transplant with rituximab induction at Osaka City University Hospital. All 47 patients underwent plasmapheresis due to removal of anti-A/B antibodies and administration of rituximab, and their transplants were carried out successfully. We investigated the correlation between ACR and delayed-onset neutropenia in ABO-incompatible renal transplant recipients who underwent administration of rituximab for 1 year after transplantation. RESULTS Fourteen patients (29.8%) experienced ACR (group A), and 33 recipients did not develop ACR (group B). The frequency of delayed-onset neutropenia was higher in group A than in group B (p=0.0503). Multivariate logistic regression analysis revealed that the frequency of ACR correlated significantly with the prevalence of delayed-onset neutropenia. CONCLUSIONS Our results indicated that ACR in ABO-incompatible renal transplant recipients receiving rituximab was associated with delayed-onset neutropenia.

Background: Retransplantation has emerged as a therapeutic option for patients experiencing respiratory failure after single lung transplantation. However, outcomes associated with the surgical option (ipsilateral, contralateral, or bilateral lung retransplantation) has not been well evaluated., Methods: The Organ Procurement and Transplantation Network database (1994 to 2012) was queried for all lung transplant procedures performed after an initial single lung transplantation. Donor and recipient demographics, before and after transplant characteristics, and outcomes were stratified by retransplant procedural choice and by interval between transplants. Risk factors for mortality were evaluated by Cox proportional hazards regression analysis., Results: Of 325 prior single lung transplant recipients, 50 underwent ipsilateral, 175 contralateral, and 100 bilateral lung retransplantation. The number of retransplant procedures performed per year increased from 3 in 1994 to 31 in 2012, with an increasing proportion of contralateral retransplantation and declining proportions of ipsilateral and bilateral retransplantation. Survival was significantly better in the contralateral and bilateral retransplant groups than in the ipsilateral retransplant group at 30 days (94% and 89% versus 80%), 1 year (72% and 67% versus 50%), and 5 years (41% and 42% versus 20%). Ipsilateral retransplantation (hazard ratio 1.48; p = 0.042), mechanical ventilation before retransplant (hazard ratio 2.39; p < 0.001), and retransplantation performed in the first half of the study period (hazard ratio 1.45; p = 0.027) were associated with increased mortality., Conclusions: After an initial single lung transplant, both the incidence of retransplantation and postoperative survival have increased with time. Although ipsilateral lung retransplantation may be the best available alternative in particular circumstances, this analysis suggests that contralateral or bilateral lung retransplantation may be preferable in patients for whom those options are medically sensible., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The immunosuppressive agents mycophenolate acid (MPA) and tacrolimus (Tac) are associated with a higher incidence of BK polyomavirus nephropathy (BKPyVAN). In this observational retrospective cohort study, the frequency of BK polyomavirus (BKPyV) complications over a 24-month period was studied., Methods: 358 renal transplant recipients (RTR) treated with MPA, with either cyclosporine A (CsA) (CsAM group) or Tac (TacM group) and mostly prednisolone, were included., Results: Incidence of BKPyV-viremia was not significantly different between the CsAM (n = 42/191) (22.0%) and the TacM (n = 36/167) (21.6%) group. Biopsy proven BKPyVAN occurred more often in the TacM group (6.6%) versus the CsAM group (2.1%) (p = 0.03). Longitudinal data analysis showed a significant earlier decline of viral load in plasma in the CsAM group compared to the TacM group (p = 0.005). The incidence of biopsy proven acute rejection (BPAR) was significantly higher in the CsAM (19.9%) compared to the TacM (10.8%) (p = 0.02) group. Graft loss, estimated glomerular filtration rate and mortality rate did not differ in both treatment groups., Conclusion: In conclusion, this study shows that immunosuppressive treatment with Tac and MPA compared to CsA and MPA is associated with a lower incidence of BPAR, but at the cost of an increased risk of developing BKPyVAN in the first two years post-transplant.

BK virus nephropathy (BKVN) and allograft rejection are two distinct disease entities which occur at opposite ends of the immune spectrum. However, they coexist in renal transplant recipients. Predisposing factors for this coexistence remain elusive. We identified nine biopsy-proven BKVN patients with coexisting acute rejection, and 21 patients with BKVN alone. We retrospectively analyzed the dosage and blood concentrations of immunosuppressants during the 3-month period prior to the renal biopsy between the two patient groups. Compared to the BKVN alone group, renal function was noticeably worse in the coexistence group (p = 0.030). Regarding the dose and average drug level of immunosuppressants, there was no difference between the two groups. Interestingly, the coefficient of variance of tacrolimus trough blood level was noticeably higher during the 3-month period prior to the renal biopsy in the coexistence group (p = 0.010). Our novel findings suggest that a higher variability of tacrolimus trough level may be associated with the coexistence of BKVN and acute rejection. Since the prognosis is poor and the treatment is challenging in patients with coexisting BKVN and acute rejection, transplant clinicians should strive to avoid fluctuations in immunosuppressant drug levels in patients with either one of these two disease entities.

Pneumocystis jirovecii pneumonia (PJP) is a potentially life-threatening infection that occurs in immunocompromised patients. The aim of this study was to evaluate risk factors for PJP in kidney transplantation recipients. We conducted a retrospective analysis of patient data from 500 consecutive kidney transplants performed at Severance Hospital between April 2011 and April 2014. Eighteen kidney transplantation recipients (3.6%) were diagnosed with PJP. In the univariate analysis, acute graft rejection, CMV infection, use of medication for diabetes mellitus, and lowest lymphocyte count were associated with PJP. Recipients who experienced acute graft rejection (odds ratio [OR] 11.81, 95% confidence interval [CI] 3.06-45.57, P < 0.001) or developed CMV infection (OR 5.42, 95% CI 1.69-17.39, P = 0.005) had high odds of PJP in multivariate analysis. In the acute graft rejection subgroup, patients treated with anti-thymocyte globulin (ATG) had significantly higher odds of PJP (OR 5.25, 95% CI 1.01-27.36, P = 0.006) than those who were not. Our data suggest that acute graft rejection and CMV infection may be risk factors for PJP in kidney transplant patients. The use of ATG for acute graft rejection may increase the risk of PJP.

Although renal graft percutaneous embolization was introduced to avoid the risk associated with graft nephrectomy, there is no universal consensus about its indications and results. In order to evaluate the efficacy of graft embolization in the treatment of graft intolerance syndrome as well as its safety compared to surgical removal with respect to complications and other morbidity measures, We performed a retrospective observational study comparing two groups of patients treated for graft intolerance syndrome: Group 1: patients who had embolization as first-line treatment and Group 2: patients directly treated by surgical removal. 72 patients were included, (32 in Group 1 and 40 in Group 2); the postintervention follow-up continued for 12 months. Patients in Group 1 are older than those in Group 2. Otherwise, the two groups are similar concerning sex, manifestations of graft intolerance syndrome, diabetes and nutritional and functional status. The overall success rate of embolization in complete resolution of graft intolerance syndrome and ultimately avoidance of surgical removal was 84.37%. The surgical removal group had more serious complications, a longer hospital stay and needed more blood transfusions. We conclude that embolization of symptomatic renal grafts has considerable efficacy with less morbidity, and no serious complications compared to the standard surgical graft removal., (© 2017 Steunstichting ESOT.)

Background & Aims: Acute rejection is detrimental to most transplanted solid organs, but is considered to be less of a consequence for transplanted livers. We evaluated risk factors for and outcomes after biopsy-proven acute rejection (BPAR) based on an analysis of a more recent national sample of recipients of liver transplants from living and deceased donors., Methods: We analyzed data from the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) from 2003 through 2014 as the exploratory cohort and the Scientific Registry of Transplant Recipients (SRTR) from 2005 through 2013 as the validation cohort. We examined factors associated with time to first BPAR using multivariable Cox regression or discrete-survival analysis. Competing risks methods were used to compare causes of death and graft failure between recipients of living and deceased donors., Results: At least 1 BPAR episode occurred in 239 of 890 recipients in A2ALL (26.9%) and 7066 of 45,423 recipients in SRTR (15.6%). In each database, risk of rejection was significantly lower when livers came from biologically related living donors (A2ALL hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.43-0.76; and SRTR HR, 0.78; 95% CI, 0.66-0.91) and higher in liver transplant recipients with primary biliary cirrhosis, of younger age, or with hepatitis C. In each database, BPAR was associated with significantly higher risks of graft failure and death. The risks were highest in the 12 month post-BPAR period in patients whose first episode occurred more than 1 year after liver transplantation: HRs for graft failure were 6.79 in A2ALL (95% CI, 2.64-17.45) and 4.41 in SRTR (95% CI, 3.71-5.23); HRs for death were 8.81 in A2ALL (95% CI, 3.37-23.04) and 3.94 in SRTR (95% CI, 3.22-4.83). In analyses of cause-specific mortality, associations were observed for liver-related (graft failure) causes of death but not for other causes., Conclusions: Contrary to previous data, acute rejection after liver transplant is associated with significantly increased risk of graft failure, all-cause mortality, and graft failure-related death, regardless of primary liver disease etiology. Living donor liver transplantation from a biologically related donor is associated with decreased risk of rejection., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Anti-tumor necrosis factor-α (TNFα) therapy has improved the prognosis of many chronic inflammatory diseases. It appears to be well-tolerated by liver-transplant patients. However, their use and their safety in kidney-transplant patients have yet to be determined.In this retrospective study, we identified 16 adult kidney-transplant patients aged 46.5 years (34-51.8) who received anti-TNFα therapy from 7 kidney transplantation centers. The indications for this treatment included: chronic inflammatory bowel disease (n = 8), inflammatory arthritis (n = 5), AA amyloidosis (n = 1), psoriasis (n = 1), and microscopic polyangiitis (n = 1).Anti-TNFα therapies resulted in a clinical response in 13/16 patients (81%). Estimated glomerular filtration rates (MDRD-4) were similar on day 0 and at 24 months (M24) after anti-TNFα treatment had been initiated (41 [12-55] and 40 [21-53] mL/min/1.73 m, respectively). Two allograft losses were observed. The 1st case was due to antibody-mediated rejection (M18), while the 2nd was the result of AA amyloidosis recurrence (M20). There were several complications: 8 patients (50%) developed 23 serious infections (18 bacterial, 4 viral, and 1 fungal) and 4 developed cancer. Five patients died (infection n = 2, cardiac AA amyloidosis n = 1, intraalveolar hemorrhage following microscopic polyangiitis n = 1, and acute respiratory distress syndrome n = 1). On univariate analysis, recipient age associated with death (P = 0.009) and infection development (P = 0.06).Using anti-TNFα therapies, remission can be achieved in chronic inflammatory diseases in kidney-transplant patients. However, concommitant anti-TNFα and immunosuppresive therapies must be used with caution due to the high risk of infection, particularly after the age of 50., Competing Interests: The authors have no conflicts of interest to disclose.

Rationale: Despite increasing evidence about the role of donor-specific human leukocyte antigen (HLA) antibodies in transplant outcomes, the incidence and impact of de novo donor-specific antibodies (dnDSA) after lung transplantation remains unclear., Objectives: To describe the incidence, characteristics, and impact of dnDSA after lung transplantation., Methods: We investigated a single-center cohort of 340 lung transplant recipients undergoing transplant during 2008 to 2011. All patients underwent HLA-antibody testing quarterly pretransplant and at regular intervals over the first 24 months after transplant. The patients received modified immunosuppression depending on their pretransplant sensitization status. Risk factors for dnDSA development, as well as the associations of dnDSA with patient survival and chronic lung allograft dysfunction (CLAD), were determined using multivariable analysis., Measurements and Main Results: The cumulative incidence of dnDSA was 47% at a median of 86 days (range, 44-185 d) after lung transplantation. Seventy-six percent of recipients with dnDSA had DQ-DSA. Male sex and the use of ex vivo lung perfusion were associated with an increased risk of dnDSA, whereas increased HLA-DQB1 matching was protective. DQ-dnDSA preceded or coincided with the diagnosis of CLAD in all cases. Developing dnDSA (vs. no dnDSA) was associated with a twofold increased risk of CLAD (hazard ratio, 2.04; 95% confidence interval, 1.13-3.69). This association appeared to be driven by the development of DQ-dnDSA., Conclusions: dnDSA are common after lung transplantation, with the majority being DQ DSA. DQ-dnDSA are associated with an increased risk of CLAD. Strategies to prevent or treat DQ-dnDSA may improve outcomes for lung transplant recipients.

Background: Although cardiac allograft vasculopathy (CAV) is typically characterized by diffuse coronary intimal thickening with pathological vessel remodeling, plaque instability may also play an important role in CAV. Previous studies of native coronary atherosclerosis have demonstrated associations between attenuated-signal plaque (ASP), plaque instability, and adverse clinical events., Objectives: This study's aim was to characterize the association between ASP and long-term mortality post-heart transplantation., Methods: In 105 heart transplant recipients, serial (baseline and 1-year post-transplant) intravascular ultrasound was performed in the first 50 mm of the left anterior descending artery. The ASP score was calculated by grading the measured angle of attenuation from grades 0 to 4 (specifically, 0°, 1° to 90°, 91° to 180°, 181° to 270°, and >270°) at 1-mm intervals. The primary endpoint was all-cause death or retransplantation., Results: At 1-year post-transplant, 10.5% of patients demonstrated ASP progression (newly developed or increased ASP). Patients with ASP progression had a higher incidence of acute cellular rejection during the first year (63.6% vs. 22.3%; p = 0.006) and tendency for greater intimal growth (percent intimal volume: 9.2 ± 9.3% vs. 4.4 ± 5.3%; p = 0.07) than those without. Over a median follow-up of 4.6 years, there was a significantly lower event-free survival rate in patients with ASP progression at 1-year post-transplant compared with those without. In contrast, maximum intimal thickness did not predict long-term mortality., Conclusions: ASP progression appears to reflect chronic inflammation related to acute cellular rejection and is an independent predictor of long-term mortality after heart transplantation. Serial assessments of plaque instability may enhance identification of high-risk patients who may benefit from closer follow-up and targeted medical therapies., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: End stage liver disease (ESLD) is associated with significant thrombotic complications. In this study, we attempted to determine if patients with ESLD, due to oncologic or autoimmune diseases, are susceptible to thrombosis to a greater extent than patients with ESLD due to other causes., Methods: In this retrospective study, we analyzed the UNOS database to determine the incidence of thrombotic complications in orthotopic liver transplant (OLT) recipients with autoimmune and oncologic conditions. Between 2000 and 2012, 65,646 OLTs were performed. We found 4,247 cases of preoperative portal vein thrombosis (PVT) and 1,233 cases of postoperative vascular thrombosis (VT) leading to graft failure., Results: Statistical evaluation demonstrated that patients with either hepatocellular carcinoma (HCC) or autoimmune hepatitis (AIC) had a higher incidence of PVT (p = 0.05 and 0.03 respectively). Patients with primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and AIC had a higher incidence of postoperative VT associated with graft failure (p < 0.0001, p < 0.0001, p = 0.05 respectively). Patients with preoperative PVT had a higher incidence of postoperative VT (p < 0.0001). Multivariable logistic regression demonstrated that patients with AIC, and BMI ≥40, having had a transjugular intrahepatic portosystemic shunt, and those with diabetes mellitus were more likely to have preoperative PVT: odds ratio (OR)(1.36, 1.19, 1.78, 1.22 respectively). Patients with PSC, PBC, AIC, BMI ≤18, or with a preoperative PVT were more likely to have a postoperative VT: OR (1.93, 2.09, 1.64, 1.60, and 2.01, respectively)., Conclusion: Despite the limited number of variables available in the UNOS database potentially related to thrombotic complications, this analysis demonstrates a clear association between autoimmune causes of ESLD and perioperative thrombotic complications. Perioperative management of patients at risk should include strategies to reduce the potential for these complications.

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by accumulation of excessive lung surfactant in the alveoli leading to restrictive lung functions and impaired gas exchange. Whole lung lavage (WLL) is the treatment modality of choice, which is usually performed using double lumen endobronchial tube insertion under general anesthesia and alternating unilateral lung ventilation and washing with normal saline. It may be difficult to perform WLL in patients with severe hypoxemia wherein patients do not tolerate single lung ventilation. Extracorporeal membrane oxygenation support (ECMO) has been used in such patients. We report a patient with autoimmune PAP following renal transplant who presented with marked hypoxemia and was managed by WLL under ECMO support.

Background: Persistent CD4 T-cell lymphopenia after kidney transplantation has been associated with an increased occurrence of opportunistic infections, malignancies and even mortality, but studies have focussed only on the first few years after kidney transplantation. In this study, we investigated the risk factors and clinical significance of long-term profound CD4 lymphopenia detected ≥10 years after renal transplantation., Methods: Between 2007 and 2010, 6206 CD4 T-cell counts, including 1507 counts <300/mm(3), were identified in an active cohort of 1876 kidney transplant patients. We identified 27 HIV-negative lymphopenic kidney transplant recipients out of 513 patients with graft survival over 10 years. We compared this cohort to 54 non-lymphopenic controls matched for the date of kidney transplantation., Results: The prevalence of CD4 lymphopenia 10 years after transplantation was 5.3%. CD4 T-cell lymphopenia was associated with significantly lower thymic output and with B-cell lymphopenia (P < 0.05). The duration of pre-transplant dialysis, but not the use of lymphopenic induction or recipient age, was significantly associated with a persistent CD4 lymphopenia (6.1 versus 3.0 years, P = 0.008). CD4 lymphopenia was associated with a higher frequency of cancer (50 versus 29.6%, P = 0.047). Most strikingly, long-term lymphopenia was significantly and independently associated with an accelerated decline in renal allograft function (P = 0.005), despite a similar rate of biopsy-proven acute rejection and comparable immunosuppression., Conclusions: Our study shows an association between long-term CD4 T-cell lymphopenia in kidney recipients and malignancy and an accelerated decline of kidney allograft function., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Few orthotopic heart transplantations have been performed in patients infected with the human immunodeficiency virus since the first such case was reported in 2001. Since that time, advances in highly active antiretroviral therapy have resulted in potent and durable suppression of the causative human immunodeficiency virus-accompanied by robust immune reconstitution, reversal of previous immunodeficiency, a marked decrease in opportunistic and other infections, and near-normal long-term survival. Although human immunodeficiency virus infection is not an absolute contraindication, few centers in the United States and Canada have performed heart transplantations in this patient population; these patients have been de facto excluded from this procedure in North America. Re-evaluation of the reasons for excluding these patients from cardiac transplantation is warranted in light of such significant advances in antiretroviral therapy. This case report documents successful orthotopic heart transplantation in 2 patients infected with human immunodeficiency virus, and we describe their antiretroviral therapy and immunosuppressive management challenges. Both patients were doing well without sequelae 43 and 38 months after transplantation.

Rationale: Transplantation, the most effective therapy for end-stage organ failure, is markedly limited by early-onset cardiovascular disease (CVD) and premature death of the host. The mechanistic basis of this increased CVD is not fully explained by known risk factors., Objective: To investigate the role of alloimmune responses in promoting CVD of organ transplant recipients., Methods and Results: We established an animal model of graft-exacerbated host CVD by combining murine models of atherosclerosis (apolipoprotein E-deficient recipients on standard diet) and of intra-abdominal graft rejection (heterotopic cardiac transplantation without immunosuppression). CVD was absent in normolipidemic hosts receiving allogeneic grafts and varied in severity among hyperlipidemic grafted hosts according to recipient-donor genetic disparities, most strikingly across an isolated major histocompatibility complex class II antigen barrier. Host disease manifested as increased atherosclerosis of the aorta that also involved the native coronary arteries and new findings of decreased cardiac contractility, ventricular dilatation, and diminished aortic compliance. Exacerbated CVD was accompanied by greater levels of circulating cytokines, especially interferon-γ and other Th1-type cytokines, and showed both systemic and intralesional activation of leukocytes, particularly T-helper cells. Serological neutralization of interferon-γ after allotransplantation prevented graft-related atherosclerosis, cardiomyopathy, and aortic stiffening in the host., Conclusions: Our study reveals that sustained activation of the immune system because of chronic allorecognition exacerbates the atherogenic diathesis of hyperlipidemia and results in de novo cardiovascular dysfunction in organ transplant recipients., (© 2015 American Heart Association, Inc.)

Heart transplantation is currently the definitive gold standard surgical approach in the treatment of refractory heart failure. However, the shortage of donors limits the achievement of a greater number of heart transplants, in which the use of mechanical circulatory support devices is increasing. With well-established indications and contraindications, as well as diagnosis and treatment of rejection through defined protocols of immunosuppression, the outcomes of heart transplantation are very favorable. Among early complications that can impact survival are primary graft failure, right ventricular dysfunction, rejection, and infections, whereas late complications include cardiac allograft vasculopathy and neoplasms. Despite the difficulties for heart transplantation, in particular, the shortage of donors and high mortality while on the waiting list, in Brazil, there is a great potential for both increasing effective donors and using circulatory assist devices, which can positively impact the number and outcomes of heart transplants.

Early renal graft injury could result in remote pulmonary injury due to kidney-lung cross talk. Here we studied the possible role of regulated necrosis in remote lung injury in a rat allogeneic transplantation model. In vitro, human lung epithelial cell A549 was challenged with TNF-α and conditioned medium from human kidney proximal tubular cells (HK-2) after hypothermia-hypoxia insults. In vivo, the Brown-Norway rat renal grafts were extracted and stored in 4 °C Soltran preserving solution for up to 24 h and transplanted into Lewis rat recipients, and the lungs were harvested on day 1 and day 4 after grafting for further analysis. Ischemia-reperfusion injury in the renal allograft caused pulmonary injury following engraftment. PARP-1 (marker for parthanatos) and receptor interacting protein kinase 1 (Rip1) and Rip3 (markers for necroptosis) expression was significantly enhanced in the lung. TUNEL assays showed increased cell death of lung cells. This was significantly reduced after treatment with necrostatin-1 (nec-1) or/and 3-aminobenzamide (3-AB). Acute immune rejection exacerbated the remote lung injury and 3-AB or/and Nec-1 combined with cyclosporine A conferred optimal lung protection. Thus, renal graft injury triggered remote lung injury, likely through regulated necrosis. This study could provide the molecular basis for combination therapy targeting both pathways of regulated necrosis to treat such complications after renal transplantation.

Vascularized pancreas transplantation is the only treatment that establishes normal glucose levels and normalizes glycosylated hemoglobin levels in type 1 diabetic patients. The first vascularized pancreas transplant was performed by William Kelly and Richard Lillehei, to treat a type 1 diabetes patient, in December 1966. In Brazil, Edison Teixeira performed the first isolated segmental pancreas transplant in 1968. Until the 1980s, pancreas transplants were restricted to a few centers of the United States and Europe. The introduction of tacrolimus and mycophenolate mofetil in 1994, led to a significant outcome improvement and consequently, an increase in pancreas transplants in several countries. According to the International Pancreas Transplant Registry, until December 31st, 2010, more than 35 thousand pancreas transplants had been performed. The one-year survival of patients and pancreatic grafts exceeds 95 and 83%, respectively. The better survival of pancreatic (86%) and renal (93%) grafts in the first year after transplantation is in the simultaneous pancreas-kidney transplant group of patients. Immunological loss in the first year after transplant for simultaneous pancreas-kidney, pancreas after kidney, and pancreas alone are 1.8, 3.7, and 6%, respectively. Pancreas transplant has 10 to 20% surgical complications requiring laparotomy. Besides enhancing quality of life, pancreatic transplant increases survival of uremic diabetic patient as compared to uremic diabetic patients on dialysis or with kidney transplantation alone.

Purpose of the Study: We present the results of a prospective study of patients with symptomatic partial ACL tears comparing the pre-operative findings with the clinical results at two years after anterior cruciate ligament (ACL) augmentation., Material and Methods: A total of 29 patients (7 women, 22 men; average age, 27.8 years) who were diagnosed with an isolated tear of the posterolateral (PL) bundle (18 patients) or the anteromedial (AM) bundle (11 patients) at 9 to 24 weeks after injury, and underwent ACL augmentation by isolated PL or AM bundle replacement, were evaluated. The characteristics assessed before surgery and at two years after it included the Lysholm and subjective IKDC scores and knee laxity measurement with a GNRB arthrometer (at 134 N and 250 N) and its assessment by the Lachman, anterior drawer and pivot shift tests. In addition, the presence of cyclop syndrome, graft failure and post-operative complications were evaluated., Results: The patients with isolated reconstruction of the PL bundle showed post-operatively statistically significant improvement in the degree of rotational knee laxity (p < 0.05) and the ventral knee laxity assessed by the Lachman test (p < 0.05). Postoperative improvement in the anterior drawer test results was not statistically significant (p = 0.07). The median value of side-to-side difference in knee laxity measured with the GNRB arthrometer decreased at 134 N from 1.7 mm pre-operatively to 0.8 mm at two years post-operatively (p < 0.05) and, at 250 N, from 2.8 mm to 1.5 mm (p < 0.05). The median Lysholm score increased from 74 to 91 points at two post-operative years and the median IKDC score improved from 76 to 92 points (p < 0.05). Graft failure was reported in one patient (5.6%) and 14 subjects (77.8%) reported return to pre-injury sports activities. The patients undergoing isolated reconstruction of the AM bundle achieved, at two years after surgery, a statistically significant decrease in positivity of the Lachman and anterior drawer tests (p < 0.05), while the results of the pivot shift test did not improve significantly (p = 0.09). The decrease in median values of side-to-side difference in knee laxity measured with the GNRB arthrometer was from pre-operative 3.1 mm to 1.2 mm at 134 N (p < 0.05) and from 6.2 mm to 1.9 mm at 250N (p < 0.05). The median Lysholm and IKDC scores increased from 68 to 92 points and from 70 to 94 points, respectively (p < 0.05). Nine patients (81.9%) reported return to pre-injury participation in sports. Apart from early wound bleeding in one patient, no complications were recorded., Discussion: By permitting maintenance of a healthy bundle and replacement of only a torn one, ACL augmentation provides several benefits. It allows for accelerated revascularization and re-innervation of the graft through mechanoreceptors of the healthy portion; it enables the surgeon to get a good anatomical orientation and achieve precise tunnel reaming; in addition the healthy bundle provides protection for the graft in the early post-operative period. Thus rehabilitation can be faster and also return to sports activities., Conclusions: Our results show that ACL augmentation using isolated replacement of either the AM or the PL bundle brings about statistically significant improvement of all subjective and most of the objective criteria by two years after surgery.

To evaluate the prevalence, risk factors, possible etiology, prognosis and management of proteinuria in renal transplant recipients, we studied 435 adult renal transplant recipient patients randomly selected from our center; 394 patients were reviewed retrospectively and 41 patients were followed-up prospectively for a period of one year. The patients were classified into three groups according to the results of urinalysis and spot urinary albumin creatinine ratio: Group A patients with normoalbuminuria; Group B patients with microalbuminuria; and Group C patients with macroalbuminuria. Persistent post-transplantation proteinuria was detected in 125 (28.8%) patients. The etiology of post-transplantation proteinuria included chronic allograft dysfunction in 44 (35.2%) patients, acute rejection in 40 (32%) patients, transplant glomerulopathy in eight (6.4%) patients, glomerular disease in 16 (12.8%) patients and other etiology in 17 (13.6%) patients. Proteinuric patients demonstrated significantly lower graft survival rates than did those without proteinuria (48.3% versus 51.7%, respectively; P = 0.017; Risk Ratio = 0.403; 95% confidence interval 0.188-0.862). We conclude that proteinuria is prevalent after kidney transplant in our population, and that it is most commonly associated with chronic allograft nephropathy, transplant glomerulopathy, glomerulonephritis and acute rejection. Post-transplant proteinuria is associated with decreased allograft survival.

Risk factors for lung cancer in lung transplant recipients are a history of smoking and immunosuppression, to which adds increasing use of lungs from donors with a smoking history. The three typical presentations are incidental diagnosis on the explanted lung, concerning less than 2%; lung cancer developing on the lung graft, accounting for less than 1%; and incidence of lung cancer on the native lung, estimated at 9%. Treatment along available guidelines may be hampered by decreased lung function owing to chronic rejection or adverse effects of immunosuppression. Prognosis is comparable to a general population in resected stage I cancer and is less favorable in advanced stages., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Quantification of proteinuria (albuminuria) in renal transplant recipients is important for diagnostic and prognostic purposes. Recent guidelines have recommended quantification of proteinuria by spot protein-to-creatinine ratio (PCR) or spot albumin-to-creatinine ratio (ACR). Validity of spot measurements remains unclear in renal transplant recipients., Methods: Systematic review of adult kidney transplant recipients. Studies that reported the diagnostic accuracy of PCR or ACR as compared with 24-h urine protein or albumin excretion in renal transplant recipients were included., Results: The search identified 8 studies involving 1871 renal transplant recipients. The correlation of the PCR to 24-h protein ranged from 0.772 to 0.998 with a median value of 0.92. PCR sensitivity ranged from 63 to 99 (50% of sensitivities were >90%); PCR specificity varied from 73 to 99 (50% of specificities were >90%). Only one study reported the bias; percent bias ranged from 12 to 21% and accuracy (within 30% of 24 h urine protein) ranged from 47 to 56% depending on the degree of proteinuria. For the ACR, percent bias ranged from 9 to 21%, and the accuracy (within 30%) ranged from 38 to 80%., Conclusions: The data regarding diagnostic accuracy of PCR and ACR is limited. Only one report studied the absolute measures of agreement (bias and accuracy). We recommend verifying PCR and ACR measurements with a 24-h protein before making any major diagnostic (e.g. biopsy) or therapeutic (e.g. change in immunosuppressive agents) decisions in this population.

Background: The immunosuppressants used in transplantation medicine significantly elevate the incidence of neoplasia, particularly in the skin. The cumulative incidence of non-melanocytic skin cancer (NMSC) in renal transplant recipients was 20.5% in a study carried out in German centers. Data on more than 35 000 renal transplant recipients in the USA document a cumulative NMSC incidence of over 7% after 3 years of immunosuppression., Method: The authors selectively review publications obtained by a PubMed search to discuss the incidence of, and major risk factors for, skin tumors and infectious diseases of the skin in immunosuppressed patients., Results: The main risk factors for skin tumors are age at the time of transplantation, light skin color, previous and present exposure to sunlight, and the type and duration of immunosuppressive treatment. Squamous-cell carcinoma (SCC) is the most common kind of skin tumor in immunosuppressed patients. Human herpesvirus 8 and Merkel-cell polyoma virus also cause neoplasia more often in immunosuppressed patients than in the general population. Surgical excision is the treatment of choice. Actinic keratosis markedly elevates the risk that SCC will arise in the same skin area (odds ratio 18.36, 95% confidence interval 3.03-111). Patients with multiple actinic keratoses can be treated with photodynamic therapy or with acitretin. To lower the skin cancer risk, organ transplant recipients should apply medical screening agents with a sun protection factor of at least 50 to exposed skin areas every day. 55% to 97% of organ transplant recipients have skin infections; these are treated according to their respective types., Conclusion: Squamous-cell carcinoma of the skin adds to the morbidity and mortality of transplant recipients and is therefore among the major oncological challenges in this patient group. Structured concepts for interdisciplinary care enable risk-adapted treatment.

To test, whether 10 genes, diagnostic of renal allograft rejection in blood, are able to diagnose and predict cardiac allograft rejection, we analyzed 250 blood samples from heart transplant recipients with and without acute rejection (AR) and with cytomegalovirus (CMV) infection by QPCR. A QPCR-based logistic regression model was built on 5 of these 10 genes (AR threshold composite score >37%  = AR) and tested for AR prediction in an independent set of 109 samples, where it correctly diagnosed AR with 89% accuracy, with no misclassifications for AR ISHLT grade 1b. CMV infection did not confound the AR score. The genes correctly diagnosed AR in a blood sample within 6 months prior to biopsy diagnosis with 80% sensitivity and untreated grade 1b AR episodes had persistently elevated scores until 6 months after biopsy diagnosis. The gene score was also correlated with presence or absence of cardiac allograft vasculopathy (CAV) irrespective of rejection grade. In conclusion, there is a common transcriptional axis of immunological trafficking in peripheral blood in both renal and cardiac organ transplant rejection, across a diverse recipient age range. A common gene signature, initially identified in the setting of renal transplant rejection, can be utilized serially after cardiac transplantation, to diagnose and predict biopsy confirmed acute heart transplant rejection.

Randomized trials showed that mTOR inhibitors prevent early development of cardiac allograft vasculopathy (CAV). However, the action of these drugs on CAV late after transplant is controversial, and their effectiveness for CAV prevention in clinical practice is poorly explored. In this observational study we included 143 consecutive heart transplant recipients who underwent serial intravascular ultrasound (IVUS), receiving either everolimus or mycophenolate as adjunctive therapy to cyclosporine. Ninety-one recipients comprised the early cohort, receiving IVUS at weeks 3-6 and year 1 after transplant, and 52 the late cohort, receiving IVUS at years 1 and 5 after transplant. Everolimus independently reduced the odds for early CAV (0.14 [0.01-0.77]; p = 0.02) but it did not appear to influence late CAV progression. High-dose statins were found to be associated with reduced CAV progression both early and late after transplant (p ≤ 0.05). Metabolic abnormalities, such as high triglycerides, were associated with late, but not with early CAV progression. By highlighting a differential effect of everolimus and metabolic abnormalities on early and late changes of graft coronary morphology, this observational study supports the hypothesis that everolimus may be effective for CAV prevention but not for CAV treatment, and that risk factors intervene in a time-dependent sequence during CAV development., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The role of antibody-mediated rejection in acute and chronic rejection after lung transplantation is poorly understood. We report the case of a prior single-lung transplant recipient undergoing an acute antibody-mediated rejection isolated to her new, contralateral single-lung transplant. A 44-year-old woman 6 years after undergoing a single-lung transplant for idiopathic pulmonary fibrosis underwent a second single-lung transplant for bronchiolitis obliterans syndrome. Despite a negative crossmatch, she subsequently exhibited severe antibody-mediated rejection to her new allograft within 6 days of transplantation. The process of allograft sensitization is dynamic, and further study is warranted to better understand this process., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Cardiogenic shock resulting from acute rejection after heart transplantation is an infrequent but life-threatening condition. Intensified immunosuppressive therapy and the timely initiation of properly selected mechanical circulatory support can be life-saving and enable recovery of graft function. The few published reports on mechanical circulatory support for acute transplantation rejection have focused on short-term devices. We present the case of a 48-year-old woman who developed cardiogenic shock due to severe allograft rejection after heart transplantation. She underwent staged mechanical circulatory support: extracorporeal membrane oxygenation for 10 days and then biventricular assist device support for 5 weeks. Allograft function recovered completely, and this enabled removal of the assist device. The patient was alive 18 months after biventricular assist device insertion. To our knowledge, this is the first description of a successful staged approach involving short- and long-term mechanical circulatory support to resolve allograft rejection and refractory cardiogenic shock after heart transplantation.