Acute Rejection Rates Research Articles

Long-Term Outcomes after Acute Rejection in Kidney Transplant Recipients: An ANZDATA Analysis.

Declining rates of acute rejection (AR) and the high rate of 1-year graft survival among patients with AR have prompted re-examination of AR as an outcome in the clinic and in trials. Yet AR and its treatment may directly or indirectly affect longer-term outcomes for kidney transplant recipients. To understand the long-term effect of AR on outcomes, we analyzed data from the Australia and New Zealand Dialysis and Transplant Registry, including 13,614 recipients of a primary kidney-only transplant between 1997 and 2017 with at least 6 months of graft function. The associations between AR within 6 months post-transplant and subsequent cause-specific graft loss and death were determined using Cox models adjusted for baseline donor, recipient, and transplant characteristics. AR occurred in 2906 recipients (21.4%) and was associated with graft loss attributed to chronic allograft nephropathy (hazard ratio [HR], 1.39; 95% confidence interval [95% CI], 1.23 to 1.56) and recurrent AR beyond month 6 (HR, 1.85; 95% CI, 1.39 to 2.46). Early AR was also associated with death with a functioning graft (HR, 1.22; 95% CI, 1.08 to 1.36), and with death due to cardiovascular disease (HR, 1.30; 95% CI, 1.11 to 1.53) and cancer (HR, 1.35; 95% CI, 1.12 to 1.64). Sensitivity analyses restricted to subgroups with either biopsy-proven, antibody-mediated, or vascular rejection, or stratified by treatment response produced similar results. AR is associated with increased risks of longer-term graft failure and death, particularly death from cardiovascular disease and cancer. The results suggest AR remains an important short-term outcome to monitor in kidney transplantation and clinical trials.

11-year experience of kidney retransplantation in elderly recipients in Sklifosovsky Research Institute for Emergency Medicine

Introduction. In spite of improvements in quality of life and lifetime of kidney transplant recipients the limited time of kidney transplant survival dictate the need for returning back to dialysis or repeat kidney transplantation. In respect that the need of repeat kidney transplantation usually observed in elderly recipients we attach importance in the analysis of outcomes of kidney retransplantation in patients over 60-s. Aim: to analyse the early outcomes of kidney re-transplantations in middle-aged and elderly recipients. Material and methods : the retrospective analysis of outcomes of 124 repeat kidney transplantations was made (16 transplantations in elderly recipients -Group I; 108 transplantations in recipients aged 20-59 yrs - Group II). The recovery of kidney transplants, acute rejection rates, the causes and the rate of kidney transplant dysfunction and failure, early patient’s and kidney transplant’ survival rates were analyzed. We used clinical, laboratory, histological and instrumental diagnostics. Results : in both groups there were no differences in kidney transplant recovery rates (p = 0,546), kidney transplant function (normal function 81,2% vs 86,1%, dysfunction 6,3% vs 4,3%, graft failure 12,5% vs 9,3% (p = 0,876), recipient 100% vs 99,1% (p = 0,34) and graft survival rates 87,5% vs 90,7% (p = 0,30). There were no episodes of acute rejection in patients of group I (0% vs 30,6% (p = 0,006). The reason of graft failure in group I - the graft’s pathology (nephroangiosclerosis (12,5%), group II - intractable acute rejection (4,6%), graft’s pathology (3,7%), patient’s death with functioning graft (0,9%). Conclusion: there were similar recipient and graft survival rates in both groups. We observed lower acute rejection rate in patients of group I using sufficient immunosuppressive regimens.

Long-Term Outcomes of Patients With Amyloidosis Following Kidney Transplant.

Reported graft and patient survival rates in amyloidosis after renal transplant differ considerably between studies. Group 1 included 24 patients who had end-stage renal disease secondary to amyloidosis. Group 2 (the control group) included 24 consecutive patients who had kidney disease secondary to various causes other than amyloidosis. Comparisons between groups were made for kidney and patient survival rates and other complications following kidney transplant. We also compared survival rates of patients in group 1 versus another control group that included patients with amyloidosis who were treated with hemodialysis (group 3; n = 25). Mean follow-up was 109.5 ± 79.8 months. Biopsy-proven acute rejection and graft failure rates were not significantly different between groups. In group 1 versus group 2, the cumulative 10-year and 20-year patient survival rates were 68.2% versus 86.1% and 36.9% versus 60.3%, respectively (P = .041). Survival was not significantly different in group 1 compared with group 2 and group 3, although patients in group 3 had significantly shorter duration of time to death after the start of renal replacement therapy. Patient survival may be lower in kidney transplant recipients with amyloidosis compared with patients with end-stage renal disease due to other causes. However, graft failure and acute rejection rates seem to be similar.

Lung Transplantation for Cystic Fibrosis and Non-cystic Fibrosis Bronchiectasis: A Single-Center Experience

ObjectivesLung transplantation is a well-established treatment for selected patients with advanced cystic fibrosis (CF)- and non-cystic fibrosis (non-CF)--related bronchiectasis. Because the number of lung transplants performed for patients with non-CF bronchiectasis is much smaller than for patients with CF, little data is available regarding patient selection, choice of procedure, and outcomes. MethodsBetween November 1997 and December 2013, 42 patients with CF and 33 patients with non-CF bronchiectasis underwent lung transplantation at the Rabin Medical Center, Israel. We analyzed and compared pretransplant evaluation data and short- and long-term results in both groups. ResultsMedian survival for the CF group in our study was 8.4 years, compared with 7.1 years for the non-CF group (P = .098), similarly to that reported by the International Society for Heart and Lung Transplantation Registry data. The main survival difference between groups was in the early postoperative period. Both groups achieved similar peak forced expiratory volume in 1 second values and had stable lung function at the 3-year follow-up. Biopsy-proven rates of acute cellular rejection were low for both groups. Rates of chronic lung allograft dysfunction development did not differ between CF and non-CF recipients. ConclusionOur institutional experience confirms that lung transplantation is feasible for non-CF bronchiectasis, and results are comparable to our CF cohort. The increased early mortality in this study occurred from 1999 to 2008 and was probably related to surgical techniques used at the time. Overall, 3-year and 5-year survival were comparable with the International Society for Heart and Lung Transplantation Registry data. Non-CF bronchiectasis patients achieved and maintained satisfactory lung function.

Conversion From Immediate-Release Tacrolimus to Prolonged-Release Tacrolimus in Stable Heart Transplant Patients: A Retrospective Study

BackgroundLifelong adherence with post-transplant immunosuppression is challenging, with nonadherence associated with greater acute rejection (AR) risk. MethodsThis retrospective study evaluated conversion from immediate-release tacrolimus (IRT) to prolonged-release tacrolimus (PRT), between January 2008 and December 2012 in stable adult heart transplant recipients. Cumulative incidence rate (IR) of AR and infection pre- and postconversion, safety, tacrolimus dose and trough levels, concomitant immunosuppression, and PRT discontinuation were analyzed (intention-to-treat population). ResultsOverall, 467 patients (mean age, 59.3 [SD, 13.3] years) converted to PRT at 5.1 (SD, 4.9) years post transplant and were followed for 3.4 (SD, 1.5) years. During the 6 months post conversion, 5 patients (1.1%; 95% CI, 0.35%–2.48%) had an AR episode and IR was 2.2/100 patient-years (95% CI, 0.91–5.26). Incidence of rejection preconversion varied by time from transplant to conversion. Infection IR was similar post- and preconversion (9.2/100 patient-years [95% CI, 7.4–11.3] vs 10.6/100 patient-years [95% CI, 8.8–12.3], respectively; P = .20). Safety variables remained similar post conversion. The IR of mortality/graft loss was 2.3/100 patient-years (95% CI, 1.7–3.1). ConclusionsConversion from IRT to PRT in heart transplant recipients in Spain was associated with no new safety concerns and appropriate immunosuppressive effectiveness.

FCGR3A and FCGR2A Genotypes Differentially Impact Allograft Rejection and Patients' Survival After Lung Transplant.

Fc gamma receptors (FcγRs) play a major role in the regulation of humoral immune responses. Single-nucleotide polymorphisms (SNPs) of FCGR2A and FCGR3A can impact the expression level, IgG affinity and function of the CD32 and CD16 FcγRs in response to their engagement by the Fc fragment of IgG. The CD16 isoform encoded by FCGR3A [158V/V] controls the intensity of antibody-dependent cytotoxic alloimmune responses of natural killer cells (NK) and has been identified as a susceptibility marker predisposing patients to cardiac allograft vasculopathy after heart transplant. This study aimed to investigate whether FCGR2A and FCGR3A polymorphisms can also be associated with the clinical outcome of lung transplant recipients (LTRs). The SNPs of FCGR2A ([131R/H], rs1801274) and FCGR3A ([158V/F], rs396991) were identified in 158 LTRs and 184 Controls (CTL). The corresponding distribution of genotypic and allelic combinations was analyzed for potential links with the development of circulating donor-specific anti-HLA alloantibodies (DSA) detected at months 1 and 3 after lung transplant (LTx), the occurrence of acute rejection (AR) and chronic lung allograft dysfunction (CLAD), and the overall survival of LTRs. The FCGR3A [158V/V] genotype was identified as an independent susceptibility factor associated with higher rates of AR during the first trimester after LTx (HR 4.8, p < 0.0001, 95% CI 2.37–9.61), but it could not be associated with the level of CD16- mediated NK cell activation in response to the LTR's DSA, whatever the MFI intensity and C1q binding profiles of the DSA evaluated. The FCGR2A [131R/R] genotype was associated with lower CLAD-free survival of LTRs, independently of the presence of DSA at 3 months (HR 1.8, p = 0.024, 95% CI 1.08–3.03). Our data indicate that FCGR SNPs differentially affect the clinical outcome of LTRs and may be of use to stratify patients at higher risk of experiencing graft rejection. Furthermore, these data suggest that in the LTx setting, specific mechanisms of humoral alloreactivity, which cannot be solely explained by the complement and CD16-mediated pathogenic effects of DSA, may be involved in the development of acute and chronic lung allograft rejection.

Comparison of clinical outcome of induction immunosuppressive therapy with thymoglobulin and standard therapy in kidney transplantation; a randomized double-blind clinical trial

Introduction: Thymoglobulin is a lymphocyte-depleting polyclonal antibody, administered for induction therapy at the time of kidney transplantation to reduce the risk of acute allograft rejection. The appropriate dosage and duration of therapy is controversial. The higher dosages are associated with infection and malignancy. Objectives: In this study efficacy and safety of lower dosage (in comparison with previous studies) of thymoglobulin in kidney transplant recipients was evaluated. Patients and Methods: In this clinical trial, 106 adult kidney transplant recipients, were randomized before transplantation in two groups (case and control). The case group (53 patients) were received induction therapy with thymoglobulin (1.5 mg/kg/d for 3 days) and the control group (53 patients) were received non-induction regiment. Delayed graft function (DGF), glomerular filtration rate (GFR), acute allograft rejection and thymoglobulin complications were evaluated during the first post-transplantation year. Results: Around 106 kidney transplant recipients were enrolled (71 or 66.98% deceased donor) to the study. No significant statistical differences were found in GFR at the time of discharge from hospital (P=0.399) and at 1 year (P=0.851) and acute allograft rejection (P= 0.304) between two groups. Graft survival (73.5% in case group versus 81.1% in control group, P=0.392) at month 12th was similar among groups. Additionally, no significant differences of acute allograft rejection in recipient from deceased or living donor between two groups were detected. There was a higher incidence of DGF in the control group (26.4%) than the thymoglobulin group (5.8%) and the difference was statistically significant (P= 0.004). Thrombocytopenia (17% versus 49.1%, P&lt;0.001) and leukopenia (11.3% versus 50.9%, P&lt;0.001) were also significantly higher in the case group. Conclusion: While the incidence of DGF was reduced in thymoglobulin group, the short-term acute allograft rejection rate was not reduced compared to the control group. However, our results require further consideration with larger samples

Efficacy and Safety of Mizoribine Combined With Tacrolimus in Living Donor Kidney Transplant Recipients: 3-Year Results by a Chinese Single Center Study

BackgroundMizoribine (MZR) was effective and safe for living Chinese donor kidney transplantation (LDKT) on tacrolimus-based treatment 1 year after transplantation. We investigated whether MZR was effective and safe for LDKT on tacrolimus-based treatment with long follow-up periods. MethodsWe compared 22 LDKT recipients who were administered MZR, tacrolimus, and corticosteroids with a control group (n = 20) treated with mycophenolate mofetil (MMF), tacrolimus, and corticosteroids. Primary efficacy endpoints were 3-year patient survival, 3-year graft survival, and acute rejection (AR) rate within 3 years after transplantation. ResultsThe 3-year patient and graft survival rates for the MZR and MMF groups were 100%. The AR rate after transplantation was 18.2% for the MZR group and 10.0% for the MMF group; the difference was not significant (P = .665). There was no significant difference in serum creatinine levels, glomerular filtration rates (eGFR), serum urate levels, blood urea nitrogen, and cystatin C levels 12, 24, and 36 months after transplantation. No significant differences in the CD3, CD4, CD8, CD4/CD8, and CD45 were observed between the 2 groups 12, 24, and 36 months after transplantation. There were no significant differences in adverse events among the MZR or the MMF group, whereas the prevalence of gastrointestinal symptoms were significantly lower in the MZR treatment group (P = .003), especially acid reflux (P = .007). Compared with the MMF group, the MZR group should lighten the burden on patients. ConclusionMZR with tacrolimus and corticosteroids provides satisfactory immunosuppression and higher safety for Chinese LDKT over a 3-year follow-up.

Effects of combined genes of CTLA4Ig and IDO in post-liver transplantation immune tolerance of rats

Background and rationale for the study. Previous studies showed that CTLA4Ig and indoleamine 2,3-dioxygenase (IDO) genes played regulatory role in organ transplantation but failed to reach satisfactory effects. In this study, we constructed an adeno-virus-mediated gene expressing CTLA4Ig-IDO and established rat liver transplantation models. Recipients were randomly divided into four groups of 10 rats each. During the operation, CTLA4Ig, IDO, and CTLA4Ig-IDO genes, as well as a blank plasmid, were infused into different rat groups via portal vein to determine their effects on inducing immune tolerance. Survival rate of recipients, histological changes of graft liver, post-transplantation liver function, and cytokine levels were observed at day 14 after operation.Results. Serum levels of alanine aminotransferase (ALT), aspartate transaminase (AST), and total bilirubin level (TBIL) in the CTLA4Ig-IDO group were lower than those in the other three groups at 14 days post-transplantation (P < 0.05); mRNA and protein expressions of IL-2 and IFN-γ were higher in the control group, but lower in the CTLA4Ig-IDO group (P < 0.05). By contrast, expressions of IL-4, TGF-b, IL-10, and T lymphocyte apoptosis were higher in the CTLA4Ig-IDO group than those in the other three groups (P < 0.05). The CTLA4Ig-IDO group exhibited mild acute rejection and higher survival rate compared with the other groups (P < 0.05).Conclusion. Compared with using CTLA4Ig or IDO alone, combined transfection of CTLA4Ig-IDO was more effective in inducing immune tolerance after liver transplantation.

Pediatric Kidney Transplantation: Experience of a Center Over 4 Decades

IntroductionChronic kidney disease in the pediatric population is associated with numerous comorbidities and an increased risk of mortality. Kidney transplantation (KT) is considered to be the option of choice in children with end-stage renal disease. AimTo characterize a single center experience in pediatric KT in the last 35 years. MethodsA retrospective analysis of epidemiologic and clinical data from KT pediatric patients from January 1981 to December 2016. For outcome analysis, cases were divided into decades (1981–89; 1990–99; 2000–09; 2010–16). ResultsOne hundred and 4 children (KT mean age 13.7 ± 3.32 years; 57.7% male) underwent 111 renal transplants (13% with living donors). Congenital anomalies of the kidney and urinary tract (36.5%) and glomerular disease (29%) were the major causes of renal disease. Peritoneal dialysis was the predominant initial therapeutic modality in 69 children (62.2%). Mean dialysis time was 19.2 months, 9 patients (8.1%) having had preemptive KT. Median follow-up was 181 months. Uncensored graft survivals rates at 5, 10, 15, and 20 years were 79.7%, 74.3%, 59.5%, and 52.8%, respectively. Graft survival improved significantly over the decades (P = .03). Higher estimated glomerular filtration rate measured at 1 year, induction immunosuppressive therapy use (thymoglobulin/basiliximab), and lower incidence of acute rejection rates were associated with superior graft survival (P < .05). ConclusionsUronephropathies were the most frequent cause of renal failure and peritoneal dialysis, which was the main renal replacement therapy according to the literature. Graft survival improved significantly over the study period; we hypothesize that this was related to surgical advances and the use of more effective immunosuppressive drugs.

The Impact of Culturing the Organ Preservation Fluid on Solid Organ Transplantation: A Prospective Multicenter Cohort Study.

BackgroundWe analyzed the prevalence, etiology, and risk factors of culture-positive preservation fluid and their impact on the management of solid organ transplant recipients.MethodsFrom July 2015 to March 2017, 622 episodes of adult solid organ transplants at 7 university hospitals in Spain were prospectively included in the study.ResultsThe prevalence of culture-positive preservation fluid was 62.5% (389/622). Nevertheless, in only 25.2% (98/389) of the cases were the isolates considered “high risk” for pathogenicity. After applying a multivariate regression analysis, advanced donor age was the main associated factor for having culture-positive preservation fluid for high-risk microorganisms. Preemptive antibiotic therapy was given to 19.8% (77/389) of the cases. The incidence rate of preservation fluid–related infection was 1.3% (5 recipients); none of these patients had received preemptive therapy. Solid organ transplant (SOT) recipients with high-risk culture-positive preservation fluid receiving preemptive antibiotic therapy presented both a lower cumulative incidence of infection and a lower rate of acute rejection and graft loss compared with those who did not have high-risk culture-positive preservation fluid. After adjusting for age, sex, type of transplant, and prior graft rejection, preemptive antibiotic therapy remained a significant protective factor for 90-day infection.ConclusionsThe routine culture of preservation fluid may be considered a tool that provides information about the contamination of the transplanted organ. Preemptive therapy for SOT recipients with high-risk culture-positive preservation fluid may be useful to avoid preservation fluid–related infections and improve the outcomes of infection, graft loss, and graft rejection in transplant patients.

Systematic review with meta-analysis: sirolimus- or everolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma.

Calcineurin-inhibitor immunosuppressants (tacrolimus and ciclosporin) have been associated with an exposure-related increase in tumour recurrence following liver transplantation for hepatocellular carcinoma (HCC). Conversely, mechanistic target of rapamycin (mTOR) inhibitors (sirolimus and everolimus) have been suggested to reduce recurrence rates and improve survival in this patient group. To clarify the potential benefit of mTOR-inhibitors in HCC transplant patients by comparing recurrence and survival outcomes with calcineurin-inhibitor-based immunosuppression. A systematic review and meta-analysis was performed. The inclusion criteria were observational or interventional studies reporting the effect of early-initiated (<6months post-transplant) mTOR-inhibitor-based immunosuppression on survival or tumour recurrence in patients transplanted with HCC, compared to a control of calcineurin-inhibitor-based therapy. Meta-analysis demonstrated that compared with calcineurin-inhibitor controls, recurrence-free-survival was significantly increased with mTOR-inhibitor-based therapy at 1-year (Risk-Ratio (RR): 1.09, 95% CI: 1.01-1.18) and 3-years (RR: 1.1, 95% CI: 1.01-1.21) post-transplant, with a nonsignificant increase at 5-years (RR: 1.15, 95% CI: 0.99-1.35). Overall survival was improved at 1-year (RR: 1.07, 95% CI: 1.02-1.12), 3-years (RR: 1.1, 95% CI: 1.02-1.19), and 5-years (RR: 1.18, 95% CI: 1.08-1.29). Recurrence-rate was lower in the mTOR-inhibitor arm (RR: 0.67, 95% CI: 0.56-0.82), with no significant increase in acute rejection (RR: 1.1, 95% CI: 0.94-1.28). mTOR-inhibitor-based immunosuppression may be a preferable option in patients transplanted with HCC. It improves recurrence-free-survival over at least three years and reduces the recurrence rate compared with standard calcineurin-inhibitor-based therapy, with no significant increase in the rate of acute rejection. Future research should clarify the effect in higher vs lower risk cohorts.

Outstanding questions in transplantation: B cells, alloantibodies, and humoral rejection.

Over the past three decades, improved immunosuppression has significantly reduced T cell-mediated acute rejection rates, but long-term graft survival rates have seen only marginal improvement. The cause of late graft loss has been under intense investigation, and chronic antibody-mediated rejection (AMR) has been identified as one of the leading causes, thus providing a strong rationale for basic science investigation into donor-specific B cells and antibodies in transplantation and ways to mitigate their pathogenicity. In 2018, the American Society of Transplantation launched a community-wide online discussion of Outstanding Questions in Transplantation, and the topic of B cell biology and donor-specific antibody prevention emerged as a major area of interest to the community, leading to a highly engaged dialogue, with comments from basic and translational scientists as well as physicians (http://community.myast.org/communities/community-home/digestviewer). We have summarized this discussion from a bedside to bench perspective and have organized this review into outstanding questions within the paradigm that AMR is a leading cause of graft loss in the clinic, and points of view that challenge aspects of this paradigm. We also highlight opportunities for basic and translational scientists to contribute to the resolution of these questions, mapping important future directions for the transplant research field.

Lung Transplant Outcomes in Patients With Pulmonary Fibrosis With Telomere-Related Gene Variants

Pulmonary fibrosis (PF) is the most common disease indication for lung transplantation. Our recent work implicated an excess of rare genetic variants in the telomere-related genes TERT, RTEL1, and PARN in PF disease risk. The impact of such variants on posttransplant outcomes is uncertain. The objective of this study was to determine if patients with these PF-associated variants have altered rates of posttransplant acute rejection (AR), chronic lung allograft dysfunction (CLAD), and survival. The study cohort consisted of 262 PF lung transplant recipients previously genetically characterized by whole exome sequencing. Thirty-one patients (11.8%) had variants in TERT, RTEL1, or PARN, whereas 231 (88.2%) did not. Multivariate Cox proportional hazards models adjusted for relevant clinical variables were used to assess the outcomes of death and CLAD. The AR burden was quantified and compared over the first posttransplant year. Patients with PF with disease-associated variants in TERT, RTEL1, or PARN had a significantly higher risk of death (adjusted hazard ratio [HR], 1.82; 95%CI, 1.07-3.08; P= .03) and CLAD (adjusted HR, 2.88; 95%CI, 1.42-5.87; P= .004) than patients without these variants. There was no difference in AR burden or rates of grade 3 primary graft dysfunction between the two groups. Rare variants in the telomere-related genes TERT, RTEL1, or PARN are associated with poor posttransplant outcomes among PF lung transplant recipients. Further research is needed to understand the biological mechanisms by which telomere-related variants increase the risk for death and CLAD.

Comparing everolimus-based immunosuppression with reduction or withdrawal of calcineurin inhibitor reduction from six months after heart transplantation: the randomized MANDELA study.

In the 12-month, open-label MANDELA study, patients were randomized at month 6 after heart transplantation to (i) convert to calcineurin inhibitor (CNI)-free immunosuppression with everolimus (EVR), mycophenolic acid and steroids (CNI-free, n=71), or to (ii) continue reduced-exposure CNI, with EVR and steroids (EVR/redCNI, n=74). Tacrolimus was administered in 48.8% of EVR/redCNI patients and 52.6% of CNI-free patients at radomization. Both strategies improved and stabilized renal function based on the primary endpoint (estimated GFR at month 18 post-transplant post-randomization) with superiority of the CNI-free group versus EVR/redCNI : mean 64.1mL/min/1.73m2 versus 52.9mL/min/1.73m2 ; difference +11.3mL/min/1.73m2 (p<0.001). By month 18, estimated GFR had increased by ≥10mL/min/1.732 in 31.8% and 55.2% of EVR/redCNI and CNI-free patients, respectively, and by ≥25 mL/min/1.73m2 in 4.5% and 20.9%. Rates of biopsy-proven acute rejection (BPAR) were 6.8% and 21.1%; all cases were without hemodynamic compromise. BPAR was less frequent with EVR/redCNI versus the CNI-free regimen (p=0.015); 6/15 episodes in CNI-free patients occurred with EVR concentration <5ng/mL. Rates of adverse events and associated discontinuations were comparable EVR/redCNI from month 6 achieved stable renal function with infrequent BPAR. One-year renal function can be improved by early conversion to EVR-based CNI-free therapy but requires close EVR monitoring. This article is protected by copyright. All rights reserved.

Evaluation of graft function in renal retransplantation at Hue Central Hospital

This study aims to assess the results of kidney retransplantations and the survival of second kidney allografts performed in our center. Methodology: of 550 kidney transplantations performed since July 2001, 26 were second kidney transplants. Many recipients were sensitized. All patients were treated with the same immunosuppressive regimen. Results: grafts were functionally effective in all patients with kidney retransplantations one month after the transplant. Graft survival was 100% after one year (17/17) and after five years (1/1). Graft survival was similar for second and primary kidney transplants performed during the same period of time. There were three cases of acute rejection, but all of these cases responded to the anti-rejection treatment. Conclusions: the rate of acute rejection was similar for both second and primary transplantations in our hospital, and the second graft outcome demonstrated effectiveness 12 months after transplantation.

Inhibition of PPARα target genes during cyclosporine A-induced nephrotoxicity and hepatotoxicity

Cyclosporine A (CsA) is an immunosuppressant used to improve the rate of acute rejection and graft survival in transplant patients. However, CsA has serious adverse effects including high blood pressure as well as liver and kidney dysfunction. Although several toxicological mechanisms of CsA have been suggested, the investigations have been limited to evaluate the initiating events of CsA-induced toxicity in liver and kidney. To understand the events during initial hepatotoxicity and nephrotoxicity induced by CsA, we analyzed the comparative gene expression profiles of CsA-treated rats. We performed the microarray experiment using Affymetrix GeneChip Rat 230 2.0 array from the liver and kidney of CsA-treated rats (10 and 25 mg/kg of body weight, once daily for 4 weeks). Differentially expressed genes (DEGs) were selected using the Gene- Spring program (analysis of variance test, fold change ≥1.3), and functional analysis of the DEGs was conducted using the Ingenuity Pathways Analysis program. The most significant biofunctions of the DEGs were fatty acid oxidation, immune response, and molecular transport. In particular, fatty acid β-oxidation and lipopolysaccharide/interleukin-mediated inhibition of retinoid X receptor function were selected as significantly changed gene sets for each DEG in the liver and kidney. Fatty acid β-oxidation is closely correlated with peroxisome proliferator activated receptor α (PPARα), which regulates the expression of genes involved in lipid and glucose metabolism. In this study, Pparα was identified as a common upstream regulator of the DEGs, and the expression of genes related to lipid metabolism, as well as the damage of renal tubules, was significantly influenced by CsA treatment. We confirmed that fatty acid β-oxidation-related genes are downregulated by CsA treatment in the liver and kidney and using quantitative real-time RT-PCR. Our findings suggest that PPARα agonists may be candidates for reducing the toxicity of CsA treatment and encourage translational research.

Duration of delayed graft function and outcomes after kidney transplantation from controlled donation after circulatory death donors: a retrospective study.

The impact of the duration of delayed graft function (DGF) on graft survival is poorly characterized in controlled donation after circulatory death (DCD) donor kidney transplantation. A retrospective analysis was performed on 225 DCD donor kidney transplants between 2011 and 2016. When patients with primary nonfunction were excluded (n=9), 141 recipients (65%) had DGF, with median (IQR) duration of dialysis dependency of 6 (2-11.75)days. Longer duration of dialysis dependency was associated with lower estimated glomerular filtration rate at 1year, and a higher rate of acute rejection. On Kaplan-Meier analysis, the presence of DGF was associated with lower graft survival (log-rank test P=0.034), though duration of DGF was not (P=0.723). However, multivariable Cox regression analysis found that only acute rejection was independently associated with lower graft survival [HR (95% CI) 4.302 (1.617-11.450); P=0.003], whereas the presence of DGF and DGF duration were not. In controlled DCD kidney transplantation, DGF duration itself may not be independently associated with graft survival; rather, it may be that acute rejection associated with prolonged DGF is the poor prognostic factor.

Combined Pediatric Heart-Liver Transplant Outcomes in the US: A 25 Year National Cohort Study

Purpose Pediatric combined heart-liver transplantation (cHLTx) remains uncommon in the United States and criteria for cHLTx are unclear. The objective of this study was to review the indications, and outcomes of pediatric cHLTx. Methods Data from the Scientific Registry for Transplant Recipients heart and liver databases were used to identify 9245 pediatric heart transplants (PHTx) alone, 14134 pediatric liver transplant alone, and 20 pediatric cHLTx (16 simultaneous HLTx [same organ donor], + 4 previous heart transplants followed by liver transplant [different organ donors]) (age ≤ 21 years) between 1992 and 2017. Outcomes included patient survival, and 1-year rates of acute heart and liver rejection. Results The median age for pediatric cHLTx was 15.6 (IQR: 10.5, 17.9) years, and included 12 males (12/20=60%). In the cHLTx group, the most common indication for heart transplant was congenital heart disease (11/20=55%), and the most common indication for liver transplant was cirrhosis (9/20=45%) due to granulomatous diseases including sarcoidosis, histiocytosis or cryptogenic. Recipients of pediatric cHLTx had a similar 5-year adjusted risk of death compared to PHTx alone (p=0.9; Figure 1). The 1, 3, and 5 year actuarial survival rates in pediatric cHLTx recipients was 80%, 80%, and 80% respectively, and was similar to isolated PHTx alone (88%, 82%, and 78% respectively. There was no heart or liver rejection reported in the cHLTx group versus 9.9% in heart only and 10.6% in liver transplant only group, respectively. Conclusion Pediatric combined heart-liver transplant is an acceptable option for recipients with combined end-organ failure, with intermediate survival outcomes comparable to those of single-organ recipients with no treated heart or liver rejection reported in the first year. Pediatric combined heart-liver transplantation (cHLTx) remains uncommon in the United States and criteria for cHLTx are unclear. The objective of this study was to review the indications, and outcomes of pediatric cHLTx. Data from the Scientific Registry for Transplant Recipients heart and liver databases were used to identify 9245 pediatric heart transplants (PHTx) alone, 14134 pediatric liver transplant alone, and 20 pediatric cHLTx (16 simultaneous HLTx [same organ donor], + 4 previous heart transplants followed by liver transplant [different organ donors]) (age ≤ 21 years) between 1992 and 2017. Outcomes included patient survival, and 1-year rates of acute heart and liver rejection. The median age for pediatric cHLTx was 15.6 (IQR: 10.5, 17.9) years, and included 12 males (12/20=60%). In the cHLTx group, the most common indication for heart transplant was congenital heart disease (11/20=55%), and the most common indication for liver transplant was cirrhosis (9/20=45%) due to granulomatous diseases including sarcoidosis, histiocytosis or cryptogenic. Recipients of pediatric cHLTx had a similar 5-year adjusted risk of death compared to PHTx alone (p=0.9; Figure 1). The 1, 3, and 5 year actuarial survival rates in pediatric cHLTx recipients was 80%, 80%, and 80% respectively, and was similar to isolated PHTx alone (88%, 82%, and 78% respectively. There was no heart or liver rejection reported in the cHLTx group versus 9.9% in heart only and 10.6% in liver transplant only group, respectively. Pediatric combined heart-liver transplant is an acceptable option for recipients with combined end-organ failure, with intermediate survival outcomes comparable to those of single-organ recipients with no treated heart or liver rejection reported in the first year.

Acute Rejection (AR) and Lymphocytic Bronchiolitis (LB) in a Multicenter Lung Transplant Cohort

Purpose Despite the importance of AR and LB in lung recipients, the incidence and associated clinical factors have not been prospectively studied in a contemporary cohort. We used a multicenter lung transplant cohort to describe the incidence of AR and LB over the first posttransplant year, examine concurrent histology at the time of an AR/LB event, and determine recipient factors associated with AR or LB. Methods The cohort was drawn from CTOT-20 (NCT02631720), an observational study collecting prospective clinical outcome data on lung recipients at 5 North American centers. The first 200 enrolled, transplanted subjects with ≥1 lung biopsy within the first posttransplant year were included. Recipients were managed according to center-specific clinical care practices. Descriptive statistics were used to summarize AR or LB events and concurrent histology. Univariate Cox modeling was used to evaluate the impact of select recipient factors on the time to first occurrence of AR or LB. Results 1007 biopsies were performed over the first posttransplant year in this cohort. 56% and 17% of patients experienced at least one AR or LB episode, respectively. Rates of minimal and mild AR and minimal LB were similar on for cause vs. surveillance biopsies. While a majority of LB events were concurrent with AR, AR events generally occurred in isolation or were concurrent with non-rejection histopathology. Univariate analyses suggested a protective effect of induction immunosuppression on the risk for AR. We also observed a significant decrease in the hazard of AR and LB in bilateral, as compared to single, lung recipients (Figure). Conclusion We observed a higher incidence of AR than that reported by the ISHLT registry. This may, in part, be attributed to the practice of surveillance biopsies in all CTOT-20 centers. While the impact of induction on AR risk is consistent with ISHLT data, the novel association between transplant type and AR/LB will be further validated over extended cohort follow up using multivariable approaches.