Influence of Cytomegalovirus on the Survival of Cytomegalovirus-Seropositive Lung Transplant

BackgroundThe primary aim of this study was to analyze the survival of patients undergoing lung transplant (LT) with cytomegalovirus (CMV)-positive serologies at the time of transplantation, according to the presence of CMV events and according to the severity of these events. The secondary objective was to assess whether there are differences in the incidence of chronic lung allograft dysfunction (CLAD) according to the presence of these events.MethodsThis was an observational, single-center, retrospective study. The inclusion criterion for the study was having undergone LT at the Hospital Universitario 12 de Octubre from October 2008 to February 2019. Survival was calculated using the Kaplan-Meier method and compared using the log-rank test. The incidence of CLAD was compared using the χ² test.ResultsInclusion criteria were met by 239 LTs. In terms of survival, no difference was found between patients with and without CMV events (log-rank P = .52), with mean survival of 3223 ± 164 days and 3024 ± 146 days, respectively. Nor did we find a difference when stratifying patients according to no CMV events, infection, syndrome, and disease (log-rank P = .6). There was also no difference in the incidence of CLAD between patients with and without CMV events (P > .178).ConclusionIn patients with positive CMV serology, the development of CMV events, including severe disease, does not seem to influence survival. The incidence of CLAD also is not increased by the presence of CMV events.     

A Retrospective Study of Posttransplant Amiodarone Exposition on Clad Development and Survival After Lung Transplantation

BackgroundLung transplantation is a lifesaving procedure, still marred by worse results than other solid organ transplants. The 1-year mortality is 10%, and within 5 years after the procedure, half of patients develop chronic lung allograft dysfunction (CLAD), which also is the main limiting factor for long-term survival. Heart arrhythmias are also common directly after a lung transplant, and 1 treatment for this is the drug amiodarone. Recent research suggests that amiodarone exposure leads to activation of fibroblasts, a cell type that synthesizes stroma in the lung, associated with acute respiratory distress syndrome and CLAD. This study aims to retrospectively investigate the effect of posttransplant amiodarone treatment on survival and CLAD.Material and MethodsAll patients transplanted at Sahlgrenska University Hospital between 2007 and 2018 were reviewed, and adult patients with a follow-up within Sweden were included. Of the 394 patients who met this inclusion criteria, retrospective data concerning postoperative complications and long-term outcomes were retrieved. A multivariable Cox proportional hazards model was applied to identify a set of independently significant predictors.ResultsPosttransplant use of amiodarone was associated with shorter survival (hazard ratio = 1.65; 95% confidence interval, 1.08-2.54; P = .02). Amiodarone exposure was not associated with CLAD (hazard ratio = 0.64; 95% confidence interval, 0.33-1.22; P = .17).ConclusionsAn increased risk of death but not CLAD was observed in patients treated with amiodarone postoperatively after lung transplantation in the current cohort.     

Clopidogrel reduces post‐transplant obliterative bronchiolitis

Survival after lung transplantation is mainly limited by the development of chronic lung allograft dysfunction (CLAD). The aim of this study was to investigate if platelet inhibition by clopidogrel has an influence on the formation of obliterative bronchiolitis, the histopathological correlate to bronchiolitis obliterans syndrome, present in the majority of patients suffering from CLAD. C57Bl/6(H2^b) donor tracheas were orthotopically transplanted into CBA.J(H2^k). Mice received different doses of clopidogrel alone or in combination with tacrolimus or everolimus. Grafts were analyzed by histology and immunofluorescence method on postoperative days 15, 30 or 60. Cytokines were analyzed by real‐time polymerase chain reaction on postoperative day 21 and alloantibodies by FACS. Mice treated with 20 mg/kg/day clopidogrel for 30 days showed reduced obliteration [34.40 ± 3.76% (20 mg/kg/day clopidogrel) vs. 49.92 ± 2.11% (control), n = 5, P < 0.05]. Platelet inhibition resulted in significant lower infiltration of T cells and macrophages, and we also found significantly lower expression of IL‐12, IL‐4, IL‐6, TNF‐α, TGF‐β, PDGFβ, MCP1, P‐/E‐selectin, ICAM1 and CD40L after treatment with clopidogrel. Combination of 1 mg/kg/day clopidogrel and 0.05 mg/kg/day everolimus or 12 mg/kg/day tacrolimus revealed a synergistic effect. Humoral immunity as manifested by donor‐specific alloantibody secretion was also impaired after treatment with clopidogrel. Here, we can show that platelet inhibition by clopidogrel as a single treatment and in combination with tacrolimus or everolimus reduced the development of fibrosis and obliteration in tracheal allografts.     

Mathematical modeling of peripheral blood neutrophil kinetics to predict CLAD after lung transplantation

BackgroundThe presence of neutrophils in the lung was identified as a factor associated with CLAD but requires invasive samples. The aim of this study was to assess the kinetics of peripheral blood neutrophils after lung transplantation as early predictor of CLAD.MethodsWe retrospectively included all recipients transplanted in our center between 2009 and 2014. Kinetics of blood neutrophils were evaluated to predict early CLAD by mathematical modeling using unadjusted and adjusted analyses.Results103 patients were included, 80 in the stable group and 23 in the CLAD group. Bacterial infections at 1 year were associated with CLAD occurrence. Neutrophils demonstrated a high increase postoperatively and then a progressive decrease until normal range. Recipients with CLAD had higher neutrophil counts (mixed effect coefficient beta over 3 years = +1.36 G/L, 95% Confidence Interval [0.99–1.92], p < .001). A coefficient of celerity (S for speed) was calculated to model the kinetics of return to the norm before CLAD occurrence. After adjustment, lower values of S (slower decrease of neutrophils) were associated with CLAD (Odds Ratio = 0.26, 95% Confidence Interval [0.08–0.66], p = .01).ConclusionA slower return to the normal range of blood neutrophils was early associated with CLAD occurrence.     

Calcineurin Inhibitor–Based Maintenance Immunosuppression in Lung Transplant Recipients: Optimal Serum Levels for Managing Acute Rejection and Renal Function

BackgroundAlthough effective for curtailing alloimmune responses, calcineurin inhibitors (CNIs) have an adverse-effect profile that includes nephrotoxicity. In lung transplant (LTx) recipients, the optimal serum levels of the CNI tacrolimus necessary to control alloimmune responses and minimize nephrotoxicity are unknown.MethodsThis retrospective, single-center study reviewed tacrolimus whole blood trough levels (BTLs), grades of acute cellular rejection (ACR), acute rejection scores, and creatinine clearance (CrCl) obtained in LTx recipients within the first year after their transplant procedure. Comparisons were made between the first 90 days post LTx (when tacrolimus BTLs were maintained >10 µg/L) and the remainder of the post-LTX year (when BTLs were <10 µg/L).ResultsDespite tacrolimus mean BTLs being higher during the first 90 days post LTx compared with the remainder of the first post-LTx year (10.4 ± 0.3 µg/L vs 9.5 ± 0.3 µg/L, P < .0001) there was no association with lower grades of ACR (P = .24). The intensity of ACR (as determined by acute rejection scores) did not correlate with tacrolimus mean BTLs at any time during the first posttransplant year (P = .79). During the first 90 days post LTx there was a significant decline in CrCl and a correlation between increasing tacrolimus mean BTLs and declining CrCl (r = −0.26, P = .03); a correlation that was not observed during the remainder of the year (r = −0.09, P = .52).ConclusionsIn LTx recipients, maintaining BTLs of the CNI tacrolimus >10µg/L did not result in superior control of acute rejection responses but was associated with declining renal function.     

Clinical Outcomes of Everolimus With Reduced-Dose Tacrolimus vs Mycophenolate Mofetil With Standard-Dose Tacrolimus in De Novo ABO-Incompatible Kidney Transplant Recipients: 1-Year Follow-up

BackgroundOne of the major barriers for long-term renal graft survival is considered to be calcineurin inhibitor nephrotoxicity, contributing to chronic graft dysfunction. Thus, recent immunosuppressive strategies are focused on regimens that can reduce or avoid exposure to calcineurin inhibitors. Herein, we carried out a small-scale pilot study to assess whether everolimus (EVR) with reduced-dose tacrolimus (Tac) is an acceptable immunosuppressive regimen for patients with de novo ABO-incompatible kidney transplant compared with mycophenolate mofetil (MMF) with standard-dose Tac.MethodsThis retrospective single-center cohort study included patients who underwent ABO-incompatible kidney transplant at our institution between January 2016 and December 2019. Those whose immunosuppressive regimen was changed by reasons other than rejection during the 1-year follow-up period were excluded.ResultsA total of 24 patients were enrolled in this study: 10 patients who received an EVR with reduced-dose Tac regimen and 14 patients who received an MMF with standard-dose Tac regimen. Tac trough levels in the EVR group were significantly lower than those in the MMF group (P < .001). No patients died or lost their grafts during the follow-up period. There were no significant differences in renal function, proteinuria, and prevalence of hyperlipidemia between the 2 groups at 1 year after transplant. There were no significant differences in the incidence of rejection (acute cellular rejection, steroid-resistant acute cellular rejection, acute antibody-mediated rejection) and infection (cytomegalovirus viremia, cytomegalovirus disease, BK viremia, BK virus nephropathy) between the 2 groups.ConclusionsComparable with MMF with standard-dose Tac, EVR with reduced-dose Tac might be an acceptable immunosuppressive regimen for patients with de novo ABO-incompatible kidney transplant.     

Everolimus-Based Immunosuppression in Patients With Hepatocellular Carcinoma at High Risk of Recurrence After Liver Transplantation: A Case Series

BackgroundLiver transplantation offers the most effective treatment in patients with hepatocellular carcinoma (HCC). However, transplant patients outside the Milan criteria have a high risk of tumor recurrence, which has been linked to standard immunosuppression regimens. Everolimus is a mammalian target of rapamycin inhibitor that has been used for immunosuppression, but its effect on recurrence and survival in HCC patients with a high risk of tumor recurrence has not been examined. We compared long-term survival and cumulative recurrence in high-risk patients receiving everolimus-based immunosuppression after liver transplantation for HCC with an historic control group.MethodsThe everolimus group comprised 21 patients receiving a liver transplant at our center from February 2005 to December 2010. The control group comprised 31 patients receiving a liver transplant from May 1994 to January 2005. All patients received cyclosporine or tacrolimus as initial post-transplant immunosuppression. Patients in the everolimus group switched to everolimus 2 weeks later.ResultsThere were no differences between the two groups in number of rejection episodes or of infectious or surgical complications. Five-year survival was 60.2% in the everolimus group and 32.3% in the control group (P = .05). Five-year cumulative recurrence rate was 61.3% in the control group and 41.3% in the everolimus group. Treatment with everolimus was identified as an independent predictor of longer survival (hazard ratio = 0.34; P = .02).ConclusionsPatients receiving liver transplantation for HCC with a high risk of tumor recurrence may well benefit from everolimus-based immunosuppression, with no added risks of rejection or other post-transplant complications.     

Association of positive pre-transplant angiotensin II type 1 receptor antibodies with clinical outcomes in lung transplant recipients

IntroductionAutoantibodies against the angiotensin II type 1 receptor (AT1R-Ab) have been previously associated with de novo donor-specific antibody (DSA) formation in lung transplantation. However, data regarding the clinical significance of AT1R-Ab in long-term graft function after lung transplantation are lacking.MethodsSeventy-one patients who underwent lung transplantation between July 2016 and January 2020 were enrolled in this study. We examined the relationship between pre-transplant AT1R-Ab levels and graft function, clinical outcomes, and human leukocyte antigen (HLA) DSA levels during the first 3 years post-transplantation.ResultsSeventeen (23.9%) patients were AT1R-Ab-positive, and 54 (76.1%) were AT1R-Ab-negative. The median antibody value of the AT1R-Ab-positive group was 18 [18–22.5] U/mL, while that of the AT1R-Ab-negative group was 5.1 [3.5–8.0] U/mL (p < 0.001). There was no significant difference in the median acute cellular rejection (ACR) scores between the two groups (median [interquartile range] 1 [0.8–3] vs. 0.7 [0–1]; p = 0.145). However, there was a significant difference in the distribution of the ACR scores between the two groups (p = 0.015). Most (41.2%) patients in the pre-transplant AT1R-positive group scored above 1. The incidence of de novo DSA was also higher in AT1R-Ab-positive than in AT1R-Ab-negative patients (52.9% vs. 20.4%, p = 0.009). The incidence of chronic lung allograft dysfunction (CLAD) within 3 years was significantly higher in AT1R-Ab-positive than in AT1R-Ab-negative patients (58.3% vs. 11.8%; p < 0.001). In the multivariate Cox regression analysis, AT1R-Ab positivity (hazard ratio, 9.46; 95% confidence interval, 2.89–30.94; p < 0.001) was significantly associated with early CLAD. Furthermore, Kaplan-Meier analysis showed that AT1R-Ab-positive patients had a shorter survival time (χ² = 39.62, p < 0.001).ConclusionHigh AT1R-Ab levels in the pre-transplant serum of lung recipients were associated with the development of de novo HLA-DSA, ACR, early CLAD, and short survival.     

Gastroesophageal Reflux and Esophageal Motility Disorder After Lung Transplant: Influence on the Transplanted Graft

BackgroundEsophageal pathology has been identified as a bad prognostic factor in lung transplantation (LTx). This study aims to assess the esophageal disorders present post-LTx, under treatment with proton pump inhibitors, and their putative impact on the graft.MethodsProspective, observational study of LTx patients. Digestive factors were assessed by manometry and pH-metry at 6 months post-LTx and under proton pump inhibitor treatment. We assessed the association between esophageal disorders and graft function and acute rejection (AR) and chronic lung allograft dysfunction (CLAD).ResultsOut of 76 post-LTx patients, 27% showed gastroesophageal reflux disease (GERD), 55% showed inadequate gastric inhibition, and 59% showed esophageal motility disorders (EMDs). We observed a greater incidence of AR from 3 months post-LTx in the presence of EMD (P ≤ .05). No significant differences were observed in GERD or EMD prevalence or in survival between patients with or without CLAD. The maximum forced expiratory volume in 1 second (FEV1) achieved after bilateral LTx was significantly (P = .022) lower in patients with EMD vs without EMD.ConclusionAt 6 months post-LTx, there is a high percentage of esophageal disorders (GERD and EMDs). No esophageal disorder is associated with CLAD or with survival, although EMDs are associated with a greater incidence of AR and lower graft function.     

Randomized controlled trial assessing the impact of everolimus and low‐exposure tacrolimus on graft outcomes in kidney transplant recipients

This was a single‐center, randomized controlled trial assessing the impact of a 3‐month (10‐16 weeks) conversion to everolimus with low‐exposure tacrolimus, as compared to remaining on full exposure tacrolimus with mycophenolate (NCT 02096107). Adult kidney transplant recipients with a functioning graft were eligible for participation. Goal troughs in the intervention arm were 2‐5 ng/mL for tacrolimus and 3‐8 ng/mL for everolimus, with tacrolimus maintained at 5‐12 ng/mL in the control arm; 60 were randomized (30 in each arm) and were well matched at baseline; mean age was 51 years and 57% were African‐American. At 12‐months, fibrosis scores (27.8% tacrolimus/mycophenolate vs 22.9% tacrolimus/everolimus, P = .391), acute rejection rates (7% tacrolimus/mycophenolate vs 3% tacrolimus/everolimus, P = .554), and graft function (mean eGFR tacrolimus/mycophenolate 56 ± 15 vs tacrolimus/everolimus 59 ± 14 mL/min/1.73 m², P = .465) were similar between arms. The everolimus arm had significantly lower rates of CMV infection, severe BK infection, and improved BK viral clearance kinetics, as compared to the MPA arm. In this population, including a significant number of African‐Americans, an immunosuppression regimen of everolimus with low‐exposure tacrolimus provided similar efficacy to tacrolimus and mycophenolate, with significantly lower rates of BK and CMV.     

Role for primary immunosuppression with everolimus after pulmonary transplantation

PurposeEverolimus is a proliferation signal inhibitor used for triple immunosuppressive therapy following solid organ transplantation. Its positive benefits, such as reduction of acute rejection episodes and reduced nephrotoxicity have been shown in kidney- as well as heart transplantation. However the role of everolimus is less well defined in lung transplantation. We thus wished to study the effect of primary immunosuppression with everolimus in a preclinical large animal lung transplantation model.MethodsLeft-sided single lung transplantation from MHC-mismatched donors was performed in 11 adult minipigs. Intravenous pharmacologic immunosuppression was maintained for 28 days with 1.5 mg/kg/d methylprednisolone, 1.0 mg/kg/d azathioprine and cyclosporine A (blood levels 300-500 ng/ml; CsA group; n = 5). A further group (CsA + Ev; n = 6) received methylprednisolone, CsA (200–300 ng/ml) and Everolimus (5–10 ng/ml). Immunosuppression was discontinued on postoperative day (POD) 28. Graft survival was monitored by sequential chest X-rays, bronchoscopies and transbronchial biopsy histology.ResultsAll animals survived the 28 day course of immunosuppressive therapy and showed healthy grafts on POD 28. Median allograft survival in the CsA group was 55 ± 15 days. CsA + Ev grafts showed median survival of 49 ± 86 days (p = 0.37).ConclusionWhereas everolimus might be advantageous as maintenance immunosuppressive agent, this data does not support an important role for everolimus in the immunosuppressive induction phase following lung transplantation.     

Edema Associated With Everolimus de Novo

BackgroundThe appearance of edema limits the use of everolimus de novo together with tacrolimus and steroids in kidney transplantation. We aimed to investigate the frequency and characteristics of patients with edema and compare them according to the type of immunosuppression.MethodsWe studied 150 kidney transplant recipients between 2015 and 2017 based on receiving everolimus de novo (group A) or mycophenolic acid derivatives (group B).ResultsWe analyzed 50 patients in group A and 100 in group B. Follow-up was 26.2 ± 10 months. Fifty-six patients presented edema (37.3%): 54% in group A and 29% in group B (P = .003). Edema was mild in 74% of patients in group A and 57.1% in group B. The probability of edema was 10.1%, 22.4%, and 41% at 3, 6, and 12 months, respectively, in group A vs 10.1%, 20.3%, and 25.4% in group B (P = .006). Patients were treated mostly with diuretics (14.3% in group A vs 27.6% in group B) and discontinuation of calcium channel blockers (46.4% in group A vs 48.3% in group B). Improvement was 70.4% in group A vs 60.7% in group B; patient worsening was 0% in group A vs 10.7% in group B; and there was no change in 29.6% in group A vs 28.6% in group B. We did not find differences in patient or graft survival in those who presented edema, regardless of the treatment group.ConclusionThe use of everolimus and standard doses of tacrolimus caused edema in 54% of patients, with no impact on renal function or survival compared with mycophenolic acid derivatives. The edema was mostly of low intensity and improved in most patients.     

Early Use of Everolimus as a Third Immunosuppressive Agent for Intestinal Transplantation: A Report of 2 Cases

BackgroundIn patients with intestinal transplantation (ITx), renal function is easily impaired because of long-term parenteral nutrition and side effects of tacrolimus. Everolimus was used in patients with renal insufficiency in our study.MethodsWe administered everolimus as a third immunosuppressive agent in addition to tacrolimus and steroids for renal sparing in patients who received ITx. We assessed everolimus levels, complications, and renal function.ResultsTwo patients received everolimus after ITx. Patient 1 was a 13-year-old boy who underwent ITx for an allied disorder of Hirschsprung's disease. After induction therapy with rabbit antithymocyte globulin, maintenance therapy consisted of tacrolimus and steroids. Everolimus was introduced 3 months after ITx for renal sparing. Seven months later, the patient required partial intestinal graft resection owing to bowel obstruction. Everolimus was suspended for only 2 weeks. Four years after ITx, the trough level of tacrolimus was maintained at 3 to 5 ng/mL. The trough level of everolimus was maintained at 3 to 5 ng/mL. Patient 2 was a 32-year-old man who underwent deceased ITx for short gut syndrome. Induction and maintenance immunosuppression was the same as for patient 1. Everolimus was introduced 1 month after surgery. Two years after ITx, trough levels of tacrolimus and everolimus were the same as in patient 1. No rejection was observed in either patient, and renal function was well maintained. We observed no side effects caused by everolimus.ConclusionsEverolimus could be used safely and effectively after ITx. Early use of everolimus after ITx did not affect wound healing.     

Viremia Negativization After BK Virus Infection in Kidney Transplantation: A National Bicentric Study

BackgroundBK virus (BKV) infection represents a potentially dreadful complication after kidney transplantation (KT). When BK viremia is detected, the best therapeutic approach remains not entirely clarified. Critical elements of BK viremia treatment are immunosuppression minimization and introduction of drugs like leflunomide, everolimus, and fluoroquinolones. The study aimed to analyze the results of the BK viremia management in 2 collaborative Italian centers.MethodsTen patients undergoing KT in the 2 collaborative Italian centers of Sapienza University of Rome and University of L’Aquila from January 2013 to December 2017 and showing a post-KT diagnosis of BK viremia were retrospectively investigated.ResultsMean time from KT to BKV positivity was 7 months (range: 1-19 months). At diagnosis, the mean viral load was 683,842 copies/mL (range: 5800-4,052,415 copies/mL), with an average zenith of 2,428,410 copies/mL (range: 6762-18,022,500 copies/mL). In the 5 patients with BKV nephropathy, we observed a switch from antimetabolite to leflunomide (n = 5), a switch from tacrolimus to everolimus (n = 3), or an introduction of fluoroquinolones (n = 3). BKV clearance was achieved in 3 patients.ConclusionsEarly BKV diagnosis and stepwise minimization of immunosuppression remain the first-line approach in patients with BK viremia. In the presence of BKV nephropathy, a combination of antiviral drugs like leflunomide and fluoroquinolones/everolimus should favor viremia clearance.     

In Vitro Study Evaluating the Effect of Different Immunosuppressive Agents on Human Polyomavirus BK Replication

BackgroundHuman polyomavirus BK (BKPyV) is the etiologic agent of polyomavirus-associated nephropathy, a leading cause of kidney transplant dysfunction. Because of the lack of antiviral therapies, immunosuppression minimization is the recommended treatment. This strategy offers suboptimal outcomes and entails a significant risk of rejection. Our aim was to evaluate the effect of different immunosuppressive drugs (leflunomide, tacrolimus, mycophenolic acid, sirolimus, and everolimus) and their combinations in an in vitro model of BKPyV infection.MethodsHuman renal tubular epithelial cells were infected with BKPyV and treated with leflunomide, tacrolimus, mycophenolic acid, sirolimus, and everolimus, administered alone or in some combination thereof. Viral replication was assessed every 24 hours (up to 72 hours) by BKPyV-specific quantitative real-time polymerized chain reaction for the VIRAL PROTEIN 1 sequence in cell supernatants and by western blot analysis targeting the viral protein 1 and the glyceraldehyde 3-phosphate dehydrogenase on total protein lysates. Results were described as viral copies/mL and compared between treatments at any prespecified time point of the study.ResultsThe highest inhibitory effects were observed using leflunomide or everolimus plus mycophenolic acid (mean BKPyV replication log reduction 0.28). The antiviral effect of everolimus persisted when it was used in combination with tacrolimus (mean BKPyV replication log reduction 0.27).ConclusionsOur experience confirms that everolimus has anti-BKPyV properties and prompts future research to investigate possible mechanisms of action. It also provides a rational basis for targeted clinical trials evaluating alternative immunosuppressive modification strategies.     

Long-Term Outcomes of Everolimus Therapy in De Novo Liver Transplantation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

BackgroundRisk of nephrotoxicity in liver transplant patients on calcineurin inhibitors (CnIs) is a concern. Several controlled trials reported benefit of everolimus (EVR) in minimizing this risk when combined with a reduced CnI dose.BackgroundTo systematically review the efficacy and safety of EVR, alone or with reduced CnI dose, as compared to CnI alone post-liver transplantation.MethodsWe searched MEDLINE, Scopus, and the Cochrane Library for randomized controlled trials comparing EVR- and CnI-based regimens post-liver transplantation. Assessment of studies and data extraction were undertaken independently.ResultsEight studies were selected, describing 769 patients. Cockcroft-Gault GFR was higher at one (P = .05), 3, and 5 years (P = .030) in patients on EVR compared to those receiving CnI therapy. The composite endpoint of efficacy failure was similar between the 2 arms after 1, 3, and 5 years of study. More patients discontinued EVR due to adverse effects in 1 year; however, no difference was noted after 3 or 5 years. A higher rates of proteinuria, peripheral edema, and incisional hernia occurred in patients on EVR.ConclusionsThe analysis confirms noninferiority of EVR and reduced CnI combination. Combination regimen resulted in better renal function compared to standard CnI therapy.     

The Immunobiogram,a novel in vitro diagnostic test to measure the pharmacodynamic response to immunosuppressive therapy in kidney transplant patients

BackgroundDiagnostic tools to measure the response to individual immunosuppressive drugs for transplant patients are currently lacking. We previously developed the blood-based Immunobiogram bioassay for in-vitro characterization of the pharmacodynamic response of patients' own immune cells to a range of immunosuppressants. We used Immunobiogram to examine the association between patients' sensitivity to their prescribed immunosuppressants and clinical outcome.MethodsWe conducted an international, multicenter, observational study in a kidney transplant population undergoing maintenance immunosuppressive therapy. Patients were selected by clinical course poor [PCC] N = 53 (with renal dysfunction, and rejection signs in biopsy or/and an increase in DSA strength in last 12 months) versus good [GCC] N = 50 (with stable renal function and treatment, no rejection and no DSA titers). Immunobiogram dose-response curve parameters were compared between both subgroups in patients treated with mycophenolate, tacrolimus, corticosteroids, cyclosporine A or everolimus. Parameters for which significant inter-group differences were observed were further analyzed by univariate and subsequent multivariate logistic regression.ResultsClinical outcome was associated with following parameters: area over the curve (AOC) and 25% (ID25) and 50% (ID50) inhibitory response in mycophenolate, tacrolimus, and corticosteroid-treated subgroups, respectively. These statistically significant associations persisted in mycophenolate (OR 0.003, CI95% <0.001–0.258; p = 0.01) and tacrolimus (OR < 0.0001, CI95% <0.00001–0.202; p = 0.016) subgroups after adjusting for concomitant corticosteroid treatment, and in corticosteroid subgroup after adjusting for concomitant mycophenolate or tacrolimus treatment (OR 0.003; CI95% <0.0001–0.499; p = 0.026).ConclusionsOur results highlight the potential of Immunobiogram as a tool to test the pharmacodynamic response to individual immunosuppressive drugs.     

Antithymocyte Globulin Treatment for Chronic Lung Allograft Dysfunction in Lung Transplant Recipients: Experience From a National Reference Transplant Center

BackgroundChronic lung allograft dysfunction (CLAD) is the leading cause of mortality after the first year of transplantation and treatments can have little impact on CLAD progression in some cases. The objective of this study was to evaluate the effectiveness and safety of antithymocyte globulin (ATG) in lung transplant recipients with CLAD.MethodsWe reviewed all patients from our center that had undergone a lung transplant between 2008 and 2019 and selected those with CLAD who were treated with ATG. The closest lung function (forced expiratory volume in the first second) to the ATG administration was recorded, as well as the values 3, 6, and 12 months before and after treatment. We followed and recorded survival during the 12 months after treatment.ResultsA total of 13 patients with CLAD received ATG treatment. A favorable positive response to treatment (improvement or stabilization on lung function) was achieved in half of the patients. Most patients (71%) who responded well to ATG were in CLAD stage 1 to 2. The fall slope of forced expiratory volume in the first second is better after treatment. The median survival was 27 months, and we found a trend toward better survival in early CLAD stages 1 to 2. There were also differences in survival between rapid decliners and nonrapid decliners.ConclusionsATG treatment could play a role in patient with CLAD who do not respond to conventional therapies. The effect of cytolytic therapy with ATG is clearly better in those patients in early stages, with little effect in those in CLAD stage 3.     

A Randomized Controlled Trial of Envarsus Versus Immediate Release Tacrolimus in Kidney Transplant Recipients With Delayed Graft Function

BackgroundThe incidence of delayed graft function (DGF) among kidney transplant recipients (KTRs) in the United States continues to increase. The effect of immediate-release tacrolimus (tacrolimus) compared with extended-release tacrolimus (Envarsus) among recipients with DGF is unknown.MethodsThis was a single-center open-label randomized control trial among KTRs with DGF (ClinicalTrials. gov, NCT03864926). KTRs were randomized either to continue on tacrolimus or switch to Envarsus at a 1:1 ratio. Duration of DGF (study period), number of dialysis treatments, and need for adjustment of calcineurin inhibitor (CNI) doses during the study period were outcomes of interest.ResultsA total of 100 KTRs were enrolled, 50 in the Envarsus arm and 50 in the tacrolimus arm; of those, 49 in the Envarsus arm and 48 in the tacrolimus arm were included for analysis. There were no differences in the baseline characteristics, all P > .5, except donors in the Envarsus arm had higher body mass index (mean body mass index 32.9 ± 11.3 vs 29.4 ± 7.6 kg/m² [P = .007]) compared with the tacrolimus arm. The median duration of DGF (5 days vs 4 days, P = .71) and the number of dialysis treatments (2 vs 2, P = .83) were similar between the groups. However, the median number of CNI dose adjustments during the study period in the Envarsus group was significantly lower (3 vs 4, P = .002).ConclusionsEnvarsus patients had less fluctuation in the CNI level, requiring fewer CNI dose adjustments. However, there were no differences in the DGF recovery duration or number of dialysis treatments.