Acute Antibody-mediated Rejection Research Articles

Treatment of antibody-mediated rejection with double-filtration plasmapheresis, low dose IVIg plus rituximab after kidney transplantation.

Antibody-mediated rejection (ABMR) at early or late post-transplantation remains challenging. We performed a single-center single-arm study where four cases of acute ABMR and nine cases of chronic active ABMR (defined by Banff classification) were treated with double-filtration plasmapheresis (two cycles of three consecutive daily sessions with a 4-day gap between). At the end of the third and sixth DFPP sessions, the patients received rituximab 375 mg/m2 . After a median follow-up of 1078 (61-1676) days, kidney-allograft survival was 50%. Before DFPP/rituximab therapy, the median donor-specific alloantibody (DSA) mean fluorescence intensity (MFI) was 9160 (4000-15 400); 45 days (D45) later it had significantly decreased to 7375 (215-18 100) (P=.018). In addition, at one-year (Y1) post-therapy, MFI had decreased further, that is, 4060 (400-7850) (P=.001). In two patients, DSA MFIs decreased and remained below 2000. The slope of estimated glomerular-filtration rate within the 6 months preceding intervention was -1.18 mL/min/month and remained unchanged at -1.29 mL/min/month within the year after intervention. Proteinuria remained unchanged. Baseline Banff scores on repeat allograft biopsies (post-therapy D45, Y1) did not show any improvement. Side-effects were mild to moderate. We conclude that the combined DFPP/rituximab significantly decreased DSAs in ABMR kidney-transplant recipients but did not improve renal function or renal histology at 1-year follow-up.

Donor-Derived Cell-Free DNA Predicts De Novo DSA after Heart Transplantation

PurposeDevelopment of de novo donor-specific HLA antibodies (dnDSA) may contribute to allograft injury and dysfunction, antibody-mediated rejection (ABMR), and potential development of cardiac allograft vasculopathy (CAV). Elevated plasma donor-derived cell-free DNA (dd-cfDNA) levels have been demonstrated during acute cellular rejection (ACR) and ABMR events after heart transplant (HT). The purpose of this study is to investigate the relationship between dd-cfDNA and subsequent DSA development.MethodsFrom the 916 HT patients enrolled in the Surveillance Heart Care Outcome Registry (SHORE), we reviewed 2136 samples of dd-cfDNA surveillance monitoring. Patients with ACR or ABMR on biopsy were excluded from analysis. The dnDSAs included HLA Class I and/or Class II epitopes and were analyzed to development of first dnDSA or last negative test, with censoring at 365 days. There were 613 DSA samples paired with dd-cfDNA levels that were obtained within 30 days of the DSA draw, with prior negative endomyocardial biopsy. Cox proportional hazards model fitting was utilized with dd-cfDNA as a covariate (p<0.05).ResultsFrom analysis of 613 paired samples, 127 (20.7%) demonstrated dnDSA with an associated median dd-cfDNA of 1.20% (IQR: 0.100 - 3.10%). 71 (11.6%) were associated with dnDSA Class I and 93 (15.2%) with Class II. When dichotomized for dd-cfDNA > 0.15%, [FIGURE] the positive likelihood ratio for development of Class I and/or Class II dnDSA (+LR) was 4.47 (p=0.03). When analyzed without censoring at 365 days, using dd-cfDNA at this cutoff, the +LR was 5.68 (p=0.02).ConclusionIn the prospective SHORE cohort, elevated dd-cfDNA levels > 0.15% were associated with increased likelihood for the subsequent development of dnDSA within the first year after heart transplantation. Development of de novo donor-specific HLA antibodies (dnDSA) may contribute to allograft injury and dysfunction, antibody-mediated rejection (ABMR), and potential development of cardiac allograft vasculopathy (CAV). Elevated plasma donor-derived cell-free DNA (dd-cfDNA) levels have been demonstrated during acute cellular rejection (ACR) and ABMR events after heart transplant (HT). The purpose of this study is to investigate the relationship between dd-cfDNA and subsequent DSA development. From the 916 HT patients enrolled in the Surveillance Heart Care Outcome Registry (SHORE), we reviewed 2136 samples of dd-cfDNA surveillance monitoring. Patients with ACR or ABMR on biopsy were excluded from analysis. The dnDSAs included HLA Class I and/or Class II epitopes and were analyzed to development of first dnDSA or last negative test, with censoring at 365 days. There were 613 DSA samples paired with dd-cfDNA levels that were obtained within 30 days of the DSA draw, with prior negative endomyocardial biopsy. Cox proportional hazards model fitting was utilized with dd-cfDNA as a covariate (p<0.05). From analysis of 613 paired samples, 127 (20.7%) demonstrated dnDSA with an associated median dd-cfDNA of 1.20% (IQR: 0.100 - 3.10%). 71 (11.6%) were associated with dnDSA Class I and 93 (15.2%) with Class II. When dichotomized for dd-cfDNA > 0.15%, [FIGURE] the positive likelihood ratio for development of Class I and/or Class II dnDSA (+LR) was 4.47 (p=0.03). When analyzed without censoring at 365 days, using dd-cfDNA at this cutoff, the +LR was 5.68 (p=0.02). In the prospective SHORE cohort, elevated dd-cfDNA levels > 0.15% were associated with increased likelihood for the subsequent development of dnDSA within the first year after heart transplantation.

In the Current Era, Heart-Liver Transplantation May Not Protect Against Acute and Chronic Rejection

<h3>Purpose</h3> Heart-liver transplant (HLvTx) has been demonstrated to show an immune protective effect with the transplanted liver protecting the heart. There are several reports suggesting less rejection in the HLvTx group. It has not been established whether this benefit is present in the current era. <h3>Methods</h3> Between 2007 and 2017, we assessed 13 HLvTx patients compared to heart alone patients (HATx, n=758). Patients were assessed for freedom from 1-year rejection [acute cellular rejection (ACR) and antibody-mediated rejection (AMR)] and donor-specific antibodies (DSA). Other endpoints included 5-year survival and freedom from cardiac allograft vasculopathy (CAV, stenosis ≥30% by angiography) and non-fatal major adverse cardiac event (NF-MACE: myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke). <h3>Results</h3> HLvTx compared to HATx showed similar freedom from 1-year rejection (ACR, AMR) and DSA. 5-year survival, freedom from CAV and NF-MACE were also similar between the two groups (see table). <h3>Conclusion</h3> In the current era, HLvTx does not appear to provide immune protection in either rejection or CAV. A larger number of heart-liver transplant patients will be needed to confirm these findings.

Apparent Immune Effect of Clostridium Difficile in Post-Heart Transplant Recipients

<h3>Purpose</h3> Heart transplant patients develop many opportunistic infections due to chronic immunosuppression. One of the more common complications is that of <i>Clostridium difficile</i> (CDif) causing gastroenteritis, usually represented as diffuse diarrhea. It appears that these opportunistic infections such as CDif may have an impact on the immune system via the microbiome. It has not been demonstrated whether patients who develop CDif are at higher risk for the subsequent development of rejection or chronic rejection known as cardiac allograft vasculopathy (CAV) years after the event. <h3>Methods</h3> Between 2010 and 2018, we assessed 69 heart transplant patients who developed CDif within the first year post-transplant. These patients were assessed for subsequent 3-year survival, 3-year freedom from CAV (stenosis ≥30% by angiography), 3-year freedom from non-fatal major adverse cardiac event (NF-MACE: MI, new CHF, PCI, ICD implant, stroke), and 1-year freedom from acute cellular rejection (ACR) and antibody-mediated rejection (AMR). These patients were compared to a group (case controlled for time from transplant, age, gender) who did not develop CDif. <h3>Results</h3> The average time of infection following transplant was 2.2 ± 3.0 months. The heart transplant patients who developed CDif had significantly lower subsequent 3-year survival, 3-year freedom from NF-MACE, and lower 1-year freedom from AMR compared to the control group. There was no significant difference in the development of CAV (see table). Assessment of specific immunosuppression, antibiotic prophylaxis, and specific CDif treatment did not have an impact on outcome. <h3>Conclusion</h3> Heart transplant patients who developed first-year CDif appeared to have immune modulation that adversely affects subsequent outcome. Further investigation to study the microbiome is needed in order to elucidate the mechanisms that are in process.

Early Antibody-Mediated Rejection in Non-Pre-Sensitized Heart Transplant Recipient

Introduction Antibody-mediated rejection (AMR) is an important cause of allograft dysfunction. It usually occurs after the first month of heart transplant (HT), but an early presentation is possible. We present an unusual case of a female HT recipient who had early AMR with no evidence of pre-sensitization to the donor. Case Report A woman, 45 years old, idiopathic dilated cardiomyopathy, two kids, with previous negative panel reactive antibody (PRA) was submitted to HT with success. The prospective crossmatch was negative and she did not receive blood cells during the surgery. The donor was a woman, 47 years old, who had a hemorrhagic stroke. After the procedure, she needed low doses of vasoactive drugs, received immunosuppression therapy according to institutional protocol and maintained normal ventricular function. On the 5th day, she developed biventricular graft dysfunction (left ventricular ejection fraction of 40%) requiring inotropes. The PRA revealed a donor specific antibody (DSA) not previously detected and the result of endomyocardial biopsy (EMB) confirmed acute AMR (pAMR2). Patient was successfully treated with methylprednisolone, plasmapheresis, immunoglobulin and rituximab. Biventricular function recovered; no DSA was detected and new EMB showed no rejection findings. Summary AMR results from recipient antibodies against donor-HLA antigens, causing complement activation, inflammation and injury to the allograft endothelium. In general, it occurs in the first two months after HT due to a rise in DSA by the contact with donor-HLA antigens. Early AMR, that occurs in the first week, is related to pre-sensitization to donor HLA antigens and associated with graft dysfunction. In this case report, no previous antibody had been detected. Two possibilities could explain such findings: the presence of non-HLA antibodies or the presence of memory B cells with levels of DSA too low to be detected on PRA. This case highlights the importance of monitoring antibodies in HT recipients with early allograft dysfunction even with previous negative PRA.

Longitudinal profiling of circulating miRNA during cardiac allograft rejection: a proof-of-concept study.

AimsAllograft rejection following heart transplantation (HTx) is a serious complication even in the era of modern immunosuppressive regimens and causes up to a third of early deaths after HTx. Allograft rejection is mediated by a cascade of immune mechanisms leading to acute cellular rejection (ACR) and/or antibody‐mediated rejection (AMR). The gold standard for monitoring allograft rejection is invasive endomyocardial biopsy that exposes patients to complications. Little is known about the potential of circulating miRNAs as biomarkers to detect cardiac allograft rejection. We here present a systematic analysis of circulating miRNAs as biomarkers and predictors for allograft rejection after HTx using next‐generation small RNA sequencing.Methods and resultsWe used next‐generation small RNA sequencing to investigate circulating miRNAs among HTx recipients (10 healthy controls, 10 heart failure patients, 13 ACR, and 10 AMR). MiRNA profiling was performed at different time points before, during, and after resolution of the rejection episode. We found three miRNAs with significantly increased serum levels in patients with biopsy‐proven cardiac rejection when compared with patients without rejection: hsa‐miR‐139‐5p, hsa‐miR‐151a‐5p, and hsa‐miR‐186‐5p. We identified miRNAs that may serve as potential predictors for the subsequent development of ACR: hsa‐miR‐29c‐3p (ACR) and hsa‐miR‐486‐5p (AMR). Overall, hsa‐miR‐486‐5p was most strongly associated with acute rejection episodes.ConclusionsMonitoring cardiac allograft rejection using circulating miRNAs might represent an alternative strategy to invasive endomyocardial biopsy.

Removal of Anti-Thymocyte Globulin by Plasma Exchange in ABO-Incompatible and Positive Crossmatch Kidney Transplant Recipients

BackgroundRecipients of ABO-incompatible (ABOI) and positive crossmatch (PXM) kidney transplants are at high risk for antibody-mediated acute rejection. Despite aggressive immunosuppression in high-risk patients, the incidence of acute rejection remains considerably higher than in other groups. No published studies have examined plasma concentrations of anti-thymocyte globulin (ATG) in patients undergoing plasma exchange. The objectives of this study were to compare plasma ATG concentrations before and after plasma exchange in ABOI and PXM kidney transplant patients to determine the amount removed. Materials and MethodsThis prospective pharmacokinetic evaluation enrolled 10 patients undergoing ABOI or PXM kidney transplant at an academic medical center. Blood and waste plasma samples from 5 patients were assayed for total and active ATG concentrations. Patient records were monitored for renal function and rejection rates in the first 6 months post-transplant. ResultsTotal ATG concentrations decreased a mean of 59.78 ± 13.91% after each plasma exchange session, and active ATG levels decreased a mean of 56.8 ± 17.08%. Mean daily concentrations reflect a lack of expected ATG accumulation. Only 1 of 4 patients had detectable ATG concentrations after 30 days. After 6 months, the incidence of acute rejection in this sample was 44% and graft survival was 89%. ConclusionsThis is the first study to show that plasma exchange removes a substantial amount of ATG in high-risk kidney transplant patients. Based on these results, we believe these high-risk patients have been traditionally underdosed.

A Safe Anti-A2 Titer for a Successful A2 Incompatible Kidney Transplantation: A Single-center Experience and Review of the Literature.

Background.Kidney allocation system allows blood type B candidates accept kidneys from A2/A2B donors. There is no mandate by UNOS on which the anti-A2 level is acceptable. We aimed to investigate the safety of kidney transplant in blood group B patients with anti-A2 titers ≤16.Methods.We performed 41 A2-incompatible kidney transplants in blood group B recipients between May 2015 and September 2019. Clinical outcomes were compared with a control group of 75 blood group B recipients who received blood group compatible kidney transplantation at the same period.Results.Of the 41 recipients, 85% were male, 48% African American, with a median age of 53 (20–73) y. Thirty-eight (93%) were deceased-donor and 3 (7%) were living-donor kidney transplant recipients. Pretransplant anti-A2 IgG titers were 2 in 16, 4 in 9, 8 in 6, and 16 in 5 and too weak to titer in 5 recipients. Eight patients had pretransplant donor-specific antibodies. During a median follow-up of 32.6 mo (6–57.3) patient and graft survival were 100% and 92% in the A2-incompatible kidney transplant group, and 91% and 92% in the blood group compatible group, respectively. Twelve A2-incompatible recipients underwent a 21 clinically indicated kidney biopsies at a median 28 d (6–390) after transplantation. None of the patients developed acute antibody-mediated rejection and 2 patients (5%) had acute T-cell–mediated rejection. Interestingly, peritubular capillary C4d positivity was seen in 7 biopsies which did not have any findings of acute rejection or microvascular inflammation but not in any of the rejection-free biopsies in the control group. C4d positivity was persistent in 5 of those patients who had follow-up biopsies.Conclusions.A2-incompatible transplantation is safe in patients with anti-A2 titers ≤16 with excellent short-term kidney allograft outcomes. C4d positivity is frequent in allograft biopsies without acute rejection.

ABO-Incompatible Living-Donor Kidney Transplantation in a Developing Country: A Multicenter Experience in Malaysia

Malaysia has a low deceased-donor donation rate and has not embarked on a paired kidney exchange program; therefore, ABO-incompatible and HLA-incompatible transplantation remain the main contributor to the sustainability of the national kidney transplantation (KT) program. There were 26 cases of ABO-incompatible KTs performed from 2011 to 2018 in 3 major transplant centers, namely, Hospital Kuala Lumpur, University Malaya Medical Centre, and Prince Court Medical Centre. We collected perioperative and follow-up data through June 2019. The desensitization protocol varies and is center specific: the localized Japanese protocol and Swedish protocol with a target anti-A/B isoagglutinin titer of 16 or 32 on the day of transplant. The induction and tacrolimus-based maintenance protocol was nearly identical. The median follow-up time was 62.3 months (interquartile range, 37.0-79.7). Fifteen subjects had the highest predesensitization anti-A/B titer of ≥32 (57.7%). The acute cellular rejection and antibody-mediated rejection incidence were 12.5% (3 cases) and 8.3% (2 cases), respectively. Patient, graft, and death-censored graft survival rates were 96.2%, 92.3%, and 96.0%, respectively, 1 year post-living-donor KT (LDKT) and 96.2%, 87.2%, and 90.7%, respectively, 5 years post-LDKT. Our experience shows that ABO-incompatible LDKT using a suitable desensitization technique could be a safe and feasible choice for LDKT even with varied desensitization regimens for recipients with relatively high baseline isoagglutinin titers.

An open-label randomized clinical trial to evaluate the efficacy of everolimus versus tacrolimus in triple maintenance immunosuppressive therapy for kidney transplant patients.

Tacrolimus (TAC), a calcineurin inhibitor, and everolimus (EVL), an mTOR inhibitor, have been used as immunosuppressive (ISS) drugs in post-kidney transplantation therapy. The objective of this study was to compare the efficacy of EVL vs TAC in the ISS maintenance triple therapy. Ninety-seven kidney transplant patients, who received triple maintenance therapy with TAC, mycophenolate mofetil (MMF), and methyl prednisone (PRED), were evaluated. After four months of post-kidney transplant therapy, 30 patients enrolled in a randomized controlled clinical trial, in which 16 patients received TAC+MMF+PRED (cohort 1), and 14 patients switched to EVL+MMF+PRED (cohort 2). The patients were followed-up for 36 months. Two patients from cohort 1 lost their grafts after one year due to non-adherence. Two patients from cohort 2 had intolerance to mTOR inhibitors and were switched back to TAC from EVL. One case (6.25%) in cohort 1 and three cases (21.43%) in cohort 2 of acute T-cell-mediated rejection was observed. Antibody-mediated acute rejection (ABMAR) was observed in four patients (25.0%) in cohort 1, and antibody-mediated chronic rejection (ABMCR) was observed in two patients (12.50%). One patient from cohort 2 lost the graft after 15 months due to polyomavirus infection. The graft survival rate was 87.50% in cohort 1 and 92.86% in cohort 2. This clinical trial showed that the EVL+MMF+PRED triple maintenance therapy was efficacious compared with TAC during 32 months of follow-up. However, further studies are needed to confirm the efficacy of this regimen for long-term graft survival.

MicroRNAs as theranostic markers in cardiac allograft transplantation: from murine models to clinical practice.

Congestive heart failure affects about 23 million people worldwide, and cardiac allograft transplantation remains one of the last options for patients with terminal refractory heart failure. Besides the infectious or oncological complications, the prognosis of patients after heart transplantation is affected by acute cellular or antibody-mediated rejection and allograft vasculopathy development. Current monitoring of both conditions requires the performance of invasive procedures (endomyocardial biopsy sampling and coronary angiography or optical coherence tomography, respectively) that are costly, time-demanding, and non-comfortable for the patient.Within this narrative review, we focus on the potential pathophysiological and clinical roles of microRNAs (miRNAs, miRs) in the field of cardiac allograft transplantation. Firstly, we provide a general introduction about the status of cardiac allograft function monitoring and the discovery of miRNAs as post-transcriptional regulators of gene expression and clinically relevant biomarkers found in the extracellular fluid. After this general introduction, information from animal and human studies are summarized to underline the importance of miRNAs both in the pathophysiology of the rejection process, the possibility of its modulation by altering miRNAs levels, and last but not least, about the use of miRNAs in the clinical practice to diagnose or predict the rejection occurrence.

Phasing out the pre-transplant cytotoxicity crossmatch: Are we missing something?

Introduction: The anti-human globulin-enhanced complement-dependent cytotoxicity crossmatch (AHG-CDCXM) assay has been used to assess the presence of donor-specific antibodies (DSA) in recipient’s serum before kidney transplantation. The flow cytometric crossmatch (FCXM) assay was first introduced as an additional test. The aim of this study was to clinically validate the single use of the FCXM assay.Methods: This study compared the outcomes of a cohort of kidney transplant patients that underwent FCXM only (FCXM group) versus a cohort of kidney transplant patients that underwent AHG-CDCXM (control group).Results: Ninety-seven patients in the FCXM group and 98 controls were included. All crossmatches in the control group were negative. One patient in the FCXM group had a positive B cell crossmatch. One year after transplantation, there were no significant differences in patient survival (p = 0.591) and graft survival (p = 0.692) between the groups. Also, no significant difference was found in the incidence of Banff ≥ 1A acute cellular rejection episodes (p = 0.289). However, acute antibody-mediated rejections occurred in 3 controls (p = 0.028).Conclusion: The results showed that discontinuing the AHG-CDCXM assay does not modify the clinical outcomes in a 1-year follow-up.

Kidney re-transplantation in a child across the barrier of persisting angiotensin II type I receptor antibodies

BackgroundApproximately 20% of antibody-mediated rejection (ABMR) episodes in the absence of donor-specific antibodies against human leucocyte antigens (HLA-DSA) in pediatric and adult kidney transplant recipients are associated with, and presumably caused by, antibodies against the angiotensin type 1 receptor (AT1R-Ab). While the role of AT1R-Ab for ABMR and graft failure is increasingly recognized, there is little information available on the management of these patients for re-transplantation over the barrier of persisting AT1R-Ab.CaseWe report on a male patient with kidney failure in infancy due to obstructive uropathy who had lost his first kidney transplant due to AT1R-Ab-mediated chronic ABMR. Because this antibody persisted during 4 years of hemodialysis, for the 2nd kidney transplantation (living-related transplantation from his mother), he underwent a desensitization regimen consisting of 15 plasmapheresis sessions, infusions of intravenous immunoglobulin G and thymoglobulin, as well as pharmacological blockade of the Angiotensin II (AT II) pathway by candesartan. This intense desensitization regimen transiently decreased elevated AT1R-Ab titers, resulting in stable short-term kidney allograft function. The subsequent clinical course, however, was complicated by acute cellular rejection and chronic ABMR due to persistent AT1R-Ab and de novo HLA-DSA, which shortened allograft survival to a period of only 4 years.ConclusionThis case highlights the difficulty of persistently decreasing elevated AT1R-Ab titers by a desensitization regimen for re-transplantation and the detrimental effect of the interplay between AT1R-Ab and HLA-DSA on kidney transplant survival.

Long-Term Outcome of ABO-Incompatible Kidney Transplantation in Patients Treated With Low-Dose Rituximab Regimen

BackgroundIntroduction of rituximab in the desensitization protocols for ABO-incompatible (ABOI) kidney transplantation (KTX) has afforded excellent results. However, the acceptability of minimal dosage of rituximab in these protocols remains to be defined. MethodsSixty-three patients who underwent ABOI KTX were included in this study. The desensitization protocol consisted of plasmapheresis, tacrolimus, mycophenolate mofetil, methylprednisolone, intravenous immunoglobulin, basiliximab, and low-dose rituximab (100 mg/body). We evaluated the efficacy, safety, and long-term outcome of this protocol (group R, n = 39) and compared them with those of patients who underwent splenectomy (group S, n = 24). ResultsGraft and patient survival at 10 years after KTX were comparable between the groups (94.4% [group R] vs 95.4% [group S] and 94.6% [group R] vs 95.8% [group S], respectively). The incidence of acute antibody-mediated rejection (AAMR) was similar in the 2 groups (10.2% vs 12.5%). There were no significant differences in the incidence of chronic active antibody-mediated rejection. Of the patients, 7 developed AAMR and 3 of these patients (1 in group R and 2 in group S) lost their grafts. There were no significant differences in the incidence of chronic active antibody-mediated rejection. The incidence of postoperative cytomegalovirus infection in group R was significantly lower than that in group S. Furthermore, the incidence of postoperative late-onset neutropenia was low in group R. ConclusionsA low-dose rituximab regimen for ABOI KTX is acceptable for preventing AAMR with a low incidence of delayed adverse events.

Combined impact of pre-sensitization and delayed graft function on the development of allograft rejection in deceased donor kidney transplantation: nationwide cohort study

Background: Both pre-sensitization to human leukocyte antigen and delayed graft function (DGF) is well documented to be asso ciated with poor allograft outcome. The aim of this study is to investigate whether development of DGF and pre-transplant highly sensitization has synergistic adverse effect on the allograft outcome after deceased donor kidney transplantation (DDKT) using Korean Transplant Registry (KOTRY) database, the nationwide prospective cohort. Methods: Between May 2014 and June 2019, total 1,945 DDKT were registered in KOTRY database and out of them, 1,370 cases were included in this study. According to pre-sensitization status and development of DGF post-transplant, they were divided into four groups: non-pre-sensitized-DGF(-) (n=1,100), non-pre-sensitized-DGF(+) (n=133), pre-sensitized-DGF(-) (n=116), and pre-sen sitized-DGF(+) (n=21). We compared allograft rejection, the change of allograft function, allograft survival, patient survival, and post-transplant complications across four groups. Results: The incidence of overall biopsy-proven rejection and acute antibody-mediated rejection (ABMR) was significantly higher in the pre-sensitized-DGF(+) group than the other three groups. In addition, multivariable analysis demonstrated that pre-sensi tization combined with DGF is an independent risk factor for both overall rejection and ABMR compared to non-pre-sensitized- DGF(-) group (hazard ratio, 10.769; 95% confidence interval, 3.717-31.198; P<0.001). Moreover, DGF and pre-sensitization showed statistically significant interaction each other (P for interaction <0.001). Pre-sensitization combined with DGF did not show a significant impact on allograft function and allograft or patient survival in this study. Conclusions: In conclusion, pre-sensitization and DGF show a synergistic adverse impact on the post-transplant allograft out come in terms of allograft rejection after DDKT. Therefore, we suggest when DGF occurred in DDKT with pre-sensitization, more careful monitoring or surveillance for allograft rejection is required.

Acute antibody mediated rejection associated with acute herpetic gingiva-stomatitis in kidney transplant patient: A case report

Introduction: Antibody-mediated rejection (AMR) is the most serious cause of renal allograft loss. Most of the acute AMR attacks occur within the first week post-transplant. Subject: In this case report, we present a case of AMR that occurred five months post-transplant in association with acute oral viral infection. This patient had history of bone marrow hypoplasia two months following onset of hemodialysis and was maintained on cyclosporine and prednisolone beside switch to hirudin as anticoagulant. During that period, she also received 6 units of whole blood till she underwent kidney transplant after 2 years on dialysis. The post-transplant course was uneventful till the patient developed severe acute herpetic gingivastomatitis 5 months post-transplant that was associated with abrupt rise of renal chemistry. Biopsy proven AMR showed resistance to treatment with plasma exchange [PE] and Intravenous immunoglobulins. The patient was readmitted to regular hemodialysis unit for 2 months together with minimization of immunosuppressive treatment. Outcome: During routine follow-up investigations, kidney function tests became near to the pre-rejection levels. We discontinued dialysis and re-administered the initial immunosuppressive regimen. Conclusion: This is the first reported case of AMR in association with acute Herpes simplex infection that shows delayed spontaneous recovery.

Free Airway C4d after Lung Transplantation - A Quantitative Analysis of Bronchoalveolar Lavage Fluid

In recent years, the utility of vascular complement factor 4d (C4d) deposition as diagnostic tool for antibody mediated rejection (AMR) after lung transplantation, has become a controversial issue. We aimed to pinpoint the problematic nature of C4d as biomarker with a simple experiment.We quantified C4d in broncho-alveolar lavage (BAL) of lung transplant patients with diverse post-transplant complications in 3 different settings of clinically clear cases of: 1/ chronic lung allograft dysfunction (CLAD); 2/ acute complications acute rejection (AR), lymphocytic bronchiolitis (LB), antibody-mediated rejection (AMR) and respiratory infection (INF); 3/ patients with parallel C4d immunostaining and Anti-HLA. All groups were compared to BAL of stable patients. C4d was measured via standard ELISA.C4d was increased in CLAD, predominantly in RAS (p = 0.0026) but not in BOS (p = 0.89). C4d was increased in all acute events, AR (p = 0.0025), LB (p < 0.0001), AMR (p = 0.0034), infections (p < 0.0001). In patients with parallel C4d immunostaining and serum HLA antibodies, C4d was increased in C4d-/HLA- (p = 0.0011); C4d-/HLA+ (p = 0.013); HLA+/C4d + (p = 0.0081). A correlation of systemic C-reactive protein (CRP) with C4d was found in all patients (r = 0.49; p < 0.0001). We hypothesize that free C4d in BAL may only be representative of a general immune response in the transplanted lung.

De novo HLA Class II antibodies are associated with the development of chronic but not acute antibody-mediated rejection after liver transplantation - a retrospective study.

Donor-specific antibodies (DSA) cause antibody-mediated rejection (AMR); however, their pathogenic role has not yet been adequately investigated after liver transplantation. The aim of our study was to analyse the clinical significance of DSA and complement-binding DSA for the prediction of AMR after liver transplantation. Our cohort included 120 liver recipients with assessed protocol biopsies one year post-transplant. All patients had defined HLA-specific and complement-binding (C1q+and C3d+) antibodies before and in regular intervals after transplantation. The incidence of DSA was evaluated in relation with clinical and histopathological data in the liver allografts. A higher occurrence of acute AMR was observed in recipients with preformed complement-binding DSA to HLA Class I antigens. Patients who developed chronic AMR had more frequently de novo-produced antibodies against HLA Class II antigens (P=0.0002). A correlation was also found between de novo-formed C1q+and C3d+-binding antibodies to HLA Class II antigens and the development of chronic AMR (P=0.043). Our study implies that preformed complement-binding DSA to HLA Class I antigens are related to increased risk of acute antibody-mediated rejection, while chronic AMR is more frequent in patients with de novo-produced antibodies to HLA Class II antigens after liver transplantation.

The effect of pre-transplant and post-transplant anti-AT1R antibodies in heart transplant recipients

BackgroundThe presence of autoantibodies to angiotensin 2 type 1 receptor (anti-AT1R) have been implicated in allograft pathobiology following organ transplantation. While the significance of these antibodies has been described in renal transplantation, relatively few studies have examined their frequency and clinical implications in heart transplant patients. MethodsWe analyzed serum collected from 291 heart transplant recipients at the time of transplantation for the presence of anti-AT1R and repeated testing on serum collected from 176 of these patients following transplantation. Patients were followed for outcomes including overall survival, rejection episodes (acute cellular and antibody mediated), coronary allograft vasculopathy, and measures of allograft structure and cardiac function. ResultsAnti-AT1R was detected in the serum of 165/291 patients pre-transplant and in 86/176 patients post-transplant. The detection of anti-AT1R (either at risk or positive) compared with no detection in serum of patients pre- or post-transplantation had no influence on 10-year survival (Log rank 0.061 and 0.228, detection pre- or post-transplant, respectively). Similarly, the detection of anti-AT1R had no influence on important clinical outcomes of heart transplantation including acute cellular rejection (ACR), antibody-mediated rejection (AMR) or cardiac allograft vasculopathy (CAV), left ventricular ejection fraction (LVEF) or left ventricular mass (LV-mass). ConclusionsThe presence of anti-AT1R detected in patient serum samples by commercially available testing pre- or post- heart transplantation was not associated with clinically important outcomes including LV-mass, LVEF, ACR, AMR, CAV and overall survival. Our data brings into question the relevance of anti-AT1R testing as a risk factor or target for therapy among heart transplant recipients.

Research Highlights

Research Highlights