Panel Reactive Antibody Research Articles

COVID-19: A global transplant perspective on successfully navigating a pandemic.

The COVID‐19 pandemic has rapidly evolved and changed our way of life in an unprecedented manner. The emergence of COVID‐19 has impacted transplantation worldwide. The impact has not been just restricted to issues pertaining to donors or recipients, but also health‐care resource utilization as the intensity of cases in certain jurisdictions exceeds available capacity. Here we provide a personal viewpoint representing different jurisdictions from around the world in order to outline the impact of the current COVID‐19 pandemic on organ transplantation. Based on our collective experience, we discuss mitigation strategies such as donor screening, resource planning, and a staged approach to transplant volume considerations as local resource issues demand. We also discuss issues related to transplant‐related research during the pandemic, the role of transplant infectious diseases, and the influence of transplant societies for education and disseminating current information.

Immune Algorithm Optimization for Organ Transplantation in Poland

The lack of a uniform method for determining unacceptable HLA mismatches (UAMs) for organ transplantation worldwide has resulted in many different algorithms for donor-recipient matching. Here we present our proposal for changes to the current algorithm for immune evaluation of potential kidney recipients in Poland based on the experience of various transplantation centers. The most important finding of this article is an algorithm that stratifies the pretransplant immunologic risk based on strict laboratory criteria, enabling harmonization between transplant centers in Poland. This is because of a step-by-step algorithm for alloantibody assessment using solid-phase assays (SPA) and clearly defined technical issues, as well as cutoffs for reporting UAMs. Our novel approach focuses on a laboratory testing extension in the scope of HLA typing; detection and characterization of alloantibodies before transplantation; desensitization; and post-transplant monitoring. The proposed changes will allow for the assessment of clinically relevant anti-HLA antibodies with complement binding properties; the determination of UAMs in the potential donor; the calculation of virtual panel reactive antibodies (vPRA); the calculation of the recipient’s immunologic rejection risk stratification; the assessment of the donor-recipient virtual cross-match (vXM); and the determination of the final recipient’s selection for the biological cross-match testing. Collectively, the optimized algorithm permit for UAM verification is based on laboratory proofed data and will firmly improve organ allocation and transplant outcomes in Poland. We hope that this novel approach also improves the individual patient’s risk stratification and future personalized treatment.

Inactivation of IgM Antibodies as a Crucial Element of Diagnostics in Sensitized Patients Awaiting Kidney Transplant

BackgroundThe positive result of complement-dependent cytotoxicity crossmatch (CDC XM) may not constitute a contraindication to renal transplantation, unless it is mediated by IgM antibodies, particularly of the autologous type. The current work presents the evaluation of the frequency of reactive IgM antibodies in sensitized kidney patients in Poland and their influence on panel-reactive antibodies (PRAs) readout and allocation status. Patients and methodsResults of PRA CDC assay with and without dithiothreitol were elaborated in 53 prospective recipients with historic PRA of ≥50%. Delta PRA (dPRA) was calculated. Retrospective analysis of the results in the context of age, sex, transplant number, and cause of end-stage renal failure was performed. ResultsReactive IgM antibodies were detected in 81% of patients. Panel reactivity completely disappeared in 4% and in 51% of recipients PRA decreased by 2 to 77 percentage points. In 14 patients, PRA increased, and in 10, its level did not change. The allocation was altered in 36% of recipients. Priority status was lost in 8 and gained in 3 cases. Additional points for high sensitization were obtained in 1 and lost in 7 patients. dPRA was significantly greater in patients awaiting the first transplant compared with the second (P = .007) and third (P = .002). Higher dPRA was also symptomatic for autoimmune patients (P = .025). ConclusionsReactive IgM antibodies affected PRA level and allocation in a considerable group of sensitized patients in Poland. Discrimination of IgM from IgG antibodies should be introduced to the recipient qualification algorithm.

Early graft survival after renal transplantation, single center experience

Aim: The best treatment for patient with end stage kidney disease is kidney transplantation which improve their quality of life and survival rate. The aim of our study is to determine the factors that affect the results of early outcomes of graft function. Method: Twenty-eight adult patients who underwent renal transplantation from 2016 to 2017 were included in our university. Results: The median age of the recipients was 38.5 (range: 19-65) and 68% (19 patients) were male. Acute rejection was detected in 8 patients. Patients who developed rejection were found to have higher panel reactive antibody positivity and higher parathyroid hormone levels. Panel reactive antibody positivity was found to be 25% in patients who developed rejection and 0% in patients who did not develop rejection (p = 0.02). The parathyroid hormone level was calculated as 963.2 ± 587 in the rejection group and 378 ± 227 in the rejection group (p = 0.003). It was observed that 37.5% of DM patients had rejection and 10% in non-diabetic patients. The difference was statistically significant (p = 0.08). Conclusion: Panel reactive antibody positivity and parathyroid hormone levels increased the likelihood of rejection. The effect of the presence of diabetes mellitus in the patient on the development of rejection was observed to be limited. Our findings were consistent with the literature. Because of the number of patients and the short follow-up period, further studies are needed.

Extracorporeal Membrane Oxygenation Support After Heart Transplantation in Children-Outcomes of a Single Center Cohort.

Extracorporeal membrane oxygenation is used for postcardiotomy low cardiac output but is less established following heart transplantation. We characterized outcomes for children supported with extracorporeal membrane oxygenation after heart transplantation. Single-center retrospective study. Large pediatric cardiac referral center. All patients who received heart transplantation and were cannulated to extracorporeal membrane oxygenation between 1995 and 2016. Primary outcome measure was mortality 12 months postextracorporeal membrane oxygenation. Patient characteristics were analyzed for association with outcome according to early graft failure (extracorporeal membrane oxygenation ≤ 7 d after heart transplantation), or late graft failure. There were 246 heart transplants during the study period and 50 extracorporeal membrane oxygenation runs in 44 patients. Median time from transplant to extracorporeal membrane oxygenation was 1 day (range, 0-11.7 yr), with early graft failure in 28 patients (median 1, range 0-2 d) and 22 extracorporeal membrane oxygenation runs in 20 late graft failure patients (median, 0.8 yr; range, 8 d to 11.7 yr), including four patients with prior extracorporeal membrane oxygenation for early graft failure. Twenty-six patients (59%) survived to hospital discharge, and survival 12 months postextracorporeal membrane oxygenation was 24 patients (55%), lower in those with late graft failure (40% vs 67%; p 0.02). Independent risk factors for 12-month mortality were congenital heart disease, higher pulmonary vascular resistance indexed to body surface area (> 2.2 Woods U/m), and higher creatinine. Higher panel reactive antibody levels were associated with 12-month mortality in the late graft failure group only. Extracorporeal membrane oxygenation can be effectively used to rescue patients with graft dysfunction after heart transplantation but is associated with high early mortality. Factors associated with mortality within 12 months include presence of congenital heart disease, renal dysfunction, elevated pulmonary vascular resistance indexed to body surface area and in those supported with extracorporeal membrane oxygenation late after heart transplantation, significant human leukocyte antigen sensitization.

PRA is Not Associated with Rejection in Combined Heart and Liver Transplantation

Combined heart liver transplantation (CHLT) is relatively rare with approximately 250 cases from 1988-2018 nationally, but with rising numbers each year due to excellent survival. CHLT outcomes have potential immunological benefits compared to heart transplant alone. Liver allografts have long been observed to be more tolerant to HLA mismatch while showing some degree of immune protection in combined organ transplantation. A retrospective analysis from our center's experience of CHLT was performed. Outcomes of patients who had pre-transplant elevated panel reactive antibodies (PRA) >50-99% were compared to those with 0% and those with a low to moderate PRA (1-50%). The hypothesis was tested with the Fisher's exact test. Between 1997 and 2019, 37 patients underwent CHLT. The average age was 42.4 years +/- 10 with 8 deaths (21.6%) ranging from day 2 to 4.5 years post-transplant (5, 13.5% within the first year). None of the deaths were due to rejection or primary graft dysfunction. There were no episodes of humoral rejection and there were 2 episodes (5.4%) of cellular rejection in hearts and 4 (10.8%) in livers (of these, one episode was dual organ rejection). There was no statistical significance at baseline between PRA and history of Fontan physiology, protein losing enteropathy, prior sternotomy, diabetes, hypertension or renal disease. Furthermore, there was no correlation between PRA and death, rejection of either organ, presence of donor specific antibodies, ejection fraction below 50% (1 month and 1 year), length of stay over 30 days, post-transplant hypertension, diabetes or renal disease (table 1). The degree of allosensitization was not associated with worse outcomes in the CHLT population. While the sample is small, it is a reassuring finding that may change the perception of risk when planning a CHLT in a highly sensitized patient.

Association between Pre-Transplant Allosensitization by ECMO Bridging and Adverse Postoperative Outcome of Lung Transplantation

Extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation has raised concerns because it can induce pre-transplant allosensitization. Panel reactive antibody (PRA) or human leukocyte antigen (HLA) are examined for confirm pre-transplant sensitization since they are known to be associated with higher occurrence of adverse outcomes such as primary graft dysfunction (PGD), acute rejection and mortality. We examined the prevalence of sensitization in ECMO bridging and evaluated its impact on outcomes of lung transplantation. A single-center retrospective analysis was conducted. We include 211 patients who received a bilateral lung transplantation between January 2013 and June 2019. We defined sensitization either by high PRA (>50%) and/or high mean fluorescence intensity (MFI) (≥5000). Pre-transplant ECMO support was conducted in 64 patients (30.3%). Level of class I PRA was 12.3% and class II was 14.0% in ECMO group while 9.2% and 13.0% in the other group. Number of patients with class I and/or class II PRA greater than 50% was not significantly different between two groups (10 patients, 15.6% in ECMO group, 22 patients, 15.0% in non-ECMO group, p = 0.902). Number of patients with MFI higher than 5000 was also not significantly different (12 patients, 18.8% in ECMO, 24 patients, 26.6% in non-ECMO, p = 0.695). Prevalence of grade 3 PGD at post-operative 72 hours was slightly higher in ECMO group, but it was also not statistically different (18, 28.1% in ECMO group and 24, 16.3% in non-ECMO group, p = 0.061). Acute rejection, chronic lung allograft dysfunction (CLAD), and overall mortality were not significantly different. On multivariable logistic regression, sensitization and grade 3 PGD were not associated with ECMO bridging. Our report demonstrates the possible connection among pre-operative ECMO support, pre-transplant sensitization, and PGD. However, pre-transplant ECMO bridging is not seemed to be risk factors for pre-transplant sensitization nor PGD. Pre-transplant allosensitization might not adversely affect outcomes after lung transplantation.

Desensitization in Mechanical Circulatory Support Patients Awaiting Heart Transplantation: What is the Post-Transplant Outcome?

Sensitization occurs with blood transfusions in recipients of left ventricular assist device (LVAD). 30% of LVAD patients develop a panel reactive antibody (PRA) screen of >= 10%. Highly sensitized patients have an increased morbidity and mortality after heart transplantation. Desensitization therapy is considered for patients with PRAs> 50%. Below are the results of desensitization therapies in mechanical circulatory support (MCS) patients. From 2010-2016, 49 MCS patients who underwent desensitization therapy were compared to a control group who underwent desensitization but did not have MCS support. Desensitization therapy used in both groups included combinations of rituximab/IVIG and plasmapheresis/bortezomib. Baseline PRAs prior to desensitization were repeated 2-4 weeks after treatment. For patients who underwent heart transplantation, outcomes included 1-year survival, freedom from cardiac allograft vasculopathy (CAV), freedom from non-fatal major adverse cardiac events (NF-MACE, defined as myocardial infarction, percutaneous coronary intervention, new congestive heart failure, pacemaker/implantable cardioverter-defibrillator placement, and stroke), and freedom from any treated rejection (ATR), acute cellular rejection (ACR), and antibody-mediated rejection (AMR). Desensitization therapy was successful in both MCS and control groups, resulting in an average of 12% decrease in PRA. When subgrouped into Class 1 versus Class 2 antibodies, Class 1 antibodies appeared to have a better response after desensitization therapy (PRA decrease of 15% in Class 1 versus a decrease of 9% in Class 2). Patients on MCS support appear to have a numerical lower incidence of AMR with comparable first-year survival, freedom from CAV, NF-MACE, ATR, and ACR. Desensitization of MCS patients appeared to be beneficial. Removal of the MCS device at the time of transplant may be a factor in potentially less AMR post-transplant.

Is Anti-Thymocyte Globulin for Sensitized Patients Undergoing Heart Transplantation Effective?

Anti-thymocyte globulin (ATG) has been used as an induction agent in heart transplant (HTx). Early studies suggest that ATG can decrease de novo donor specific antibody (DSA) production after HTx. It has not been established as to the efficacy of ATG in various levels of sensitized pts undergoing HTx. Between 2010-18, we assessed 370 sensitized pts who were divided into panel reactive antibody (PRA) groups including a control group without sensitization but who received ATG: Group A: 0% (control); Group B: 1-25%; Group C: 26-50%; and Group D: >50%. Pts received ATG immediately post-transplant x5 days. Blood was drawn for antibody detection at baseline, 1, 3, 6, and 12 months after HTx. Groups were assessed for freedom from 1-year survival, rejection (any treated rejection (ATR), acute cellular rejection (ACR), and antibody mediated rejection (AMR)), freedom from non-fatal major adverse cardiac events (NF-MACE: myocardial infarction, percutaneous coronary intervention/angioplasty, new congestive heart failure, pacemaker/implantable cardioverter-defibrillator placement, and stroke), and freedom from cardiac allograft vasculopathy (CAV). Pts in Groups C and D had decreased freedom from DSA compared to the Control. Furthermore, there was lower freedom from AMR in pts in Group D compared to Control. There were no differences in outcome between each Group and the Control in 1-year survival, freedom from CAV, freedom from NF-MACE, freedom from any treated rejection, and freedom from ACR (see Table). ATG induction may be beneficial in sensitized patients with PRA under 50% but did not appear to decrease the development of AMR and DSA in those pts with PRA >50% compared to control. Larger studies and longer follow-up will need to be performed to assess ATG's impact on antibodies and the development of chronic rejection (CAV).

De-Novo Human Leukocyte Antigen Allosensitization on HeartMate 3 versus HeartMate II Left Ventricular Assist Device Recipients

MOMENTUM 3 trial demonstrated superiority of Heartmate 3 (HM 3) compared to Heartmate II (HM 2) with regards to hemocompatibility, however, their differential effects on de-novo HLA allosensitization, which may create a challenge for future transplantation, remains unknown. Patients who underwent HM2 or HM3 implantation and had no prior HLA antibodies by solid-phase assay (Luminex) testing at a major academic center were included for the study. Complement dependent cytotoxicity (CDC) panel reactive antibody (PRA) levels as well as Luminex antibody profiles were followed until cardiac transplantation, device explantation, or death. 34 HM3 and 34 HM2 patients with no HLA antibodies by Luminex testing prior to LVAD implant were identified with a mean follow-up duration of 1.71 ± 1.1 years on device support. HM3 and HM2 groups had similar age at implant (56.1±8.6 vs 54.7±12.0, p=0.575), female gender (11.8% vs. 14.7%, p=0.720), ischemic HF etiology (38.2% vs 35.3%, p=0.801), and bridge strategy at implant (44.1% vs 58.8%, p=0.225). Over the follow-up period, 41.2% of HM3 and 47.1% of HM2 patients had detectable HLA antibodies by Luminex testing (p=0.625). Development of high level (MFI>10, 000) Class I HLA antibodies were significantly lower in HM3 patients (2.9% vs 17.9%, p=0.046) compared to high-level Class II HLA antibodies which were similar in two device groups (2.9% vs 5.9%, p=0.555). CDC PRA testing showed lower proportion of HM3 patients with a positive result (PRA >0%) for T cell (32.4% vs. 55.9%, p=0.050) compared to positive B cell panel which was comparable in two groups (32.4% vs 47.1%, p=0.215). Peak PRA levels in patients who turned positive was comparable for T cell (5.8% vs 6.5%, p=0.775) and B cell (10.2% vs. 12.4%, p=0.568) in HM3 vs. HM2 patients. Our findings suggest that HM3 is associated with a lower likelihood of de-novo HLA sensitization than HM2 specifically against Class I antigens.

Prevalence of Acute Cellular Rejection and Its Impact on Survival Post Heart Transplantation in the Contemporary Era

Identify the prevalence and associates of ISHLT grade ≥2R acute cellular rejection (≥2CR) and its impact on survival post heart transplantation in a well-phenotyped, modern era Irish cohort all of whom receive induction therapy. Retrospective analysis of 88 patients who underwent heart transplantation between 2014 and 2019 (mean age 49.8 ± 13.02 years; female 29.5%). Data was collected on recipient and donor anthropometrics, HLA profile, panel reactive antibodies (PRAs) ischaemia time, cytomegalovirus (CMV) serostatus and endomyocardial biopsy results over a median follow up of 2.04 years (IQR 3.18). Kaplan Meier survival, univariate and multivariate cox regression analysis were performed. Standard immunosuppression was with basiliximab induction, a calcineurin inhibitor, steroid and antimetabolite. All-cause mortality at 1 year was 14%. In those patients surviving to first biopsy (n=82), 55% experienced at least 1 episode of ≥2CR at a median time of 53.5 days (IQR 149) and cumulative survival was reduced in this group (p=0.04). More than 1 episode of ≥2CR was not associated with an incremental mortality risk. Intermediate-high risk CMV serostatus was independently associated with increased mortality on multivariate analysis (HR 3.16; 95%CI 1.04-9.65; p=0.04) but not with an increased risk of ≥2CR. There was no association between ischaemic time, PRAs, other recipient/donor matching characteristics, number of HLA mismatches or mismatches confined to any of the 6 HLA subclasses on survival or development of ≥2CR. In a modern era Irish cohort where induction therapy is standard, patients who experienced ≥1 episode of ≥2CR post transplant had reduced survival. Intermediate-high risk CMV serostatus was the only independent associate of increased mortality but not for ≥2CR. Further work in an extended cohort will focus on understanding the mechanisms underpinning rejection in this contemporary population and its consequences.

Outcomes of Pre- Heart Transplantation Desensitization in Highly Sensitized Patients Bridged with Left Ventricular Assist Devices

Desensitization therapy in orthotopic heart transplantation (OHT) candidates can shorten wait time and improve outcomes of highly sensitized patients, especially those bridged with left ventricular assist devices (LVADs) who are prone to complications. No specific guidelines exist for desensitization in OHT and studies have yielded varying results. We aim to study outcomes in these patients. We retrospectively reviewed patients on OHT waitlist in our center from 01/01/2013 to 10/01/2019. We identified 10 OHT-waitlisted, LVAD-bridged patients undergoing pre-OHT desensitization. All of those were highly sensitized with panel-reactive antibody (PRA)>80% and with significant comorbidities (LVAD infection/malfunction, severe right ventricular dysfunction, ventricular tachycardia and aortic insufficiency). All patients had complications related to coagulopathy and/or bone marrow suppression. Other complications include infection (x3), bleeding (x3), gastritis (x1), ischemic stroke (x1), hypotension (x1) and neuropathy (x3). Three patients were delisted and did not complete desensitization (inability to tolerate desensitization x2, non-compliance x1). Seven patients tolerated desensitization and were transplanted (Table 1) at a mean age of 52 years and mean time to transplant of 437 days. Mean decrease in total and unacceptable PRA were 22% and 34% respectively. Transplanted patients had a mean survival of 627 days. They had infectious complications early after transplant with mean time to first infection of 20 days. One patient had clinically significant rejection episode 390 days after OHT and one patient had cardiac allograft vasculopathy 536 days after OHT. When tolerated, pre-OHT desensitization at our center was effective and beneficial for sick sensitized patients on LVADs. Side effects are a significant limitation. Further studies are needed to guide therapy in those individuals.

The Role of Human Leukocyte Antigen Sensitization as a Risk Factor for Mortality in Patients Bridged to Heart Transplantation with VA-ECMO

Patients bridged to heart transplantation (BTT) with VA-ECMO have increased mortality in the first post-transplant year. This has been observed even after robust adjustment for recipient and donor comorbidities, suggesting either residual unmeasured risk or possible exacerbation of risk in the VA-ECMO BTT patient. Human leukocyte antibody (HLA) sensitization is observed more frequently with mechanical circulatory support. We hypothesize an increased risk of mortality in VA-ECMO BTT as a function of HLA sensitization. We analyzed all 27,495 adult patients in the United Network for Organ Sharing database who underwent heart transplantation between 6/30/2004 and 12/30/2018, excluding re-transplantation or multiple organ transplantation. HLA sensitization was assessed by panel reactive antibody (direct or calculated). Odds of early graft failure (within 48 hours) or acute rejection (during the index hospitalization), hazard of all-cause mortality, and cause-specific relative hazard (csRH) of graft failure were modeled with pre-transplant VA-ECMO with and without PRA. Models were adjusted for recipient, donor, and operative risk factors including center and transplant year. VA-ECMO was used as BTT in 176 patients (0.64%), who were younger than those without VA-ECMO (mean age 44 vs 53, p<0.001) but with similar sex and ethnicity. VA-ECMO BTT patients had higher PRA (p=0.003) and more frequently had PRA>20% (18% vs 12%, p=0.034). After risk adjustment, VA-ECMO patients had more early graft failure (OR 5.6; 95% 2.2, 14.5), shorter time to graft failure (csRH 3.6; 2.1,6.2), and shorter time to mortality (HR 3.5; 2.6, 4.7), but no difference in acute rejection. PRA was independently associated with early graft failure (OR 1.09 per 10%; 1.01, 1.18), acute rejection (1.07; 1.04, 1.09), time to graft failure (1.05; 1.0, 1.09), and time to mortality (1.03; 1.01, 1.06), but did not modify the association between VA-ECMO and mortality (HR 1.1; 0.99, 1.3). VA-ECMO as BTT is independently associated with higher odds of early graft failure, shorter time to graft failure, and shorter time to all-cause mortality. HLA sensitization is independently associated with the same outcomes and with acute rejection, but with a small effect size. HLA sensitization did not modify the association of VA-ECMO with outcomes.

A Comparison of Intra-Operative Human Leukocyte Antigen Antibody Removal Techniques in Pediatric Heart Transplantation

Many potential pediatric heart transplant (HT) recipients develop sensitization to potential donor Human Leukocyte Antigens (HLA) from prior tissue and blood product exposure. HT in the face of allosensitization carries elevated risk of morbidity and mortality. We sought to determine and compare the degree and timing of HLA-antibody removal between centrifuge-based plasmapheresis (cPP) and membrane-based plasmapheresis (mPP) during cardiopulmonary bypass (CBP). Two mPP and two cPP systems were each incorporated into CPB circuits. The prime consisted of highly sensitized pooled donor whole blood. Blood was considered sensitized if any HLA-antibody exceeded 3000 mean fluorescence intensity (MFI) units by Luminex assay. Fresh frozen plasma was utilized to replenish the plasmapheresis circuits. Samples to determine the panel reactive antibody (PRA) were taken at baseline, then at 30 minute intervals until the end-point at 2 hours. The pooled donor blood was sensitized to HLA Class II but not Class I per institutional threshold. Reduction of anti-HLA class II antibody to below threshold levels (MFI <3000) was achieved in both the cPP and mPP systems. In the cPP circuits, there was a gradual decrease in antibody levels at each 30-minute interval, reaching a nadir at 90 minutes with a 2 to 3.5-fold reduction at completion. In the mPP circuit, there was an initial rapid decrease in antibody levels at 30-minute mark followed by a plateau corresponding to a 1.7 to 2.5-fold decrease in MFI at 2 hours. The incorporation of cPP or mPP systems into the CPB circuit can effectively reduce circulating HLA-antibodies. This can be accomplished within the time period of CPB for implantation before graft reperfusion and may be done more efficiently using cPP. This technology may have important utility for sensitized transplant recipients at increased risk for early antibody-mediated rejection.

HLA Allosensitization in Patients on Continuous Flow LVAD Support: Are Patients at Increased Risk?

Allosensitization poses a challenge in identifying appropriate donors for patients (pts) awaiting cardiac transplantation. Continuous flow left ventricular assist device (LVAD) can induce significant allosensitization to human leucocyte antigens (HLA). With advances in surgical approaches and improved LVAD hemocompatibility, the prevalence of allosensitization is not well studied. We evaluated the development of allosensitization in a contemporary LVAD cohort including centrifugal and axial LVADs. In consecutive pts who underwent LVAD in a single center from 2014 to 2018, we examined HLA immune status prior to LVAD and at time of transplant if less than one year or up to one year of LVAD support. Serum alloantibodies were detected with single-antigen beads using a Luminex platform. HLA allosensitization was defined as having a calculated panel reactive antibody (cPRA) >10%. LVAD-associated allosensitization was defined as having a cPRA >10% and cPRA <10% before LVAD. A total of 50 pts who underwent LVAD implantation as bridge to transplant had available cPRA prior to and after LVAD implantation. Mean follow up was 268±91 days. Mean age was 53±13 years, and 26% were female. 18 pts (36%) had centrifugal LVAD. At 1 year, 28 pts (56%) were transplanted, 18 pts (36%) remained on LVAD support, and 4 pts (8%) expired. Of the 50 patients, 14% (n=7) had PRA over 10%. Though the proportion of patients with allosensitization after LVAD increased to 24%, this was not statistically significant (Fig 1A&B). Eight pts had LVAD-associated allosensitization, and in this group, type of device (centrifugal vs axial) was not associated with allosensitization. In our single-center, contemporary cohort, allosensitization before LVAD was not common. LVAD associated allosensitization occurred in about one-fifth of patients.

Regular Immunological Evaluations for Progression of Cardiac Allograft Vasculopathy

The methods for detection of post-transplant rejection, especially antibody-mediated rejection (AMR) have been developed for the past three decades and contributed the elucidation of the cardiac allograft vasculopathy (CAV) progression from AMR. However, variation in individual cases is found and it is important to a prediction of the clinical CAV extension to know how various technique is involved on a true clinic. The contribution of alloimmune factors has been increasingly recognized, and thus it is useful to evaluate antibody patterns to prevent CAV. Subjects consisted of 43 patients (10 women; average age at heart transplantation (HTX), 26.1±17.5 years; observation period, 12.1±7.9 years after HTX) who underwent HTX at least 2 years earlier, as well as regular immunological testing, such as panel reactive antibody testing. Clinical data were retrospectively analyzed. (1) Twelve patients showed significant progression of CAV (more than ISHLT CAV2) during follow-up after transplantation, and eight patients demonstrated positive for HLA Class 1 or Class 2 antibodies. Five of these eight patients showed positive donor-specific antibodies and negative for Class 1 C1q antibodies, but four of these five showed positive for Class 2 C1q antibodies. These four patients demonstrated rapid progression of CAV. (2) Four of the 43 patients had a history of C4d-positive antibody-related rejection (AMR), and two of these four patients showed persistent positive Class 2 C1q antibodies. (3) Nine of 12 patients who showed significant progression of CAV demonstrated positive for Class 1 or Class 2 antibodies, or positive for Class 2 C1q antibodies, or had a history of AMR. Alloimmune response is greatly involved in CAV progression, but a difference is found in the extension mechanism in individual cases. Regular immunological evaluations for not only HLA IgG antibodies but also C1q antibodies are useful to better characterize CAV progression.

Immunosuppression with Calcineurin Inhibitor after Renal Transplant Failure Inhibits Allosensitization.

Immunosuppression withdrawal after graft failure seems to favor sensitization. A high percentage of calculated panel-reactive antibody (cPRA) and the development of de novo donor specific antibodies (dnDSA) indicate human leukocyte antigen (HLA) sensitization and may hinder the option of retransplantation. There are no established protocols on the immunosuppressive treatment that should be maintained after transplant failure. A retrospective analysis including 77 patients who lost their first renal graft between 1 January 2006–31 December 2015 was performed. Two sera were selected per patient, one immediately prior to graft loss and another one after graft failure. cPRA was calculated by Single Antigen in all patients. It was possible to analyze the development of dnDSA in 73 patients. By multivariate logistic regression analysis, the absence of calcineurin inhibitor (CNI) at 6 months after graft failure was related to cPRA > 75% (OR 4.8, CI 95% 1.5–15.0, p = 0.006). The absence of calcineurin inhibitor (CNI) at 6 months after graft loss was significantly associated with dnDSA development (OR 23.2, CI 95% 5.3–100.6, p < 0.001). Our results suggest that the absence of CNI at the sixth month after graft loss is a risk factor for sensitization. Therefore, maintenance of an immunosuppressive regimen based on CNI after transplant failure should be considered when a new transplant is planned, since it seems to prevent HLA allosensitization.

Effect of Panel-Reactive Antibody on Graft Survival in Living Kidney Donor Transplantation: Analysis of 10 Years in a Transplant Center in Veracruz, Mexico

BackgroundPretransplant anti-HLA antibodies are a risk factor for graft rejection and loss, and its percentage estimate is known as panel-reactive antibody (PRA). Our objective was to evaluate the influence of PRA on the survival of renal grafts from living donors over a period of 10 years. MethodsRetrospective analysis was completed in all living donor transplants with PRA class I and class II from October 2008 to December 2018 with follow-up until June 2019. The methods used for the PRA were flow cytometry and Luminex. Graft survival (not censored) was evaluated by Kaplan-Meier (log-rank) and Cox regression. P < .05 was considered significant. ResultsThe study included 393 patients. PRA class I mean was 9.8 ± 20% (0%-98%) and class II mean was 8.6 ± 17.8% (0%-97.8%). Of the patients, 81.9% had a PRA <20% for any class. Uncensored graft survival at 1, 5, and 10 years was 90.3%, 76.2%, and 69.3%, respectively. Mean estimated uncensored graft survival in PRA <20% patients (103.9 ± 2.7, 95% confidence interval [CI] 96.6-11.2) was higher than that of PRA >20% patients (61.5 ± 5.7, 95% CI 50.3-72.8) (P = .005 log-rank). Cox regression (univariate) was statistically significant for PRA class I (Exp [B] 1.01, 95% CI 1.003-1.02, P = .009) and for PRA >20% any class (Exp [B] 2.074, 95% CI 1.222-3.520, P = .007). ConclusionPRA class I and PRA >20% any class are associated with lower graft survival. PRA must be considered to determine immunologic risk and to choose an immunosuppressive regimen in kidney transplantation.

Preliminary assessment of safety and adherence to a once-daily immunosuppression regimen in kidney transplantation: Results of a randomized controlled pilot study.

Medication non-adherence is common after transplant and a major contributor to graft loss. The objective of this pilot study was to obtain preliminary safety and adherence data of a complete once-daily immunosuppression regimen of Extended-release-tacrolimus (LCP-tac), everolimus, and prednisone vs LCP-tac, mycophenolate Twice daily (BID), and prednisone through a randomized controlled pilot study of 40 patients (20 in each arm). At 3±2months post-transplant, patients were randomized to receive LCP-tac and everolimus once daily or LCP-tac and mycophenolate BID (control arm) for 6months; 80 met eligibility, and 40 were randomized. Mean age was 51±14years, 33% were female, 45% African American, and 55% had a Calculated panel reactive antibody (cPRA) >20%. Both regimens were well-tolerated, and medication side effect burden tended to be less severe in the intervention group. Self-reported high medication adherence decreased in the control arm from baseline to 6months (80%-59%), while remaining the same in the intervention arm throughout the study (45%-47%). For safety assessment, there was no rejection, graft loss, or death in either arm. These results provide preliminary evidence of the safety of a novel once-daily immunosuppression regimen. The impact of this once-daily regimen on medication adherence requires a larger long-term study.

Low-dose Thymoglobulin vs Basiliximab Induction Therapy in Low-Risk Living Related Kidney Transplant Recipients: A Prospective Randomized Trial

ContextThymoglobulin is used effectively as induction agent in kidney transplantation but the optimal dose is not well established. ObjectiveDemonstrate that low-dose thymoglobulin (3 mg/kg) has similar efficacy and safety compared to basiliximab induction in low-risk kidney transplantation under standard maintenance immunosuppression Design, Setting, ParticipantsProspective randomized study in kidney transplant patients (12/2016-05/2018). Inclusion criteria: Recipients > 18 years, first living donor transplant. Exclusion criteria: Second and multiorgan transplant, ABO incompatibility, positive cross-match, panel reactive antibodies (PRA) > 30%, positive donor-specific antibody, human immunodeficiency virus, hepatitis B surface antigen, hepatitis C virus positive, white blood cells < 2000 cells/mm3, platelets < 75,000 cells/mm3 and malignancy. InterventionGroup A: basiliximab (20 mg D0 and D4). Group B: thymoglobulin (3 mg/kg total). Maintenance immunosuppression: tacrolimus, mycophenolate mofetil, and steroids. Main Outcome MeasuresBiopsy-proven acute rejection (BPAR), delayed graft function, slow graft function, leukopenia, infections, adverse events, graft loss, estimated glomerular filtration rate, and death within 12 months. Results100 patients (basiliximab, n = 53) (thymoglobulin, n = 47) were included. Donor and recipient characteristics were similar except for longer dialysis (basiliximab), PRA class I (1.2% basiliximab, 4.5% thymoglobulin), HLA match (basiliximab 2.8, thymoglobulin 2.2), and cytomegalovirus status. BPAR rate was basiliximab 3.8% and thymoglobulin 6.4% (P = ns). Delayed graft function (basiliximab 3.8%; thymoglobulin 4.3%), slow graft function, and 12-month leukopenia (basiliximab 11.3%, thymoglobulin 21.3%) were similar between groups (P = ns). There was no difference in infections and adverse events between groups. Patient and graft survival were as follows: basiliximab 98.1% and 92.5%, thymoglobulin 100% and 93.6% (P = ns). ConclusionLow-dose thymoglobulin induction (3 mg/kg) can be used effectively and safely in low-risk kidney transplantation with good results during the first year post-transplant.