One major disadvantage of ventricular assist device (VAD) therapy is the development of human-leukocyte antigen (HLA) antibodies. We aimed to identify factors associated with HLA antibodies during ...continuous flow (CF)-VAD support and assess the effect on transplant probability and outcomes.
We included 143 consecutive heart failure patients who received a CF-VAD as a bridge-to-transplant at 3 institutions. Factors associated with post-VAD peak panel reactive antibodies (PRA) among several measurements were identified using multivariable linear regression. A parametric survival model was used to assess transplant waiting time and probability, risk of rejection, and a composite outcome of rejection, graft failure, and death.
Thirty-six patients (25%) were female; mean age was 47 ± 13 years. Eighty-one patients (57%) had a pre-VAD PRA of 0%, and 16 were highly sensitized (PRA > 80%). Age, female sex, and pre-VAD PRA were independently associated with post-VAD PRA. A 10-year increase in age was associated with a 5% decrease in post-VAD PRA (p = 0.03). Post-VAD PRA was 19% higher in women vs men (p < 0.01). A 10%-increase in pre-VAD PRA was associated with a 4.7% higher post-VAD PRA (p < 0.01). During a mean follow-up of 12 ± 11 months, 90 patients underwent cardiac transplantation. A 20% increase in post-VAD PRA was associated with 13% lower probability of transplant (hazard ratio, 0.87; 95% confidence interval, 0.76-0.99). A high PRA was not associated with adverse post-transplant outcomes.
Younger age, female sex, and pre-VAD PRA were independent predictors of elevated PRA post-VAD. Higher PRA was significantly associated with lower transplant probability but not increased rejection, graft failure, or death after transplant.
There are challenges in achieving and maintaining therapeutic tacrolimus levels after solid organ transplantation (SOT). The purpose of this genome-wide association study was to generate an ...integrated clinical and genetic prediction model for tacrolimus levels in pediatric SOT.
In a multicenter prospective observational cohort study (2015-2018), children <18 years old at their first SOT receiving tacrolimus as maintenance immunosuppression were included (455 as discovery cohort; 322 as validation cohort). Genotyping was performed using a genome-wide single nucleotide polymorphism (SNP) array and analyzed for association with tacrolimus trough levels during 1-y follow-up.
Genome-wide association study adjusted for clinical factors identified 25 SNPs associated with tacrolimus levels; 8 were significant at a genome-wide level (P < 1.025 × 10-7). Nineteen SNPs were replicated in the validation cohort. After removing SNPs in strong linkage disequilibrium, 14 SNPs remained independently associated with tacrolimus levels. Both traditional and machine learning approaches selected organ type, age at transplant, rs776746, rs12333983, and rs12957142 SNPs as the top predictor variables for dose-adjusted 36- to 48-h posttacrolimus initiation (T1) levels. There was a significant interaction between age and organ type with rs776476*1 SNP (P < 0.05). The combined clinical and genetic model had lower prediction error and explained 30% of the variation in dose-adjusted T1 levels compared with 18% by the clinical and 12% by the genetic only model.
Our study highlights the importance of incorporating age, organ type, and genotype in predicting tacrolimus levels and lays the groundwork for developing an individualized age and organ-specific genotype-guided tacrolimus dosing algorithm.
Specific B‐cell tolerance toward donor blood group antigens develops in infants after ABO‐incompatible heart transplantation, whereas their immune response toward protein antigens such as HLA has not ...been investigated. We assessed de novo HLA‐antibodies in 122 patients after pediatric thoracic transplantation (28 ABO‐incompatible) and 36 controls. Median age at transplantation was 1.7 years (1 day to 17.8 year) and samples were collected at median 3.48 years after transplantation. Antibodies were detected against HLA‐class I in 21 patients (17.2%), class II in 18 (14.8%) and against both classes in 10 (8.2%). Using single‐antigen beads, donor‐specific antibodies (DSAs) were identified in six patients (all class II, one additional class I). Patients with DSAs were significantly older at time of transplantation. In patients who had undergone pretransplant cardiac surgeries, class II antibodies were more frequent, although use of homografts or mechanical heart support had no influence. DSAs were absent in ABO‐incompatible recipients and class II antibodies were significantly less frequent than in children with ABO‐compatible transplants. This difference was present also when comparing only children transplanted below 2 years of age. Therefore, tolerance toward the donor blood group appears to be associated with an altered response to HLA beyond age‐related effects.
Cardiac transplantation in childhood is associated with less frequent de novo development of anti‐HLA antibodies than reported in older individuals, and in this experience, recipients of ABO‐incompatible transplants produced class II antibodies donor‐specific HLA antibodies less frequently.
Primary sclerosing cholangitis (PSC) is an indication for liver transplantation, but recurrence after liver transplantation is associated with poor outcomes often requiring repeat transplantation. We ...investigated whether autologous hematopoietic stem cell transplantation (aHSCT) could be used to stop progression of recurrent PSC and promote operational tolerance.
Twelve patients with recurrent PSC were fully evaluated and 5 were selected for aHSCT. Autologous hematopoietic stem cells were collected, purified by CD34 immunomagnetic selection, and cryopreserved. Immunoablation using busulfan, cyclophosphamide, and rabbit antithymocyte globulin was followed by aHSCT. The primary endpoint of the study was the establishment of operational tolerance defined as lack of biochemical, histologic, and clinical evidence of rejection while off immunosuppression at 2 y post-aHSCT.
Two of the 5 patients achieved operational tolerance with no clinical or histologic evidence of PSC progression or allorejection. A third patient developed sinusoidal obstruction syndrome following aHSCT requiring repeat liver transplantation but has no evidence of PSC recurrence while on sirolimus monotherapy now >3 y after aHSCT. A fourth patient was weaned off immunosuppression but died 212 d after aHSCT from pericardial constriction. A fifth patient died from multiorgan failure. Immunosuppression-free allograft acceptance was associated with deletion of T-cell clones, loss of autoantibodies, and increases in regulatory T cells, transitional B cells, and programmed cell death protein-1 expressing CD8+ T cells in the 2 long-term survivors.
Although operational tolerance occurred following aHSCT, the high morbidity and mortality observed render this specific protocol unsuitable for clinical adoption.
An increasing percentage of potential organ donors are infected with hepatitis C virus (HCV). After transplantation from an infected donor, establishment of HCV infection in uninfected recipients is ...near-universal, with the requirement for post-transplant antiviral treatment. The aim of this study was to determine if antiviral drugs combined with an HCV entry blocker given before and for 7 days after transplant would be safe and reduce the likelihood of HCV infection in recipients of organs from HCV-infected donors.
HCV-uninfected organ recipients without pre-existing liver disease were treated with ezetimibe (10 mg; an HCV entry inhibitor) and glecaprevir-pibrentasvir (300 mg/120 mg) before and after transplantation from HCV-infected donors aged younger than 70 years without co-infection with HIV, hepatitis B virus, or human T-cell leukaemia virus 1 or 2. Recipients received a single dose 6-12 h before transplant and once a day for 7 days after surgery (eight doses in total). HCV RNA was assessed once a day for 14 days and then once a week until 12 weeks post-transplant. The primary endpoint was prevention of chronic HCV infection, as evidenced by undetectable serum HCV RNA at 12 weeks after transplant, and assessed in the intention-to-treat population. Safety monitoring was according to routine post-transplant practice. 12-week data are reported for the first 30 patients. The trial is registered on ClinicalTrials.gov, NCT04017338. The trial is closed to recruitment but follow-up is ongoing.
30 patients (23 men and seven women; median age 61 years (IQR 48-66) received transplants (13 lung, ten kidney, six heart, and one kidney-pancreas) from 18 HCV-infected donors. The median donor viral load was 5·11 log
IU/mL (IQR 4·55-5·63) and at least three HCV genotypes were represented (nine 50% donors with genotype 1, two 11% with genotype 2, five 28% with genotype 3, and two 11% with unknown genotype). All 30 (100%) transplant recipients met the primary endpoint of undetectable HCV RNA at 12 weeks post-transplant, and were HCV RNA-negative at last follow-up (median 36 weeks post-transplant IQR 25-47). Low-level viraemia was transiently detectable in 21 (67%) of 30 recipients in the early post-transplant period but not after day 14. Treatment was well tolerated with no dose reductions or treatment discontinuations; 32 serious adverse events occurred in 20 (67%) recipients, with one grade 3 elevation in alanine aminotransferase (ALT) possibly related to treatment. Non-serious transient elevations in ALT and creatine kinase during the study dosing period resolved with treatment completion. Among the serious adverse events were two recipient deaths due to causes unrelated to study drug treatment (sepsis at 49 days and subarachnoid haemorrhage at 109 days post-transplant), with neither patient ever being viraemic for HCV.
Ezetimibe combined with glecaprevir-pibrentasvir given one dose before and for 7 days after transplant prevented the establishment of chronic HCV infection in recipients of different organs from HCV-infected donors. This study shows that an ultra-short course of direct-acting antivirals and ezetimibe can prevent the establishment of chronic HCV infection in the recipient, alleviating many of the concerns with transplanting organs from HCV-infected donors.
Canadian Institutes of Health Research; the Organ Transplant Program, University Health Network.
Acute rejection episodes and 6-month protocol biopsy acute pathology are highly correlated with long-term outcomes in renal transplant recipients. Recurrent, vascular, and late rejections are ...particularly deleterious.
We determined the relative contribution of human leukocyte antigen matching, cytokine genotypes, delayed graft function (DGF), and baseline immunosuppression to the development of acute rejection and allograft pathology in 118 renal transplant recipients.
Multivariate logistic regression modeling demonstrated that the adjusted odds ratio and 95% confidence interval for recurrent (> or =2) early rejections (0-3 months) increased linearly for high (H) > intermediate (I) > low (L) interferon-gamma (1.8; 1.1-3.2) and tumor necrosis factor (TNF)alpha (3.0; 1.3-6.9) genotype, whereas every 1 microg/L increase in the cyclosporine A level was protective (0.991; 0.984-0.999). The odds ratio for recurrent late rejections (4-6 months) increased for H > I > L TNFalpha (5.1; 1.8-14.7) genotype and DGF (7.1; 1.6-30.2), whereas H > I/L transforming growth factor-beta1 genotype decreased the relative risk (0.09: 0.02-0.49). Vascular rejection was only predicted by H > I > L TNFalpha phenotype (3.0; 1.2-7.9). The odds ratio for the 6-month Banff Acute Score (6A > or= 4) increased for H > I > L TNFalpha (2.7; 1.1-6.7) and interleukin-10 (3.4; 1.2-6.2) genotype, and DGF (3.4; 1.1-11.5). Treatment of early subclinical rejection decreased the relative risk (0.20; 0.07-0.62).
High transforming growth factor-beta1 producer phenotype seems to be protective against acute inflammation, whereas H and I interferon-gamma, TNFalpha, and interleukin-10 producer genotypes correlate with adverse outcomes. Cytokine genotyping identifies individuals who may benefit from more intensive surveillance and treatment posttransplant.
Sensitization to human leukocyte antigens remains an important barrier to successful renal transplantation.
Herein we describe our center's experience with a plasmapheresis-based desensitization ...protocol for highly sensitized patients. Twenty-nine patients had a positive T-cell or positive B-cell lymphocytotoxicity crossmatch against their donors. In some cases, baseline crossmatches were of high titer (e.g., 11 had baseline titers > or =1:32).
Twenty-eight of 29 patients were rendered T-cell crossmatch negative and B-cell crossmatch negative/low positive and transplanted. None had hyperacute rejection but 11 (39%) had acute antibody mediated rejection. Median follow-up is 22 months: 25 of the 28 (89%) of allografts are still functioning with mean plasma creatinine 1.5 mg/dL. There was one death because of the transplant or immunsuppression, one case of cytomegalovirus disease and no cases of lymphoproliferative disease.
This series provides further evidence of the high efficacy of plasmapheresis-based desensitization protocols. Even patients with high baseline crossmatch titers can be successfully desensitized and transplanted. Short- and medium-term outcomes are encouraging but longer-term data are needed.
The purpose of this study was to determine whether screening for anti-human leukocyte antigen (HLA) antibodies (Abs) could predict development of acute rejection (AR) before clinical evidence of ...kidney allograft dysfunction in nonsensitized recipients.
Eighty-four non-HLA identical kidney transplant recipients were prospectively tested for anti-HLA Abs (FlowPRA analysis and anti-HLA Ab specificity determination) at 0, 10, 20, 30, 60, 90, 180 and 365 posttransplantation, and at the time of clinical suspicion of AR. Allograft biopsies were performed at the time of engraftment, 3 and 12 months posttransplantation, when patients developed new anti-HLA Abs, or when clinically indicated.
Among the 70 patients without preformed anti-HLA Abs, 11 developed de novo anti-HLA Abs (8 donor-specific Abs) at a median of 30 days (q1-q3=10-180 days) after transplantation. Patients with de novo anti-HLA Abs had a shorter time to AR than patients without de novo anti-HLA Abs, P=0.06. However, in all cases, de novo anti-HLA Abs developed concomitantly or after a clinically evident AR.
Although de novo anti-HLA Abs were associated with AR, routine screening for anti-HLA Abs was not useful in identifying patients at risk for AR before clinical evidence of allograft dysfunction.
Human leukocyte antigen (HLA) sensitization is a common problem in patients being assessed for organ transplantation. Two overarching principles that must be adhered to when evaluating approaches to ...sensitized patients are: (1) ensuring equitable access for potential recipients to transplantable organs; and (2) maintaining optimal long-term patient and graft outcomes post-transplant. Approaches increasingly used to manage sensitized heart transplant candidates are crossmatching (virtual VXM, based on comparison of donor HLA to recipient antibody specificities, or prospective real-time XM) to avoid donor-specific antibodies, or desensitization to reduce the amount of antibodies that are present. We propose that the best strategy for management of highly sensitized patients awaiting heart transplantation is combining mechanical circulatory support as a bridge to a (-) VXM or XM together with adoption of a national prioritized sharing algorithm for highly sensitized patients.
Summary
Antibody‐mediated rejection (AMR) occurs in 10–20% of patients after heart transplantation. C4d immunostaining is one parameter used in its diagnosis. This study aimed to determine whether ...C4d staining has prognostic significance for mortality, coronary allograft vasculopathy (CAV), cell‐mediated rejection (CMR), and graft dysfunction in patients post‐transplantation. Consecutive patients receiving an endomyocardial biopsy between 2007 and 2008 were selected. Left ventricular function, angiography, episodes of AMR/CMR, and death were noted. C4d was graded from 0 to 3 (immunostaining). Cox proportional models (recurrent events analysis) were used to evaluate C4d staining with mortality, graft dysfunction, CAV (≥grade 2), and episodes of ≥2R‐CMR. We analyzed 2525 biopsy specimens (n = 217). During a follow‐up of 4.5 ± 2 years, 35 died, 49 had graft dysfunction, seven had ≥grade 2 CAV, and 95 episodes of CMR occurred. A one‐grade increase in C4d staining was associated with an increase in mortality (HR 1.57; 95% CI 1.0–2.5), a higher risk of CAV (HR 2.4, 95% CI 1.04–5.4), and a trend toward graft dysfunction (HR 1.42; 95% CI 1.0–2.09). C4d was not associated with CMR. C4d immunostaining was a significant predictor of CAV and death but not subsequent episodes of CMR. There was also a trend toward increased graft failure.
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