dnDSA Development Research Articles

Safety and Efficacy of a Steroid Avoidance Immunosuppression Regimen in Renal Transplant Patients With De Novo or Preformed Donor-Specific Antibodies: A Single-Center Study

Although interest in the role of donor-specific antibodies (DSAs) in kidney transplant rejection, graft survival, and histopathological outcomes is increasing, their impact on steroid avoidance or minimization in renal transplant populations is poorly understood. Primary outcomes of graft survival, rejection, and histopathological findings were assessed in 188 patients who received transplants between 2012 and 2015 at the Scripps Center for Organ Transplantation, which follows a steroid avoidance protocol. Analyses were performed using data from the United Network for Organ Sharing. Cohorts included kidney transplant recipients with de novo DSAs (dnDSAs; n = 27), preformed DSAs (pfDSAs; n = 15), and no DSAs (nDSAs; n = 146). Median time to dnDSA development (classes I and II) was shorter (102 days) than in previous studies. Rejection of any type was associated with DSAs to class I HLA (P < .05) and class II HLA (P < .01) but not with graft loss. Although mean fluorescence intensity (MFI) independently showed no association with rejection, an MFI >5000 showed a trend toward more antibody-mediated rejection (P < .06), though graft loss was not independently associated. Banff chronic allograft nephropathy scores and a modified chronic injury score were increased in the dnDSA cohort at 6 months, but not at 2 years (P < .001 and P < .08, respectively). Our data suggest that dnDSAs and pfDSAs impact short-term rejection rates but do not negatively impact graft survival or histopathological outcomes at 2 years. Periodic protocol post-transplant DSA monitoring may preemptively identify patients who develop dnDSAs who are at a higher risk for rejection.

Human leukocyte antigen-DR/DQ eplet mismatch analysis for primary alloimmune risk stratification of non-sensitized kidney transplant recipients

Background: Human leukocyte antigen (HLA) analysis has been suggested as a predictive tool for alloimmune risk stratification in kidney transplantation (KT). We investigated whether the whole or single molecule HLA class II eplet mismatch was related to the de-novo donor-specific-antibody (dnDSA) development or antibody-mediated rejection (AMR). Methods: Total 300 kidney transplants performed at Seoul St. Mary’s Hospital between 2016 December and 2020 January with out preformed DSA have been analyzed. HLA class II eplet mismatches were determined by high resolution HLA DRB1/DQB1 typing results and HLA Matchmaker program. Results: During the 22.6 months (median) follow-up period, 24 recipients developed HLA class II dnDSA and 20 patients diag nosed as AMR. Using receiver operating characteristic analysis, we identified eplet mismatch thresholds associated with dnDSA development and stratified recipients into low-, intermediate-, and high-risk categories. In whole eplet mismatch analysis, risk categories were significantly correlated with dnDSA development (log-rank P-value 8 predicted dnDSA development with 75% sensitivity and 63.4% specificity. Risk categories by single molecular eplet mis match also had significant correlation with dnDSA development (log-rank P-value= 0.001) with significant difference between low (HLA-DR ≤7 and HLA-DQ ≤4) (n=78) and intermediate (HLA-DR ≥8 and HLA-DQ ≤6 or HLA-DR 0-7 and HLA-DQ 5-6) (n=95) group (P=0.026). High-risk group (HLA-DR 0-20 and HLA DQ 7-17) predicted dnDSA development with 75% sensitivity and 60.5% specificity. Both eplet mismatch risk categories were significantly associated with AMR, but no differences were found among risk groups. Conclusions: HLA class II eplet mismatches showed the possibility of being used as a clinically relevant parameter in alloim mune risk assessments of KT.

Induction and Donor Specific Antibodies in Low Immunologic Risk Kidney Transplant Recipients.

Optimal induction for patients without pretransplant donor-specific antibodies (DSAs) is poorly defined. The goal of this study was to compare the incidence of de novo DSA (dnDSA) and graft outcomes between induction therapies in patients with a negative virtual crossmatch (VXM). A retrospective chart review was performed, identifying 782 patients with a negative VXM who underwent kidney transplantation at a single, high-volume institution between January 2013 and May 2017. Kaplan-Meier analysis was used to assess the incidence of dnDSA and allograft survival between induction therapies in this group. dnDSA is defined as the development of new post-transplant DSA, at any MFI level. Induction therapy included alemtuzumab (N=87, 11%), basiliximab (N=522, 67%), and anti-thymocyte globulin (ATG; N=173, 22%). One-year graft survival was similar between groups (alemtuzumab, 100%; basiliximab, 98%; ATG, 99%). Incidence of acute rejection at 1 year was <2% and not different between the three groups. Alemtuzumab was associated with the highest incidence of dnDSA at 14%, compared with 5% and 8% in basiliximab and ATG groups, respectively, at 1 year (P=0.009). In multivariate regression analyses, alemtuzumab retained its significant association with a dnDSA HR of 2.5 (95% CI, 1.51 to 4.25; P=0.0004). In summary, alemtuzumab was associated with a higher rate of dnDSA development in patients with a negative VXM; however, this finding was not associated with rejection or graft failure.

HLA class II eplet mismatch load improves prediction of dnDSA development after living donor kidney transplantation.

HLA donor-specific antibodies developed de novo after transplant remain a major cause of chronic allograft dysfunction. Our study main purpose was to determine whether HLA MM, assessed traditionally and by HLA total and AbVer eplet mismatch load (EptMM and EpvMM) assessed with HLAMatchMaker, had impact on dnDSA development after living donor kidney transplantation (LDKT). We retrospectively analysed a cohort of 96 LDKT between 2008 and 2017 performed in Hospital Santo António. Seven patients developed dnDSA-II and EpvMM and EptMM were greater in dnDSA-II group compared to the no dnDSA-II (18.0±8.7 versus 9.9±7.9, p=.041 and 41.3±18.9 versus 23.1±16.7, p=.018), which is not observed for AgMM (2.29 versus 1.56; p=.09). In a multivariate analysis, we found that preformed DSA (HR=7.983; p=.023), living unrelated donors (HR=8.052; p=.024) and retransplantation (HR=14.393; p=.009) were predictors for dnDSA-II (AUC=0.801; 0.622-0.981). HLA-II EpvMM (HR=1.105; p=.028; AUC=0.856) showed to be a superior predictor of dnDSA-II, when compared to AgMM (HR=1.740; p=.113; AUC=0.783), when adjusted for these clinical variables. Graft survival was significantly lower within dnDSA-II patient group (36% versus 88%, p<.001). HLA molecular mismatch analysis is extremely important to minimize risk for HLA-II dnDSA development improving outcome and increasing chance of retransplant lowering allosensitization.

The Effect of Tacrolimus Trough Variability on Kidney Transplant Outcomes

PurposeVariability in tacrolimus levels has been associated with increased rejection, graft loss, and de novo donor-specific antibody (dnDSA) development in kidney transplant recipients (KTRs); however, limited data on alemtuzumab induction or infection exist. We sought to determine the impact of tacrolimus variability in KTRs on dnDSAs, graft outcomes, and infections 3 years posttransplant after alemtuzumab induction. MethodsAdult KTRs from January 1, 2013, to December 31, 2017, receiving alemtuzumab and tacrolimus-based immunosuppression at a single center were included. Tacrolimus variability was calculated using coefficient of variability (CV), and high CV was defined as ≥30%. Graft and infectious outcomes were assessed between high and low CV groups. ResultsTwo hundred fourteen KTRs were included. The median tacrolimus CV from 0 to 3 months and from 3 to 12 months was 28.1% and 25.8%, respectively. Recipients with high CV had decreased glomerular filtration rate at 3 and 12 months (67.7 ± 35.48 vs 80.7 ± 29.3, P = .01 and 70.9 ± 35.4 vs 83.3 ± 30.2, P = .015). High CV was also associated with increased cytomegalovirus viremia and disease (19.6% vs 9.3%, P = .046 and 6.4% vs 17.9%, P = .015). No difference in biopsy-proven acute rejection, survival, or dnDSA development at 3 years was observed. ConclusionsHigh tacrolimus variability was associated with significantly reduced graft function and increased cytomegalovirus viremia and disease but not biopsy-proven acute rejection, survival, or dnDSA development.

LATE INTRA-PATIENT TACROLIMUS VARIABILITY PREDICTS DE NOVO DONOR-SPECIFIC ANTIBODY AND GRAFT LOSS

Introduction: Intra-patient variability (IPV) of tacrolimus level has been associated with poor outcomes after kidney transplantation. However, these findings were limited mainly to measurements early after transplantation, and little is known about the effects of late IPV. We evaluated whether late IPV of tacrolimus level is associated with de novo donor-specific antibody (dnDSA) development and graft failure in a cohort of 703 transplant recipients. Methods: We analyzed the late IPV on the basis of trough levels for two years before dnDSA monitoring, and grouped patients into low IPV (n=411; coefficient of variation [CV]≤ 30%) and high IPV groups (n=292; CV> 30%). Monitoring of dnDSA was performed at a median 70 months (IQR 36-104) post-transplant. Results: During the follow-up, 206 developed dnDSA and 36 lost their graft excluding death. A total of 104 patients (35.6%) with high IPV and 102 (24.8%) with low IPV developed dnDSA (P=0.002). Mean tacrolimus trough levels of two groups were not significantly different (4.6 ± 1.3 for low IPV vs. 4.7 ± 1.3 for high IPV, P=0.714). High IPV (OR, 1.62; 95% CI, 1.16 to 2.28; P=0.005) and DR mismatches (OR, 2.25; 95% CI, 1.16 to 3.06; P<0.001) were the independent risk factors for dnDSA development. As compared to the low IPV group, high death-censored graft loss was observed in the high IPV group (P<0.001). Conclusion: High IPV of tacrolimus in late phases of transplantation was significantly associated with dnDSA development and graft loss. Late IPV of tacrolimus may serve as a useful tool for long-term post-transplant management.

Early conversion to a CNI-free immunosuppression with SRL after renal transplantation-Long-term follow-up of a multicenter trial.

Early conversion to a CNI-free immunosuppression with SRL was associated with an improved 1- and 3- yr renal function as compared with a CsA-based regimen in the SMART-Trial. Mixed results were reported on the occurrence of donor specific antibodies under mTOR-Is. Here, we present long-term results of the SMART-Trial. N = 71 from 6 centers (n = 38 SRL and n = 33 CsA) of the original SMART-Trial (ITT n = 140) were enrolled in this observational, non-interventional extension study to collect retrospectively and prospectively follow-up data for the interval since baseline. Primary objective was the development of dnDSA. Blood samples were collected on average 8.7 years after transplantation. Development of dnDSA was not different (SRL 5/38, 13.2% vs. CsA 9/33, 27.3%; P = 0.097). GFR remained improved under SRL with 64.37 ml/min/1.73m2 vs. 53.19 ml/min/1.73m2 (p = 0.044). Patient survival did not differ between groups at 10 years. There was a trend towards a reduced graft failure rate (11.6% SRL vs. 23.9% CsA, p = 0.064) and less tumors under SRL (2.6% SRL vs. 15.2% CsA, p = 0.09). An early conversion to SRL did not result in an increased incidence of dnDSA nor increased long-term risk for the recipient. Transplant function remains improved with benefits for the graft survival.

Third-party vessel allografts in kidney and pancreas transplantation: Utilization, de novo DSAs, and outcomes.

Third-party vascular allografts (VAs) are an invaluable resource in kidney and pancreas transplantation when vascular reconstruction is needed and additional vessels from the organ donor are not available. We report the largest single-center experience to date on VA use, at a high-volume U.S. transplant center. Over a 7-year period, VAs were used for vascular reconstruction of 65 kidneys and 5 pancreases, in 69 recipients. The renal vein required reconstruction more often with right kidney transplantation (72.5% vs 27.5%, P<.001), and the renal artery required reconstruction more often with left kidney transplantation (67.6% vs 32.4%, P=.003). Eleven patients (15.9%) developed anti-VA de novo HLA donor-specific antibodies (dnDSAs) at a median time after transplantation of 19.0months. Higher number of HLA mismatches between the VA donor and the recipient, and development of anti-organ allograft dnDSAs were significant predictors of anti-VA dnDSA development. Those with anti-VA dnDSAs had a higher rate of organ allograft rejection (45.4% vs 13.8%, P=.03) compared to those without, but there was no significant difference in incidence of vascular complications or graft outcomes. VAs can help circumvent challenging surgical situations. Anti-VA dnDSAs do not adversely affect organ allograft outcomes; however, they can contribute to HLA sensitization in the recipients.

P1739IMMUNOSUPPRESSION WITH CALCINEURIN INHIBITOR AFTER RENAL TRANSPLANT FAILURE PREVENTS ALLOSENSITIZATION

Abstract Background and Aims Retransplantation is an important option to consider in patients who return to dialysis after graft failure since it reduces mortality. HLA allosensitization hinders retransplantation, and immunosuppression withdrawal after graft failure seems to favor sensitization. There are no established protocols on the immunosuppressive treatment that should be maintained after transplant failure in order to reduce the development of anti-HLA antibodies. The aim of the study is to evaluate the effect of immunosuppression withdrawal on the development of anti-HLA antibodies after graft loss. Method A retrospective analysis including 77 patients who lost their first renal graft between 1/1/2006-12/31/2015 was performed. 22 patients with preemptive second kidney transplant were included. Maintenance immunosuppression was collected in months 1, 3 and 6 after graft failure. Patients were divided into two groups according to the presence or not of calcineurin inhibitor (CNI) as maintenance treatment. Two sera were analyzed per patient, one immediately prior to graft loss and another one after graft failure (Luminex®, Single Antigen). In patients in whom transplantectomy was performed, the selected serum after transplant failure was already after graft nephrectomy. PRA was calculated (cPRA) in each serum and the development of de novo donor-specific antibodies (dnDSA) was evaluated. Results Selected sera were extracted 1.0 month before graft failure (interquartile range 0.3-2.0) and 7.6 months after transplant failure (interquartile range 6.0-12.2). By multivariate logistic regression analysis, graft nephrectomy was an independent risk factor for cPRA&amp;gt;75% after transplant failure (OR 4.9, CI 95% 1.0-22.2, p=0.038). Similarly, the absence of CNI at 6 months after graft failure was significantly related to cPRA&amp;gt;75% in the multivariate analysis (OR 4.8, CI 95% 1.5-15.0, p=0.006). It was possible to analyze dnDSA formation in 73 patients. The absence of CNI at 6 months after graft loss was an independent risk factor for dnDSA development (OR 23.2, CI 95% 5.3-100.6, p &amp;lt;0.001). There were no differences in the management of other immunosuppressive drugs. Conclusion The absence of maintenance treatment with CNI at the sixth month after graft loss is a risk factor for sensitization. Therefore, immunosuppressive maintenance treatment based on CNI after transplant failure should be considered, since it seems to prevent HLA allosensitization.

HLA-DQ mismatches stimulate de novo donor specific antibodies in heart transplant recipients

The development of donor specific antibody is associated with graft rejection and increased mortality in solid organ transplant recipients. The majority of de novo donor specific antibodies (dnDSA) are against HLA-DQ antigens, but it has not been investigated if this is caused by more mismatches in the HLA-DQ locus between the recipient and donor. Here we examined the impact of HLA mismatches in eight HLA loci on the development of dnDSA and on rejection in a large cohort of heart transplant recipients. We evaluated HLA mismatches at the antigen level, the eplet level using HLAMatchmaker, and the epitope level using the PIRCHE algorithm. We found that the majority of dnDSA were against HLA-DQ antigens, and the number of dnDSA per mismatch is highest for HLA-DQ compared to other HLA loci. Furthermore, mismatches of HLA-DQ at the epitope level were associated with antibody-mediated rejection. Our results suggest that HLA mismatches at the HLA-DQ locus are more immunogenic than mismatches at other HLA loci to stimulate the development of dnDSA and to cause graft rejection.

Evidence for the alloimmune basis and prognostic significance of Borderline T cell-mediated rejection.

Prognostic biomarkers of T cell–mediated rejection (TCMR) have not been adequately studied in the modern era. We evaluated 803 renal transplant recipients and correlated HLA‐DR/DQ molecular mismatch alloimmune risk categories (low, intermediate, high) with the severity, frequency, and persistence of TCMR. Allograft survival was reduced in recipients with Banff Borderline (hazard ratio [HR] 2.4, P = .003) and Banff ≥ IA TCMR (HR 4.3, P < .0001) including a subset who never developed de novo donor‐specific antibodies (P = .002). HLA‐DR/DQ molecular mismatch alloimmune risk categories were multivariate correlates of Banff Borderline and Banff ≥ IA TCMR and correlated with the severity and frequency of rejection episodes. Recipient age, HLA‐DR/DQ molecular mismatch category, and cyclosporin vs tacrolimus immunosuppression were independent correlates of Banff Borderline and Banff ≥ IA TCMR. In the subset treated with tacrolimus (720/803) recipient age, HLA‐DR/DQ molecular mismatch category, and tacrolimus coefficient of variation were independent correlates of TCMR. The correlation of HLA‐DR/DQ molecular mismatch category with TCMR, including Borderline, provides evidence for their alloimmune basis. HLA‐DR/DQ molecular mismatch may represent a precise prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.

Current status of pediatric intestinal transplant in Europe.

This review features articles published during 2018 and 2019 regarding pediatric visceral transplantation in Europe. In this biannual review, the authors identify and summarize key articles pertinent to clinical and research areas. There is a trend to a lower use of intestinal transplantation in pediatric population in Europe. Most articles were focused in long-term follow-up. The burden of the disease 10 years after intestinal transplantation is still significant, including the need of several medications, readmissions, and the need of specific follow-up, mostly because of psychiatric problems. Regarding eating behaviors, promoting eating pretransplant may be protective and there may be eating difficulty predictors that could be used to facilitate targeted interventions. Two different articles were consistent in the identification of C1q-fixing DSA as a marker of poor outcome, and capillaritis was identified as a predictor of C4d positivity in intestinal graft biopsies. The inclusion of the liver emerged as the main protective factor against dnDSA development. The incidence of PTLD (specially the monomorphic type) was significantly higher following ITx than after LTx (14.9 vs. 2.8%). The European societies and the EU have made an effort to promote networking, collaborative registries, and sharing of knowledge in pediatric transplantation. Recent articles focused mostly on long-term follow-up issues, although translational research has also been sustained by some groups.

Evaluation of Carfilzomib for Antibody Mediated Rejection in Lung Transplant Recipients

Though definition and recognition of antibody mediated rejection (AMR) in lung transplant (LTx) has improved over the past few years, treatment of AMR remains poorly defined. Data supporting use of carfilzomib (CFZ) for treatment of AMR in combination with plasmapheresis and intravenous immunoglobulin (IVIG) suggest positive outcomes through donor specific antibody (DSA) depletion or conversion to noncomplement-activating antibodies. The aim of this retrospective analysis was to describe our center's experience treating AMR with CFZ. All adult LTx recipients who received CFZ for AMR from 2014-2018 were included. Patients were excluded if they received CFZ prior to transplant for desensitization. Per institution protocol, all patients received induction with basiliximab followed by maintenance immunosuppression with tacrolimus, mycophenolate, and prednisone. Acute rejection was diagnosed on trans-bronchial lung biopsy at week 2 and months 1, 2, 3, 6, 8, and 12 post-transplant, or when bronchoscopy was performed for clinical indication. Frequency of DSA checks and decision to use CFZ was per clinician discretion. A positive response to CFZ was defined as: 1) loss of DSA C1q-fixing ability after last CFZ dose, 2) clearance of de novo DSA (dnDSA) or 3) decrease in dnDSA MFI of >3000. Data on pulmonary function, infections, and incidence of acute kidney injury were also collected. During the study period, 21 patients with 24 AMR episodes were treated with CFZ in combination with plasmapheresis and IVIG. A positive response to CFZ was observed in 70.8% of AMR episodes and 76.1% of patients. This response was driven by loss of C1q-fixation (69.2%), elimination of class I DSAs (60.0%), and reduction in class II DSA MFI (median 3621, 26% reduction from baseline). Analysis of responders to CFZ revealed that delaying therapy with CFZ for ≥30 days after dnDSA development was associated with lack of response to therapy (p=0.002). Our cohort is the largest to date describing use of CFZ for treatment of AMR in LTx. The positive response the majority of our patients experienced was determined by decrease in both class I and II DSA MFI, elimination of dnDSAs, and reversal of C1q positivity. Larger prospective studies investigating the ideal time from dnDSA development to initiating AMR treatment, and defining the most appropriate time to utilize CFZ are needed.

Can Avoiding So-Called HLA High Risk Epitope Mismatches (REM) Improve Lung Transplant (LTx) Outcomes?

HLA epitope mismatches can determine risk of graft rejection and de novo Donor Specific Antibodies (dnDSA) formation. Recently (McCaughan 2018) noted some epitopes posed a greater risk of developing dnDSA post-LTx and assumed this correlated with CLAD and survival. Using these reported REM we aim to determine associations between REM and actual LTx outcomes. We retrospectively analysed all 310 primary LTx undertaken Aug 2008-Dec 2015, with both patients and donors' high resolution HLA typed for all HLA loci. Using HLAMatchmaker (v2.1), LTx were assessed for the presence of REM (45GE3 or 45EV/55PP) and DQA1*05. BOS and RAS were determined using the most recent 2019 ISHLT guidelines. Kaplan Meier analysis with log-ranked tests compared groups. Within our cohort, 82 (27%) LTx occurred in the presence of a REM from the donor. Of these, 43 developed CLAD (BOS n=28 RAS n=15). REM was not a predictor of overall patient survival (fig 1a) (p=0.52) or time to CLAD (fig 1b) (p=0.32). As previously published (McCaughan 2018) the development of dnDSA directed to HLA-DQ was frequent (ie 75% of those tested post-LTx) this did not correlate to time to CLAD or overall patient survival in our cohort. Although avoiding REM has been reported to reduce risk of dnDSA following LTx, in our cohort this does not strongly correlate to overall patient survival or time to CLAD. Further studies are still warranted to identify the riskiest of epitopes to avoid in LTx and how the correlate to LTx outcomes.

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.

The association between human leukocyte antigen eplet mismatches, de novo donor-specific antibodies, and the risk of acute rejection in pediatric kidney transplant recipients.

The longitudinal relationship between HLA class I and II eplet mismatches, de novo donor-specific antibodies (dnDSA) development, and acute rejection after transplantation in childhood is unknown. Eplet mismatches at HLA class I and II loci were calculated retrospectively for each donor/recipient pair transplanted between 2005 and 2015 at a single Australian center. Logistic regression analyses were conducted to determine the association between the number of eplet mismatches, dnDSA, and acute rejection. The cohort comprised 59 children (aged 0-18years) who received their first kidney allograft and were followed for median (interquartile range) 4.5 (± 2.6) years. Overall, 32% (19/59) developed dnDSA (class I 3% (2/59), class II 14% (8/59), 15% class I and II (9/59)), and 24% (14/59) developed biopsy-proven acute rejection. Every unit increase in class I and II eplet mismatches corresponded to an increase in risk of class I (odds ratio (OR) 1.22, 95% CI 1.07-1.39, p < 0.01) and class II (OR 1.06, 95% CI 1.01-1.11, p = 0.02) dnDSA development. Compared with recipients without dnDSA, class I and II dnDSA were associated with direction of effect towards increased risk of acute cellular rejection (class I: OR 5.87, 95% CI 0.99-34.94, p = 0.05; class II: OR 12.00, 95% CI 1.25-115.36, p = 0.03) and acute antibody-mediated rejection (class I: OR 25.67, 95% CI 3.54-186.10, p < 0.01; class II: OR 9.71, 95% CI 1.64-57.72, p = 0.01). Increasing numbers of HLA class I or II eplet mismatches were associated with the development of dnDSA. Children who developed dnDSA were also more likely to develop acute rejection compared with children without dnDSA.

Human leukocyte antigen molecular mismatch to risk stratify kidney transplant recipients.

Stalled drug development and the lack of improvement in long-term graft survival reflect the unmet need for prognostic and predictive biomarkers in transplantation. Although conventional human leukocyte antigen (HLA) mismatch is too imprecise to fulfill this need, HLA molecular mismatch increases the precision in alloimmune risk assessment by quantifying the difference between donors and recipients at the molecular level. Within each conventional HLA mismatch, recipients exhibit a wide range of HLA molecular mismatches with their donors. Quantifying HLA molecular mismatch improves the precision of alloimmune risk assessment for de novo donor-specific antibody development (dnDSA). Alloimmune risk categories developed analyzing dnDSA development were also found to correlate with T-cell-mediated rejection, antibody-mediated rejection, and all cause graft loss in adjusted and unadjusted models. All alloimmunity is driven by differences between donors and recipients at the molecular level. HLA molecular mismatch may represent a fast, reproducible, cost-effective, way to improve alloimmune risk assessment at the time of transplantation to move the field towards precision medicine.

Circulating de novo Donor Specific Antibodies and Carotid Intima-media Thickness in Pediatric Kidney Transplant Recipients, A Pilot Study.

Background: The presence of circulating de novo donor specific anti-HLA antibodies (dnDSA) has been implicated in an immune-mediated form of accelerated systemic arteriosclerosis in adult heart and kidney transplant recipients, however this has not been previously investigated in pediatric kidney transplant recipients. Carotid intima-media thickness (CIMT) is a reliable method for detection of arteriosclerosis. We hypothesized that children who develop dnDSA after kidney transplant would have increased CIMT compared with those who remain dnDSA negative.Methods: A prospective, controlled pilot cohort study of 38 transplant patients and 20 healthy controls was conducted to investigate the association between CIMT and development of dnDSA after kidney transplant. CIMT, anthropometrics, blood pressure and lipid panel were measured at 1, 18, and 30 months post-transplant. DSA was checked at 6, 12, 18, 24 and 30 months post-transplant. CIMT of DSA positive transplant recipients was compared to DSA negative and controls.Results: Of the 38 transplant recipients, 7 patients developed dnDSA by 18–30 months post-transplant. Among 5 dnDSA positive patients who did not receive treatment for DSA prior to CIMT measurement (n=6 observations), the median CIMT was 0.505 mm (95% CI 0.454–0.560 mm) at 18–30 months post-transplant, compared to 0.455 mm (95% CI 0.440–0.470) in DSA negative transplant recipients (n = 54 observations of 30 patients) and 0.450 mm (95% CI 0.436–0.460) in the healthy controls (20 observations of 20 patients). Presence of dnDSA was independently associated with a 7.8% increase in CIMT compared to those without dnDSA (p=0.006), after adjusting for race, hypertension, dyslipidemia, and abdominal obesity.Conclusions: Development of dnDSA was associated with increased CIMT, an indicator of arteriosclerosis, in a cohort of dnDSA positive pediatric kidney transplant recipients. The association between dnDSA and CIMT was independent of traditional CV risk factors, including hypertension, dyslipidemia, and abdominal obesity.

Clinical Relevance of Posttransplant DSAs in Patients Receiving Desensitization for HLA-incompatible Kidney Transplantation.

Highly HLA-sensitized (HS) patients have an increased risk for the development of donor-specific antibodies (DSA) and antibody-mediated rejection (AMR) posttransplant. Here, we examined the risk for AMR in HS patients transplanted after desensitization (DES) who were DSA+ versus DSA- at transplant. We also examined the incidence and clinical impact of de novo DSAs (dnDSAs) and compared with dnDSA- patients. From January 2013 to October 2016, 90 HS patients (PRA > 80%, DSA+ = 50 versus DSA- = 40) received kidney transplantation after DES with IVIG + rituximab ± PLEX (plasma exchange) ± tocilizumab. DSAs were monitored at transplant and at 1, 3, 6, 12, 24, 36, and 48 months posttransplant. Patients were divided into 4 groups: DSA+/+ (n = 31), DSA+/- (n=19), DSA-/+ (n=10), and DSA-/- (n = 30). Median follow-up time was 2.9 years. DSA-negative patients who developed dnDSA had the highest incidence of AMR (70%) compared with the DSA+/+ (45%), DSA+/- (11%), and DSA-/- (10%) patients (P < 0.0001). Among patients who developed AMR, Banff 2013 AMR scores did not differ among the 4 groups. Graft survival and estimated glomerular filtration rate determinations at 4 years were similar. Persistence of preexisting DSAs or development of dnDSA after transplant is associated with an increased risk for AMR. Despite this, we did not observe a difference in Banff biopsy scores, graft survival, or patient survival compared with those without DSAs after transplant. Thus, for HS patients undergoing HLA-incompatible kidney transplant, DES therapy and frequent monitoring for dnDSAs appears critical for good long-term survival in at-risk groups.

Association of immunosuppressive agents and cytomegalovirus infection with de novo donor-specific antibody development within 1 year after renal transplantation

The association between immunosuppressive therapy or cytomegalovirus (CMV) infection and detection of de novo donor-specific antibody (dnDSA) at 1 year after transplantation was evaluated. The impact of dnDSA positivity at 1 year after transplantation on long-term death-censored renal graft survival was also evaluated. One hundred and sixty adults receiving living renal allografts were studied. Inclusion criteria were renal graft survival for at least 1 year and a standard regimen of immunosuppressive therapy with tacrolimus, mycophenolate mofetil (MMF), steroids, and basiliximab. DSA were measured retrospectively by the Luminex assay. The coefficient of variation (CV) was calculated and receiver operating characteristic (ROC) analysis was employed to clarify the association of tacrolimus with development of dnDSA. Seven of the 160 patients (4.4%) were positive for dnDSA. The intra-patient minimum trough level of tacrolimus (cutoff value: 3.2 ng/mL) was associated with development of dnDSA. Discontinuation of MMF and treatment of CMV infection were more frequent in patients with dnDSA than in those without dnDSA. In multivariate analysis, a low trough level of tacrolimus, discontinuation of MMF, and treatment of CMV infection within 1 year after transplantation were independently associated with detection of dnDSA at 1 year. In patients with or without dnDSA at 1 year, the 10-year allograft survival rate was 51.4 versus 87.9%, respectively (P = 0.002). A lower tacrolimus trough level, discontinuation of MMF, and treatment of CMV infection were associated with dnDSA positivity. Further investigation is needed to determine whether a new immunosuppressive regimen that avoids these factors can reduce dnDSA positivity.