Age-associated decrease in de novo donor-specific antibodies in renal transplant recipients reflects changing humoral immunity.
ABSTRACT: Background:Older age at organ transplantation is associated with increased risk of infection and malignancy but reduced risk of cellular rejection. De novo donor-specific anti-HLA antibodies (dnDSA), are key biomarkers associated with reduced long-term allograft survival, yet there is a lack of data focusing on age-associated changes. Methods:Development of dnDSA was restrospectively analyzed in all subjects who received a kidney transplant at the University Hospital Zurich between 01/2006 and 02/2015. Follow up continued until 03/2016. The incidence of dnDSA in different age categories was compared with special focus on the extremes of age: children < 10 years (n = 19) and adults ≥60 years of age (n = 110). Results:Incidence of dnDSA gradually decreased with age, with older recipients having a significantly lower risk (HR 0.21, p = 0.0224) compared to pediatric recipients. Cumulative incidence of dnDSA at 2, 5 and 10 years was 6.2, 9.1 and 36% in the older recipients versus 5.3, 29.5 and 47.1% in pediatric recipients. Median time to development of dnDSA was similar (older 720 days, min 356, max 3646 days; children 1086 days, min 42, max 2474 days). Annual incidence was highest within the first two years after transplantation in the older recipients and peaked in years two to four in pediatric recipients. DnDSA were predominantly class II. More dnDSA were observed with cyclosporine as compared to tacrolimus. Conclusion:Older kidney transplant recipients have a lower risk of developing dnDSA than pediatric recipients, pointing towards reduced humoral immune reactivity with increasing age. This observation raises the question of adjustment in immunosuppression.
Project description:Despite more than two decades of use, the optimal maintenance dose of tacrolimus for kidney transplant recipients is unknown. We hypothesized that HLA class II de novo donor-specific antibody (dnDSA) development correlates with tacrolimus trough levels and the recipient's individualized alloimmune risk determined by HLA-DR/DQ epitope mismatch. A cohort of 596 renal transplant recipients with 50,011 serial tacrolimus trough levels had HLA-DR/DQ eplet mismatch determined using HLAMatchmaker software. We analyzed the frequency of tacrolimus trough levels below a series of thresholds <6 ng/ml and the mean tacrolimus levels before dnDSA development in the context of HLA-DR/DQ eplet mismatch. HLA-DR/DQ eplet mismatch was a significant multivariate predictor of dnDSA development. Recipients treated with a cyclosporin regimen had a 2.7-fold higher incidence of dnDSA development than recipients on a tacrolimus regimen. Recipients treated with tacrolimus who developed HLA-DR/DQ dnDSA had a higher proportion of tacrolimus trough levels <5 ng/ml, which continued to be significant after adjustment for HLA-DR/DQ eplet mismatch. Mean tacrolimus trough levels in the 6 months before dnDSA development were significantly lower than the levels >6 months before dnDSA development in the same patients. Recipients with a high-risk HLA eplet mismatch score were less likely to tolerate low tacrolimus levels without developing dnDSA. We conclude that HLA-DR/DQ eplet mismatch and tacrolimus trough levels are independent predictors of dnDSA development. Recipients with high HLA alloimmune risk should not target tacrolimus levels <5 ng/ml unless essential, and monitoring for dnDSA may be advisable in this setting.
Project description:De novo donor-specific antibody (dnDSA) is associated with antibody-mediated rejection (AMR) and allograft loss, yet the allograft histology associated with dnDSA remains unclear. The aim of this study was to examine the allograft histology associated with dnDSA in patients with serial surveillance biopsies. We retrospectively studied adult conventional solitary kidney transplant recipients from October 2007 to May 2014. The definition of dnDSA was new donor-specific antibody (DSA) with mean fluorescence intensity (MFI) >1000. The incidence of dnDSA was 7.0% (54 of 771) over mean follow-up of 4.2 ± 1.9 years. Patients with dnDSA had reduced death-censored allograft survival (87.0% vs. 97.0% no dnDSA, p < 0.01). Moreover, 94% of patients received a biopsy after dnDSA (mean of three biopsies per patient). AMR was present in 25.0% and 52.9% of patients at dnDSA detection and at 1 year, respectively. Patients with both class I and II dnDSA had the highest rate of allograft loss. The higher the sum MFI at dnDSA detection, the higher the incidence of AMR. In conclusion, patients with dnDSA without AMR at time of detection may benefit from a follow-up biopsy within 1 year because AMR can be missed initially. In addition, the dnDSA class and sum MFI at baseline appear to be prognostic. The higher the sum MFI of dnDSA at baseline, the higher the incidence of AMR.
Project description:INTRODUCTION:Complement binding activity of donor-specific HLA antibodies (DSA) has been suggested as a new tool to stratify immunologic risk in kidney transplantation (KT). The objective of this study was to evaluate the clinical implication of C1q/C3d binding activity of de novo DSA (dnDSA) in KT recipients. MATERIAL AND METHODS:A total of 161 pretransplant DSA-negative recipients were monitored for dnDSA at the time of biopsy. C1q/C3d binding activities of dnDSA were assessed using C1qScreen assay (One lambda, USA) and Lifecodes C3d detection assay (Immucor, USA), respectively. Clinical outcomes including biopsy-proven antibody mediated rejection (AMR), C4d detection and post-biopsy graft survival were investigated. RESULTS:De-novo DSAs were detected in fifty-four (33.5%) patients (HLA class I only, n = 19; class II only, n = 29; both class I and II, n = 6). Of them, complement binding activities were detected in 26 (48.1%) patients, including 17 C1q+ and 24 C3d+ patients. Both C1q and C3d positivity were associated with increased mean fluorescence intensity values of dnDSA. Complement binding activity of dnDSA enhanced the incidence of AMR (25.0% in C1q-C3d-, 36.4% in C1q+/C3d- or C1q-/C3d+, and 60.0% in C1q+/C3d+ patients) (P <0.001). The incidence of AMR was not different between patients with C1q+ and those with C3d+ dnDSA (64.7%, 11/17 versus 45.8%, 11/24, P = 0.238). In comparison between C1q and C3d assay according to HLA specificity, C1q+ HLA class I ± II dnDSA was the best predictor for AMR (odds ratio: 27.2). C1q+/C3d+ dnDSA was associated with more C4d deposition in allograft tissue and inferior post-biopsy graft survival. Clinical outcomes were not significantly different between C1q+ and C3d+ dnDSA-positive patients. CONCLUSION:Detection of complement binding activity using both C1q and C3d assays can be a further prognostic marker for predicting AMR and allograft outcome in dnDSA+ kidney transplant patients.
Project description:Background:Children undergoing hematopoietic stem cell transplantation (HSCT) are at high risk for hospital-associated bloodstream infections (HA-BSIs). This study aimed to describe the incidence, microbiology, and risk factors for HA-BSI in pediatric HSCT recipients. Methods:We performed a single-center retrospective cohort study of children and adolescents (<18 years of age) who underwent HSCT over a 20-year period (1997-2016). We determined the incidence and case fatality rate of HA-BSI by causative organism. We used multivariable Poisson regression to identify risk factors for HA-BSI. Results:Of 1294 patients, the majority (86%) received an allogeneic HSCT, most commonly with umbilical cord blood (63%). During the initial HSCT hospitalization, 334 HA-BSIs occurred among 261 (20%) patients. These were classified as gram-positive bacterial (46%), gram-negative bacterial (24%), fungal (12%), mycobacterial (<1%), or polymicrobial (19%). During the study period, there was a decline in the cumulative incidence of HA-BSI (P?=?.021) and, specifically, fungal HA-BSIs (P?=?.002). In multivariable analyses, older age (incidence rate ratio [IRR], 1.03; 95% confidence interval [CI], 1.01-1.06), umbilical cord blood donor source (vs bone marrow; IRR, 1.69; 95% CI, 1.19-2.40), and nonmyeloablative conditioning (vs myeloablative; IRR, 1.85; 95% CI, 1.21-2.82) were associated with a higher risk of HA-BSIs. The case fatality rate was higher for fungal HA-BSI than other HA-BSI categories (21% vs 6%; P?=?.002). Conclusions:Over the past 2 decades, the incidence of HA-BSIs has declined among pediatric HSCT recipients at our institution. Older age, umbilical cord blood donor source, and nonmyeloablative conditioning regimens are independent risk factors for HA-BSI among children undergoing HSCT.
Project description:Approximately 25% of kidney transplant recipients develop de novo anti-HLA donor-specific antibodies (dnDSA) leading to acute antibody-mediated rejection (ABMR) in 30% of patients. Preemptive therapeutic strategies are not available.We conducted a prospective observational study including 11 kidney transplant recipients. Inclusion criteria were dnDSA occurring within the first year after transplant and normal allograft biopsy. All patients were treated with high-dose IVIG (2 g/kg 0, 1 and 2 months post-dnDSA). The primary efficacy outcome was incidence of clinical and subclinical acute ABMR within 12 months after dnDSA detection as compared to a historical control group (IVIG-).Acute ABMR occurred in 2 or 11 patients in the IVIG+ group and in 1 of 9 patients in the IVIG- group. IVIG treatment did not affect either class I or class II DSA, as observed at the end of the follow-up. IVIG treatment significantly decreased Fc?RIIA mRNA expression in circulating leukocytes, but did not affect the expression of any other markers of B cell activation.In this first pilot study including kidney allograft recipients with early dnDSA, preemptive treatment with high-dose IVIG alone did not prevent acute ABMR and had minimal effects on DSA outcome and B cell phenotype.
Project description:BACKGROUND:Antibody-mediated rejection is a major cause of premature graft loss in kidney transplantation. Multiple scoring systems are available to assess the HLA mismatch between donors and recipients at the molecular level; however, their correlation with the development of de novo donor-specific antibody (dnDSA) has not been compared in recipients on active immunosuppression. METHODS:HLA-DR?1/3/4/5/DQ?1?1 molecular mismatch was determined using eplet analysis, amino acid mismatch, and electrostatic mismatch for 596 renal transplant recipients and correlated with HLA-DR/DQ dnDSA development. The molecular mismatch scores were evaluated in multivariate models of posttransplant dnDSA-free survival. RESULTS:Eplet mismatch correlated with amino acid mismatch and electrostatic mismatch (R = 0.85-0.96). HLA-DR dnDSA-free survival correlated with HLA-DR eplet mismatch (hazards ratio [HR], 2.50 per 10 eplets mismatched; P < 0.0001), amino acid mismatch (HR, 1.49 per 10 amino acids mismatched; P < 0.0001), and electrostatic mismatch (HR, 1.23 per 10 units mismatched; P < 0.0001). HLA-DQ dnDSA-free survival correlated with HLA-DQ eplet mismatch (HR, 1.98 per 10 eplets mismatched; P < 0.0001), amino acid mismatch (HR, 1.24 per 10 amino acids mismatched; P < 0.0001), and electrostatic mismatch (HR, 1.14 per 10 units mismatched; P < 0.0001). All 3 methods were significant multivariate correlates of dnDSA development after adjustment for recipient age, baseline immunosuppression, and nonadherence. CONCLUSIONS:HLA molecular mismatch represents a precise method of alloimmune risk assessment for renal transplant patients. The method used to determine the molecular mismatch is likely to be driven by familiarity and ease of use as highly correlated results are produced by each method.
Project description:We aimed to evaluate patient factors including nonadherence and viral infection and de novo donor-specific antibody (dnDSA) characteristics [total immunoglobulin G (IgG), C1q, IgG3, and IgG4] as predictors of renal allograft failure in a multicenter cohort with dnDSA. We performed a retrospective observational study of 113 kidney transplant recipients with dnDSA and stored sera for analysis. Predictors of death-censored allograft loss were assessed by Cox proportional modeling. Death-censored allograft survival was 77.0% (87/113) during a median follow-up of 2.2 (IQR 1.2-3.7) years after dnDSA detection. Predictors of allograft failure included medication nonadherence [HR 6.5 (95% CI 2.6-15.9)], prior viral infection requiring immunosuppression reduction [HR 5.3 (95% CI 2.1-13.5)], IgG3 positivity [HR 3.8 (95% CI 1.5, 9.3)], and time post-transplant (years) until donor-specific antibody (DSA) detection [HR 1.2 (95% CI 1.0, 1.3)]. In the 67 patients who were biopsied at dnDSA detection, chronic antibody-mediated rejection [HR 11.4 (95% CI 2.3, 56.0)] and mixed rejection [HR 7.4 (95% CI 2.2, 24.8)] were associated with allograft failure. We conclude that patient factors, including a history of viral infection requiring immunosuppression reduction or medication nonadherence, combined with DSA and histologic parameters must be considered to understand the risk of allograft failure in patients with dnDSA.
Project description:Medulloblastoma (MB) is the most common pediatric brain tumor and is an aggressive neoplasia arising in the cerebellum. MB includes four major histological subsets commonly subdivided in: classic, desmoplastic, anaplastic or large-cell, and nodular. The current patients risk stratification is based on the age at diagnosis (> or < 3 years at diagnosis), the extent of residual tumor mass post-operative, and disease dissemination. An average risk is assigned to patients older than 3 years of age with minimal or no tumor residual. These patients are more than 60% of overall MBs and have an overall survival between 50-70% at 5 years. It is widely accepted that tumor aggressiveness and progression depend on genetic abnormalities. We performed the genome-wide study, focused on classic MB belonging to pediatric patients at standard risk. We analyzed 31 MB samples using high resolution oligonucleotide Human Genome CGH 244K (Agilent Technologies). The present study may help to identify novel molecular prognostic markers useful to refining current criteria of patients´ relapse risk estimation in this subgroup of patients. We analyzed 31 samples of classic medulloblastoma from patients older than 3 years of age at diagnosis
Project description:Medulloblastoma (MB) is the most common pediatric brain tumor and is an aggressive neoplasia arising in the cerebellum. MB includes four major histological subsets commonly subdivided in: classic, desmoplastic, anaplastic or large-cell, and nodular. The current patients risk stratification is based on the age at diagnosis (> or < 3 years at diagnosis), the extent of residual tumor mass post-operative, and disease dissemination. An average risk is assigned to patients older than 3 years of age with minimal or no tumor residual. These patients are more than 60% of overall MBs and have an overall survival between 50-70% at 5 years. It is widely accepted that tumor aggressiveness and progression depend on genetic abnormalities. We performed the genome-wide study, focused on classic MB belonging to pediatric patients at standard risk. We analyzed 31 MB samples using high resolution oligonucleotide Human Genome CGH 244K (Agilent Technologies). The present study may help to identify novel molecular prognostic markers useful to refining current criteria of patients´ relapse risk estimation in this subgroup of patients. Overall design: We analyzed 31 samples of classic medulloblastoma from patients older than 3 years of age at diagnosis
Project description:The Immune Development in Pediatric Transplantation (IMPACT) study was conducted to evaluate relationships among alloimmunity, protective immunity, immune development, physical parameters, and clinical outcome in children undergoing kidney transplantation. We prospectively evaluated biopsy-proven acute rejection (BPAR), de novo donor-specific antibody (dnDSA) formation, viremia, viral infection, T cell immunophenotyping, and body mass index (BMI)/weight Z scores in the first year posttransplantation in 106 pediatric kidney transplant recipients. Outcomes were excellent with no deaths and 98% graft survival. Rejection and dnDSAs occurred in 24% and 22%, respectively. Pretransplant cytomegalovirus (CMV) and Epstein-Barr virus (EBV) serologies and subsequent viremia were unrelated to BPAR or dnDSA. Viremia occurred in 73% of children (EBV, 34%; CMV, 23%; BMK viremia, 23%; and JC virus, 21%). Memory lymphocyte phenotype at baseline was not predictive of alloimmune complications. Patients who developed viral infection had lower weight (-2.1) (p = 0.028) and BMI (-1.2) (p = 0.048) Z scores at transplantation. The weight difference persisted to 12 months compared with patients without infection (p = 0.038). These data indicate that there is a high prevalence of viral disease after pediatric kidney transplantation, and underweight status at transplantation appears to be a risk factor for subsequent viral infection. The occurrence of viremia/viral infection is not associated with alloimmune events.