RESUMO
BACKGROUND: Little is known about the relationship between cytomegalovirus (CMV) infections and donor-derived cell-free DNA (dd-cfDNA) in heart transplant recipients. METHODS: In our study, CMV and dd-cfDNA results were prospectively collected on single-organ heart transplant recipients. If the CMV study was positive, a CMV study with dd-cfDNA was repeated 1-3 months later. The primary aim was to compare dd-cfDNA between patients with positive and negative CMV results. RESULTS: Of 44 patients enrolled between August 2022 and April 2023, 12 tested positive for CMV infections, 25 were included as controls, and seven patients with a viral infection without CMV were excluded. Baseline characteristics did not differ significantly between CMV-positive and CMV-negative patients with the exception of a later median time post-transplant in the CMV-positive group (253 days vs. 120 days, p = .03). Dd-cfDNA levels were significantly higher in patients with CMV infections compared to those without (p < .001) with more patients in the CMV positive group showing dd-cfDNA results ≥.12% (75% vs. 8%, p < .001) and ≥.20% (58% vs. 8%, p = .002). Each 1 log10 copy/ml reduction in CMV viral load from visit 1 to visit 2 was associated with a.23% reduction in log10 dd-cfDNA (p = .002). CONCLUSION: Our findings suggest that active CMV infections may raise dd-cfDNA levels in patients following heart transplantation. Larger studies are needed to validate these preliminary findings.
Assuntos
Ácidos Nucleicos Livres , Infecções por Citomegalovirus , Transplante de Coração , Humanos , Citomegalovirus/genética , Doadores de Tecidos , Transplantados , Rejeição de EnxertoRESUMO
BACKGROUND: The study purpose was to add to limited literature assessing anti-HLA donor-specific antibody (DSA) appearance, clearance, specificity, and impact in intestinal/multivisceral (MV) transplant as well as the value of serial monitoring following an institutional protocol shift implementing serial monitoring. METHODS: This single-center retrospective review included intestinal/MV recipients transplanted 1/1/15-9/31/17 with completed DSA testing. Patients were divided into groups based on DSA presence post-transplant. The primary outcome was biopsy-proven acute rejection (BPAR). Secondary outcomes included graft loss and death. Descriptive analysis of DSA was completed. RESULTS: Of the 35 intestinal/MV recipients (60% pediatric) with DSA testing, 24 patients had post-transplant DSA. Fifteen patients in the DSA(+) group had T-cell-mediated BPAR versus five in the DSA(-) group (63% vs 45%, p = .47). Days to BPAR were 25 [IQR 19-165] (DSA(+) group) versus 232 [IQR 25.5-632.5] (DSA(-) group) (p = .066). There were no differences between groups for graft loss or death. One hundred and five DSA were identified in the DSA(+) group with 63% being class II, and 54% cleared during follow-up. DSA were directed against 50 different HLA alleles, with the most common being directed against HLA- DQ (35%). Time to first DSA and to clearance did not differ between class I and II. CONCLUSION: Findings confirm previous data that suggest post-transplant DSA in this population may lead to increased BPAR or shorter time to BPAR, although not statistically significant. Most DSA were identified within the first month after transplant, and ahead of rejection identification on biopsy. DSA therefore may have utility as an early rejection biomarker and use may be considered in place of early protocol biopsies, particularly in pediatric patients. We identified novel findings of DSA directed against a large breadth of HLA in intestinal/MV patients.
Assuntos
Transplante de Rim , Transplantados , Adulto , Humanos , Criança , Antígenos HLA , Anticorpos , Doadores de Tecidos , Estudos Retrospectivos , Soro Antilinfocitário , Rejeição de Enxerto/diagnóstico , Sobrevivência de Enxerto , IsoanticorposRESUMO
Donor-derived cell-free DNA (dd-cfDNA) has been evaluated as a rejection marker in organ transplantation. This study sought to assess the utility of dd-cfDNA to diagnose graft injury in liver transplant recipients (LTR) and as a predictive biomarker prior to different causes of graft dysfunction. Plasma from single and multicenter LTR cohorts was analyzed for dd-cfDNA. Phenotypes of treated biopsy-proven acute rejection (AR, N = 57), normal function (TX, N = 94), and acute dysfunction no rejection (ADNR; N = 68) were divided into training and test sets. In the training set, dd-cfDNA was significantly different between AR versus TX (AUC 0.95, 5.3% cutoff) and AR versus ADNR (AUC 0.71, 20.4% cutoff). Using these cutoffs in the test set, the accuracy and NPV were 87% and 100% (AR vs. TX) and 66.7% and 87.8% (AR vs. ADNR). Blood samples collected serially from LTR demonstrated incremental elevations in dd-cfDNA prior to the onset of graft dysfunction (AR > ADNR), but not in TX. Dd-cfDNA also decreased following treatment of rejection. In conclusion, the serial elevation of dd-cfDNA identifies pre-clinical graft injury in the context of normal liver function tests and is greatest in rejection. This biomarker may help detect early signs of graft injury and rejection to inform LTR management strategies.
Assuntos
Ácidos Nucleicos Livres , Transplante de Rim , Transplante de Fígado , Biomarcadores , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/genética , Humanos , Transplante de Fígado/efeitos adversos , Doadores de Tecidos , TransplantadosRESUMO
Simultaneous liver-kidney transplant (SLKT) in the presence of antihuman leukocyte antigen (HLA) donor-specific antibodies (DSA) is a well-accepted practice. Herein, we describe the evolution of alloantibodies in a patient who received an SLKT. The pre-SLKT serum sample showed multiple strong DSA. As expected, all DSA cleared in a sample collected 4 days after the SLKT. Because of the primary nonfunction of the liver in the SLKT, the patient had a second liver transplant 4 days later. An abrupt increase in DSA levels against the kidney was detected 10 days after the second liver transplant. These DSA were refractory to treatment, and the transplanted kidney was lost due to antibody-mediated rejection (AMR). A detailed study of the HLA epitopes recognized by DSA and, after normalization with third-party alloantibodies to address the effect of multiple transfusions and liver allograft neutralization, showed that the elimination of these antibodies depended on the HLA antigens expressed by the transplanted liver cells. The return of DSA after removal of the first transplanted liver was associated with AMR in the transplanted kidney.
Assuntos
Transplante de Rim , Transplante de Fígado , Rejeição de Enxerto , Sobrevivência de Enxerto , Antígenos HLA , Humanos , Isoanticorpos , Rim , Transplante de Rim/efeitos adversos , Fígado , Transplante de Fígado/efeitos adversos , ReoperaçãoRESUMO
Chronic lung allograft dysfunction (CLAD) is the major barrier to long-term survival following lung transplantation, and new mechanistic biomarkers are needed. Lymphocytic bronchitis (LB) precedes CLAD and has a defined molecular signature. We hypothesized that this LB molecular signature would be associated with CLAD in small airway brushings independent of infection. We quantified RNA expression from small airway brushings and transbronchial biopsies, using RNAseq and digital RNA counting, respectively, for 22 CLAD cases and 27 matched controls. LB metagene scores were compared across CLAD strata by Wilcoxon rank sum test. We performed unbiased host transcriptome pathway and microbial metagenome analysis in airway brushes and compared machine-learning classifiers between the two tissue types. This LB metagene score was increased in CLAD airway brushes (p = .002) and improved prediction of graft failure (p = .02). Gene expression classifiers based on airway brushes outperformed those using transbronchial biopsies. While infection was associated with decreased microbial alpha-diversity (p ≤ .04), neither infection nor alpha-diversity was associated with LB gene expression. In summary, CLAD was associated with small airway gene expression changes not apparent in transbronchial biopsies in this cohort. Molecular analysis of airway brushings for diagnosing CLAD merits further examination in multicenter cohorts.
Assuntos
Rejeição de Enxerto , Transplante de Pulmão , Aloenxertos , Rejeição de Enxerto/genética , Humanos , Inflamação/genética , Pulmão , Transplante de Pulmão/efeitos adversosRESUMO
Clinicians have few tools to predict the risk of alloimmune injury that would guide immunosuppression management in renal transplant patients. We evaluated human leukocyte antigen (HLA)-DR/DQ molecular mismatch to predict de novo donor-specific antibodies (DSAs) during the first year of transplant and explored how differences in tacrolimus exposure may modulate this risk. HLA-DR and -DQ eplet mismatches were determined between 444 donor-recipient pairs in Denver, Colorado between 2007 and 2013. Previously defined mismatch thresholds stratified recipients into low- (N = 119), intermediate- (N = 153), and high- (N = 172) risk categories. The area under the curve for DSA at 1 year was 0.84 and 0.82 for HLA-DR and HLA-DQ eplet mismatches, respectively. Compared to low-risk patients, there was a graded increase in risk of DR/DQ DSA in intermediate (HR 15.39, 95% CI 2.01-118.09, p = .009) and high-risk (HR 23.81, 95% CI 3.17-178.66, p = 0.002) categories. Intermediate- and high-risk patients with a mean tacrolimus <6 ng/ml versus >8 ng/ml had increased risk of DR/DQ DSA at 1 year (HR 2.34, 95% CI 1.05-5.22, p = .04). HLA molecular mismatch represents a reproducible, objective, and clinically relevant tool to stratify patients by alloimmune risk and may help guide personalized immunosuppression management.
Assuntos
Rejeição de Enxerto , Tacrolimo , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Antígenos HLA/genética , Antígenos HLA-DR , Teste de Histocompatibilidade , Humanos , Estados UnidosRESUMO
Islet transplantation is an effective therapy for life-threatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized islet-specific T cells in recipients within an islet transplant program favoring alemtuzumab (ATZ) lymphodepleting induction and examined associations with graft function. Fifty-eight recipients were studied: 23 pretransplant and 40 posttransplant (including 5 with pretransplant phenotyping). The proportion with islet-specific T cell responses was not significantly different over time (pre-Tx: 59%; 1-6 m posttransplant: 38%; 7-12 m: 44%; 13-24 m: 47%; and >24 m: 45%). However, phenotype shifted significantly, with IFN-γ-dominated response in the pretransplant group replaced by IL-10-dominated response in the 1-6 m posttransplant group, reverting to predominantly IFN-γ-oriented response in the >24 m group. Clustering analysis of posttransplant responses revealed two main agglomerations, characterized by IFN-γ and IL-10 phenotypes, respectively. IL-10-oriented posttransplant response was associated with relatively low graft function. Recipients within the IL-10+ cluster had a significant decline in C-peptide levels in the period preceding the IL-10 response, but stable graft function following the response. In contrast, an IFN-γ response was associated with subsequently decreased C-peptide. Islet transplantation favoring ATZ induction is associated with an initial altered islet-specific T cell phenotype but reversion toward pretransplant profiles over time. Posttransplant autoreactive T cell phenotype may be a predictor of subsequent graft function.
Assuntos
Diabetes Mellitus Tipo 1 , Transplante de Células-Tronco Hematopoéticas , Transplante das Ilhotas Pancreáticas , Alemtuzumab/uso terapêutico , Sobrevivência de Enxerto , Humanos , Fenótipo , Linfócitos TRESUMO
Immunosuppressed organ-transplanted patients are considered at risk for severe forms of COVID-19. Moreover, exaggerated innate and adaptive immune responses might be involved in severe progression of the disease. However, no data on the immune response to SARS-CoV-2 in transplanted patients are currently available. Here, we report the first assessment of antibody and T cell responses to SARS-CoV-2 in 11 kidney-transplanted patients recovered from RT-PCR-confirmed (n = 5) or initially suspected (n = 6) COVID-19. After reduction of immunosuppressive therapy, RT-PCR-confirmed COVID-19 transplant patients were able to mount vigorous antiviral T cell and antibody responses, as efficiently as two nontherapeutically immunosuppressed COVID-19 patients on hemodialysis. By contrast, six RT-PCR-negative patients displayed no antibody response. Among them, three showed very low numbers of SARS-CoV-2-reactive T cells, whereas no T cell response was detected in the other three, potentially ruling out COVID-19 diagnosis. Low levels of T cell reactivity to SARS-CoV-2 were also detected in seronegative healthy controls without known exposure to the virus. These results suggest that during COVID-19, monitoring both T cell and serological immunity might be helpful for the differential diagnosis of COVID-19 but are also needed to evaluate a potential role of antiviral T cells in the development of severe forms of the disease.
Assuntos
Anticorpos Antivirais/imunologia , Formação de Anticorpos , COVID-19/imunologia , Hospedeiro Imunocomprometido , Transplante de Rim , Complicações Pós-Operatórias/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Anticorpos Antivirais/metabolismo , Antígenos Virais/imunologia , Biomarcadores/metabolismo , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/etiologia , Teste de Ácido Nucleico para COVID-19 , Estudos de Casos e Controles , ELISPOT , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Diálise Renal , Linfócitos T/metabolismoRESUMO
Whether immunosuppression impairs severe acute respiratory syndrome coronavirus 2-specific T cell-mediated immunity (SARS-CoV-2-CMI) after liver transplantation (LT) remains unknown. We included 31 LT recipients in whom SARS-CoV-2-CMI was assessed by intracellular cytokine staining (ICS) and interferon (IFN)-γ FluoroSpot assay after a median of 103 days from COVID-19 diagnosis. Serum SARS-CoV-2 IgG antibodies were measured by ELISA. A control group of nontransplant immunocompetent patients were matched (1:1 ratio) by age and time from diagnosis. Post-transplant SARS-CoV-2-CMI was detected by ICS in 90.3% (28/31) of recipients, with higher proportions for IFN-γ-producing CD4+ than CD8+ responses (93.5% versus 83.9%). Positive spike-specific and nucleoprotein-specific responses were found by FluoroSpot in 86.7% (26/30) of recipients each, whereas membrane protein-specific response was present in 83.3% (25/30). An inverse correlation was observed between the number of spike-specific IFN-γ-producing SFUs and time from diagnosis (Spearman's rho: -0.418; p value = .024). Two recipients (6.5%) failed to mount either T cell-mediated or IgG responses. There were no significant differences between LT recipients and nontransplant patients in the magnitude of responses by FluoroSpot to any of the antigens. Most LT recipients mount detectable-but declining over time-SARS-CoV-2-CMI after a median of 3 months from COVID-19, with no meaningful differences with immunocompetent patients.
Assuntos
COVID-19 , Transplante de Fígado , Anticorpos Antivirais , Teste para COVID-19 , Humanos , Transplante de Fígado/efeitos adversos , SARS-CoV-2 , Linfócitos T , TransplantadosRESUMO
Recently published studies have found an impaired immune response after SARS-CoV-2 vaccination in solid organ recipients. However, most of these studies have not assessed immune cellular responses in liver and heart transplant recipients. We prospectively studied heart and liver transplant recipients eligible for SARS-CoV-2 vaccination. Patients with past history of SARS-CoV-2 infection or SARS-CoV-2 detectable antibodies (IgM or IgG) were excluded. We assessed IgM/IgG antibodies and ELISpot against the S protein 4 weeks after receiving the second dose of the mRNA-1273 (Moderna) vaccine. Side effects, troponin I, liver tests and anti-HLA donor-specific antibodies (DSA) were also assessed. A total of 58 liver and 46 heart recipients received two doses of mRNA-1273 vaccine. Median time from transplantation to vaccination was 5.4 years (IQR 0.3-27). Sixty-four percent of the patients developed SARS-CoV-2 IgM/IgG antibodies and 79% S-ELISpot positivity. Ninety percent of recipients developed either humoral or cellular response (87% in heart recipients and 93% in liver recipients). Factors associated with vaccine unresponsiveness were hypogammaglobulinemia and vaccination during the first year after transplantation. Local and systemic side effects were mild or moderate, and none presented DSA or graft dysfunction after vaccination. Ninety percent of our patients did develop humoral or cellular responses to mRNA-1273 vaccine. Factors associated with vaccine unresponsiveness were hypogammaglobulinemia and vaccination during the first year after transplantation, highlighting the need to further protect these patients.
Assuntos
COVID-19 , Transplante de Coração , Anticorpos Antivirais , Vacinas contra COVID-19 , Humanos , Imunidade Humoral , Fígado , SARS-CoV-2 , TransplantadosRESUMO
Graft-versus-host disease after liver transplantation (LT-GVHD) is rare, frequently fatal, and associated with bone marrow failure (BMF), cytopenias, and hyperferritinemia. Given hyperferritinemia and cytopenias are present in hemophagocytic lymphohistiocytosis (HLH), and somatic mutations in hematopoietic cells are associated with hyperinflammatory responses (clonal hematopoiesis of indeterminate potential, CHIP), we identified the frequency of hemophagocytosis and CHIP mutations in LT-GVHD. We reviewed bone marrow aspirates and biopsies, quantified blood/marrow chimerism, and performed next-generation sequencing (NGS) with a targeted panel of genes relevant to myeloid malignancies, CHIP, and BMF. In all, 12 marrows were reviewed from 9 LT-GVHD patients. In all, 10 aspirates were evaluable for hemophagocytosis; 7 had adequate DNA for NGS. NGS was also performed on marrow from an LT cohort (n = 6) without GVHD. Nine of 10 aspirates in LT-GVHD patients showed increased hemophagocytosis. Five (71%) of 7 with LT-GVHD had DNMT3A mutations; only 1 of 6 in the non-GVHD LT cohort demonstrated DNMT3A mutation (p = .04). Only 1 LT-GVHD patient survived. BMF with HLH features was associated with poor hematopoietic recovery, and DNMT3A mutations were over-represented, in LT-GVHD patients. Identification of HLH features may guide prognosis and therapeutics. Further studies are needed to clarify the origin and impact of CHIP mutations on the hyperinflammatory state.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Fígado , Linfo-Histiocitose Hemofagocítica , Transtornos da Insuficiência da Medula Óssea , Transplante de Medula Óssea/efeitos adversos , Doença Enxerto-Hospedeiro/genética , Humanos , Transplante de Fígado/efeitos adversos , Linfo-Histiocitose Hemofagocítica/genética , Mutação/genéticaRESUMO
Short-term outcomes in kidney transplantation are marred by progressive transplant failure and mortality secondary to immunosuppression toxicity. Immune modulation with autologous polyclonal regulatory T cell (Treg) therapy may facilitate immunosuppression reduction promoting better long-term clinical outcomes. In a Phase I clinical trial, 12 kidney transplant recipients received 1-10 × 106 Treg per kg at Day +5 posttransplantation in lieu of induction immunosuppression (Treg Therapy cohort). Nineteen patients received standard immunosuppression (Reference cohort). Primary outcomes were rejection-free and patient survival. Patient and transplant survival was 100%; acute rejection-free survival was 100% in the Treg Therapy versus 78.9% in the reference cohort at 48 months posttransplant. Treg therapy revealed no excess safety concerns. Four patients in the Treg Therapy cohort had mycophenolate mofetil withdrawn successfully and remain on tacrolimus monotherapy. Treg infusion resulted in a long-lasting dose-dependent increase in peripheral blood Tregs together with an increase in marginal zone B cell numbers. We identified a pretransplantation immune phenotype suggesting a high risk of unsuccessful ex-vivo Treg expansion. Autologous Treg therapy is feasible, safe, and is potentially associated with a lower rejection rate than standard immunosuppression. Treg therapy may provide an exciting opportunity to minimize immunosuppression therapy and improve long-term outcomes.
Assuntos
Transplante de Rim , Estudos de Viabilidade , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Doadores Vivos , Monitorização Imunológica , Linfócitos T ReguladoresRESUMO
BACKGROUND: Donor-derived cell-free DNA (dd-cfDNA) is a marker of allograft injury in transplant recipients; however, the relationship between dd-cfDNA and other clinical parameters associated with adverse allograft outcomes is not well-characterized. METHODS: We performed a retrospective analysis of kidney transplant recipients from the DART cohort (ClinicalTrials.gov Identifier: NCT02424227) to evaluate the associations between eGFR decline, de novo donor-specific antibodies (dnDSA), and dd-cfDNA. RESULTS: Both elevated dd-cfDNA (≥1%) and dd-cfDNA variability (≥.34%) in the first post-transplant year were associated with decline in eGFR ≥25% in the second year (21.4% vs. 4.1%, P = .005; 25% vs. 3.6%, P = .002, respectively). Compared to samples from DSA negative patients, samples from patients with concurrent de novo HLA DSAs had higher dd-cfDNA levels (P < .0001). DISCUSSION: Abnormalities in dd-cfDNA levels are associated with clinical parameters commonly used as surrogate endpoints for adverse allograft outcomes, raising the possibility that molecular injury as characterized by dd-cfDNA could help identify patients at risk of these outcomes.
Assuntos
Ácidos Nucleicos Livres , Transplante de Rim , Rejeição de Enxerto/etiologia , Antígenos HLA , Humanos , Isoanticorpos , Transplante de Rim/efeitos adversos , Estudos Retrospectivos , Doadores de TecidosRESUMO
We recently developed a high throughput T cell receptor ß chain (TCRß) sequencing-based approach to identifying and tracking donor-reactive T cells. To address the role of clonal deletion in liver allograft tolerance, we applied this method in samples from a recent randomized study, ITN030ST, in which immunosuppression withdrawal was attempted within 2 years of liver transplantation. We identified donor-reactive T cell clones via TCRß sequencing following a pre-transplant mixed lymphocyte reaction and tracked these clones in the circulation following transplantation in 3 tolerant and 5 non-tolerant subjects. All subjects showed a downward trend and significant reductions in donor-reactive TCRß sequences were detected post-transplant in 6 of 8 subjects, including 2 tolerant and 4 non-tolerant recipients. Reductions in donor-reactive TCRß sequences were greater than those of all other TCRß sequences, including 3rd party-reactive sequences, in all 8 subjects, demonstrating an impact of the liver allograft after accounting for repertoire turnover. Although limited by patient number and heterogeneity, our results suggest that partial deletion of donor-reactive T cell clones may be a consequence of liver transplantation and does not correlate with success or failure of early immunosuppression withdrawal. These observations underscore the organ- and/or protocol-specific nature of tolerance mechanisms in humans.
Assuntos
Deleção Clonal/fisiologia , Terapia de Imunossupressão , Linfócitos T/imunologia , Linfócitos T/fisiologia , Humanos , Transplante de Fígado/efeitos adversos , Doadores de Tecidos , Tolerância ao Transplante/fisiologiaRESUMO
Mesenchymal stromal cells (MSC) hold promise as a novel immune-modulatory therapy in organ transplantation. First clinical studies have used autologous MSCs; however, the use of allogeneic "off-the-shelf" MSCs is more sustainable for broad clinical implementation, although with the risk of causing sensitization. We investigated safety and feasibility of allogeneic MSCs in renal transplantation, using a matching strategy that prevented repeated mismatches. Ten patients received two doses of 1.5 × 106 /kg allogeneic MSCs 6 months after transplantation in a single-center nonrandomized phase Ib trial, followed by lowering of tacrolimus (trough level 3 ng/mL) in combination with everolimus and prednisone. Primary end point was safety, measured by biopsy proven acute rejection (BPAR) and graft loss 12 months after transplantation. Immune monitoring was performed before and after infusion. No BPAR or graft loss occurred and renal function remained stable. One patient retrospectively had DSAs against MSCs, formed before infusion. No major alterations in T and B cell populations or plasma cytokines were observed upon MSC infusion. Administration of HLA selected allogeneic MSCs combined with low-dose tacrolimus 6 months after transplantation is safe at least in the first year after renal transplantation. This sets the stage to further explore the efficacy of third-party MSCs in renal transplantation.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Transplante de Rim , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Antígenos HLA , Humanos , Netuno , Estudos RetrospectivosRESUMO
The nonpathogenic and ubiquitous torque teno virus (TTV) is associated with immunosuppression in solid organ transplant recipients. Studies in kidney transplant patients proposed TTV quantification for risk stratification of graft rejection and infection. In this prospective trial (DRKS00012335) 386 consecutive kidney transplant recipients were subjected to longitudinal per-protocol monitoring of plasma TTV load by polymerase chain reaction for 12 months posttransplant. TTV load peaked at the end of month 3 posttransplant and reached steady state thereafter. TTV load after the end of month 3 was analyzed in the context of subsequent rejection diagnosed by indication biopsy and infection within the first year posttransplant, respectively. Each log increase in TTV load decreased the odds for rejection by 22% (odds ratio [OR] 0.78, 95% confidence interval [CI] 0.62-0.97; P = .027) and increased the odds for infection by 11% (OR 1.11, 95% CI 1.06-1.15; P < .001). TTV was quantified at a median of 14 days before rejection was diagnosed and 27 days before onset of infection, respectively. We defined a TTV load between 1 × 106 and 1 × 108 copies/mL as optimal range to minimize the risk for rejection and infection. These data support the initiation of an interventional trial assessing the efficacy of TTV-guided immunosuppression to reduce infection and graft rejection in kidney transplant recipients.
Assuntos
Transplante de Rim , Torque teno virus , DNA Viral/genética , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia , Humanos , Transplante de Rim/efeitos adversos , Estudos Prospectivos , Medição de Risco , Torque teno virus/genética , Carga ViralRESUMO
The clinical importance of subclinical, early T cell-mediated rejection (Banff TCMR 1A and borderline lesions) remains unclear, due, in part to the fact that histologic lesions used to characterize early TCMR can be nonspecific. Donor-derived cell-free DNA (dd-cfDNA) is an important molecular marker of active graft injury. Over a study period from June 2017 to May 2019, we assessed clinical outcomes in 79 patients diagnosed with TCMR 1A/borderline rejection across 11 US centers with a simultaneous measurement of dd-cfDNA. Forty-two patients had elevated dd-cfDNA (≥0.5%) and 37 patients had low levels (<0.5%). Elevated levels of dd-cfDNA predicted adverse clinical outcomes: among patients with elevated cfDNA, estimated glomerular filtration rate declined by 8.5% (interquartile rate [IQR] -16.22% to -1.39%) (-3.50 mL/min/1.73 m2 IQR -8.00 to -1.00) vs 0% (-4.92%, 4.76%) in low dd-cfDNA patients (P = .004), de novo donor-specific antibody formation was seen in 40% (17/42) vs 2.7% (P < .0001), and future or persistent rejection occurred in 9 of 42 patients (21.4%) vs 0% (P = .003). The use of dd-cfDNA may complement the Banff classification and to risk stratify patients with borderline/TCMR 1A identified on biopsy.
Assuntos
Ácidos Nucleicos Livres , Transplante de Rim , Aloenxertos , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia , Humanos , Transplante de Rim/efeitos adversos , Doadores de TecidosRESUMO
Simultaneous pancreas and kidney transplants offer significant therapeutic advantages but present a diagnostic approach dilemma in the diagnosis of rejection. Because both organs are from the same donor, the kidney has been treated traditionally as the "sentinel" organ to biopsy, presumably representing the status of both allografts. Truly concurrent biopsy studies, however, are needed to confirm this hypothesis. We examined 101 concurrent biopsies from 70 patients with dysfunction in either or both organs. Results showed concurrent rejection in 23 of 57 (40%) of cases with rejection; 19 of 57 (33.5%) and 15 of 57 (26.5%) showed kidney or pancreas only rejection, respectively. The degree and type of rejection differed in the majority (13 of 23, 56.5%) of cases with concurrent rejection, with the pancreas more often showing higher rejection grade. Taking into account pancreas dysfunction, a positive kidney biopsy should correctly predict pancreas rejection in 86% of the instances. However, the lack of complete concordance between the 2 organs, the discrepancies in grade and type of rejection, and the tendency for higher rejection grades in concurrent or pancreas only rejections, all support the rationale for pancreas biopsies. The latter provide additional data on the overall status of the organ, as well as information on nonrejection-related pathologies.
Assuntos
Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Transplante de Rim/efeitos adversos , Transplante de Pâncreas/efeitos adversos , Complicações Pós-Operatórias , Adulto , Aloenxertos , Biópsia , Feminino , Seguimentos , Rejeição de Enxerto/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Fatores de RiscoRESUMO
Antibody-mediated rejection (ABMR) is defined by specific histopathological lesions and evidence of circulating donor-specific antibodies (DSA). Although DSA are not always detectable, monitoring donor-reactive memory B cells (mBC) could identify patients at risk of developing ABMR. Peripheral donor-reactive mBC using a novel HLA B cell ELISpot assay, serum DSA, and numbers of different B cell subsets were assessed in 175 consecutive kidney transplants undergoing either for-cause or 6- and 24-month surveillance biopsies for their association with main histological lesions of ABMR and impact on allograft outcome. In 85 incident for-cause biopsies, high frequencies of donor-reactive mBC were detected in all 16 (100%) acute ABMR/DSA+ and most chronic ABMR, with or without DSA (24/30[80%] and 21/29[72.4%], respectively). In a longitudinal cohort of 90 nonsensitized patients, a progressively higher expansion of donor-reactive mBC than de novo DSA was observed at 6 and 24 months (8.8% vs 7.7% and 15.5% vs 11.1%, respectively) and accurately identified patients with ongoing subclinical ABMR (area under the curve = 0.917 and area under the curve = 0.809, respectively). An unsupervised hierarchical cluster analysis revealed a strong association between donor-reactive mBC with main fundamental allograft lesions associated with ABMR and conferred a significant deleterious impact on graft outcome. Monitoring donor-reactive mBC may be useful to further characterize humoral rejection after kidney transplantation.
Assuntos
Linfócitos B/imunologia , Rejeição de Enxerto/diagnóstico , Sobrevivência de Enxerto/imunologia , Memória Imunológica/imunologia , Isoanticorpos/imunologia , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Aloenxertos , Estudos Transversais , Feminino , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Antígenos HLA/imunologia , Humanos , Isoanticorpos/sangue , Testes de Função Renal , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Prognóstico , Estudos Prospectivos , Fatores de Risco , Doadores de Tecidos/estatística & dados numéricosRESUMO
Lymphocytic bronchitis (LB) precedes chronic lung allograft dysfunction. The relationships of LB (classified here as Endobronchial or E-grade rejection) to small airway (A- and B-grade) pathologies are unclear. We hypothesized that gene signatures common to allograft rejection would be present in LB. We studied LB in two partially overlapping lung transplant recipient cohorts: Cohort 1 included large airway brushes (6 LB cases and 18 post-transplant referents). Differential expression using DESeq2 was used for pathway analysis and to define an LB-associated metagene. In Cohort 2, eight biopsies for each pathology subtype were matched with pathology-free biopsies from the same subject (totaling 48 samples from 24 subjects). These biopsies were analyzed by multiplexed digital counting of immune transcripts. Metagene score differences were compared by paired t tests. Compared to referents in Cohort 1, LB demonstrated upregulation of allograft rejection pathways, and upregulated genes in these cases characterized an LB-associated metagene. We observed statistically increased expression in Cohort 2 for this LB-associated metagene and four other established allograft rejection metagenes in rejection vs paired non-rejection biopsies for both E-grade and A-grade subtypes, but not B-grade pathology. Gene expression-based categorization of allograft rejection may prove useful in monitoring lung allograft health.