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1.
Transpl Int ; 33(2): 149-160, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31529538

RESUMO

Antibody-mediated rejection (ABMR) is a major cause of graft loss in renal transplantation. We assessed the predictive value of clinical, pathological, and immunological parameters at diagnosis for graft survival. We investigated 54 consecutive patients with biopsy-proven ABMR. Patients were treated according to our current standard regimen followed by triple maintenance immunosuppression. Patient characteristics, renal function, and HLA antibody status at diagnosis, baseline biopsy results, and immunosuppressive treatment were recorded. The risk of graft loss at 24 months after diagnosis and the eGFR slope were assessed. Multivariate analysis showed that eGFR at diagnosis and chronic glomerulopathy independently predict graft loss (HR 0.94; P = 0.018 and HR 1.57; P = 0.045) and eGFR slope (beta 0.46; P < 0.001 and beta -5.47; P < 0.001). Cyclophosphamide treatment (6× 15 mg/m2 ) plus high-dose intravenous immunoglobulins (IVIG) (1.5 g/kg) was superior compared with single-dose rituximab (1× 500 mg) plus low-dose IVIG (30 g) (HR 0.10; P = 0.008 and beta 10.70; P = 0.017) and one cycle of bortezomib (4× 1.3 mg/m2 ) plus low-dose IVIG (HR 0.16; P = 0.049 and beta 11.21; P = 0.010) regarding the risk of graft loss and the eGFR slope. In conclusion, renal function at diagnosis and histopathological signs of chronic ABMR seem to predict graft survival independent of the applied treatment regimen. Stepwise modifications of the treatment regimen may help to improve outcome.

2.
Sci Rep ; 9(1): 19037, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31836826

RESUMO

Donor-reactive immunity plays a major role in rejection after kidney transplantation, but analysis of donor-reactive T-cells is not applied routinely. However, it has been shown that this could help to identify patients at risk of acute rejection. A major obstacle is the limited quantity or quality of the required allogenic stimulator cells, including a limited availability of donor-splenocytes or an insufficient HLA-matching with HLA-bank cells. To overcome these limitations, we developed a novel assay, termed the TreaT (Transplant reactive T-cells)-assay. We cultivated renal tubular epithelial cells from the urine of kidney transplant patients and used them as stimulators for donor-reactive T-cells, which we analyzed by flow cytometry. We could demonstrate that using the TreaT-assay the quantification and characterization of alloreactive T-cells is superior to other stimulators. In a pilot study, the number of pre-transplant alloreactive T-cells negatively correlated with the post-transplant eGFR. Frequencies of pre-transplant CD161+ alloreactive CD4+ T-cells and granzyme B producing alloreactive CD8+ T-cells were substantially higher in patients with early acute rejection compared to patients without complications. In conclusion, we established a novel assay for the assessment of donor-reactive memory T-cells based on kidney cells with the potential to predict early acute rejection and post-transplant eGFR.

3.
BMJ Open ; 9(10): e032695, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666276

RESUMO

INTRODUCTION: Haemophagocytic lymphohistiocytosis (HLH) in adults is characterised by toxic immune activation and a sepsis-like syndrome, leading to high numbers of undiagnosed cases and mortality rates of up to 68%. Early diagnosis and specific immune suppressive treatment are mandatory to avoid fatal outcome, but the diagnostic criteria (HLH-2004) are adopted from paediatric HLH and have not been validated in adults. Experimental studies suggest biomarkers to sufficiently diagnose HLH. However, biomarkers for the diagnosis of adult HLH have not yet been investigated. METHODS AND ANALYSIS: The HEMICU (Diagnostic biomarkers for adult haemophagocytic lymphohistiocytosis in critically ill patients) study aims to estimate the incidence rate of adult HLH among suspected adult patients in intensive care units (ICUs). Screening for HLH will be performed in 16 ICUs of Charité - Universitätsmedizin Berlin. The inclusion criteria are bicytopaenia, hyperferritinaemia (≥500 µg/L), fever or when HLH is suspected by the clinician. Over a period of 2 years, we expect inclusion of about 100 patients with suspected HLH. HLH will be diagnosed if at least five of the HLH-2004 criteria are fulfilled, together with an expert review; all other included patients will serve as controls. Second, a panel of potential biomarker candidates will be explored. DNA, plasma and serum will be stored in a biobank. The primary endpoint of the study is the incidence rate of adult HLH among suspected adult patients during ICU stay. Out of a variety of measured biomarkers, this study furthermore aims to find highly potential biomarkers for the diagnosis of adult HLH in ICU. The results of this study will contribute to improved recognition and patient outcome of adult HLH in clinical routine. ETHICS AND DISSEMINATION: The institutional ethics committee approved this study on 1 August 2018 (Ethics Committee of Charité - Universitätsmedizin Berlin, EA4/006/18). The results of the study will be disseminated in an international peer-reviewed journal and presented at international conferences. TRIAL REGISTRATION NUMBER: NCT03510650.

4.
Clin J Am Soc Nephrol ; 14(7): 1056-1066, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31213508

RESUMO

BACKGROUND AND OBJECTIVES: The prognostic value of preformed donor-specific HLA antibodies (DSA), which are only detectable by sensitive methods, remains controversial for kidney transplantation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The outcome of 4233 consecutive kidney transplants performed between 2012 and 2015 in 18 German transplant centers was evaluated. Most centers used a stepwise pretransplant antibody screening with bead array tests and differentiation of positive samples by single antigen assays. Using these screening results, DSA against HLA-A, -B, -C, -DRB1 and -DQB1 were determined. Data on clinical outcome and possible covariates were collected retrospectively. RESULTS: Pretransplant DSA were associated with lower overall graft survival, with a hazard ratio of 2.53 for living donation (95% confidence interval [95% CI], 1.49 to 4.29; P<0.001) and 1.59 for deceased donation (95% CI, 1.21 to 2.11; P=0.001). ABO-incompatible transplantation was associated with worse graft survival (hazard ratio, 2.09; 95% CI, 1.33 to 3.27; P=0.001) independent from DSA. There was no difference between DSA against class 1, class 2, or both. Stratification into DSA <3000 medium fluorescence intensity (MFI) and DSA ≥3000 MFI resulted in overlapping survival curves. Therefore, separate analyses were performed for 3-month and long-term graft survival. Although DSA <3000 MFI tended to be associated with both lower 3-month and long-term transplant survival in deceased donation, DSA ≥3000 MFI were only associated with worse long-term transplant survival in deceased donation. In living donation, only strong DSA were associated with reduced graft survival in the first 3 months, but both weak and strong DSA were associated with reduced long-term graft survival. A higher incidence of antibody-mediated rejection within 6 months was only associated with DSA ≥3000 MFI. CONCLUSIONS: Preformed DSA were associated with an increased risk for graft loss in kidney transplantation, which was greater in living than in deceased donation. Even weak DSA <3000 MFI were associated with worse graft survival. This association was stronger in living than deceased donation.

5.
Trials ; 20(1): 37, 2019 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-30635033

RESUMO

BACKGROUND: Late antibody-mediated rejection (ABMR) triggered by donor-specific antibodies (DSA) is a cardinal cause of kidney allograft dysfunction and loss. Diagnostic criteria for this rejection type are well established, but effective treatment remains a major challenge. Recent randomized controlled trials (RCT) have failed to demonstrate the efficacy of widely used therapies, such as rituximab plus intravenous immunoglobulin or proteasome inhibition (bortezomib), reinforcing a great need for new therapeutic concepts. One promising target in this context may be interleukin-6 (IL-6), a pleiotropic cytokine known to play an important role in inflammation and adaptive immunity. METHODS: This investigator-driven RCT was designed to assess the safety and efficacy of clazakizumab, a genetically engineered humanized monoclonal antibody directed against IL-6. The study will include 20 DSA-positive kidney allograft recipients diagnosed with ABMR ≥ 365 days after transplantation. Participants will be recruited at two study sites in Austria and Germany (Medical University of Vienna; Charité University Medicine Berlin). First, patients will enter a three-month double-blind RCT (1,1 randomization, stratification according to ABMR phenotype and study site) and will receive either clazakizumab (subcutaneous administration of 25 mg in monthly intervals) or placebo. In a second open-label part of the trial (months 4-12), all patients will receive clazakizumab at 25 mg every month. The primary endpoint is safety and tolerability. Secondary endpoints are the pharmacokinetics and pharmacodynamics of clazakizumab, its effect on drug metabolism in the liver, DSA characteristics, morphological ABMR lesions and molecular gene expression patterns in three- and 12-month protocol biopsies, serum/urinary biomarkers of inflammation and endothelial activation/injury, Torque Teno viral load as a measure of overall immunosuppression, kidney function, urinary protein excretion, as well as transplant and patient survival. DISCUSSION: Currently, there is no treatment proven to be effective in halting the progression of late ABMR. Based on the hypothesis that antagonizing the effects of IL-6 improves the outcome of DSA-positive late ABMR by counteracting DSA-triggered inflammation and B cell/plasma cell-driven alloimmunity, we suggest that our trial has the potential to provide proof of concept of a novel treatment of this type of rejection. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03444103 . Registered on 23 February 2018 (retrospective registration).


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Rejeição de Enxerto/tratamento farmacológico , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/administração & dosagem , Isoanticorpos/imunologia , Transplante de Rim/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Áustria , Método Duplo-Cego , Alemanha , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/mortalidade , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Transplante de Rim/mortalidade , Estudos Multicêntricos como Assunto , Projetos Piloto , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Resultado do Tratamento
6.
Clin Transplant ; 32(12): e13429, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30341925

RESUMO

CONTEXT: Antibody-mediated rejection (ABMR) after kidney transplantation (KTx) remains the crucial obstacle to successful long-term graft function. The identification of gene signatures involved in ABMR could grant the basis for better prevention and treatment strategies. OBJECTIVE: The identification of gene signatures in whole blood cells specific for ABMR after KTx. MATERIALS AND METHODS: Total RNA from blood cells of 16 kidney-transplanted patients with ABMR, stable graft function (SGF), and with T-cell-mediated rejection (TCMR) was isolated. Gene expression was determined by high-throughput sequencing followed by validation and analyses of differentially expressed candidates on mRNA level and on protein level in a large patient cohort (n = 185) in patients with SGF, urinary tract infection (UTI), borderline rejection (BL), TCMR, ABMR, and interstitial fibrosis and tubular atrophy. RESULTS: From the 570 genes detected, 111 discriminated ABMR from SGF and TCMR. A distinct enrichment of interferon (IFN) type I and type II signature gene set was observed. The expression of candidate genes IFIT1, ETV7, and RSAD2 distinguished ABMR patients from patients with SGF and also TCMR, whereas ETV7 and RSAD2 differentiated ABMR also from BL. CONCLUSION: The IFN-inducible genes ETV7 and RSAD2 represent specific biomarkers for ABMR episodes after KTx.


Assuntos
Biomarcadores/análise , Rejeição de Enxerto/diagnóstico , Isoanticorpos/efeitos adversos , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias/diagnóstico , Proteínas/genética , Proteínas Proto-Oncogênicas c-ets/genética , Estudos de Casos e Controles , Estudos de Coortes , Seguimentos , Perfilação da Expressão Gênica , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/genética , Sobrevivência de Enxerto , Humanos , Falência Renal Crônica/cirurgia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/genética , Prognóstico , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-ets/metabolismo , Fatores de Risco
7.
PLoS One ; 13(8): e0201925, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30102719

RESUMO

Interstitial fibrosis/tubular atrophy (IFTA) is associated with reduced allograft survival, whereas antibody-mediated rejection (ABMR) is the major cause for renal allograft failure. To identify specific microRNAs and their regulation involved in these processes, total RNA from blood cells of 16 kidney transplanted (KTx) patients with ABMR, stable graft function (SGF) and with T-cell mediated rejection (TCMR) was isolated. MicroRNA expression was determined by high-throughput sequencing. Differentially expressed candidate microRNAs were analyzed with RT-PCR in patients with SGF (n = 53), urinary tract infection (UTI) (n = 17), borderline rejection (BL) (n = 19), TCMR (n = 40), ABMR (n = 22) and IFTA (n = 30). From the 301 detected microRNAs, 64 were significantly regulated between the three cohorts. Selected candidate microRNAs miR-223-3p, miR-424-3p and miR-145-5p distinguished TCMR and ABMR from SGF, but not from other pathologies. Most importantly, miR-145-5p expression in IFTA patients was significantly downregulated and displayed a high diagnostic accuracy compared to SGF alone (AUC = 0.891) and compared to SGF, UTI, BL, TCMR and ABMR patients combined (AUC = 0.835), which was verified by cross-validation. The identification of miR-145-5p as IFTA specific marker in blood constitutes the basis for evaluating this potentially diagnostic microRNA as biomarker in studies including high numbers of patients and different pathologies and also the further analysis of fibrosis causing etiologies after kidney transplantation.


Assuntos
Células Sanguíneas/metabolismo , Regulação da Expressão Gênica , Rejeição de Enxerto/etiologia , Nefropatias/etiologia , Transplante de Rim/efeitos adversos , MicroRNAs/genética , Atrofia , Feminino , Fibrose , Perfilação da Expressão Gênica , Rejeição de Enxerto/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Nefropatias/patologia , Túbulos Renais/patologia , Masculino , Curva ROC , Reprodutibilidade dos Testes , Transcriptoma , Transplante Homólogo
9.
J Immunol Res ; 2017: 6872046, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28255562

RESUMO

Throughout the past years we stepwise modified our immunosuppressive treatment regimen for patients with antibody-mediated rejection (ABMR). Here, we describe three consecutive groups treated with different regimens. From 2005 until 2008, we treated all patients with biopsy-proven ABMR with rituximab (500 mg), low-dose (30 g) intravenous immunoglobulins (IVIG), and plasmapheresis (PPH, 6x) (group RLP, n = 12). Between 2009 and June 2010, patients received bortezomib (1.3 mg/m2, 4x) together with low-dose IVIG and PPH (group BLP, n = 11). In July 2010, we increased the IVIG dose and treated all subsequent patients with bortezomib, high-dose IVIG (1.5 g/kg), and PPH (group BHP, n = 11). Graft survival at three years after treatment was 73% in group BHP as compared to 45% in group BLP and 25% in group RLP. At six months after treatment median serum creatinine was 2.1 mg/dL, 2.9 mg/dL, and 4.2 mg/dL in groups BHP, BLP, and RLP, respectively (p = 0.02). Following treatment, a significant decrease of donor-specific HLA antibody (DSA) mean fluorescence intensity from 8467 ± 6876 to 5221 ± 4711 (p = 0.01) was observed in group BHP, but not in the other groups. Our results indicate that graft survival, graft function, and DSA levels could be improved along with stepwise modifications to our treatment regimen, that is, the introduction of bortezomib and high-dose IVIG treatment.


Assuntos
Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/terapia , Sobrevivência de Enxerto/efeitos dos fármacos , Imunoglobulinas Intravenosas/uso terapêutico , Transplante de Rim/efeitos adversos , Rituximab/uso terapêutico , Adulto , Idoso , Biópsia , Creatinina/sangue , Feminino , Antígenos HLA/imunologia , Humanos , Rim/patologia , Masculino , Pessoa de Meia-Idade , Plasmaferese , Resultado do Tratamento
10.
Nephrol Dial Transplant ; 32(5): 880-889, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28340245

RESUMO

Background: The assignment of human leucocyte antigens (HLAs) against which antibodies are detected as unacceptable antigens (UAGs) avoids allocation of HLA- incompatible allografts. There is uncertainty as to what extent UAGs decrease the probability of receiving a kidney offer. Methods: Kidney transplantations in 3264 patients on the waiting lists of six German transplant centres were evaluated for a period of at least 2 years. The proportion of excluded offers due to UAGs was calculated as virtual panel-reactive antibodies (vPRAs). Results: In the common Eurotransplant Kidney Allocation Scheme, the transplant probability was unaffected by vPRAs in exploratory univariate analyses. In the multivariable model, a 1% increase in vPRA values was outweighed by an additional waiting time of 2.5 weeks. The model was confirmed using an external validation cohort of 1521 patients from seven centres. If only patients with standard risk were considered (e.g. no simultaneous transplantation of other organs), only 1.3 weeks additional waiting time was needed. In the Eurotransplant Senior Program, patients with vPRA values >50% had a strongly reduced transplant probability in the unadjusted analyses. In the multivariable model, a 1% increase in vPRA values was outweighed by an additional waiting time of 5 weeks. Conclusions: This study demonstrates that the assignment of UAGs decreases the transplant probability in both main Eurotransplant allocation programs because of insufficient compensatory mechanisms. At present, for immunized patients, a prolonged waiting time has to be weighed against the increased immunologic risk due to donor-specific antibodies not assigned as UAGs.


Assuntos
Antígenos HLA/imunologia , Falência Renal Crônica/cirurgia , Transplante de Rim/estatística & dados numéricos , Rim/imunologia , Doadores de Tecidos , Obtenção de Tecidos e Órgãos/métodos , Listas de Espera , Adulto , Idoso , Feminino , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo
11.
Transplantation ; 101(9): 2165-2174, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-27653301

RESUMO

BACKGROUND: De novo donor specific anti-HLA antibodies (dnDSA) may cause graft loss in renal transplant recipients. The capability to bind the complement may help to stratify the risk for inferior outcomes associated with dnDSA. We developed a modified C1q-binding assay and hypothesized that C1q-binding dnDSA could differentiate between indolent and harmful dnDSA causing antibody-mediated rejection (AMR) and graft loss. METHODS: We retrospectively identified 59 renal transplant recipients who developed dnDSA and had serum available and complete follow-up. All patients were analyzed for C1q-binding dnDSA at the time of dnDSA detection, and 1-year later or at time of AMR. AMR-positive patients were also tested 6 to 12 months before the event if IgG dnDSA was present. RESULTS: Thirty-seven of 59 dnDSA patients developed AMR during 5.9 ± 3.1 years follow-up. AMR-positive patients had more dnDSA with a significant higher frequency of class I, a higher frequency and a higher mean fluorescence intensity value of C1q-dnDSA at all time-points. Death-censored AMR-free and allograft survivals were significantly lower in C1q-dnDSA patients. In multivariate analysis, C1q-dnDSA was an independent risk factor for AMR. CONCLUSIONS: C1q-binding dnDSA is associated with inferior outcomes, yet not in all patients. Nevertheless, C1q-dnDSA was shown to be an independent risk factor of AMR and graft loss and may be a useful tool to stratify the immunological risk for AMR.


Assuntos
Complemento C1q/imunologia , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Imunoglobulina G/imunologia , Isoanticorpos/imunologia , Transplante de Rim/efeitos adversos , Adulto , Idoso , Distribuição de Qui-Quadrado , Complemento C1q/metabolismo , Feminino , Fluorimunoensaio , Rejeição de Enxerto/sangue , Rejeição de Enxerto/metabolismo , Sobrevivência de Enxerto , Humanos , Imunoglobulina G/sangue , Isoanticorpos/sangue , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Ligação Proteica , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Testes Sorológicos , Fatores de Tempo , Resultado do Tratamento
12.
Transplantation ; 101(9): 2017-2025, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-27926596

RESUMO

BACKGROUND: Glucocorticoid (GC)-refractory acute rejection (AR) is a risk factor for inferior renal allograft outcome. We investigated genetic predisposition to the response to steroid treatment of acute allograft rejection. METHODS: Single nucleotide polymorphisms of genes involved in GC signaling (GR, GLCCI1) and drug metabolism and transport (CYP3A5, ABCB1, and PXR) were analyzed in kidney transplant recipients (1995-2005, Leiden cohort, n = 153) treated with methylprednisolone. Significant associations were verified in a second cohort (Berlin cohort, n = 66). RESULTS: Patients who received a CYP3A5*1 allele expressing allograft had a lower risk of resistance to methylprednisolone during AR (odds ratio, 0.29; 95% confidence interval, 0.11-0.79; P = 0.016 in combined cohorts analysis). No differences were observed for GC signaling or other drug metabolism/transport-related genes. Both before transplantation (n = 69) and at time of AR (n = 88), tissue CYP3A5 mRNA expression was significantly higher in CYP3A5*1 allele expressing donor kidneys than in CYP3A5*3/*3 allografts (P < 0.00001). Moreover, steroid-responsive patients (n = 64) expressed significantly higher intragraft CYP3A5 mRNA levels compared to steroid-refractory patients (n = 42) in AR (P = 0.006). CONCLUSIONS: CYP3A5 protein expression was detected in tubular epithelial cells and inflammatory cells within the grafts. Our findings show that steroid resistance during AR is associated with donor genotype and intragraft expression levels of CYP3A5.


Assuntos
Citocromo P-450 CYP3A/genética , Glucocorticoides/uso terapêutico , Rejeição de Enxerto/tratamento farmacológico , Transplante de Rim/efeitos adversos , Rim/efeitos dos fármacos , Rim/cirurgia , Metilprednisolona/uso terapêutico , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Doadores de Tecidos , Doença Aguda , Aloenxertos , Distribuição de Qui-Quadrado , Citocromo P-450 CYP3A/metabolismo , Resistência a Medicamentos/genética , Feminino , Frequência do Gene , Genótipo , Alemanha , Glucocorticoides/metabolismo , Rejeição de Enxerto/enzimologia , Rejeição de Enxerto/genética , Rejeição de Enxerto/imunologia , Humanos , Estimativa de Kaplan-Meier , Rim/enzimologia , Modelos Logísticos , Masculino , Metilprednisolona/metabolismo , Pessoa de Meia-Idade , Países Baixos , Razão de Chances , Farmacogenética , Testes Farmacogenômicos , Fenótipo , Modelos de Riscos Proporcionais , RNA Mensageiro/genética , Fatores de Risco , Resultado do Tratamento
13.
Transplantation ; 101(1): 141-149, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27495766

RESUMO

BACKGROUND: Non-HLA alloantibodies and autoantibodies are involved in allograft rejection in kidney and heart transplantation. Their role in intestinal transplantation has not yet been described. We examined the development of antiangiotensin II type I receptor antibodies (anti-AT1R) and antiendothelin type A receptor antibodies associated with the clinical course and histopathological findings of intestinal transplantation recipients. METHODS: Thirty-seven patients underwent intestinal or multivisceral transplantation. Non-HLA antibodies (non-HLAabs) were screened in 29 transplant recipients. Antibody-levels greater than 12 U/L were considered positive and were evaluated retrospectively regarding rejection episodes. RESULTS: Twenty patients developed anti-AT1R and/or antiendothelin type A receptor antibodies (non-HLAabs group), 9 did not (control group). The non-HLAabs group had a higher rate of allograft rejection than controls (80% vs 55%), especially a higher rate of antibody-mediated rejections (55% vs 11%, P < 0.01) with detection of donor-specific anti-HLAabs. All rejection episodes in the non-HLAabs group appeared around the time of positive non-HLAabs detection. Five patients had acute cellular rejections at the time of non-HLAabs development, 4 had viral infections. CONCLUSIONS: Our data suggest that antibody-mediated mechanisms targeting antigens beyond HLA may trigger and accelerate immune responses. Given the possibility of pharmacologic targeting of non-HLA receptors, future studies will focus on the explanation of mechanisms how non-HLAabs may enhance rejection and affect long-term allograft survival.


Assuntos
Autoanticorpos/sangue , Rejeição de Enxerto/imunologia , Intestinos/transplante , Isoanticorpos/sangue , Transplante de Órgãos/efeitos adversos , Receptor Tipo 1 de Angiotensina/imunologia , Receptor de Endotelina A/imunologia , Vísceras/transplante , Doença Aguda , Adulto , Aloenxertos , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Alemanha , Rejeição de Enxerto/sangue , Rejeição de Enxerto/prevenção & controle , Humanos , Imunidade Humoral , Hospedeiro Imunocomprometido , Imunossupressores/uso terapêutico , Intestinos/imunologia , Intestinos/virologia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Viroses/imunologia , Vísceras/imunologia , Adulto Jovem
14.
Transplantation ; 101(10): 2545-2552, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28009783

RESUMO

BACKGROUND: Antibody-mediated rejection (AMR) is a major risk for renal allograft survival. Throughout decades, cyclophosphamide treatment has been proven to be effective in patients with antibody-associated autoimmune diseases. We investigated whether cyclophosphamide combined with plasmapheresis and intravenous immunoglobulins is an option for patients with AMR. METHODS: Between March 2013 and November 2015, we initiated treatment of 13 consecutive patients with biopsy-proven acute AMR with intravenous cyclophosphamide pulses (15 mg/kg adapted to age and renal function) at 3-week intervals, PPH (6×), and high-dose intravenous immunoglobulin (1.5 g/kg). Treatment was completed after 6 cyclophosphamide pulses or in case of return to baseline serum creatinine together with reduction of donor-specific HLA antibodies (DSA) below 500 mean fluorescence intensity. RESULTS: Eleven of 13 patients completed treatment. Median follow-up was 18 (12-44) months. At the end of follow-up, graft survival was 77% (10/13). The 3 graft losses were caused at least in part by nonadherence and premature termination of treatment. Serum creatinine increased from 1.7±0.4 mg/dL at 3 months before diagnosis to 3.7±2.4 mg/dL at diagnosis (P = 0.01), and decreased to 2.1 ± 0.7 mg/dL at 3 months after diagnosis (P = 0.01). In 7 (64%) of 11 patients, who completed treatment, DSA decreased, in 4 (36%) of 11 DSA were below 500 mean fluorescence intensity after treatment. Dose reductions had to be performed in 3 of 13 patients for leukopenia. We observed 14 hospitalizations in 9 of 13 patients. CONCLUSIONS: To our knowledge, this is the first systematic report on cyclophosphamide-based treatment of acute AMR based on modern diagnostics. Treatment was effective and relatively safe. Future studies will show, whether cyclophosphamide proves to be a valuable alternative for the treatment of AMR.


Assuntos
Ciclofosfamida/administração & dosagem , Rejeição de Enxerto/tratamento farmacológico , Sobrevivência de Enxerto/efeitos dos fármacos , Antígenos HLA/imunologia , Isoanticorpos/imunologia , Transplante de Rim/efeitos adversos , Doença Aguda , Adulto , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Rejeição de Enxerto/imunologia , Antígenos HLA/sangue , Humanos , Imunossupressores/administração & dosagem , Injeções Intravenosas , Isoanticorpos/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo , Resultado do Tratamento
15.
Transplant Direct ; 2(8): e91, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27819032

RESUMO

BACKGROUND: Current treatment strategies for antibody-mediated renal allograft rejection (AMR) are not sufficiently effective. In most centers, "standard of care" treatment includes plasmapheresis (PPH) and IVIG preparations. Since several years, modern therapeutics targeting B cells and plasma cells have become available. We investigated, whether combined administration of rituximab and bortezomib in addition to PPH and high-dose IVIG is useful. METHODS: Between November 2011 and January 2013, we treated 10 consecutive patients with biopsy-proven AMR with rituximab (500 mg), bortezomib (4× 1.3 mg/m2), PPH (6×), and high-dose IVIG (1.5 g/kg) (group A). This group was compared with a group of 11 consecutive patients treated with an identical regimen without rituximab between July 2010 and November 2011 (group B). RESULTS: Median follow-up was 41(33-46) months in group A and 55(47-63) months in group B. At 40 months after treatment, graft survival was 60% in group A and 64% in group B, respectively (P = 0.87). Before and after treatment, serum creatinine, estimated glomerular filtration rate, and proteinuria were not different between groups. A significant reduction in donor-specific HLA antibody mean fluorescence intensity was observed in group A (25.2%, P = 0.046) and B (38.3%, P = 0.01) at 3 months posttreatment. In group A, more patients suffered from side effects compared with group B (infections: 70% vs 18%, P = 0.02). CONCLUSIONS: The addition of rituximab to bortezomib, PPH, and high-dose IVIG did not further improve graft survival. Instead, we observed an increase of side effects. Therefore, combined administration of bortezomib and rituximab in addition to PPH and IVIG should be regarded with caution.

16.
Nephrol Dial Transplant ; 31(12): 2143-2149, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27369852

RESUMO

BACKGROUND: The Eurotransplant Senior Program (ESP) neglects HLA matching for elderly (≥65 years) kidney transplant recipients (KTR). Few data regarding the influence of DR matching on clinical and immunologic outcome in elderly KTR exist. METHODS: This retrospective long-term observational study included 244 elderly out of n = 972 adult KTR between 2004 and 2014. Data analysis included patient and graft survival, biopsy-proven rejections [T-cell-mediated rejections (TCMR) and antibody-mediated rejections] and development of de novo donor-specific HLA antibodies (DSA). Outcome data were assessed over a maximum period of 10 years. RESULTS: Due to the nature of the ESP, elderly KTR showed significantly more HLA mismatches, shorter time on dialysis and shorter cold ischaemia time. Elderly KTR had significantly worse graft and patient survival, and after 7 years, the rate of de novo DSA (33 versus 25%, P = 0.034) and TCMR (39 versus 27%, P < 0.001) was significantly higher compared with younger KTR. Multivariate analysis identified donor age, delayed graft function and HLA-DR mismatches as independent risk factors for TCMR. Within the group of elderly KTR, HLA-DR mismatches were associated with a significantly higher incidence of TCMR and development of de novo DSA. Occurrence of TCMR and de novo DSA in elderly KTR resulted in significantly worse graft survival. CONCLUSIONS: In elderly KTR, HLA-DR mismatches are independent risk factors for TCMR and the development of all classes of de novo DSA, both of which significantly impair graft survival. Introduction of HLA-DR matching in elderly KTR might significantly improve immunologic and overall outcome.


Assuntos
Rejeição de Enxerto/imunologia , Antígenos HLA-DR/imunologia , Falência Renal Crônica/cirurgia , Adulto , Idoso , Seleção do Doador , Feminino , Rejeição de Enxerto/epidemiologia , Sobrevivência de Enxerto/imunologia , Teste de Histocompatibilidade , Humanos , Incidência , Rim/imunologia , Rim/metabolismo , Rim/cirurgia , Transplante de Rim , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Fatores de Risco , Transplantados , Resultado do Tratamento
17.
Nephrol Dial Transplant ; 31(8): 1351-9, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27190369

RESUMO

BACKGROUND: A considerable proportion of patients awaiting kidney transplantation is immunized by previous transplantation(s). We investigated how allograft nephrectomy (Nx) and withdrawal of maintenance immunosuppression (WD-MIS) in patients with a failed renal allograft contribute to allosensitization. METHODS: HLA antibodies (HLAabs) were analyzed before and after Nx and/or WD-MIS using a single antigen bead assay. Patients were grouped as follows: (A) Nx and concomitant WD-MIS (n = 28), (B) Nx (n = 14) and (C) WD-MIS (n = 12). In a subgroup of patients, the epitope specificity of HLAabs was determined by adsorption and elution of sera with recombinant single HLA allele-expressing cell lines. RESULTS: Following Nx and/or WD-MIS, HLAabs were detectable in 100, 100 and 92% of patients in Groups A, B and C, respectively. In patients of all groups, de novo donor-specific HLAabs (DSAs) were found. After Nx, an increase in the breadth [percent panel reactive antibody (%PRA)] and mean fluorescence intensity of class I HLAabs was predominant. In contrast, an increase of class II HLAabs prevailed following WD-MIS. Experimental analysis of the epitope specificities revealed that 64% of the class I HLAabs classically denoted as non-DSA were donor epitope-specific HLAabs (DESA). CONCLUSIONS: Both Nx and WD-MIS contribute to alloimmunization with differing patterns concerning class I and II HLAabs. Nx preferentially increased class I HLAabs and most of the observed class I HLAabs were DESA. Considering that class I, but not class II, HLA molecules are constitutively expressed, our results support the hypothesis that the increase of HLAabs following Nx might have been caused by removal of the adsorbing donor tissue (sponge hypothesis).


Assuntos
Anticorpos/imunologia , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Imunossupressão/métodos , Transplante de Rim , Nefrectomia/métodos , Doadores de Tecidos , Adolescente , Adulto , Idoso , Criança , Epitopos , Feminino , Seguimentos , Rejeição de Enxerto/prevenção & controle , Humanos , Falência Renal Crônica/cirurgia , Masculino , Pessoa de Meia-Idade , Transplante Homólogo , Adulto Jovem
19.
Transplantation ; 100(4): 898-907, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26444957

RESUMO

BACKGROUND: MicroRNAs (miRNAs, miR) hold important roles in the posttranscriptional regulation of gene expression. Their function has been correlated with kidney disease, and they might represent a new class of biomarkers for frequent evaluation of renal graft status. We analyzed their potential in identifying severe T cell-mediated vascular rejection (TCMVR) (Banff 4-II/III) in kidney transplanted patients. METHODS: Microarray experiments and semiquantitative real-time reverse transcription polymerase chain reaction were performed with total RNA isolated from blood cells of kidney graft recipients. Initial microarray analysis revealed 23 differentially expressed miRNAs distinguishing patients with TCMVR from patients with stable grafts. From these, we validated and further determined the expression of 6 differentially expressed miRNAs and 2 control miRNAs in 161 samples from patients with T cell-mediated rejection (Banff 3-Borderline, Banff 4-I/II/III), Banff-2 antibody-mediated rejection, Banff-5 interstitial fibrosis/tubular atrophy, in samples from stable patients and in samples from patients with urinary tract infection using real-time reverse transcription polymerase chain reaction. RESULTS: Expression levels of all 6 candidate miRNAs were significantly downregulated in blood of TCMVR patients compared to the other groups and displayed high sensitivities and specificities for diagnosing TCMVR. The combination of 5 miRNAs, identified by an unbiased multivariate logistic regression followed by cross-validation, enhanced the sensitivity and specificity for the diagnosis of TCMVR after renal transplantation. CONCLUSIONS: The combined measurement of miRNA-15B, miRNA-16, miRNA-103A, miRNA-106A, and miRNA-107 may help to better identify TCMVR after renal transplantation in a precise and clinically applicable way.


Assuntos
Rejeição de Enxerto/sangue , Rejeição de Enxerto/genética , Imunidade Celular/genética , Transplante de Rim/efeitos adversos , MicroRNAs/sangue , MicroRNAs/genética , Linfócitos T/imunologia , Área Sob a Curva , Análise por Conglomerados , Regulação para Baixo , Perfilação da Expressão Gênica/métodos , Marcadores Genéticos , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/imunologia , Humanos , Modelos Logísticos , Análise Multivariada , Análise de Sequência com Séries de Oligonucleotídeos , Valor Preditivo dos Testes , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Resultado do Tratamento
20.
Exp Mol Pathol ; 100(1): 45-50, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26615783

RESUMO

BACKGROUND: We have found antibodies against denatured HLA class I antigens in the serum of allograft recipients which were not significantly associated with graft failure. It is unknown whether transplant recipients also have denatured HLA class II and MICA antibodies. The effects of denatured HLA class I, class II, and MICA antibodies on long-term graft outcome were further investigated based on their ability to fix complement c1q. MATERIALS AND METHODS: In this 4-year retrospective cohort study, post-transplant sera from 975 kidney transplant recipients were tested for antibodies against denatured HLA/MICA antigens and these antibodies were further classified based on their ability to fix c1q. RESULTS: Thirty percent of patients had antibodies against denatured HLA class I, II, or MICA antigens. Among them, 8.5% and 21.5% of all patients had c1q-fixing and non c1q-fixing antibodies respectively. There was no significant difference on graft survival between patients with or without antibodies against denatured HLA/MICA. However, when these antibodies were further classified according to their ability to fix c1q, patients with c1q-fixing antibodies had a significantly lower graft survival rate than patients without antibodies or patients with non c1q-fixing antibodies (p=0.008). In 169 patients who lost renal grafts, 44% of them had c1q-fixing antibodies against denatured HLA/MICA antigens, which was significantly higher than that in patients with functioning renal transplants (25%, p<0.0001). C1q-fixing antibodies were more significantly associated with graft failure caused by AMR (72.73%) or mixed AMR/CMR (61.9%) as compared to failure due to CMR (35.3%) or other causes (39.2%) (p=0.026). CONCLUSIONS: Transplant recipients had antibodies against denatured HLA class I, II, and MICA antigens. However, only c1q-fixing antibodies were associated with graft failure which was related to antibody mediated rejection.


Assuntos
Anticorpos/imunologia , Complemento C1q/imunologia , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Transplante de Rim , Adulto , Idoso , Feminino , Sobrevivência de Enxerto/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo/métodos
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