RESUMO
BACKGROUND: Surgical complications following kidney transplantation compromise immediate graft survival. However, the role of early surgical complications in the impairment of long-term survival is not completely established due to various other influences, such as patient comorbidities. The purpose of this study was to characterize the impact of surgical complications and overlapping patient comorbidities on graft function and survival after living donor kidney transplantation (LDKT). METHODS: Two groups of patients following LDKT between 1995 and 2014 with (n = 65) or without (n = 294) Clavien-Dindo grade 3 and 4 complications were analyzed. Type of surgical revision, graft and patient survival, general patient characteristics, pre-transplant renal function, immunosuppression, and immunological characteristics (HLA mismatch, panel-reactive antibodies, rejections) were determined. Post-transplant graft function as well as long-term graft and patient survival were quantified. RESULTS: Graft survival was 84.4/97.6% (1y), 75.2/92.7% (3y), and 62.1/87.6% (5y) with/without surgical revision, patient survival was 95.3/99.3%, 90.0/97.5%, and 84.7/93.7%, respectively. Surgical revision was required in 18%, which affected graft survival (p = 0.008) to a comparable extent as pre-existing cardiopulmonary/-vascular disease. Initially impaired graft function recovered to an equal level without complications following surgical revision. Whereas pre-existing cardiopulmonary/-vascular disease affected graft loss and patient survival, surgical revision had no particular impact on patient survival. These observations were confirmed by Cox regression. CONCLUSION: Long-term graft survival following LDKT is independently impaired by both postoperative complications and cardiovascular comorbidities. Although both factors may interact, a complication-free postsurgical course may improve graft survival, thereby reducing the need for dialysis restart and enhancing long-term recipient survival.
Assuntos
Doenças Cardiovasculares/epidemiologia , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Doadores Vivos , Adulto , Comorbidade , Feminino , Sobrevivência de Enxerto , Humanos , Falência Renal Crônica/epidemiologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Sistema de Registros , Reoperação , Estudos RetrospectivosRESUMO
Renal function of potential living kidney donors is routinely assessed with scintigraphy. Kidney anatomy is evaluated by imaging techniques such as magnetic resonance imaging (MRI). We evaluated if a MRI-based renal volumetry is a good predictor of kidney function pre- and postdonation. We retrospectively analyzed the renal volume (RV) in a MRI of 100 living kidney donors. RV was correlated with the tubular excretion rate (TER) of MAG3-scintigraphy, a measured creatinine clearance (CrCl), and the estimated glomerular filtration rate (eGFR) by Cockcroft-Gault (CG), CKD-EPI, and modification of diet in renal disease (MDRD) formula pre- and postdonation during a follow-up of 3 years. RV correlated significantly with the TER (total: r = 0.6735, P < 0.0001). Correlation between RV and renal function was the highest for eGFR by CG (r = 0.5595, P < 0.0001), in comparison with CrCl, MDRD-GFR, and CKD-EPI-GFR predonation. RV significantly correlated with CG-GFR postdonation and predicted CG-GFR until 3 years after donation. MRI renal volumetry might be an alternative technique for the evaluation of split renal function and prediction of renal function postdonation in living kidney donors.
Assuntos
Testes de Função Renal , Rim/diagnóstico por imagem , Doadores Vivos , Adulto , Idoso , Feminino , Humanos , Rim/fisiologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Cintilografia , Estudos RetrospectivosRESUMO
Impaired cytomegalovirus (CMV)-specific cell-mediated immunity (CMV-CMI) is a major cause of CMV reactivation and associated complications in solid-organ transplantation. Reliably assessing CMV-CMI is desirable to individually adjust antiviral and immunosuppressive therapy. This study aimed to evaluate the suitability of T-Track® CMV, a novel IFN-γ ELISpot assay based on the stimulation of peripheral blood mononuclear cells with pp65 and IE-I CMV proteins, to monitor CMV-CMI following kidney transplantation. A prospective longitudinal multicenter study was conducted in 86 intermediate-risk renal transplant recipients. CMV-CMI, CMV viral load, and clinical complications were monitored over 6 months post-transplantation. Ninety-five percent and 88-92% ELISpot assays were positive pre- and post-transplantation, respectively. CMV-specific response was reduced following immunosuppressive treatment and increased in patients with graft rejection, indicating the ability of the ELISpot assay to monitor patients' immunosuppressive state. Interestingly, median pp65-specific response was ninefold higher in patients with self-clearing viral load compared to antivirally treated patients prior to first viral load detection (P < 0.001), suggesting that reactivity to pp65 represents a potential immunocompetence marker. Altogether, T-Track® CMV is a highly sensitive IFN-γ ELISpot assay, suitable for the immunomonitoring of CMV-seropositive renal transplant recipients, and with a potential use for the risk assessment of CMV-related clinical complications (ClinicalTrials.gov Identifier: NCT02083042).
Assuntos
Infecções por Citomegalovirus/diagnóstico , Ensaio de Imunoadsorção Enzimática/métodos , Imunidade Celular , Fosfoproteínas/imunologia , Complicações Pós-Operatórias/diagnóstico , Proteínas da Matriz Viral/imunologia , Adulto , Idoso , Citomegalovirus/imunologia , Infecções por Citomegalovirus/imunologia , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/virologia , Humanos , Imunossupressores , Transplante de Rim , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Infecções Oportunistas , Complicações Pós-Operatórias/imunologia , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis causes end-stage renal failure in up to a third of cases even with treatment. The disease recurs occasionally after kidney transplantation, but new onset of ANCA-associated vasculitis after transplantation is highly unusual. The use of rituximab or plasmapheresis for de novo disease after transplantation has not previously been reported. CASE PRESENTATION: Routine post-transplant follow-up for a 66-year old asymptomatic woman revealed a rise in creatinine from 1.8 to 2.6 mg/dl and increased proteinuria. She had received a cadaveric kidney transplant 20 months previously for end-stage autosomal dominant polycystic kidney disease. Renal allograft biopsy unexpectedly demonstrated pauci-immune glomerulonephritis with extracapillary proliferation and interstitial inflammation. Concurrent serum tested strongly positive for ANCA specific to proteinase 3 (PR3), but stored pre- and post-transplantation serum samples tested negative. These findings established a diagnosis of de novo ANCA-associated vasculitis in the renal allograft. We started treatment with high-dose corticosteroid and rituximab. Despite this, serum creatinine continued to rise and glomerulonephritis remained active in a repeat biopsy. Escalation of the treatment with seven sessions of plasmapheresis led to a temporary improvement in creatinine. No further features of vasculitis emerged and PR3-ANCA titres declined. However, multiple infections complicated the recovery period and were associated with progressive loss of renal transplant function. Four months after the index presentation, transplant function became insufficient and dialysis was restarted. CONCLUSIONS: De novo ANCA-associated vasculitis after renal transplantation is exceptionally rare. It poses a significant risk to graft survival even in the context of intensified immunosuppression. Management relies on clinical evidence from populations with native renal function, yet post-transplant patients may be at increased risk of treatment-related adverse events. Precautions against these risks are crucial in the delivery of care.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/etiologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/terapia , Fatores Imunológicos/administração & dosagem , Transplante de Rim/efeitos adversos , Troca Plasmática/métodos , Rituximab/administração & dosagem , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Terapia Combinada/métodos , Feminino , Humanos , Transplante de Rim/tendênciasRESUMO
The current paradigm regarding sodium handling in animals and humans postulates that total body sodium is regulated predominately via regulation of extracellular volume. Active sodium storage independent of volume retention is thought to be negligible. However, studies in animals, hypertensive patients, and healthy humans suggest water-free storage of sodium in skin. We hypothesized that tissue sodium concentrations ([Na]T) found in humans vary and reflect regulation due to variable glycosaminoglycan content due to variable expression of XYLT-1. Twenty seven patients on dialysis and 21 living kidney transplant donors free of clinically detectable edema were studied. During surgery, abdominal skin, muscle, and arteries were biopsied. [Na]T was determined by inductively coupled plasma-optical emission spectrometry, semiquantitative glycosaminoglycan content with Alcian stain, and XYLT-1 expression by real-time PCR. [Na]T of arteries were ranging between 0.86 and 9.83 g/kg wet wt and were significantly higher in arteries (4.52 ± 1.82 g/kg) than in muscle (2.03 ± 1.41 g/kg; P < 0.001) or skin (3.24 ± 2.26 g/kg wet wt; P = 0.038). For individual patients [Na]T correlated for skin and arterial tissue (r = 0.440, P = 0.012). [Na]T also correlated significantly with blinded semiquantitative analysis of glycosaminoglycans staining (r = 0.588, P = 0.004). In arteries XYLT-1 expression was also correlated with [Na]T (r = 0.392, P = 0.003). Our data confirm highly variable [Na]T in human skin and muscle and extend this observation to [Na]T in human arteries. These data support the hypothesis of water-independent sodium storage via regulated glycosaminoglycan synthesis in human tissues, including arteries.
Assuntos
Músculos Abdominais/química , Artérias Epigástricas/química , Glicosaminoglicanos/análise , Nefropatias/metabolismo , Pele/química , Sódio/análise , Adulto , Idoso , Biópsia , Estudos de Casos e Controles , Linhagem Celular , Feminino , Fibroblastos/enzimologia , Humanos , Nefropatias/diagnóstico , Nefropatias/terapia , Masculino , Pessoa de Meia-Idade , Osmose , Pentosiltransferases/genética , Pentosiltransferases/metabolismo , Diálise Renal , Espectrofotometria/métodos , UDP Xilose-Proteína XilosiltransferaseRESUMO
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 HomólogoRESUMO
Many aspects of post-transplant monitoring of donor-specific (DSA) and non-donor-specific (nDSA) anti-HLA antibodies on renal allograft survival are still unclear. Differentiating them by their ability to bind C1q may offer a better risk assessment. We retrospectively investigated the clinical relevance of de novo C1q-binding anti-HLA antibodies on graft outcome in 611 renal transplant recipients. Acute rejection (AR), renal function, and graft survival were assessed within a mean follow-up of 6.66 years. Post-transplant 6.5% patients developed de novo DSA and 11.5% de novo nDSA. DSA (60.0%; P < 0.0001) but not nDSA (34.1%, P = 0.4788) increased rate of AR as compared with controls (27.4%). C1q-binding anti-HLA antibodies did not alter rate of AR in both groups. Renal function was only significantly diminished in patients with DSAC1q+ . However, DSA significantly impaired 5-year graft survival (65.2%; P < 0.0001) in comparison with nDSA (86.7%; P = 0.0054) and controls (90.7%). While graft survival did not differ between DSAC1q- and DSAC1q+ recipients, 5-year allograft survival was reduced in nDSAC1q+ (80.9%) versus nDSAC1q- (90.7%, P = 0.0251). De novo DSA independently of their ability to bind C1q are associated with diminished graft survival.
Assuntos
Anticorpos/imunologia , Complemento C1q/imunologia , Antígenos HLA/imunologia , Transplante de Rim/efeitos adversos , Insuficiência Renal/cirurgia , Adulto , Idoso , Biópsia , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Chronic rejection remains a major obstacle in transplant medicine. Recent studies suggest a crucial role of the chemokine SDF-1 on neointima formation after injury. Here, we investigate the potential therapeutic effect of inhibiting the SDF-1/CXCR4/CXCR7 axis with an anti-SDF-1 Spiegelmer (NOX-A12) on the development of chronic allograft vasculopathy. Heterotopic heart transplants from H-2bm12 to B6 mice and aortic transplants from Balb/c to B6 were performed. Mice were treated with NOX-A12. Control animals received a nonfunctional Spiegelmer (revNOX-A12). Samples were retrieved at different time points and analysed by histology, RT-PCR and proliferation assay. Blockade of SDF-1 caused a significant decrease in neointima formation as measured by intima/media ratio (1.0 ± 0.1 vs. 1.8 ± 0.1, P < 0.001 AoTx; 0.35 ± 0.05 vs. 1.13 ± 0.27, P < 0.05 HTx). In vitro treatment of primary vascular smooth muscle cells with NOX-A12 showed a significant reduction in proliferation (0.42 ± 0.04 vs. 0.24 ± 0.03, P < 0.05). TGF-ß, TNF-α and IL-6 levels were significantly reduced under SDF-1 inhibition (3.42 ± 0.37 vs. 1.67 ± 0.33, P < 0.05; 2.18 ± 0.37 vs. 1.0 ± 0.39, P < 0.05; 2.18 ± 0.26 vs. 1.6 ± 0.1, P < 0.05). SDF-1/CXCR4/CXCR7 plays a critical role in the development of chronic allograft vasculopathy (CAV). Therefore, pharmacological inhibition of SDF-1 with NOX-A12 may represent a therapeutic option to ameliorate chronic rejection changes.
Assuntos
Quimiocina CXCL12/metabolismo , Rejeição de Enxerto/etiologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Receptores CXCR4/metabolismo , Receptores CXCR/metabolismo , Aloenxertos , Animais , Aorta Torácica/transplante , Aptâmeros de Nucleotídeos/farmacologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Quimiocina CXCL12/antagonistas & inibidores , Citocinas/genética , Citocinas/metabolismo , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/patologia , Transplante de Coração/efeitos adversos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neointima/patologia , Neointima/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacosRESUMO
INTRODUCTION: Neutrophil gelatinase-associated lipocalin (NGAL) is a powerful biomarker for the early detection of acute kidney injury. However, recent data suggest that NGAL also plays an important role in chronic kidney disease (CKD), reflecting the level of acute kidney damage within the CKD condition. To study whether elevated NGAL levels in CKD are a consequence of damaged tubular cells or rather due to extrarenal production, we investigated NGAL levels in anephric patients on dialysis. METHODS: Plasma NGAL levels were investigated in 14 dialysis patients who underwent bilateral nephrectomy (anephric group), 18 anuric dialysis patients with remaining kidneys (dialysis group) and 12 healthy patients (healthy group). RESULTS: Plasma NGAL levels were significantly lower in the healthy group compared with the anephric group (143 vs. 981 ng/mL; P < 0·001) or the dialysis group (143 vs. 838 ng/mL; P < 0·001), respectively. However, NGAL levels did not differ between the anephric group and the dialysis group (981 vs. 838 ng/mL; P = 0·19). DISCUSSION: Assuming that NGAL is highly expressed in chronically damaged kidneys due to tubular stress, there should be significantly less NGAL in anephric patients compared with anuric dialysis patients with remaining kidneys. In contrast to this hypothesis, we found no difference in NGAL expression between these two groups, proving the entire extrarenal NGAL production in anephric patients and suggesting that the tubular NGAL expression seems to be negligible in anuric dialysis patients.
Assuntos
Falência Renal Crônica/diagnóstico , Lipocalinas/sangue , Proteínas Proto-Oncogênicas/sangue , Diálise Renal , Proteínas de Fase Aguda , Biomarcadores/sangue , Estudos de Casos e Controles , Creatinina/metabolismo , Taxa de Filtração Glomerular/fisiologia , Humanos , Falência Renal Crônica/fisiopatologia , Falência Renal Crônica/cirurgia , Lipocalina-2 , Nefrectomia/métodos , Nefrite/metabolismo , Estudos RetrospectivosRESUMO
BACKGROUND: ABO incompatibility is no longer a barrier in kidney transplantation. C4d is frequently positive in ABO-incompatible (iABO) biopsies without further signs of microcirculation injury. This phenomenon is assumed to represent graft accommodation. However, ultrastructural examination of glomerular and peritubular capillary endothelium might reveal subtle endothelial damage. METHODS: We studied the ultrastructural appearance of the endothelium in 67 biopsies from 21 patients with iABO allografts and compared it with 20 patients (29 biopsies) with ABO-compatible (cABO) grafts with C4d positivity and 25 ABO-compatible control patients (25 biopsies) without serological or histological evidence of humoral rejection (C4d negative). Ten ultrastructural parameters indicative of chronic and acute glomerular and peritubular capillary damage in transmission electron microscopy (TEM) were semi-quantitatively graded and expressed in a sum score. Clinico-pathological data were compared as well as graft function at the time of biopsy and follow-up. RESULTS: Ultrastructural parameters did not significantly differ between iABO and controls. In contrast, C4d-positive cABO had the highest TEM sum score (P = 0.001 versus iABO, P = 0.002 versus controls). The sum score did not differ between C4d-positive and C4d-negative iABO but did differ between patients with and without anti-HLA donor-specific antibodies (DSA). Graft function in iABO at the time of biopsy and at follow-up was similar to controls. CONCLUSIONS: Our ultrastructural observations support the concept of endothelial accommodation in iABO renal transplants. C4d positivity in the ABO-incompatible situation does not indicate injurious activation of the complement cascade and does not seem to impact on the graft function, in contrast to C4d deposition in cABO with antibody-mediated rejection.
Assuntos
Sistema ABO de Grupos Sanguíneos/imunologia , Complemento C4b/imunologia , Endotélio/patologia , Rejeição de Enxerto/imunologia , Nefropatias/patologia , Fragmentos de Peptídeos/imunologia , Adulto , Idoso , Aloenxertos , Incompatibilidade de Grupos Sanguíneos/imunologia , Estudos de Casos e Controles , Ativação do Complemento , Feminino , Seguimentos , Antígenos HLA/imunologia , Humanos , Nefropatias/terapia , Transplante de Rim , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Transplante HomólogoRESUMO
INTRODUCTION: BK nephropathy has emerged as an important cause for allograft failure in renal transplant patients. The kidney tubules are the main target of BK virus infiltration. Neutrophil gelatinase-associated lipocalin (NGAL) has been proven to be a powerful biomarker for tubular damage. Therefore, we investigated the suitability of plasma NGAL as new diagnostic tool in patients with BK infection. MATERIAL AND METHODS: We retrospectively analyzed 240 renal transplant recipients. Systematic BKV screening by plasma PCR was performed one month after transplantation and every three month thereafter for two yr. Plasma NGAL concentration was investigated using a commercial ELISA. Medical records and electronic databases were reviewed for clinical parameters. RESULTS: BK viremia (BKV+) was diagnosed in 5.0% (12/240) and BK nephropathy in 3.3% (8/240) of our patients. BKV+ patients received more induction therapy (p = 0.03) and experienced a higher rate of biopsy-proven rejections compared to 13 control patients with similar graft function but negative BKV PCR. Contrary to our hypothesis, there was no difference in plasma NGAL expression between both groups (128.6 vs. 172.2 ng/mL; p = 0.68). CONCLUSIONS: Intensified immunosuppressive therapy is associated with an increased risk for BK nephropathy. Plasma NGAL is neither suitable for diagnosing BK nephropathy nor helpful in predicting the individual course of patients with BKV infection.
Assuntos
Vírus BK , Nefropatias/diagnóstico , Transplante de Rim , Lipocalinas/sangue , Infecções por Polyomavirus/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Proteínas Proto-Oncogênicas/sangue , Infecções Tumorais por Vírus/diagnóstico , Proteínas de Fase Aguda , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Terapia de Imunossupressão/efeitos adversos , Nefropatias/sangue , Nefropatias/etiologia , Lipocalina-2 , Masculino , Pessoa de Meia-Idade , Infecções Oportunistas/sangue , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/etiologia , Infecções por Polyomavirus/sangue , Infecções por Polyomavirus/etiologia , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Infecções Tumorais por Vírus/sangue , Infecções Tumorais por Vírus/etiologiaRESUMO
Kidney transplantation in HIV-infected patients is associated with a higher rate of graft rejection as well as an increased toxicity of the immunosuppressive therapy. Specifically, the use of the calcineurin inhibitor tacrolimus is problematic because of a narrow therapeutic range, a high interindividual variability of trough levels, and multiple interactions with combination antiretroviral therapy (cART). Our objective was to establish the optimal individual immunosuppressive dose for the time after kidney transplantation. We administered a temporary course of immunosuppressive therapy in three HIV-infected patients with end-stage renal disease (ESRD) after wait-listing and prior to transplantation for deceased donor kidney transplantation. Starting with a tacrolimus dose of 1 mg twice daily, the dose was titrated to reach a tacrolimus trough level of 8-12 ng/ml. HIV had been diagnosed 7-14 years prior. All patients had no detectable HIV-1 RNA while on cART. All three patients had been on chronic dialysis for 4, 7, and 10 years. In two patients, the intended tacrolimus trough levels of 8-12 ng/ml were achieved within a month. The required tacrolimus dose ranged from 0.5 mg thrice weekly to 10 mg daily. In one case, ventricular tachycardia occurred, so the immunosuppressive therapy was switched to cyclosporine A. So far, two patients have been transplanted successfully. In summary, dose-finding of immunosuppressive therapy with tacrolimus in patients on cART before renal transplantation is feasible and appears useful to minimize immunosuppressive therapy-related complications in the post-transplantation period.
Assuntos
Inibidores de Calcineurina , Infecções por HIV/diagnóstico , Imunossupressores/administração & dosagem , Falência Renal Crônica/cirurgia , Transplante de Rim/métodos , Tacrolimo/administração & dosagem , Adulto , Antirretrovirais/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Sobrevivência de Enxerto , Infecções por HIV/tratamento farmacológico , Infecções por HIV/cirurgia , Humanos , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/imunologia , Transplante de Rim/imunologia , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Cuidados Pré-Operatórios/métodos , Medição de Risco , Estudos de Amostragem , Resultado do TratamentoRESUMO
CD4+ T cells contribute to the pathogenesis of ischemia-reperfusion injury, which is the primary cause of delayed graft failure after kidney transplantation. The TIM-1:TIM-4 pathway participates in the activation/differentiation of CD4+ T cells, suggesting that it may modulate ischemia-reperfusion injury. Here, we studied the role of TIM-1 in a murine uninephrectomized renal ischemia-reperfusion injury model. Blocking the TIM-1:TIM-4 pathway with an antagonistic monoclonal antibody protected renal function and diminished reperfusion injury resulting from 30 minutes of ischemia. Histologic examination showed significantly less evidence of renal damage as evidenced by diminished tubular necrosis, preservation of the brush border, fewer cast formations, and less tubular dilation. Blocking TIM-1 also reduced the number of apoptotic cells and diminished local inflammation within ischemic kidneys, the latter shown by decreased recruitment of macrophages, neutrophils, and CD4+ T cells and by reduced local production of proinflammatory cytokines. Furthermore, TIM-1 blockade significantly improved survival after ischemia-reperfusion injury. Taken together, these data suggest that the TIM-1:TIM-4 pathway enhances injury after renal ischemia-reperfusion injury and may be a therapeutic target.
Assuntos
Rim/irrigação sanguínea , Proteínas de Membrana/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/fisiologia , Animais , Anticorpos Monoclonais/farmacologia , Apoptose/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Receptor Celular 1 do Vírus da Hepatite A , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Rim/patologia , Rim/cirurgia , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Necrose , Nefrectomia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controleRESUMO
Timely recognition and treatment of acute kidney graft rejection is important to prevent premature graft failure. A predefined urinary marker set for acute T cell-mediated rejection (TCMR) containing 14 peptides was tested for this purpose in a multicenter in-place validation study. Methods: Three hundred twenty-nine prospectively collected and 306 archived urine samples from 11 transplant centers in Germany, France, and Belgium were examined. Samples were taken immediately before a biopsy, performed for graft dysfunction within the first transplant year. Primary outcomes were sensitivity and specificity of the marker set for the diagnosis of biopsy-proven acute TCMR, with prespecified thresholds of 83% for sensitivity and 70% for specificity. Results: Eighty-two patients (13%) had acute TCMR grade I-III. In relation to the biopsy diagnosis of TCMR, the sensitivity of the urine test was 0.66 (95% confidence interval, 0.56-0.76) and the specificity 0.47 (95% confidence interval, 0.43-0.51), with an area under the curve (AUC) of 0.60. The different TCMR grades I-III were not reflected by the marker set, and borderline TCMR was not specifically detected. Secondary independent masked assessment of biopsies consented by 2 pathologists revealed an interobserver kappa value of 0.49 for diagnosing TCMR, compared with the local center's diagnosis. Using this consensus diagnosis, the AUC of the urine test was 0.63 (sensitivity 0.73, specificity 0.45). Post hoc optimization of the marker set improved the diagnostic performance in the study cohort (AUC 0.67) and in an independent patient cohort (AUC 0.69). Conclusions: This study illustrates the difficulty of proteomics-based diagnosis of TCMR and highlights the need for rigorous independent in-place validation and optimization of diagnostic biomarkers.
RESUMO
Fetal survival during gestation implies that tolerance mechanisms suppress the maternal immune response to paternally inherited alloantigens. Here we show that the inhibitory T cell costimulatory molecule, programmed death ligand 1 (PDL1), has an important role in conferring fetomaternal tolerance in an allogeneic pregnancy model. Blockade of PDL1 signaling during murine pregnancy resulted in increased rejection rates of allogeneic concepti but not syngeneic concepti. Fetal rejection was T cell- but not B cell-dependent because PDL1-specific antibody treatment caused fetal rejection in B cell-deficient but not in RAG-1-deficient females. Blockade of PDL1 also resulted in a significant increase in the frequency of IFN-gamma-producing lymphocytes in response to alloantigen in an ELISPOT assay and higher IFN-gamma levels in placental homogenates by ELISA. Finally, PDL1-deficient females exhibited decreased allogeneic fetal survival rates as compared with littermate and heterozygote controls and showed evidence of expansion of T helper type 1 immune responses in vivo. These results provide the first evidence that PDL1 is involved in fetomaternal tolerance.
Assuntos
Antígeno B7-1/imunologia , Reabsorção do Feto/imunologia , Tolerância Imunológica , Troca Materno-Fetal/imunologia , Glicoproteínas de Membrana/imunologia , Peptídeos/imunologia , Animais , Antígeno B7-1/genética , Antígeno B7-H1 , Feminino , Reabsorção do Feto/genética , Reabsorção do Feto/patologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/imunologia , Tolerância Imunológica/genética , Interferon gama/imunologia , Troca Materno-Fetal/genética , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Peptídeos/genética , Gravidez , Células Th1/imunologiaRESUMO
T cell Ig mucin 1 (TIM-1) plays an important role in regulating immune responses in autoimmune and asthma models, and it is expressed on both Th1 and Th2 cells. Using an antagonistic TIM-1-specific antibody, we studied the role of TIM-1 in alloimmunity. A short course of TIM-1-specific antibody monotherapy prolonged survival of fully MHC-mismatched vascularized mouse cardiac allografts. This prolongation was associated with inhibition of alloreactive Th1 responses and preservation of Th2 responses. TIM-1-specific antibody treatment was more effective in Th1-type cytokine-deficient Stat4(-/-) recipients as compared with Th2-type cytokine-deficient Stat6(-/-) recipients. Subtherapeutic doses of rapamycin plus TIM-1-specific antibody resulted in allograft acceptance and prevented the development of chronic allograft vasculopathy. Allograft survival via this treatment was accompanied by a Th1- to Th2-type cytokine switch. Depletion of natural Tregs abrogated the graft-protecting effect of the TIM-1-specific antibody. Importantly, CD4(+)CD25(+) Tregs obtained from long-term survivors had enhanced regulatory activity as compared with naive CD4(+)CD25(+) Tregs. Consistent with this, TIM-1-specific antibody treatment both preserved Tregs and prevented the expansion of alloreactive effector Th1 cells in an alloreactive TCR transgenic adoptive transfer model. These studies define previously unknown functions of TIM-1 in regulating alloimmune responses in vivo and may provide a novel approach to promoting transplantation tolerance.
Assuntos
Sobrevivência de Enxerto/imunologia , Proteínas de Membrana/fisiologia , Linfócitos T Reguladores/imunologia , Tolerância ao Transplante/imunologia , Animais , Anticorpos Bloqueadores/farmacologia , Anticorpos Monoclonais/farmacologia , Citocinas/metabolismo , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Coração/imunologia , Transplante de Coração/patologia , Receptor Celular 1 do Vírus da Hepatite A , Imunossupressores/farmacologia , Depleção Linfocítica , Proteínas de Membrana/antagonistas & inibidores , Camundongos , Camundongos Transgênicos , Modelos Animais , Sirolimo/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th1/imunologia , Células Th2/imunologia , Tolerância ao Transplante/efeitos dos fármacosRESUMO
BACKGROUND: Due to the shortage of deceased donors ABO-incompatible (ABOi) living kidney transplantation has become a popular alternative to deceased kidney transplantation. In recent years, recipient desensitization with a combination of anti-CD20 treatment (rituximab), antigen-specific immunoadsorptions (IA) and intravenous immunoglobulin (IVIG), led to promising short-term and intermediate-term results. However, little is known about the impact of this intensified desensitization protocol on the risk of surgical and infectious complications. METHODS: We retrospectively analysed 21 consecutive recipients who underwent ABOi renal transplantation. Pre-transplant desensitization included administration of rituximab (375 mg/m(2)), mycophenolate mofetil (MMF), tacrolimus and prednisolone 4 weeks prior of scheduled transplantation as well as IA and IVIG. Forty-seven patients who underwent ABO-compatible (ABOc) renal transplantation served as the control group. Medical records and electronic databases were reviewed for patient and graft survival, renal function, rate of rejections, viral and bacterial infections as well as for surgical complications (SCs) post-transplantation. RESULTS: All patients showed an immediate graft function. During a mean follow-up of 15.7 ± 8.3 months (interquartile range 11.9) patient survival was 95 and 98% in the ABOi and ABOc group, respectively. Allograft survival and function, as assessed by serum creatinine levels and calculated glomerular filtration rate at 1 year, did not differ between ABOi and ABOc recipients. Furthermore, the rate of biopsy-proven acute rejections was comparable between the two groups. However, there was a trend towards more SCs within the ABOi group (29 versus 11%, non-significant). In addition, the rate of viral infections including cytomegalovirus, Herpes simplex virus, Varicella zoster virus and polyoma virus was significantly increased among the ABOi recipients (50 versus 21%; P = 0.038) despite comparable tacrolimus trough levels and MMF and steroid doses. CONCLUSIONS: Our results, in line with the extended experience of other groups, demonstrate favourable short-term allograft survival and function after ABOi renal transplantation after desensitization with antigen-specific IA, IVIG and rituximab. However, the intensified desensitization was associated with an increased risk of infectious complications. This observation prompted us to briefly escalate the desensitization protocol in ABOi kidney recipients in our centre.
Assuntos
Sistema ABO de Grupos Sanguíneos , Incompatibilidade de Grupos Sanguíneos/imunologia , Dessensibilização Imunológica/efeitos adversos , Infecções/epidemiologia , Infecções/etiologia , Transplante de Rim/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
INTRODUCTION: Early conversion to a CNI-free immunosuppression with SRL was associated with an improved 1- and 3- yr renal function as compared with a CsA-based regimen in the SMART-Trial. Mixed results were reported on the occurrence of donor specific antibodies under mTOR-Is. Here, we present long-term results of the SMART-Trial. METHODS AND MATERIALS: N = 71 from 6 centers (n = 38 SRL and n = 33 CsA) of the original SMART-Trial (ITT n = 140) were enrolled in this observational, non-interventional extension study to collect retrospectively and prospectively follow-up data for the interval since baseline. Primary objective was the development of dnDSA. Blood samples were collected on average 8.7 years after transplantation. RESULTS: Development of dnDSA was not different (SRL 5/38, 13.2% vs. CsA 9/33, 27.3%; P = 0.097). GFR remained improved under SRL with 64.37 ml/min/1.73m2 vs. 53.19 ml/min/1.73m2 (p = 0.044). Patient survival did not differ between groups at 10 years. There was a trend towards a reduced graft failure rate (11.6% SRL vs. 23.9% CsA, p = 0.064) and less tumors under SRL (2.6% SRL vs. 15.2% CsA, p = 0.09). CONCLUSIONS: An early conversion to SRL did not result in an increased incidence of dnDSA nor increased long-term risk for the recipient. Transplant function remains improved with benefits for the graft survival.
Assuntos
Inibidores de Calcineurina/administração & dosagem , Terapia de Imunossupressão/métodos , Imunossupressores/administração & dosagem , Transplante de Rim , Sirolimo/administração & dosagem , Adulto , Especificidade de Anticorpos , Esquema de Medicação , Feminino , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Humanos , Estimativa de Kaplan-Meier , Transplante de Rim/efeitos adversos , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Serina-Treonina Quinases TOR/antagonistas & inibidores , Fatores de Tempo , Doadores de TecidosRESUMO
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.