RESUMO
BACKGROUND: Pneumocystis pneumonia (PCP) is associated with morbidity and mortality in solid organ transplant (SOT) recipients. In this case-control study, we determined the association between posttransplant PCP and 3 variables: cytomegalovirus (CMV) infection, allograft rejection, and prophylaxis. METHODS: Eight transplant centers participated. For each case (SOT recipient with PCP), 3-5 controls (SOT recipients without PCP) were included. Controls were matched to the cases based on transplant center, type of allograft, and date of transplantation (±6 months). RESULTS: We enrolled 53 cases and 209 controls. Transplant types included kidney (n = 198), heart (n = 30), liver (n = 15), kidney-pancreas (n = 14), and lung (n = 5). PCP occurred beyond 12 months after transplantation in 43 (81.1%) cases. Thirty-four cases (64.1%) required admission to the intensive care unit, and 28 (52.8%) had mechanical ventilation. Allograft failure occurred in 20 (37.7%) cases, and 14 (26.9%) died. No patient developed PCP prophylaxis breakthrough. The proportion of female sex (P = .009), kidney dysfunction (P = .001), cardiac diseases (P = .005), diabetes mellitus (P = .03), allograft rejection (P = .001), CMV infection (P = .001), and severe lymphopenia (P = .001) were significantly higher in cases. In the logistic regression model, CMV infection (adjusted odds ratio [aOR], 4.6 [95% confidence interval {CI}, 2.0-10.5]) and allograft rejection (aOR, 3.0 [95% CI, 1.5-6.1]) significantly increased the likelihood of PCP. CONCLUSIONS: PCP was mostly a late-onset disease occurring after complete course of prophylaxis, particularly among patients with CMV infection or allograft rejection. PCP is associated with significant allograft loss. Extended prophylaxis targeting recipients with allograft rejection or CMV infection may reduce the risk of PCP.
Assuntos
Infecções por Citomegalovirus/imunologia , Rejeição de Enxerto/imunologia , Pneumonia por Pneumocystis/imunologia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Transplantados , Transplante HomólogoRESUMO
Pretransplant autoantibodies to LG3 and angiotensin II type 1 receptors (AT1R) are associated with acute rejection in kidney transplant recipients, whereas antivimentin autoantibodies participate in heart transplant rejection. Ischemia-reperfusion injury (IRI) can modify self-antigenic targets. We hypothesized that ischemia-reperfusion creates permissive conditions for autoantibodies to interact with their antigenic targets and leads to enhanced renal damage and dysfunction. In 172 kidney transplant recipients, we found that pretransplant anti-LG3 antibodies were associated with an increased risk of delayed graft function (DGF). Pretransplant anti-LG3 antibodies are inversely associated with graft function at 1 year after transplantation in patients who experienced DGF, independent of rejection. Pretransplant anti-AT1R and antivimentin were not associated with DGF or its functional outcome. In a model of renal IRI in mice, passive transfer of anti-LG3 IgG led to enhanced dysfunction and microvascular injury compared with passive transfer with control IgG. Passive transfer of anti-LG3 antibodies also favored intrarenal microvascular complement activation, microvascular rarefaction and fibrosis after IRI. Our results suggest that anti-LG3 antibodies are novel aggravating factors for renal IRI. These results provide novel insights into the pathways that modulate the severity of renal injury at the time of transplantation and their impact on long-term outcomes.
Assuntos
Autoanticorpos/sangue , Função Retardada do Enxerto/etiologia , Sobrevivência de Enxerto/imunologia , Proteoglicanas de Heparan Sulfato/imunologia , Transplante de Rim/efeitos adversos , Traumatismo por Reperfusão/etiologia , Animais , Autoanticorpos/imunologia , Função Retardada do Enxerto/sangue , Função Retardada do Enxerto/patologia , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Falência Renal Crônica/cirurgia , Testes de Função Renal , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Prognóstico , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/patologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
Transplant vasculopathy is associated with neointimal accumulation of recipient-derived mesenchymal stem cells. Increased circulating levels of LG3, a C-terminal fragment of perlecan, were found in renal transplant patients with vascular rejection. Here, we evaluated whether LG3 regulates the migration and homing of mesenchymal stem cells and the accumulation of recipient-derived neointimal cells. Mice were transplanted with a fully-MHC mismatched aortic graft followed by intravenous injection of recombinant LG3. LG3 injections increased neointimal accumulation of α-smooth muscle actin positive cells. When green fluorescent protein (GFP)-transgenic mice were used as recipients, LG3 injection favored accumulation of GFP+ cells to sites of neointima formation. LG3 increased horizontal migration and transmigration of mouse and human MSC in vitro and led to increased ERK1/2 phosphorylation. Neutralizing ß1 integrin antibodies or use of mesenchymal stem cells from α2 integrin-/- mice decreased migration in response to recombinant LG3. Reduced intima-media ratios and decreased numbers of neointimal cells showing ERK1/2 phosphorylation were found in α2-/- recipients injected with recombinant LG3. Collectively, our results suggest that LG3, through interactions with α2ß1 integrins on recipient-derived cells leading to activation of ERK1/2 and increased migration, favors myointimal thickening.
Assuntos
Rejeição de Enxerto/patologia , Proteoglicanas de Heparan Sulfato/química , Integrina alfa2beta1/metabolismo , Células-Tronco Mesenquimais/citologia , Neointima/patologia , Enxerto Vascular , Animais , Aorta/patologia , Aorta/transplante , Prótese Vascular , Espessura Intima-Media Carotídea , Movimento Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Humanos , Integrina beta1/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Miócitos de Músculo Liso/citologia , Fenótipo , Estrutura Terciária de Proteína , Ratos , Proteínas Recombinantes/metabolismoRESUMO
Acute vascular rejection (AVR) is characterized by immune-mediated vascular injury and heightened endothelial cell (EC) apoptosis. We reported previously that apoptotic ECs release a bioactive C-terminal fragment of perlecan referred to as LG3. Here, we tested the possibility that LG3 behaves as a neoantigen, fuelling the production of anti-LG3 antibodies of potential importance in regulating allograft vascular injury. We performed a case-control study in which we compared anti-LG3 IgG titers in kidney transplant recipients with AVR (n=15) versus those with acute tubulo-interstitial rejection (ATIR) (n=15) or stable graft function (n=30). Patients who experienced AVR had elevated anti-LG3 titers pre and posttransplantation compared to subjects with ATIR or stable graft function (p<0.05 for both mediators). Elevated pretransplant anti-LG3 titers (OR: 4.62, 95% CI: 1.08-19.72) and pretransplant donor-specific antibodies (DSA) (OR 4.79, 95% CI: 1.03-22.19) were both independently associated with AVR. To address the functional role of anti-LG3 antibodies in AVR, we turned to passive transfer of anti-LG3 antibodies in an animal model of vascular rejection based on orthotopic aortic transplantation between fully MHC-mismatched mice. Neointima formation, C4d deposition and allograft inflammation were significantly increased in recipients of an ischemic aortic allograft passively transferred with anti-LG3 antibodies. Collectively, these data identify anti-LG3 antibodies as novel accelerators of immune-mediated vascular injury and obliterative remodeling.
Assuntos
Rejeição de Enxerto/imunologia , Proteoglicanas de Heparan Sulfato/imunologia , Imunoglobulina G/sangue , Doenças Vasculares/imunologia , Adulto , Animais , Antígenos/imunologia , Aorta/patologia , Apoptose , Estudos de Casos e Controles , Células Endoteliais/patologia , Feminino , Rejeição de Enxerto/sangue , Humanos , Imunização Passiva , Imunoglobulina G/imunologia , Inflamação/patologia , Rim/irrigação sanguínea , Rim/patologia , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteínas Recombinantes/imunologia , Estudos Retrospectivos , Doenças Vasculares/sangueRESUMO
The pathogenic role of antineutrophil cytoplasmic autoantibodies (ANCA) remains controversial because of the difficulty in explaining how extracellular ANCA can interact with intracellular primary granule constituents. It has been postulated that cytokine priming of neutrophils (PMN), as may occur during a prodromal infection, is an important trigger for mobilization of granules to the cell surface, where they may interact with ANCA. We show by electron microscopy that apoptosis of unprimed PMN is also associated with the translocation of cytoplasmic granules to the cell surface and alignment just beneath an intact cell membrane. Immunofluorescent microscopy and FACS analysis demonstrate reactivity of ANCA-positive sera and antimyeloperoxidase antibodies with apoptotic PMN, but not with viable PMN. Moreover, we show that apoptotic PMN may be divided into two subsets, based on the presence or absence of granular translocation, and that surface immunogold labeling of myeloperoxidase occurs only in the subset of PMN showing translocation. These results provide a novel mechanism that is independent of priming, by which ANCA may gain access to PMN granule components during ANCA-associated vasculitis.
Assuntos
Anticorpos Anticitoplasma de Neutrófilos/imunologia , Apoptose , Grânulos Citoplasmáticos/imunologia , Neutrófilos/imunologia , Neutrófilos/fisiologia , Anticorpos Anticitoplasma de Neutrófilos/sangue , Especificidade de Anticorpos , Antígenos CD/análise , Autoanticorpos , Membrana Celular/imunologia , Membrana Celular/ultraestrutura , Sobrevivência Celular , Grânulos Citoplasmáticos/ultraestrutura , Citometria de Fluxo , Humanos , Técnicas In Vitro , Microscopia Eletrônica , Microscopia Imunoeletrônica , Neutrófilos/ultraestruturaRESUMO
BACKGROUND: The impact of renal function recovery on graft survival was examined using estimated glomerular filtration rate (eGFR) slope after kidney transplantation (GAP classification); this was compared to the conventional classification of immediate graft function (IGF), slow graft function (SGF), and delayed graft function (DGF). MATERIALS AND METHODS: Overall, 541 cases of cadaveric renal transplants were reviewed from a prospective transplant database. eGFR and its slope were measured using the harmonic mean over the first week post-transplantation. Next, 495 kidney transplant recipients from an independent institution were assessed to determine the prognostic value of graft function based on the eGFR slope. RESULTS: The main discrimination of eGFR slopes occurred within the first 7 days. Three groups in the GAP classification (Good graft function, Average graft function, Poor graft function) were defined based on eGFR slope tertiles: good graft function (GGF), average graft function (AGF), and poor graft function (PGF) were defined based on the ΔCrCL per day over the first 7 days: <1 mL/min, 1-4 mL/min, and >4 mL/min, respectively. When applied to the validation cohort, the 5-year graft failure was 20% for the PGF group, 4% for the AGF group, and 3% for the GGF group. Multivariable Cox regression analysis demonstrated better prediction of long-term graft function with the new classification (C statistic 0.49 [old)] vs 0.61 [new]). CONCLUSION: The new GAP criteria were better at predicting long-term graft survival and renal function compared to the conventional classification system, and deserve further consideration in future studies.
Assuntos
Função Retardada do Enxerto/classificação , Taxa de Filtração Glomerular , Sobrevivência de Enxerto , Transplante de Rim , Rim/fisiopatologia , Recuperação de Função Fisiológica , Adulto , Idoso , Estudos de Coortes , Função Retardada do Enxerto/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de Risco , Fatores de TempoRESUMO
Coronary artery disease (CAD) is the leading cause of death in patients with end-stage renal disease (ESRD). Recent evidence suggests that the expression of Fas, a molecule implicated in the initiation of apoptosis in various cell types, is increased at sites of atherosclerotic plaques. However, the significance of plasma levels of the soluble form of Fas (sFas) and its ligand (sFas-L) as markers of atherosclerosis has yet to be defined. The present report is a cross-sectional analysis of baseline data from an ongoing prospective study designed to evaluate the role of sFas and sFas-L as markers of CAD in ESRD. We evaluated the association between plasma levels of sFas and sFas-L and evidence of CAD in a cohort of 107 chronic hemodialysis patients. Plasma levels of sFas were significantly greater (P = 0.04) among subjects with (n = 64) than without evidence of CAD (n = 43). Plasma levels of sFas-L were similar in both groups. Using multivariate analysis, sFas level was found to be independently associated with CAD (P = 0.01) after adjustment for classic risk factors for CAD (hyperlipidemia, diabetes, hypertension, and smoking), markers of inflammation (C-reactive protein [CRP], intercellular adhesion molecule 1), and other confounders. An increase of one quintile in plasma concentration of sFas was associated with an odds ratio for CAD of 1.64 (95% confidence interval, 1.11 to 2.41). Models that incorporated sFas were significantly better at identifying patients with CAD than models limited to classic risk factors for atherosclerosis, alone (P = 0.008) or in combination with CRP levels (P = 0.006). In summary, increased plasma levels of sFas are associated with CAD in stable patients with ESRD. These results suggest that sFas may represent a novel and independent marker of CAD.
Assuntos
Doença das Coronárias/complicações , Doença das Coronárias/diagnóstico , Falência Renal Crônica/complicações , Receptor fas/sangue , Idoso , Apoptose , Biomarcadores/sangue , Proteína C-Reativa/análise , Intervalos de Confiança , Doença das Coronárias/sangue , Feminino , Humanos , Molécula 1 de Adesão Intercelular/sangue , Interleucina-2/sangue , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Molécula 1 de Adesão de Célula Vascular/sangueRESUMO
When loss of graft function occurs more than six months after transplantation, allograft nephrectomy is not routinely performed at the time of graft failure. It is usually performed only on those patients who subsequently develop specific complications. However, little is known about the characteristics that make patients more likely to require allograft nephrectomy. The purpose of our study was to identify risk factors for the subsequent need for allograft nephrectomy in patients with graft failure occurring more than 6 months after transplantation. Forty-one patients were studied. Inclusion criteria were: loss of graft function > or = 6 months after transplantation, resumption of dialysis and initiation of weaning from immunosuppression. Thirty patients were treated with cyclosporine + prednisone +/- azathioprine and 11 with azathioprine + prednisone. Mean follow-up time was 17.8 months, ranging from 6 months to 6.1 years. Recipient age, sex and race, original renal disease, donor, donor source (cadaveric vs living related), HLA compatibility, levels of panel reactive antibodies, occurrence of initial delayed graft function, causes of graft failure and tapering of immunosuppression were similar in patients with and without allograft nephrectomy. Using univariate analysis, allograft nephrectomy was found to be significantly more frequent in patients with a history of 2 or more episodes of acute rejection than in patients with no rejection episode: 83% vs 30% (p = 0.03). In addition, allograft nephrectomy was found to be significantly more frequent if the immunosuppressive regimen included cyclosporine (62% vs 27.3%; p = 0.04). Using multivariate analysis however, the number of previous episodes of rejection was found to be the only significant predictor for allograft nephrectomy. None of the other variables considered in the multivariate analysis, including the type of immunosuppressive therapy, was identified as a significant predictor for the need to perform allograft nephrectomy. In summary, the need for late allograft nephrectomy was correlated with the number of previous episodes of acute rejection. Patients with a history of numerous rejection episodes should thus be considered more likely to require allograft nephrectomy once immunosuppression is withdrawn. Possible interventions to reduce or prevent the need for nephrectomy include more gradual tapering of immunosuppression at the time of graft failure or indefinite low-dose immunosuppressive therapy.
Assuntos
Rejeição de Enxerto/cirurgia , Transplante de Rim/imunologia , Nefrectomia , Adulto , Feminino , Seguimentos , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Masculino , Estudos Retrospectivos , Fatores de RiscoRESUMO
The aim of this study was to assess the relationship between cyclosporine (CyA) trough level (C0) and 2-hour postdose (C2) and total cholesterol (TC) in kidney transplant (KT) recipients on Neoral maintenance immunosuppression. In KT recipients who had more than 5 years of follow-up, stable graft function, and stable Neoral dose, we measured C2 and C0 blood levels, serum creatinine, mean total cholesterol (TC) over the last 5 years, prednisone dose, use of beta-blockers and thiazides. Correlations between C0 and C2 levels and TC were performed with the Pearson coefficient. Receiver operating characteristics (ROCs) were used to define the threshold with greater accuracy for significant variables at the correlation test. Statistical tests were performed with SPSS 9.5 The C2 correlated with TC (0.31; P=.008) whereas C0 did not. The C2 level was an independent predictor for TC after adjusting for recipient age, gender, dose of prednisone, creatinine clearance, and use of beta-blockers and thiazides (B coefficient=1.124(E-3); P=.009). A threshold C2 value of 700 microg/L yielded to a TC level of 5.2 mmol/L. This is the first study to report a correlation between C2 levels and TC. Although C2 explained a small fraction of TC variability, it is an independent predictor of TC in KT recipients on Neoral maintenance immunosuppression. A long-term C2 value under 700 microg correlates with better control of hypercholesterolemia.
Assuntos
Colesterol/sangue , Ciclosporina/sangue , Ciclosporina/uso terapêutico , Transplante de Rim/fisiologia , Ciclosporina/farmacocinética , Feminino , Seguimentos , Humanos , Transplante de Rim/imunologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos RetrospectivosRESUMO
The apoptotic program incorporates a paracrine component of importance in fostering tissue repair at sites of apoptotic cell deletion. As this paracrine pathway likely bears special importance in maladaptive intercellular communication leading to vascular remodeling, we aimed at further defining the mediators produced by apoptotic endothelial cells (EC), using comparative and functional proteomics. Apoptotic EC were found to release nanovesicles displaying ultrastructural characteristics, protein markers and functional activity that differed from apoptotic blebs. Tumor susceptibility gene 101 and translationally controlled tumor protein (TCTP) were identified in nanovesicle fractions purified from medium conditioned by apoptotic EC and absent from purified apoptotic blebs. Immunogold labeling identified TCTP on the surface of nanovesicles purified from medium conditioned by apoptotic EC and within multivesicular blebs in apoptotic EC. These nanovesicles induced an extracellular signal-regulated kinases 1/2 (ERK 1/2)-dependent antiapoptotic phenotype in vascular smooth muscle cells (VSMC), whereas apoptotic blebs did not display antiapoptotic activity on VSMC. Caspase-3 biochemical inhibition and caspase-3 RNA interference in EC submitted to a proapoptotic stimulus inhibited the release of nanovesicles. Also, TCTP siRNAs in EC attenuated the antiapoptotic activity of purified nanovesicles on VSMC. Collectively, these results identify TCTP-bearing nanovesicles as a novel component of the paracrine apoptotic program of potential importance in vascular repair.
Assuntos
Apoptose , Biomarcadores Tumorais/metabolismo , Caspase 3/metabolismo , Comunicação Celular , Animais , Células Endoteliais/citologia , Células Endoteliais/enzimologia , Células Endoteliais/ultraestrutura , Ativação Enzimática , Exossomos/ultraestrutura , Humanos , Nanoestruturas/ultraestrutura , Transporte Proteico , Ratos , Soro , Proteína Tumoral 1 Controlada por Tradução , Veias Umbilicais/citologiaRESUMO
Apoptosis of endothelial cells (ECs) is an early pathogenic event in various fibrotic diseases. In this study, we evaluated whether paracrine mediators produced by apoptotic ECs play direct roles in fibrogenesis. C3H mice injected subcutaneously with serum-free medium conditioned by apoptotic ECs (SSC) showed increased skin thickness and heightened protein levels of alpha-smooth-muscle actin (alphaSMA), vimentin and collagen I as compared with mice injected with medium conditioned by non-apoptotic ECs. Fibroblasts exposed to SSC in vitro showed cardinal features of myofibroblast differentiation with increased stress fiber formation and expression of alphaSMA. Caspase-3 silencing in ECs prevented the release of mediators favoring myofibroblast differentiation. To identify the fibrogenic factor(s) released by ECs, the protein contents of media conditioned by either apoptotic or non-apoptotic ECs were compared using SDS-PAGE-liquid chromatography (LC)-tandem mass spectrometry (MS/MS) and two-dimensional LC-MS/MS. Connective tissue growth factor (CTGF) was the only fibrogenic protein found increased in SSC. Pan-caspase inhibition with ZVAD-FMK or caspase-3 silencing in ECs confirmed that CTGF was released downstream of caspase-3 activation. The fibrogenic signaling signatures of SSC and CTGF on fibroblasts in vitro were similarly Pyk2-, Src-family kinases- and PI3K dependent, but TGF-beta-independent. CTGF-immunodepleted SSC failed to induce myofibroblast differentiation in vitro and skin fibrosis in vivo. These results identify caspase-3 activation in ECs as a novel inducer of CTGF release and fibrogenesis.
Assuntos
Caspase 3/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Dermatopatias/metabolismo , Dermatopatias/patologia , Animais , Apoptose/fisiologia , Diferenciação Celular/fisiologia , Modelos Animais de Doenças , Células Endoteliais/citologia , Feminino , Fibroblastos/citologia , Fibrose , Humanos , Camundongos , Camundongos Endogâmicos C3H , Comunicação Parácrina/fisiologia , Transdução de Sinais/fisiologia , Veias Umbilicais/citologiaRESUMO
INTRODUCTION: BK polyomavirus-associated nephropathy (BKPVAN) is a major cause of renal failure early after kidney transplantation. The present study reports the preliminary results of prospective monitoring including a preemptive strategy for BKPVAN during the first year after kidney transplantation. METHODS: We monitored BK virus DNA in blood at months 1, 2, 3, 6, 9, and 12 among 92 subjects who received induction therapy (basiliximab or antithymocyte globulin), and maintenance immunosuppression with prednisone, mycophenolate mofetil, and tacrolimus. Patients with two or more consecutive measurements of viral load >10(4) copies/mL were treated with a stepwise approach including dose reduction or discontinuation of mycophenolate mofetil eventually followed by reduction of tacrolimus and introduction of leflunomide. RESULTS: Within 1 year, seven (7%) patients displayed sustained BK viremia at a median of 92 days after transplantation. Among 68 patients who underwent a renal allograft biopsy, seven were diagnosed as BKPVAN at a median of 15 weeks after transplantation. The diagnosis was achieved by a surveillance biopsy in four patients with stable renal function. BKPVAN was preceded by asymptomatic viremia except for two cases in whom BK viremia occurred at 6 or 11 months, after the histological diagnosis. At 12 months, six patients had cleared their viremia. Serum creatinine levels had stabilized in six recipients with BKPVAN estimated renal function was 43.7 ± 16.3 mL/min in patients with viremia and/or BKPVAN versus 61.3 ± 20.1 mL/min among patients who never became viremic (P = .03). None of the patients with viremia and/or BKPVAN lost the allograft. CONCLUSION: BKPVAN may occur early after kidney transplantation, at a low or undetectable viremia or at some weeks after the first positive viremia. Intensive monitoring during the first 4 months after transplantation together with early protocol biopsies or interventions prompted by BK viremia may optimize BKPVAN diagnosis at a subclinical stage, thus avoiding renal dysfunction.
Assuntos
Vírus BK/fisiologia , Nefropatias/cirurgia , Transplante de Rim , Adulto , Feminino , Humanos , Nefropatias/fisiopatologia , Nefropatias/virologia , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosAssuntos
Nefropatias/patologia , Transplante de Rim/patologia , Adulto , Biópsia , Peso Corporal , Doença Crônica , Creatinina/sangue , Feminino , Humanos , Nefropatias/sangue , Nefropatias/etiologia , Transplante de Rim/fisiologia , Masculino , Complicações Pós-Operatórias/classificação , Complicações Pós-Operatórias/epidemiologia , Valor Preditivo dos Testes , Transplante HomólogoAssuntos
Densidade Óssea/efeitos dos fármacos , Glucocorticoides/efeitos adversos , Transplante de Rim/efeitos adversos , Prednisona/efeitos adversos , Doenças Ósseas Metabólicas/induzido quimicamente , Feminino , Humanos , Região Lombossacral , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Osteoporose/induzido quimicamente , Estudos ProspectivosAssuntos
Infecções por Citomegalovirus/etiologia , Imunossupressores/efeitos adversos , Transplante de Rim , Ácido Micofenólico/efeitos adversos , Tacrolimo/efeitos adversos , Antivirais/uso terapêutico , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/prevenção & controle , Ganciclovir/uso terapêutico , Humanos , Hospedeiro Imunocomprometido , Ácido Micofenólico/análogos & derivados , Estudos RetrospectivosAssuntos
Corticosteroides/efeitos adversos , Transplante de Rim/fisiologia , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/uso terapêutico , Prednisona/efeitos adversos , Tacrolimo/uso terapêutico , Adolescente , Adulto , Idoso , Cadáver , Criança , Esquema de Medicação , Monitoramento de Medicamentos , Feminino , Humanos , Transplante de Rim/imunologia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/análogos & derivados , Estudos Retrospectivos , Doadores de TecidosAssuntos
Ciclosporina/uso terapêutico , Sobrevivência de Enxerto , Transplante de Rim/imunologia , Administração Oral , Adulto , Ciclosporina/administração & dosagem , Ciclosporina/sangue , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Doadores de Tecidos , Transplante HomólogoRESUMO
BACKGROUND: Replacing a calcineurin inhibitor (CNI) with sirolimus (SRL) may preserve kidney graft function. However, at the present time, only short follow-up after conversion is available. The aim of this study was to assess whether conversion from a CNI-based to an SRL-based maintenance regimen was safe and effective. MATERIALS AND METHODS: We performed a retrospective cohort study among kidney graft patients whose CNI was withdrawn to be replaced by SRL. Two-tailed paired t tests were used to compare glomerular filtration rates (GFRs) and proteinuria levels before and up to 2 years after conversion. We used linear regression to determine the factors associated with changes in renal function after conversion. RESULTS: The 193 study subjects had a mean GFR at conversion of 41 +/- 16 mL/min/1.73 m(2) a median proteinuria level of 0 g/L (interquartile range = 0-0.15). After conversion, the GFR was stable: at 1 year, the change was -0.34 mL/min/1.73 m(2) (95% confidence interval [CI] = -2.71, 2.03) and at 2 years, -0.96 mL/min/1.73 m(2) (95% CI = 4.26, 2.34). There was a small but significant increase in dipstick proteinuria at 1 year of +0.5 g/L, (95% CI = 0.20, 0.75). On multivariate analysis, proteinuria > or = 1 g/L at the time of conversion was the only predictor of deteriorating GFR at 1 year (beta: -7.91 mL/min/1.73 m(2); 95% CI = -14.10, -1.70). SRL had to be discontinued in 31% of patients. CONCLUSION: Conversion from CNI to SRL resulted in stable graft function at 2 years and in a slight increase in proteinuria. Despite the relatively high reconversion rate, this strategy offers a reasonable alternative to CNIs for most patients.
Assuntos
Inibidores de Calcineurina , Ciclosporina/uso terapêutico , Taxa de Filtração Glomerular/efeitos dos fármacos , Imunossupressores/uso terapêutico , Transplante de Rim/imunologia , Sirolimo/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Calcineurina/uso terapêutico , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Proteinúria/epidemiologia , Análise de Regressão , Estudos Retrospectivos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Falha de Tratamento , Resultado do TratamentoRESUMO
Chronic transplant vasculopathy (CTV) is a progressive form of vascular obliteration affecting the arteries, arterioles and capillaries of solid organ transplants. It is characterized by intimal accumulation of mononuclear cells, vascular smooth muscle cells (VSMC), myofibroblasts and connective tissue. Mounting evidence, based on animal models and human biopsy results, suggests that acute and persistent rejection triggering apoptosis of endothelial cells (EC) plays a pivotal role in CTV. The precise mechanisms that underlie the induction of fibroproliferative changes in association with endothelial apoptosis have yet to be clearly delineated. Recent observations in the field of apoptosis research provide some important mechanistic clues. First, endothelial apoptosis creates a state of hyperadhesiveness for mononuclear cells, thus facilitating sustained leukocyte infiltration. Second, phosphatidylserine-dependent engulfment of apoptotic cells by infiltrating mononuclear leukocytes promotes transforming growth factor-beta1 production. Third, apoptosis of EC triggers extracellular matrix (ECM) proteolysis thus initiating the production of fibroproliferative/fibrogenic ECM fragments. The relative importance of these mechanisms in the pathophysiology of CTV will need to be addressed in vivo. Yet, these recent developments provide a new mechanistic framework that will help better define the importance of immune-mediated EC apoptosis in the regulation of vascular repair.
Assuntos
Endotélio Vascular/fisiopatologia , Complicações Pós-Operatórias/patologia , Doenças Vasculares/patologia , Apoptose , Doença Crônica , Endotélio Vascular/patologia , Humanos , Modelos Cardiovasculares , Complicações Pós-Operatórias/fisiopatologia , Transplante Homólogo/patologia , Doenças Vasculares/fisiopatologiaRESUMO
Diabetic mellitus confers a major risk of congenital malformations, and is associated with diabetic embryopathy, affecting multiple organs including the kidney. The DNA paired box-2 (Pax-2) gene is essential in nephrogenesis. We investigated whether high glucose alters Pax-2 gene expression and aimed to delineate its underlying mechanism(s) of action using both in vitro (mouse embryonic mesenchymal epithelial cells (MK4) and ex vivo (kidney explant from Hoxb7-green florescent protein (GFP) mice) approaches. Pax-2 gene expression was determined by reverse transcriptase-polymerase chain reaction, Western blotting, and immunofluorescent staining. A fusion gene containing the full-length 5'-flanking region of the human Pax-2 promoter linked to a luciferase reporter gene, pGL-2/hPax-2, was transfected into MK4 cells with or without dominant negative IkappaBalpha (DN IkappaBalpha) cotransfection. Fusion gene expression level was quantified by cellular luciferase activity. Reactive oxygen species (ROS) generation was measured by lucigenin assay. Embryonic kidneys from Hoxb7-GFP mice were cultured ex vivo. High D(+) glucose (25 mM), compared to normal glucose (5 mM), specifically induced Pax-2 gene expression in MK4 cells and kidney explants. High glucose-induced Pax-2 gene expression is mediated, at least in part, via ROS generation and activation of the nuclear factor kappa B signaling pathway, but not via protein kinase C, p38 mitogen-activated protein kinase (MAPK), and p44/42 MAPK signaling.