RESUMO
Kidney transplant recipients develop atypical infections in their epidemiology, presentation and outcome. Among these, meningitis and meningoencephalitis require urgent and adapted anti-infectious therapy, but published data is scarce in KTRs. The aim of this study was to describe their epidemiology, presentation and outcome, in order to improve their diagnostic and management. We performed a retrospective, multicentric cohort study in 15 French hospitals that included all 199 cases of M/ME in KTRs between 2007 and 2018 (0.9 case per 1,000 KTRs annually). Epidemiology was different from that in the general population: 20% were due to Cryptococcus neoformans, 13.5% to varicella-zoster virus, 5.5% to Mycobacterium tuberculosis, and 4.5% to Enterobacteria (half of which produced extended spectrum beta-lactamases), and 5% were Post Transplant Lymphoproliferative Disorders. Microorganisms causing M/ME in the general population were infrequent (2%, for Streptococcus pneumoniae) or absent (Neisseria meningitidis). M/ME caused by Enterobacteria, Staphylococci or filamentous fungi were associated with high and early mortality (50%-70% at 1 year). Graft survival was not associated with the etiology of M/ME, nor was impacted by immunosuppression reduction. Based on these results, we suggest international studies to adapt guidelines in order to improve the diagnosis and the probabilistic treatment of M/ME in SOTRs.
Assuntos
Encefalite , Transplante de Rim , Meningite , Humanos , Estudos Retrospectivos , Estudos de Coortes , Transplante de Rim/efeitos adversos , Meningite/complicações , Meningite/diagnóstico , Encefalite/diagnóstico , Encefalite/epidemiologia , Encefalite/etiologiaRESUMO
Urinary messenger RNA (mRNA) quantification is a promising method for noninvasive diagnosis of renal allograft rejection (AR), but the quantification of mRNAs in urine remains challenging due to degradation. RNA normalization may be warranted to overcome these issues, but the strategies of gene normalization have been poorly evaluated. Herein, we address this issue in a case-control study of 108 urine samples collected at time of allograft biopsy in kidney recipients with (n = 52) or without (n = 56) AR by comparing the diagnostic value of IP-10 and CD3ε mRNAs-two biomarkers of AR-after normalization by the total amount of RNA, normalization by one of the three widely used reference RNAs-18S, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Hypoxanthine-guanine phosphoribosyltransferase (HPRT)-or normalization using uroplakin 1A (UPK) mRNA as a possible urine-specific reference mRNA. Our results show that normalization based on the total quantity of RNA is not substantially improved by additional normalization and may even be worsened with some classical reference genes that are overexpressed during rejection. However, considering that normalization by a reference gene is necessary to ensure polymerase chain reaction (PCR) quality and reproducibility and to suppress the effect of RNA degradation, we suggest that GAPDH and UPK1A are preferable to 18S or HPRT RNA.
Assuntos
Biomarcadores/urina , Rejeição de Enxerto/diagnóstico , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Reação em Cadeia da Polimerase/normas , RNA Mensageiro/urina , Feminino , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/urina , Humanos , Testes de Função Renal , Masculino , Prognóstico , RNA Mensageiro/genética , Padrões de Referência , Estudos Retrospectivos , Fatores de Risco , Transplante HomólogoRESUMO
The literature including correlates of parental distress as related to childhood cancer is abundant. It is important to identify predictive factors and outcomes of this distress in parents. The objective of this review was to update previous syntheses on factors of distress and to identify outcomes of parents' distress in the recent literature (2007-2012). We performed a systematic review to identify all quantitative studies including measures of parental distress and associated factors during the study period. We found 56 eligible studies, of which 43 had a Low risk of bias (Cochrane guidelines). Forty-two reports included potential predictive factors. Significant relationships were found with clinical history of the child, sex of the parent, coping response and personal resources, pre-diagnosis family functioning, but not education/income or marital status. Twenty-five reports studied potential consequences of distress and focused on psychological adjustment in parents and children. Compared to past periods, a higher proportion of studies included fathers. Measures used to evaluate distress were also more homogeneous in certain domains of distress. This review underscores the need for appropriate methods for selecting participants and reporting results in future studies. Appropriate methods should be used to demonstrate causality between factors/consequences and distress.
Assuntos
Neoplasias/psicologia , Pais/psicologia , Estresse Psicológico/etiologia , Adolescente , Criança , Pré-Escolar , Métodos Epidemiológicos , Feminino , Humanos , Lactente , Recém-Nascido , MasculinoRESUMO
Markers of epithelial-mesenchymal transition (EMT) may identify patients at high risk of graft fibrogenesis who could benefit from early calcineurin inhibitor (CNI) withdrawal. In a randomized, open-label, 12-month trial, de novo kidney transplant patients received cyclosporine, enteric-coated mycophenolate sodium (EC-MPS) and steroids to month 3. Patients were stratified as EMT+ or EMT- based on month 3 biopsy, then randomized to start everolimus with half-dose EC-MPS (720 mg/day) and cyclosporine withdrawal (CNI-free) or continue cyclosporine with standard EC-MPS (CNI). The primary endpoint was progression of graft fibrosis (interstitial fibrosis/tubular atrophy [IF/TA] grade increase ≥1 between months 3-12) in EMT+ patients. 194 patients were randomized (96 CNI-free, 98 CNI); 153 (69 CNI-free, 84 CNI) were included in histological analyses. Fibrosis progression occurred in 46.2% (12/26) CNI-free EMT+ patients versus 51.6% (16/31) CNI EMT+ patients (p = 0.68). Biopsy-proven acute rejection (BPAR, including subclinical events) occurred in 25.0% and 5.1% of CNI-free and CNI patients, respectively (p < 0.001). In conclusion, early CNI withdrawal with everolimus initiation does not prevent interstitial fibrosis. Using this CNI-free protocol, in which everolimus exposure was relatively low and administered with half-dose EC-MPS, CNI-free patients were overwhelmingly under-immunosuppressed and experienced an increased risk of BPAR.
Assuntos
Ciclosporina/administração & dosagem , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Everolimo/administração & dosagem , Transplante de Rim , Rim/patologia , Insuficiência Renal/cirurgia , Adolescente , Adulto , Idoso , Biópsia , Inibidores de Calcineurina/administração & dosagem , Progressão da Doença , Feminino , Fibrose , Sobrevivência de Enxerto , Humanos , Terapia de Imunossupressão , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
Atypical hemolytic and uremic syndrome (aHUS) is a severe disease strongly associated with genetic abnormalities in the complement alternative pathway. In renal posttransplantation, few data are available on recurrence risk and graft outcome according to genetic background in aHUS patients. The aim of this study was to identify risk factors for recurrence and transplant outcome and, in particular, the role of complement gene abnormalities. We retrospectively studied 57 aHUS patients who had received 71 renal transplants. A mutation in complement gene was identified in 39 (68%), in factor H (CFH), factor I (CFI), membrane cofactor-protein (MCP), C3 and factor B (CFB). At 5 years, death-censored graft survival was 51%. Disease recurrence was associated with graft loss (p = 0.001). Mutations in complement genes were associated with higher risk of recurrence (p = 0.009). Patients with CFH or gain of function (C3, CFB) mutations had a highest risk of recurrence. M-TOR inhibitor was associated with significant risk of recurrence (p = 0.043) but not calcineurin inhibitor immunosuppressive treatment (p = 0.29). Preemptive plasmatherapy was associated with a trend to decrease recurrence (p = 0.07). Our study highlights that characterization of complement genetic abnormalities predicts the risk of recurrence-related graft loss and paves the way for future genetically based individualized prophylactic therapeutic strategies.
Assuntos
Biomarcadores/análise , Proteínas do Sistema Complemento/genética , Testes Genéticos , Rejeição de Enxerto/genética , Sobrevivência de Enxerto/genética , Síndrome Hemolítico-Urêmica/terapia , Transplante de Rim , Adolescente , Adulto , Idoso , Síndrome Hemolítico-Urêmica Atípica , Biomarcadores/metabolismo , Complemento C3/genética , Fator B do Complemento/genética , Fator H do Complemento/genética , Feminino , Fibrinogênio/genética , Síndrome Hemolítico-Urêmica/genética , Humanos , Masculino , Proteína Cofatora de Membrana/genética , Pessoa de Meia-Idade , Mutação/genética , Prognóstico , Recidiva , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
Eculizumab (anti-C5) has been sporadically reported as an efficient therapy for atypical hemolytic uremic syndrome (aHUS). However, the lack of series precludes any firm conclusion about the optimal use of anti-C5 for preventing or treating aHUS posttransplant aHUS recurrence. We thoroughly studied 22 renal transplant recipients with aHUS who received off-label therapy with anti-C5, including 12 cases, which have not been reported yet. Nine patients, all carrying a complement genetic abnormality associated with a high risk of aHUS recurrence, received prophylactic anti-C5 therapy to prevent posttransplant recurrence. Eight of them had a successful recurrence-free posttransplant course and achieved a satisfactory graft function, while the remaining patient experienced early arterial thrombosis of the graft. Thirteen renal transplant recipients were given anti-C5 for posttransplant aHUS recurrence. A complete reversal of aHUS activity was obtained in all of them. Importantly, the delay of anti-C5 initiation after the onset of the aHUS episode inversely correlated with the degree of renal function improvement. Three patients in whom anti-C5 was subsequently stopped experienced a relapse. Altogether these data suggest that long-term eculizumab is highly effective for preventing and treating posttransplant aHUS recurrence. Our study also indicates that anti-C5 should be promptly started if a recurrence occurs.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica/tratamento farmacológico , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias , Prevenção Secundária , Adolescente , Adulto , Síndrome Hemolítico-Urêmica Atípica , Criança , Pré-Escolar , Complemento C5/antagonistas & inibidores , Complemento C5/imunologia , Feminino , Síndrome Hemolítico-Urêmica/etiologia , Humanos , Lactente , Masculino , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
Recent findings in idiopathic membranous nephropathy (MN) suggest that in most patients, the disease is because of anti-phospholipase A(2) receptor (PLA(2) R1) autoantibodies. Our aim was to analyze the prevalence and significance of anti-PLA(2) R1 antibodies in recurrent and de novo MN after transplantation. We assessed circulating PLA(2) R1 autoantibodies by a direct immunofluorescence assay based on human embryonic kidney cells transfected with a PLA(2) R1 cDNA, and the presence of PLA(2) R1 antigen in immune deposits. We showed that PLA(2) R1 was involved in 5 of 10 patients with recurrent MN, but in none of the 9 patients with de novo MN. We also showed a marked heterogeneity in the kinetics and titers of anti-PLA(2) R1, which may relate to different pathogenic potential. We provide evidence that some patients with PLA(2) R1-related idiopathic MN and anti-PLA(2) R1 antibodies at the time of transplantation will not develop recurrence. Because PLA(2) R1 autoantibody was not always associated with recurrence, its predictive value should be carefully analyzed in prospective studies.
Assuntos
Autoanticorpos/imunologia , Glomerulonefrite Membranosa/imunologia , Receptores da Fosfolipase A2/imunologia , Adulto , Autoanticorpos/sangue , DNA Complementar , Feminino , Técnica Direta de Fluorescência para Anticorpo , Humanos , Masculino , Pessoa de Meia-Idade , Receptores da Fosfolipase A2/genética , RecidivaRESUMO
BACKGROUND: Urinary tract infections (UTIs), the most common form of bacterial infection in kidney transplant recipients, recently have been demonstrated to be detrimental for long-term graft outcome. Therefore, reinforcing antibiotic prophylaxis might be vital, in addition to basic hygiene recommendations, surgical care, and prophylaxis by trimethoprim-sulfamethoxazole. METHODS: In 2006, a Legionella pneumophila contamination of our department's water pipes meant that all the patients undergoing renal transplantation underwent a 1-month regimen of ofloxacin (OFLO) (200 mg every other day). We took this opportunity to measure the incidence of UTI, including acute pyelonephritis (APN), in 100 consecutive patients transplanted before (n = 50) and after (n = 50) this treatment decision was reached. We also studied the antimicrobial resistance profiles in our department and in the rest of the hospital. RESULTS: No patient developed Legionnaire's disease. A dramatic decrease in the incidence of UTI (-63%) was also seen in patients undergoing OFLO treatment. Logistic regression analysis demonstrated that the use of OFLO was independently associated with a reduction in UTI (odd ratio [OR] = 0.31%, 95% confidence interval [CI] 0.11-0.84, P = 0.02) and APN (OR = 0.21%, 95% CI 0.07-0.98, P = 0.045). This protection was sustained during the whole first year post transplantation. As for resistance rates, we observed a decrease in the susceptibility of Pseudomonas aeruginosa to ciprofloxacin in our nephrology department, compared with that observed in the rest of the hospital. The incidence of multi-resistant bacteria was stable. DISCUSSION: Our unintentional extension of prophylactic antibiotherapy with OFLO gave rise to a dramatic decrease in the 1-year incidence of UTI and APN in kidney recipients. Emergence of resistant strains is, however, a major concern.
Assuntos
Antibacterianos/uso terapêutico , Antibioticoprofilaxia , Infecções por Bactérias Gram-Negativas/epidemiologia , Transplante de Rim/efeitos adversos , Ofloxacino/uso terapêutico , Pielonefrite/epidemiologia , Infecções Urinárias/epidemiologia , Doença Aguda , Adulto , Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Quimioterapia Combinada , Feminino , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/isolamento & purificação , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por Bactérias Gram-Negativas/prevenção & controle , Humanos , Incidência , Legionella pneumophila/efeitos dos fármacos , Doença dos Legionários/epidemiologia , Doença dos Legionários/microbiologia , Doença dos Legionários/prevenção & controle , Masculino , Pessoa de Meia-Idade , Ofloxacino/farmacologia , Pielonefrite/microbiologia , Pielonefrite/prevenção & controle , Combinação Trimetoprima e Sulfametoxazol/farmacologia , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Infecções Urinárias/prevenção & controleRESUMO
Animal domestication and artificial selection give rise to gradual changes at the genomic level in populations. Subsequent footprints of selection, known as selection signatures or selective sweeps, have been traced in the genomes of many animal livestock species by exploiting variation in linkage disequilibrium patterns and/or reduction of genetic diversity. Domestication of most aquatic species is recent in comparison with land animals, and salmonids are one of the most important fish species in aquaculture. Coho salmon (Oncorhynchus kisutch), cultivated primarily in Chile, has been subjected to breeding programs to improve growth, disease resistance traits, and flesh color. This study aimed to identify selection signatures that may be involved in adaptation to culture conditions and traits of productive interest. To do so, individuals of two domestic populations cultured in Chile were genotyped with 200 thousand SNPs, and analyses were conducted using iHS, XP-EHH and CLR. Several signatures of selection on different chromosomal regions were detected across both populations. Some of the identified regions under selection contained genes such anapc2, alad, chp2 and myn, which have been previously associated with body weight in Atlantic salmon, or sec24d and robo1, which have been associated with resistance to Piscirickettsia salmonis in coho salmon. Findings in our study can contribute to an integrated genome-wide map of selection signatures, to help identify the genetic mechanisms of phenotypic diversity in coho salmon.
Assuntos
Aquicultura , Estudo de Associação Genômica Ampla , Oncorhynchus kisutch/genética , Animais , Doenças dos Peixes/microbiologia , Genótipo , Humanos , Oncorhynchus kisutch/microbiologia , Fenótipo , Piscirickettsia/patogenicidade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
To investigate the phagocytic capability of glomerular mesangial cells and the biochemical events associated with phagocytosis, rat cultured mesangial cells were incubated in the presence of opsonized zymosan (STZ) and production of reactive-oxygen species and lipoxygenase products were determined. Mesangial cells were identified on the basis of morphologic (presence of microfilaments and pattern of staining by an anti-myosin antiserum) and physiologic (contractile activity in response to angiotensin II) characteristics. No contamination by esterase-positive cells was observed. Electron microscopy revealed that the phagocytic process started after 5 min of incubation, and affected approximately 50% of the cells. Superoxide anion (.O2-) and hydrogen peroxide (H2O2) generation by mesangial cells exposed to STZ increased with time and STZ concentration. Cells incubated with zymosan particles treated with heated serum produced undetectable amounts of .O2- and 6 times less H2O2 than cells exposed to STZ. Pretreatment by cytochalasin B produced a marked decrease in STZ-stimulated production of reactive oxygen species. [3H]Arachidonic acid was incorporated into mesangial cell phospholipids and its release and conversion into monohydroxyeicosatetraenoic acids (HETE) was measured by radiometric high performance liquid chromatography (HPLC). Incubation with STZ markedly stimulated the release of arachidonic acid from its phospholipid stores and its transformation into 11-, 12-, and 15-HETE. Lipoxygenase inhibitors inhibited STZ-stimulated H2O2 production, whereas they did not modify the phagocytic process as shown by the absence of any effect on the uptake of 125I-STZ by the mesangial cells. This study demonstrates that a high percentage of rat cultured mesangial cells phagocytose opsonized particles. The phagocytic process results in an oxidative burst that appears to be dependent on stimulation of the lipoxygenase pathway.
Assuntos
Mesângio Glomerular/metabolismo , Lipoxigenase/metabolismo , Oxigênio/metabolismo , Fagocitose , Animais , Ácidos Araquidônicos/metabolismo , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Citocalasina B/farmacologia , Mesângio Glomerular/fisiologia , Mesângio Glomerular/ultraestrutura , Peróxido de Hidrogênio/metabolismo , Compostos de Amônio Quaternário/metabolismo , Ratos , Ratos Endogâmicos , Superóxidos/metabolismo , Zimosan/imunologiaRESUMO
Protease-activated receptor (PAR)-1 is a cellular receptor for thrombin that is activated after proteolytic cleavage. The contribution of PAR-1 to inflammatory cell-mediated renal injury was assessed in murine crescentic glomerulonephritis (GN). A pivotal role for thrombin in this model was demonstrated by the capacity of hirudin, a selective thrombin antagonist, to attenuate renal injury. Compared with control treatment, hirudin significantly reduced glomerular crescent formation, T cell and macrophage infiltration, fibrin deposition, and elevated serum creatinine, which are prominent features of GN. PAR-1-deficient (PAR-1(-/-)) mice, which have normal coagulation, also showed significant protection from crescentic GN compared with wild-type mice. The reductions in crescent formation, inflammatory cell infiltration, and serum creatinine were similar in PAR-1(-/-) and hirudin-treated mice, but hirudin afforded significantly greater protection from fibrin deposition. Treatment of wild-type mice with a selective PAR-1-activating peptide (TRAP) augmented histological and functional indices of GN, but TRAP treatment did not alter the severity of GN in PAR(-/-) mice. These results indicate that activation of PAR-1 by thrombin or TRAP amplifies crescentic GN. Thus, in addition to its procoagulant role, thrombin has proinflammatory, PAR-1-dependent effects that augment inflammatory renal injury.
Assuntos
Glomerulonefrite/fisiopatologia , Glomérulos Renais/fisiopatologia , Receptores de Trombina/metabolismo , Trombina/farmacologia , Animais , Antitrombinas/farmacologia , Glomerulonefrite/etiologia , Glomerulonefrite/genética , Hirudinas/farmacologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Masculino , Camundongos , Tempo de Tromboplastina Parcial , Fragmentos de Peptídeos/farmacologia , Contagem de Plaquetas , Inibidores de Proteases/farmacologia , Receptor PAR-1 , Receptores de Trombina/agonistas , Receptores de Trombina/genética , Trombina/fisiologiaRESUMO
Definition of acute renal allograft rejection (AR) markers remains clinically relevant. Features of T-cell-mediated AR are tubulointerstitial and vascular inflammation associated with excessive extracellular matrix (ECM) remodeling, regulated by metzincins, including matrix metalloproteases (MMP). Our study focused on expression of metzincins (METS), and metzincins and related genes (MARGS) in renal allograft biopsies using four independent microarray data sets. Our own cases included normal histology (N, n = 20), borderline changes (BL, n = 4), AR (n = 10) and AR + IF/TA (n = 7). MARGS enriched in all data sets were further examined on mRNA and/or protein level in additional patients. METS and MARGS differentiated AR from BL, AR + IF/TA and N in a principal component analysis. Their expression changes correlated to Banff t- and i-scores. Two AR classifiers, based on METS (including MMP7, TIMP1), or on MARGS were established in our own and validated in the three additional data sets. Thirteen MARGS were significantly enriched in AR patients of all data sets comprising MMP7, -9, TIMP1, -2, thrombospondin2 (THBS2) and fibrillin1. RT-PCR using microdissected glomeruli/tubuli confirmed MMP7, -9 and THBS2 microarray results; immunohistochemistry showed augmentation of MMP2, -9 and TIMP1 in AR. TIMP1 and THBS2 were enriched in AR patient serum. Therefore, differentially expressed METS and MARGS especially TIMP1, MMP7/-9 represent potential molecular AR markers.
Assuntos
Transplante de Rim/patologia , Rim/patologia , Adulto , Biomarcadores , Matriz Extracelular/patologia , Feminino , Genes , Rejeição de Enxerto/metabolismo , Rejeição de Enxerto/patologia , Humanos , Imuno-Histoquímica , Masculino , Metaloproteinase 2 da Matriz , Metaloproteinase 7 da Matriz , Pessoa de Meia-Idade , RNA Mensageiro , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Kidney transplantation is now considered as a reasonable option for HIV-infected patients with end-stage renal disease. We describe here a retrospective study conducted in five transplantation centers in Paris. Twenty-seven patients were included. Immunosuppressive protocol associated an induction therapy and a long-term treatment combining mycophenolate mofetil, steroids and either tacrolimus or cyclosporine. All the patients had protocol biopsies at 3 months and 1 year. Patient's survival was 100% at 1 year and 98% at 2 years. Graft survival at 1 and 2 years is 98% and 96% at 1 and 2 years, respectively. The mean glomerular filteration rate values at 12 and 24 months were 60.6 mL/min/1.73 m² (range 23-98) and 65.4 mL/min/1.73 m² (range 24-110), respectively. Acute cellular rejection was diagnosed in four cases (15%). Because of high trough levels of calcineurin inhibitor, protease-inhibitor therapies were withdrawn in 11 cases. HIV disease progression was not observed. One patient developed B-cell lymphoma. In conclusion, our study confirms the safety of renal transplantation in HIV-infected patients with few adverse events and a low incidence of acute rejection.
Assuntos
Infecções por HIV/complicações , Falência Renal Crônica/cirurgia , Transplante de Rim , Adulto , Ciclosporina/administração & dosagem , Feminino , Rejeição de Enxerto/epidemiologia , Sobrevivência de Enxerto , Infecções por HIV/cirurgia , Humanos , Imunossupressores/administração & dosagem , Falência Renal Crônica/etiologia , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Paris/epidemiologia , Estudos Retrospectivos , Tacrolimo/administração & dosagemRESUMO
Chronic renal allograft injury is often reflected by interstitial fibrosis (IF) and tubular atrophy (TA) without evidence of specific etiology. In most instances, IF/TA remains an irreversible disorder, representing a major cause of long-term allograft loss. As members of the protease family metzincins and functionally related genes are involved in fibrotic and sclerotic processes of the extracellular matrix (ECM), we hypothesized their deregulation in IF/TA. Gene expression and protein level analyses using allograft biopsies with and without Banff'05 classified IF/TA illustrated their deregulation. Expression profiles of these genes differentiated IF/TA from Banff'05 classified Normal biopsies in three independent microarray studies and demonstrated histological progression of IF/TA I to III. Significant upregulation of matrix metalloprotease-7 (MMP-7) and thrombospondin-2 (THBS-2) in IF/TA biopsies and sera was revealed in two independent patient sets. Furthermore, elevated THBS-2, osteopontin (SPP1) and beta-catenin may play regulatory roles on MMP. Our findings further suggest that deregulated ECM remodeling and possibly epithelial to mesenchymal transition (EMT) are implicated in IF/TA of kidney transplants, and that metzincins and related genes play an important role in these processes. Profiling of these genes may be used to complement IF/TA diagnosis and to disclose IF/TA progression in kidney transplant recipients.
Assuntos
Regulação da Expressão Gênica/genética , Transplante de Rim , Adulto , Atrofia/genética , Feminino , Fibrose/genética , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Nefropatias/genética , Nefropatias/metabolismo , Nefropatias/fisiopatologia , Nefropatias/cirurgia , Transplante de Rim/classificação , Masculino , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 7 da Matriz/metabolismo , Pessoa de Meia-Idade , RNA Mensageiro/genética , Trombospondinas/genética , Transplante HomólogoRESUMO
Advanced glycation end products (AGEs) may play a role in the pathogenesis of diabetic nephropathy, by modulating extracellular matrix turnover. AGEs are known to activate specific membrane receptors, including the receptor for AGE (RAGE). In the present study, we analyzed the various receptors for AGEs expressed by human mesangial cells and we studied the effects of glycated albumin and of carboxymethyl lysine on matrix protein and remodelling enzyme synthesis. Membrane RAGE expression was confirmed by FACS analysis. Microarray methods, RT-PCR, and Northern blot analysis were used to detect and confirm specific gene induction. Zymographic analysis and ELISA were used to measure the induction of tPA and PAI-1. We show herein that cultured human mesangial cells express AGE receptor type 1, type 2 and type 3 and RAGE. AGEs (200 microg/ml) induced at least a 2-fold increase in mRNA for 10 genes involved in ECM remodelling, including tPA, PAI-1 and TIMP-3. The increase in tPA synthesis was confirmed by fibrin zymography. The stimulation of PAI-1 synthesis was confirmed by ELISA. AGEs increased PAI-1 mRNA through a signalling pathway involving reactive oxygen species, the MAP kinases ERK-1/ERK-2 and the nuclear transcription factor NF-kappaB, but not AP-1. Carboxymethyl lysine (CML, 5 microM), which is a RAGE ligand, also stimulated PAI-1 synthesis by mesangial cells. In addition, a blocking anti-RAGE antibody partially inhibited the AGE-stimulated gene expression and decreased the PAI-1 accumulation induced by AGEs and by CML. Inhibition of AGE receptors or neutralization of the protease inhibitors TIMP-3 and PAI-1 could represent an important new therapeutic strategy for diabetic nephropathy.
Assuntos
Proteínas da Matriz Extracelular/genética , Produtos Finais de Glicação Avançada/farmacologia , Metaloproteinase 2 da Matriz/genética , Células Mesangiais/efeitos dos fármacos , Anticorpos/farmacologia , Northern Blotting , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Proteínas da Matriz Extracelular/metabolismo , Flavonoides/farmacologia , Citometria de Fluxo , Expressão Gênica/efeitos dos fármacos , Humanos , Lisina/análogos & derivados , Lisina/farmacologia , Metaloproteinase 2 da Matriz/metabolismo , Células Mesangiais/citologia , Células Mesangiais/metabolismo , Norleucina/farmacologia , Análise de Sequência com Séries de Oligonucleotídeos , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Inibidor Tecidual de Metaloproteinase-3/genética , Inibidor Tecidual de Metaloproteinase-3/metabolismo , Ativador de Plasminogênio Tecidual/genética , Ativador de Plasminogênio Tecidual/metabolismo , alfa-Macroglobulinas/genética , alfa-Macroglobulinas/metabolismoRESUMO
Long-term survival of patients with chronic lymphocytic leukemia (CLL) is over 10 years, and such patients are thus potential kidney recipients in the case of superimposed end-stage renal disease. However, the renal and patient outcome in this condition is unknown. We report the charts of four patients with CLL who were engrafted in France with a deceased-donor kidney and underwent routine triple immunosuppressive therapy. The results show that these patients developed severe infectious episodes (fatal in one case) and tumoral complications including rapid progression of CLL in two cases. Moreover, the graft may be infiltrated and damaged by monoclonal B cells: one patient lost his graft 14 months after transplantation. Various therapeutic options (modifications of the immunosuppressive regimen, anti-CD20 antibodies, irradiation of the graft) showed little (if any) efficacy. Therefore, we believe that CLL is a too hazardous condition to envisage solid organ transplantation with a routine immunosuppressive regimen, and we propose a more appropriate approach.
Assuntos
Nefropatias/terapia , Falência Renal Crônica/terapia , Transplante de Rim/métodos , Leucemia Linfocítica Crônica de Células B/terapia , Idoso , Biópsia , Progressão da Doença , Feminino , Humanos , Imunofenotipagem , Terapia de Imunossupressão , Imunossupressores/uso terapêutico , Rim/patologia , Nefropatias/complicações , Leucemia Linfocítica Crônica de Células B/complicações , Masculino , Pessoa de Meia-IdadeRESUMO
Human immunodeficiency virus (HIV) infection is a risk factor for thrombotic microangiopathy (TMA). We sought whether a severe deficiency in ADAMTS13, the enzyme specifically involved in the cleavage of von Willebrand factor, was associated with specific presenting features and outcome in HIV-associated TMA. In this prospective, multicentre, case-control study, 29 patients of 236 in the French Network on TMA had an HIV-associated TMA. Seventeen patients with severe ADAMTS13 deficiency (ADAMTS13 <5% HIV(+) group) were compared to 12 patients with a detectable ADAMTS13 activity (ADAMTS13 >or=5% HIV(+) group). HIV(+) patients were also compared to 62 patients with idiopathic TMA, either with (45 patients, ADAMTS13 <5% idiopathic group) or without (17 patients, ADAMTS13 >or=5% idiopathic group) severe ADAMTS13 deficiency. ADAMTS13 <5% HIV(+) patients had less AIDS-related complications than ADAMTS13 >or=5% HIV(+) patients (23.5% versus 91.6%, respectively, P = 0.0005) and their median CD4(+) T cell count was higher (P = 0.05). TMA-associated death rate was higher in ADAMTS13 >or=5% HIV(+) patients than in ADAMTS13 <5% HIV(+) patients (50% versus 11.7%, respectively, P = 0.04). In ADAMTS13 <5% patients, TMA-associated death rate was comparable between HIV(+) and idiopathic patients (15.5% in idiopathic patients, P-value was non-significant). By contrast, TMA-associated death rate in ADAMTS13 >or=5% HIV(+) patients was higher than in idiopathic patients (11.7% in idiopathic patients, P = 0.04). In conclusion, HIV-associated TMA with severe ADAMTS13 deficiency have less AIDS-related complications and a higher CD4(+) T cell count. TMA prognosis is better and comparable to this of idiopathic forms.
Assuntos
Proteínas ADAM/fisiologia , Síndrome da Imunodeficiência Adquirida/complicações , HIV , Púrpura Trombocitopênica Trombótica/complicações , Púrpura Trombocitopênica Trombótica/fisiopatologia , Fator de von Willebrand/fisiologia , Proteína ADAMTS13 , Adulto , Contagem de Linfócito CD4 , Estudos de Casos e Controles , Morte , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Púrpura Trombocitopênica Trombótica/diagnósticoRESUMO
INTRODUCTION: McArdle's disease is an autosomal recessive glycogenosis caused by deficiency of muscle glycogen phosphorylase resulting in glycogen accumulation in the skeletal muscle. Typically, McArdle's disease is characterized by exercise intolerance with muscle cramps and myoglobinuria. CASE REPORT: We report a 20-year-old woman with massive rhabdomyolysis and acute renal failure revealing a McArdle's disease. DISCUSSION: Although muscle impairment is constant in McArdle's disease, massive rhabdomyolysis with severe acute renal failure has been rarely reported as a presenting feature. The mechanisms and therapeutic implications of renal injury are discussed.
Assuntos
Doença de Depósito de Glicogênio Tipo V/diagnóstico , Rabdomiólise/etiologia , Injúria Renal Aguda/etiologia , Adulto , Feminino , Taxa de Filtração Glomerular , Doença de Depósito de Glicogênio Tipo V/complicações , Doença de Depósito de Glicogênio Tipo V/fisiopatologia , HumanosRESUMO
Thrombotic microangiopathies (TMA) represent an eclectic group of conditions, which share hemolytic anemia and thrombocytopenia as a common defining basis. Remarkable breakthroughs in the physiopathological setting have allowed for a thorough recomposition of the disparate syndromes, which form the constellation of TMA. In this view, clinicians now discriminate thrombocytopenic thrombotic purpura (TTP) defined by a severe deficiency in ADAMTS13, which is rarely associated with a severe renal involvement and the hemolytic and uremic syndrome (HUS) in which renal impairment is the most prominent clinical feature. HUS can result from toxins stemming from bacterial infections of the digestive tract, alternate complement pathway abnormalities, metabolic or coagulation disorders or, lastly, drug and various toxic compounds. The diverse forms of HUS reflect the insights gained in the understanding of the pathophysiological mechanisms underpinning TMA. In this first part, a broad overview of the epidemiological, physiopathological and clinical aspects of HUS and related TMA syndromes is presented.
Assuntos
Síndrome Hemolítico-Urêmica , Microangiopatias Trombóticas , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Síndrome Hemolítico-Urêmica Atípica/complicações , Síndrome Hemolítico-Urêmica Atípica/epidemiologia , Síndrome Hemolítico-Urêmica/complicações , Síndrome Hemolítico-Urêmica/diagnóstico , Síndrome Hemolítico-Urêmica/epidemiologia , Humanos , Púrpura Trombocitopênica Trombótica/complicações , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/epidemiologia , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/epidemiologia , Microangiopatias Trombóticas/etiologiaRESUMO
Major achievements in the understanding of thrombotic microangiopathies (TMA) have not only resulted in a reclassification of TMA but most of all they have culminated in the design of new treatments and have enabled clinicians to better delineate their prognosis. Recent multicenter studies have improved our understanding of the prognosis of atypical hemolytic and uremic syndromes (aHUS). More specifically, they have highlighted the role of genetic testing on predicting the recurrence of aHUS, the risk of chronic kidney disease and the recurrence following kidney transplantation. A major advance consisted of the identification of the alternative complement pathway in the pathogenesis of aHUS, thus paving the way for the use of the C5a inhibitor eculizumab in this indication. Eculizumab has thereafter dramatically improved the management of patients affected with aHUS. During spring 2011, a great epidemic of entero-hemorrhagic Escherichia coli (EHEC) associated HUS occurred in Germany, providing clinicians the opportunity to examine the relevance of antibiotic prophylaxis, plasma exchange and eculizumab in EHEC-associated HUS. In this work, we herein present advances achieved in the setting of therapeutic management and prognosis in HUS and other related TMA syndromes.