RESUMEN
The aim of this study (CTOTC-09) was to assess the impact of "preformed" (at transplant) donor-specific anti-HLA antibody (DSA) and first year newly detected DSA (ndDSA) on allograft function at 3 years after pediatric heart transplantation (PHTx). We enrolled children listed at 9 North American centers. The primary end point was pulmonary capillary wedge pressure (PCWP) at 3 years posttransplant. Of 407 enrolled subjects, 370 achieved PHTx (mean age, 7.7 years; 57% male). Pre-PHTx sensitization status was nonsensitized (n = 163, 44%), sensitized/no DSA (n = 115, 31%), sensitized/DSA (n = 87, 24%), and insufficient DSA data (n = 5, 1%); 131 (35%) subjects developed ndDSA. Subjects with any DSA had comparable PCWP at 3 years to those with no DSA. There were also no significant differences overall between the 2 groups for other invasive hemodynamic measurements, systolic graft function by echocardiography, and serum brain natriuretic peptide concentration. However, in the multivariable analysis, persistent first-year DSA was a risk factor for 3-year abnormal graft function. Graft and patient survival did not differ between groups. In summary, overall, DSA status was not associated with worse allograft function or inferior patient and graft survival at 3 years, but persistent first-year DSA was a risk factor for late graft dysfunction.
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Trasplante de Corazón , Isoanticuerpos , Humanos , Niño , Masculino , Femenino , Antígenos HLA , Donantes de Tejidos , Trasplante de Corazón/efectos adversos , Trasplante Homólogo , Suero Antilinfocítico , Supervivencia de Injerto , Rechazo de Injerto , Estudios RetrospectivosRESUMEN
BACKGROUND: Long-term survival after lung transplantation (LTx) is limited by chronic lung allograft dysfunction (CLAD). METHODS: We report an analysis of cytokine profiles in bronchoalveolar lavage samples collected during a prospective multicenter non-interventional trial primarily designed to determine the impact of community-acquired respiratory viral infections (CARV) in outcomes after pediatric LTx. In this analysis, we identify potential biomarkers of auto-inflammation and auto-immunity associated with survival and risk of bronchiolitis obliterans (BOS) after LTx with cytokine analysis of bronchoalveolar lavage fluid (BALF) from 61 pediatric recipients. RESULTS: Higher IL-23 (p = .048) and IL-31 (p = .035) levels were associated with the risk of BOS, and lower levels of epithelial growth factor (EGF) (p = .041) and eotaxin (EOX) (p = .017) were associated with BOS. Analysis using conditional inference trees to evaluate cytokines at each visit associated with survival identified soluble CD30 (p < .001), pro-inflammatory cytokine IL-23 (p = .02), and sTNFRI (p = .01) below cutoff levels as associated with BOS-free survival. CONCLUSIONS: Our results indicate that post-LTx survival in children may be linked to activation of alternate pathways of the immune system that affect airway remodeling in addition to activation of "classical" pathways that have been described in adult LTx recipients. These may indicate pathways to target for intervention.
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Bronquiolitis Obliterante , Trasplante de Pulmón , Adulto , Bronquiolitis Obliterante/diagnóstico , Bronquiolitis Obliterante/etiología , Niño , Citocinas/metabolismo , Humanos , Inflamación , Interleucina-23 , Estudios ProspectivosRESUMEN
BACKGROUND: For young children with peanut allergy, dietary avoidance is the current standard of care. We aimed to assess whether peanut oral immunotherapy can induce desensitisation (an increased allergic reaction threshold while on therapy) or remission (a state of non-responsiveness after discontinuation of immunotherapy) in this population. METHODS: We did a randomised, double-blind, placebo-controlled study in five US academic medical centres. Eligible participants were children aged 12 to younger than 48 months who were reactive to 500 mg or less of peanut protein during a double-blind, placebo-controlled food challenge (DBPCFC). Participants were randomly assigned by use of a computer, in a 2:1 allocation ratio, to receive peanut oral immunotherapy or placebo for 134 weeks (2000 mg peanut protein per day) followed by 26 weeks of avoidance, with participants and study staff and investigators masked to group treatment assignment. The primary outcome was desensitisation at the end of treatment (week 134), and remission after avoidance (week 160), as the key secondary outcome, were assessed by DBPCFC to 5000 mg in the intention-to-treat population. Safety and immunological parameters were assessed in the same population. This trial is registered on ClinicalTrials.gov, NCT03345160. FINDINGS: Between Aug 13, 2013, and Oct 1, 2015, 146 children, with a median age of 39·3 months (IQR 30·8-44·7), were randomly assigned to receive peanut oral immunotherapy (96 participants) or placebo (50 participants). At week 134, 68 (71%, 95% CI 61-80) of 96 participants who received peanut oral immunotherapy compared with one (2%, 0·05-11) of 50 who received placebo met the primary outcome of desensitisation (risk difference [RD] 69%, 95% CI 59-79; p<0·0001). The median cumulative tolerated dose during the week 134 DBPCFC was 5005 mg (IQR 3755-5005) for peanut oral immunotherapy versus 5 mg (0-105) for placebo (p<0·0001). After avoidance, 20 (21%, 95% CI 13-30) of 96 participants receiving peanut oral immunotherapy compared with one (2%, 0·05-11) of 50 receiving placebo met remission criteria (RD 19%, 95% CI 10-28; p=0·0021). The median cumulative tolerated dose during the week 160 DBPCFC was 755 mg (IQR 0-2755) for peanut oral immunotherapy and 0 mg (0-55) for placebo (p<0·0001). A significant proportion of participants receiving peanut oral immunotherapy who passed the 5000 mg DBPCFC at week 134 could no longer tolerate 5000 mg at week 160 (p<0·001). The participant receiving placebo who was desensitised at week 134 also achieved remission at week 160. Compared with placebo, peanut oral immunotherapy decreased peanut-specific and Ara h2-specific IgE, skin prick test, and basophil activation, and increased peanut-specific and Ara h2-specific IgG4 at weeks 134 and 160. By use of multivariable regression analysis of participants receiving peanut oral immunotherapy, younger age and lower baseline peanut-specific IgE was predictive of remission. Most participants (98% with peanut oral immunotherapy vs 80% with placebo) had at least one oral immunotherapy dosing reaction, predominantly mild to moderate and occurring more frequently in participants receiving peanut oral immunotherapy. 35 oral immunotherapy dosing events with moderate symptoms were treated with epinephrine in 21 participants receiving peanut oral immunotherapy. INTERPRETATION: In children with a peanut allergy, initiation of peanut oral immunotherapy before age 4 years was associated with an increase in both desensitisation and remission. Development of remission correlated with immunological biomarkers. The outcomes suggest a window of opportunity at a young age for intervention to induce remission of peanut allergy. FUNDING: National Institute of Allergy and Infectious Disease, Immune Tolerance Network.
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Alérgenos/administración & dosificación , Arachis/inmunología , Desensibilización Inmunológica , Hipersensibilidad al Cacahuete/prevención & control , Administración Oral , Alérgenos/inmunología , Niño , Preescolar , Método Doble Ciego , Femenino , Humanos , Tolerancia Inmunológica , Masculino , Hipersensibilidad al Cacahuete/inmunología , Resultado del TratamientoRESUMEN
We conducted a randomized, placebo-controlled, double-blind study of pediatric lung transplant recipients, hypothesizing that rituximab plus rabbit anti-thymocyte globulin induction would reduce de novo donor-specific human leukocyte antigen antibodies (DSA) development and improve outcomes. We serially obtained clinical data, blood, and respiratory samples for at least one year posttransplant. We analyzed peripheral blood lymphocytes by flow cytometry, serum for antibody development, and respiratory samples for viral infections using multiplex PCR. Of 45 subjects enrolled, 34 were transplanted and 27 randomized to rituximab (n = 15) or placebo (n = 12). No rituximab-treated subjects versus five placebo-treated subjects developed de novo DSA with mean fluorescence intensity >2000. There was no difference between treatment groups in time to the primary composite outcome endpoint (death, bronchiolitis obliterans syndrome [BOS] grade 0-p, obliterative bronchiolitis or listing for retransplant). A post-hoc analysis substituting more stringent chronic lung allograft dysfunction criteria for BOS 0-p showed no difference in outcome (p = .118). The incidence of adverse events including infection and rejection episodes was no different between treatment groups. Although the study was underpowered, we conclude that rituximab induction may have prevented early DSA development in pediatric lung transplant recipients without adverse effects and may improve outcomes (Clinical Trials: NCT02266888).
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Bronquiolitis Obliterante , Trasplante de Pulmón , Bronquiolitis Obliterante/tratamiento farmacológico , Bronquiolitis Obliterante/etiología , Niño , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/etiología , Rechazo de Injerto/prevención & control , Humanos , Pulmón , Trasplante de Pulmón/efectos adversos , Rituximab , Receptores de TrasplantesRESUMEN
Remote interventions are increasingly used in transplant medicine but have rarely been rigorously evaluated. We investigated a remote intervention targeting immunosuppressant management in pediatric lung transplant recipients. Patients were recruited from a larger multisite trial if they had a Medication Level Variability Index (MLVI) ≥2.0, indicating worrisome tacrolimus level fluctuation. The manualized intervention included three weekly phone calls and regular follow-up calls. A comparison group included patients who met enrollment criteria after the subprotocol ended. Outcomes were defined before the intent-to-treat analysis. Feasibility was defined as ≥50% of participants completing the weekly calls. MLVI was compared pre- and 180 days postenrollment and between intervention and comparison groups. Of 18 eligible patients, 15 enrolled. Seven additional patients served as the comparison. Seventy-five percent of participants completed ≥3 weekly calls; average time on protocol was 257.7 days. Average intervention group MLVI was significantly lower (indicating improved blood level stability) at 180 days postenrollment (2.9 ± 1.29) compared with pre-enrollment (4.6 ± 2.10), p = .02. At 180 days, MLVI decreased by 1.6 points in the intervention group but increased by 0.6 in the comparison group (p = .054). Participants successfully engaged in a long-term remote intervention, and their medication blood levels stabilized. NCT02266888.
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Trasplante de Hígado , Trasplante de Órganos , Niño , Humanos , Inmunosupresores/uso terapéutico , Tacrolimus , Receptores de TrasplantesRESUMEN
Based on reports in adult lung transplant recipients, we hypothesized that community-acquired respiratory viral infections (CARVs) would be a risk factor for poor outcome after pediatric lung transplant. We followed 61 pediatric lung transplant recipients for 2+ years or until they met a composite primary endpoint including bronchiolitis obliterans syndrome/obliterative bronchiolitis, retransplant, or death. Blood, bronchoalveolar lavage, and nasopharyngeal specimens were obtained with standard of care visits. Nasopharyngeal specimens were obtained from recipients with respiratory viral symptoms. Respiratory specimens were interrogated for respiratory viruses by using multiplex polymerase chain reaction. Donor-specific HLA antibodies, self-antigens, and ELISPOT reactivity were also evaluated. Survival was 84% (1 year) and 68% (3 years). Bronchiolitis obliterans syndrome incidence was 20% (1 year) and 38% (3 years). The primary endpoint was met in 46% of patients. CARV was detected in 156 patient visits (74% enterovirus/rhinovirus). We did not find a relationship between CARV recovery from respiratory specimens and the primary endpoint (hazard ratio 0.64 [95% confidence interval: 0.25-1.59], P = .335) or between CARV and the development of alloimmune or autoimmune humoral or cellular responses. These findings raise the possibility that the immunologic impact of CARV following pediatric lung transplant is different than that observed in adults.
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Bronquiolitis Obliterante/cirugía , Infecciones Comunitarias Adquiridas/virología , Rechazo de Injerto/virología , Supervivencia de Injerto/inmunología , Trasplante de Pulmón/efectos adversos , Infecciones del Sistema Respiratorio/virología , Virosis/virología , Adolescente , Niño , Preescolar , Infecciones Comunitarias Adquiridas/epidemiología , Infecciones Comunitarias Adquiridas/inmunología , Femenino , Estudios de Seguimiento , Rechazo de Injerto/epidemiología , Rechazo de Injerto/inmunología , Humanos , Incidencia , Lactante , Estudios Longitudinales , Masculino , Pronóstico , Estudios Prospectivos , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/inmunología , Factores de Riesgo , Receptores de Trasplantes , Virosis/epidemiología , Virosis/inmunología , Virus/aislamiento & purificaciónRESUMEN
BACKGROUND AND OBJECTIVES: Endemic renal insufficiency (RI) of unknown etiology is a major public health issue with high mortality in the Pacific coastal regions of Central America. We studied RI in León and Chinandega, Nicaragua, evaluating associations with known risk factors and hypothesized exposures. METHODS: A cross-sectional survey was conducted with assessment of medical, social, and occupational history and exposures in conjunction with measurement of serum creatinine. Cases were defined by an estimated glomerular filtration rate (eGFR)
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Enfermedades de los Trabajadores Agrícolas/epidemiología , Consumo de Bebidas Alcohólicas/epidemiología , Insuficiencia Renal/epidemiología , Adulto , Enfermedades de los Trabajadores Agrícolas/etiología , Consumo de Bebidas Alcohólicas/efectos adversos , Estudios de Casos y Controles , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nicaragua , Insuficiencia Renal/etiologíaRESUMEN
BACKGROUND: Anemia is common in chronic kidney disease (CKD), and suboptimal management of anemia can lead to serious health complications and poor quality of life (QOL). OBJECTIVES: (1) To describe health-related and overall QOL among patients entering a clinic focused on anemia management; (2) to compare their baseline QOL with other relevant populations; (3) to explore predictors of QOL before anemia management; and (4) to explore changes in QOL over 1 year for patients managed in the clinic. METHODS: The Kidney Disease Quality of Life questionnaire-short form (KDQOL-SF, Rand Corporation, Santa Monica, CA) was used to measure kidney disease specific and overall QOL in a cohort of predialysis CKD patients (n=79) enrolled in the clinic from January 2003 to September 2004. Baseline measures were compared to previously published measurements. The influence of demographic and clinical characteristics on baseline QOL was explored. Changes in QOL were evaluated over time. RESULTS: Patients with CKD entering the clinic had lower overall QOL compared with estimates from the general U.S. population (physical composite 35.7 vs 48.4 and mental composite 46.0 vs 50.2, respectively). Clinic patients had better kidney disease-specific scores than patients with end-stage kidney disease (ESRD). General QOL scores were similar regardless of kidney disease severity, with the exception of physical functioning which was lowest for patients with end-stage disease. Hemoglobin was the only factor predictive of QOL. Over time, QOL improved among patients managed in the CKD clinic, with statistically significant improvements in sleep (change of 6.2+/-15.2; P<.05) and social function (change of 11.6+/-27.7; P<.05). CONCLUSIONS: Patients with anemia of CKD reported reduced QOL compared to populations without kidney disease, but better QOL compared to populations with ESRD on dialysis. QOL generally improved among patients managed in the multidisciplinary anemia clinic.
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Anemia/tratamiento farmacológico , Enfermedades Renales/complicaciones , Calidad de Vida , Adulto , Anciano , Anemia/etiología , Enfermedad Crónica , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Hematínicos/uso terapéutico , Hemoglobinas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Sueño , Conducta Social , Encuestas y CuestionariosRESUMEN
OBJECTIVE: Predictors of treatment resistance and relapse have been identified in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in the Glomerular Disease Collaborative Network (GDCN) in the southeastern US. This study was undertaken to evaluate the applicability of those predictors in an independent cohort followed up by the French Vasculitis Study Group. METHODS: Predictors of treatment resistance were evaluated using logistic regression models and reported as odds ratios (ORs) with 95% confidence intervals (95% CIs). Predictors of relapse were evaluated using Cox proportional hazards models and reported as hazard ratios (HRs) with 95% CIs. Models were controlled for age, sex, race, baseline serum creatinine level, and cyclophosphamide therapy. RESULTS: The French cohort (n = 434) and the GDCN cohort (n = 350) had similar median followup periods (44 months versus 45 months) and initial percentages of patients taking cyclophosphamide (82% versus 78%). The French cohort included more patients with proteinase 3 (PR3) ANCA (58% versus 40%), lung involvement (58% versus 49%), and upper respiratory tract involvement (62% versus 31%). Of the predictors of treatment resistance in the GDCN cohort (female sex, African American race, presence of myeloperoxidase ANCA, elevated creatinine level, and age), only age predicted treatment resistance in the French cohort (OR 1.32 per 10 years [95% CI 1.05-1.66]). Predictors of relapse in the GDCN cohort were PR3 ANCA (HR 1.77 [95% CI 1.11-2.82]), lung involvement (HR 1.68 [95% CI 1.10-2.57), and upper respiratory tract involvement (HR 1.58 [95% CI 1.00-2.48]), while predictors in the French cohort were PR3 ANCA (HR 1.66 [95% CI 1.15-2.39]) and lung involvement (HR 1.56 [95% CI 1.11-2.20]), but not upper respiratory tract involvement (HR 0.96 [95% CI 0.67-1.38]). CONCLUSION: Our findings indicate that older age is a predictor of treatment resistance, and that PR3 ANCA and lung involvement are predictors of relapse in both cohorts. Discrepancies in predictors of treatment tract resistance may reflect differences in access to care, and differences in predictors of relapse may reflect variations in disease expression.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Distribución de Chi-Cuadrado , Estudios de Cohortes , Ciclofosfamida/uso terapéutico , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Selección de Paciente , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Recurrencia , Análisis de Regresión , Factores de Riesgo , Factores Sexuales , Insuficiencia del Tratamiento , Resultado del Tratamiento , Estados UnidosRESUMEN
Patients with inflammatory vascular disease caused by anti-neutrophil cytoplasmic autoantibodies (ANCA) can harbor antibodies not only to the autoantigen proteinase 3 (PR3) but also to complementary PR3 (cPR3(105-201)), a recombinant protein translated from the antisense strand of PR3 cDNA. The purpose of this study was to identify potential endogenous targets of anti-cPR3(105-201) antibodies. Patients' plasmapheresis material was tested for the presence of antigens reactive with affinity-purified rabbit and chicken anti-cPR3(105-201) polyclonal antibodies. Antigen-containing fractions were tested with patients' anti-cPR3(105-201) affinity-purified IgG, and putative protein targets were sequenced by mass spectrometry. Unexpectedly, plasminogen was identified as a target of anti-cPR3(105-201). Reactivity of affinity-purified antibodies from two patients was lost when plasminogen was converted to plasmin, indicating restricted specificity. Antiplasminogen antibodies from five patients bound plasminogen at a surface-exposed loop structure within the protease domain. This loop contains an amino acid motif that is also found in a portion of recombinant cPR3(105-201); site-directed mutagenesis of this sequence decreased antibody reactivity by 30%. Functionally, antiplasminogen antibodies delayed the conversion of plasminogen to plasmin and increased the dissolution time of fibrin clots. Serologically, antiplasminogen antibody levels were higher in PR3-ANCA patients (n = 72) than healthy control subjects (n = 63), myeloperoxidase-ANCA patients (n = 34), and patients with idiopathic thrombosis (n = 57; P = 0.001). Of the patients with PR3-ANCA, nine had documented deep venous thrombosis events, five of whom were positive for antiplasminogen antibodies. In summary, capitalizing on interactions with complementary proteins, specifically complementary PR3, this study identified plasminogen as a previously undescribed autoantigen in PR3-ANCA vasculitis.
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Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Mieloblastina/inmunología , Plasminógeno/inmunología , Vasculitis/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos/inmunología , Femenino , Humanos , Inmunoglobulina G/química , Inflamación , Masculino , Persona de Mediana EdadRESUMEN
Some patients with proteinase 3 specific anti-neutrophil cytoplasmic autoantibodies (PR3-ANCA) also have antibodies that react to complementary-PR3 (cPR3), a protein encoded by the antisense RNA of the PR3 gene. To study whether patients with anti-cPR3 antibodies have cPR3-responsive memory T cells we selected conditions that allowed cultivation of memory cells but not naïve cells. About half of the patients were found to have CD4+TH1 memory cells responsive to the cPR3(138-169)-peptide; while only a third of the patients had HI-PR3 protein responsive T cells. A significant number of T cells from patients responded to cPR3(138-169) peptide and to HI-PR3 protein by proliferation and/or secretion of IFN-gamma, compared to healthy controls while there was no response to scrambled peptide. Cells responsive to cPR3(138-169)-peptide were not detected in MPO-ANCA patients suggesting that this response is specific. The HLADRB1(*) 15 allele was significantly overrepresented in our patient group and is predicted to bind cPR3(138-169) peptide with high affinity. Regression analysis showed a significant likelihood that anti-cPR3 antibodies and cPR3-specific T cells coexist in individuals, consistent with an immunological history of encounter with a PR3-complementary protein. We suggest that the presence of cells reacting to potential complementary protein pairs might provide an alternative mechanism for auto-immune diseases.
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Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Mieloblastina/inmunología , Fragmentos de Péptidos/inmunología , Linfocitos T/inmunología , Adulto , Anciano , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/inmunología , Estudios de Casos y Controles , Femenino , Antígenos HLA-DR/análisis , Antígenos HLA-DR/metabolismo , Cadenas HLA-DRB1 , Humanos , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Células TH1/inmunología , Adulto JovenRESUMEN
Anti-neutrophil cytoplasmic autoantibodies directed toward myeloperoxidase or proteinase 3 are detected in sera of patients with small vessel vasculitis and participate in the pathogenesis of this disease. Autoantibodies develop when self-reactive B cells escape the regulation that ensures self-tolerance. In this study, regulation of anti-myeloperoxidase B cells was examined in mice that express an anti-myeloperoxidase Vkappa1C-Jkappa5 light-chain transgene, which confers anti-myeloperoxidase specificity when combined with a variety of heavy chains. Vkappa1C-Jkappa5 transgenic mice have splenic anti-myeloperoxidase B cells but do not produce circulating anti-myeloperoxidase antibodies. Two groups of transgenic mice that differed by their relative dosage of the transgene were compared; high-copy mice had a mean relative transgene dosage of 1.92 compared with 1.02 in the low-copy mice. These mice exhibited a 90 and 60% decrease in mature follicular B cells, respectively. High-copy mice were characterized by a large population of anti-myeloperoxidase B cells, a preponderance of B-1 cells, and an increased percentage of apoptotic myeloperoxidase-binding B cells. Low-copy mice had similar changes in B cell phenotype with the exception of an expanded marginal zone population. B cells from low-copy mice but not high-copy mice produced anti-myeloperoxidase antibodies after stimulation with lipopolysaccharide. These results indicate that tolerance to myeloperoxidase is maintained by central and peripheral deletion and that some myeloperoxidase-binding B cells are positively selected into the marginal zone and B-1 B cell subsets. A defect in these regulatory pathways could result in autoimmune disease.
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Linfocitos B/inmunología , Tolerancia Inmunológica , Cadenas kappa de Inmunoglobulina/metabolismo , Peroxidasa/inmunología , Animales , Anticuerpos/metabolismo , Apoptosis , Enfermedades Autoinmunes/metabolismo , Linfocitos B/metabolismo , Células de la Médula Ósea/citología , Recuento de Células , Cadenas kappa de Inmunoglobulina/genética , Ratones , Ratones Transgénicos , Bazo/citologíaRESUMEN
BACKGROUND: Dialysis patients have many underlying traditional and nontraditional risk factors that may predispose them to a high prevalence of cardiovascular disease. The effects of statins (eg, atorvastatin) on altering nontraditional lipoprotein measures in dialysis patients have not been extensively investigated. OBJECTIVE: To evaluate the efficacy of atorvastatin compared with a control group in inducing changes in lipoprotein(a) [Lp(a)], apolipoprotein (Apo) A-1, Apo-B, and fibrinogen levels, as well as the conventional lipoprotein profile, in hemodialysis patients over 36 weeks; secondary objectives were to assess changes in C-reactive protein, albumin, and safety measures. METHODS: Forty-five hemodialysis patients with low-density lipoprotein cholesterol (LDL-C) levels greater than 100 mg/dL were randomized to parallel groups: atorvastatin (n = 19) or no treatment (n = 26). The atorvastatin dose was titrated from 10 mg to achieve an LDL-C goal of 100 mg/dL or less and therapy was continued for 36 weeks. Biochemical and lipoprotein laboratory tests for efficacy outcomes were obtained at baseline, 12 weeks, and 36 weeks. RESULTS: The atorvastatin group exhibited clinically significant reductions (mean +/- SD) compared with controls in total cholesterol (-21.7 +/- 41.7 vs -3.2 +/- 40.0 mg/dL, respectively; p = 0.017) and LDL-C (-13.1 +/- 32.0 vs -1.1 +/- 38.4 mg/dL, respectively; p = 0.058) levels, as well as Lp(a) (-10.6 +/- 27 vs 3.5 +/- 17.8 mg/dL, respectively; p = 0.046). Statistical analyses included analysis of variance on ranked measures for multivariable modeling and paired t-test to determine changes in efficacy measures between baseline and 36 weeks within groups. CONCLUSIONS: Atorvastatin was safe and effective in reducing Lp(a), total cholesterol, and LDL-C levels. Given the prevalence of atherosclerosis in hemodialysis patients, therapy aimed at reducing traditional and nontraditional risk factors may be beneficial.
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Anticolesterolemiantes/farmacología , Ácidos Heptanoicos/farmacología , Hipercolesterolemia/tratamiento farmacológico , Lipoproteínas/efectos de los fármacos , Pirroles/farmacología , Diálisis Renal , Anciano , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/efectos adversos , Apolipoproteína A-I/efectos de los fármacos , Apolipoproteínas B/efectos de los fármacos , Atorvastatina , Proteína C-Reactiva/efectos de los fármacos , Proteína C-Reactiva/metabolismo , Colesterol/sangre , LDL-Colesterol/sangre , LDL-Colesterol/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Fibrinógeno/efectos de los fármacos , Ácidos Heptanoicos/administración & dosificación , Ácidos Heptanoicos/efectos adversos , Humanos , Lipoproteína(a)/efectos de los fármacos , Lipoproteínas/sangre , Masculino , Persona de Mediana Edad , Pirroles/administración & dosificación , Pirroles/efectos adversos , Albúmina Sérica/efectos de los fármacosRESUMEN
BACKGROUND AND OBJECTIVES: Obesity has been associated with kidney disease in adults. This study was designed to evaluate the association of obesity with an early marker of kidney disease, albuminuria, among young adults. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Urinalysis (n = 9371), albumin-to-creatinine ratio (n = 4463), and body mass index (kg/m2) were measured in the Add Health Wave III cohort (2001 to 2002), a multiethnic sample of young adults followed for approximately 6 yr. Multivariate logistic regression modeled the association of sex-specific albuminuria with body mass index, adjusted for sample weights, sex, race, ethnicity, and glycosuria. RESULTS: Urinalysis revealed that 0.8% had proteinuria, 4.6% had hematuria, 0.2% had combined hematuria and proteinuria, and 1.5% had glycosuria. Albuminuria prevalence was 4.4%. Mean body mass index was higher among those with albuminuria compared with those without. There were no associations between body mass index categories of 25 to < 30 or 30 to < 35 kg/m2 with albuminuria compared with the lowest body mass index (< 25 kg/m2); however, the highest category (> or = 35 kg/m2) was associated with albuminuria, compared with the lowest category (OR = 1.76, 95% CI: 1.02 to 3.04). Glycosuria (OR = 4.0; 95% CI: 1.5 to 11.1, p < 0.01) as well as increasing body mass index during the 6-yr follow-up (OR: 1.07 per unit change in kg/m2; 95% CI: 1.00 to 1.13, p = 0.04) were also associated with albuminuria. CONCLUSIONS: Given the increasing prevalence of obesity, the association of albuminuria associated with obesity in young adults is particularly concerning. Obesity may be a target for primary prevention of kidney and cardiovascular disease.
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Albuminuria/epidemiología , Obesidad/orina , Adolescente , Adulto , Índice de Masa Corporal , Niño , Enfermedad Crónica , Creatinina/orina , Femenino , Glucosuria/epidemiología , Hematuria/epidemiología , Humanos , Enfermedades Renales/etiología , Masculino , Obesidad/complicaciones , Obesidad/epidemiología , Obesidad/etnología , Proteinuria/epidemiología , Factores Sexuales , Estados Unidos/epidemiologíaRESUMEN
Anti-neutrophil cytoplasmic autoantibodies (ANCA) are associated with a category of small-vessel vasculitis (SVV) with frequent glomerulonephritis. The goal of this study was to evaluate the association of lifetime silica exposure with development of ANCA-SVV, with particular attention to exposure dosage, intensity, and time since last exposure. A southeastern United States, population-based, case-control study was conducted. Case patients had ANCA-SVV with pauci-immune crescentic glomerulonephritis. Population-based control subjects were frequency-matched to case patients by age, gender, and state. Jobs were assessed in a telephone interview. Silica exposure scores incorporated exposure duration, intensity, and probability for each job and then were categorized as none, low/medium, or high lifetime exposure. Logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Silica exposure was found in 78 (60%) of 129 case patients and in 49 (45%) of 109 control subjects. There was no increased risk for disease from low/medium exposure relative to no exposure (OR 1.0; 95% CI 0.4 to 2.2) but increased risk with high exposure (OR 1.9; 95% CI 1.0 to 3.5; P = 0.05). Crop harvesting was associated with elevated risk (OR 2.5; 95% CI 1.1 to 5.4; P = 0.03). However, both agricultural and traditional occupational sources contributed to the cumulative silica exposure scores; therefore, the overall effect could not be attributed to agricultural exposures alone. There was no evidence of decreasing by duration of time since last exposure. High lifetime silica exposure was associated with ANCA-SVV. Exposure to silica from specific farming tasks related to harvesting may be of particular importance in the southeastern United States. Interval of time since last exposure did not influence development of ANCA-SVV.
Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Enfermedades Profesionales/inmunología , Exposición Profesional/efectos adversos , Dióxido de Silicio/efectos adversos , Vasculitis/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Case reports have described the onset of antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis (ANCA SVV) with use of anti-thyroid agents, but an association with thyroid disease in general has not been described. This association was evaluated in a southeastern US population-based case-control study. METHODS: Cases (n = 158) had ANCA SVV with biopsy-proven glomerular involvement. Controls (n = 99) were frequency matched by age, gender and state. Use of drugs and comorbidities prior to diagnosis of ANCA SVV were assessed by telephone interview. Information on medications used for thyroid conditions was available in a subset of cases (n = 129). Logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Estimates among females were also of interest. RESULTS: History of thyroid disease was reported in 31 cases (20%) and 7 controls (7%) (OR = 3.7; 95% CI 1.5-9.2; P = 0.005); among females 25/65 (38%) cases and 5/53 (9%) controls (OR = 5.6; 95% CI 1.9-16.8; P = 0.002). Use of anti-thyroid agents was reported in 2 cases and 0 controls (OR not calculable). Among cases, myeloperoxidase (MPO)-ANCA was more common (86%) than proteinase 3 (PR3)-ANCA in those with a history of thyroid disease than those without (53%) (P = 0.007). CONCLUSIONS: Thyroid disease was associated with ANCA SVV, especially among women, and was most frequently associated with MPO-ANCA. The specific diagnosis and detailed clinical history of thyroid disease were not known; a limitation of the study. Use of anti-thyroid agents was uncommon. The association of thyroid disease with ANCA SVV may reflect a propensity for autoimmune disease.
Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos , Enfermedades Autoinmunes/complicaciones , Enfermedades de la Tiroides/complicaciones , Enfermedades de la Tiroides/tratamiento farmacológico , Vasculitis/complicaciones , Vasculitis/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: To describe the clinic design, clinical evaluations, and treatment approaches used in a multidisciplinary clinic for management of anemia of chronic kidney disease (CKD), and to evaluate several selected clinical outcomes associated with this approach to anemia management. SETTING: University-affiliated, division of nephrology, outpatient multidisciplinary model CKD clinic headed by a clinical pharmacist. PATIENTS: One hundred sixty-six patients with anemia of CKD who were referred by nephrologists and primary care providers to the multidisciplinary clinic from March 1, 2002-July 31, 2004. MEASUREMENTS AND MAIN RESULTS: Patients received darbepoetin alfa dosed on an every-other-week basis. If patients were already receiving once-weekly recombinant human erythropoietin (r-HuEPO), the darbepoetin alfa dose was calculated by using the darbepoetin alfa package insert conversion table. If patients were naïve to previous erythropoietic therapy, the darbepoetin alfa dose was either 60 microg or 0.7 microg/kg. The dose and frequency of darbepoetin alfa and oral iron supplements were adjusted to achieve the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) targets for hemoglobin levels and iron measures. The primary outcome analyzed was the proportion of patients with at least 30 days of treatment who achieved a target hemoglobin level of 11.0 g/dl or greater. Of 128 patients who received at least 30 days of treatment, 100 (78%) attained the hemoglobin level (mean +/- SD 11.7 +/- 7 g/dl). Ninety-nine of 128 patients were originally naïve to erythropoietic therapy; 77 (78%) of these 99 patients achieved the hemoglobin target in a mean +/- SD of 7.9 +/- 7.5 weeks. These data contrast with the data of 29 patients seen in the year previous to the reengineered clinic process, whereby only 12 (41%) of these comparable patients reached hemoglobin target with r-HuEPO therapy. Of the 77 previously erythropoietic-naïve patients, 82% were receiving darbepoetin alfa every other week, 14% every 3 weeks, and 4% every 4 weeks at the time the hemoglobin target was achieved. Oral iron administration significantly increased the chance of achieving the K/DOQI targets for hemoglobin and iron. CONCLUSION: Redefining roles and practices of members of a clinical practice and reengineering processes for anemia management were effective in achieving and maintaining target hemoglobin and iron levels.
Asunto(s)
Atención Ambulatoria/organización & administración , Anemia/tratamiento farmacológico , Fallo Renal Crónico/complicaciones , Grupo de Atención al Paciente/organización & administración , Garantía de la Calidad de Atención de Salud/organización & administración , Anciano , Atención Ambulatoria/métodos , Anemia/etiología , Darbepoetina alfa , Eritropoyetina/administración & dosificación , Eritropoyetina/análogos & derivados , Eritropoyetina/uso terapéutico , Femenino , Compuestos Ferrosos/uso terapéutico , Hematínicos/administración & dosificación , Hematínicos/uso terapéutico , Hemoglobinas/efectos de los fármacos , Humanos , Hierro/uso terapéutico , Masculino , Persona de Mediana Edad , Farmacéuticos , Polisacáridos/uso terapéutico , Rol Profesional , Desarrollo de ProgramaRESUMEN
Focal segmental glomerulosclerosis (FSGS) is the leading cause of steroid-resistant nephrotic syndrome in childhood and the most common form of end stage renal disease (ESRD) from glomerular disease. In order to assess the risk of progression of children with primary FSGS and the impact of proteinuria remission status on disease progression, we undertook this study to describe a cohort of 60 children and adolescents from the Glomerular Disease Collaborative Network. Of the 60 patients included in the cohort, 58% were African American. Median age was 16 years. Proteinuria ranged from 1.0-24.0 g/day/1.73 m(2); 57% were hypertensive, and the median estimated glomerular filtration rate (eGFR) was 90.2 ml/min/1.73 m(2). Complete remission was achieved in 20%, partial remission in 33%, and 47% have not achieved remission during follow-up with all prescribed therapy. Only ACE-I/ARB therapy was predictive of proteinuria remission in multivariate analysis (hazard ratio [HR] 3.35; 95% confidence interval [CI] 1.42-7.92). Renal survival was much improved in patients with complete or partial remission compared with no remission in univariate analysis. In multivariate analysis comparing no remission status, complete remission was associated with a 90% decreased risk of ESRD (HR 0.10, 95% CI 0.01-0.79, p =0.03). In summary, proteinuria remission status is a valid predictor of long-term renal survival in children with FSGS.
Asunto(s)
Glomeruloesclerosis Focal y Segmentaria/complicaciones , Fallo Renal Crónico/etiología , Adolescente , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Niño , Estudios de Cohortes , Progresión de la Enfermedad , Tasa de Filtración Glomerular , Glomeruloesclerosis Focal y Segmentaria/tratamiento farmacológico , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/fisiopatología , Humanos , Fallo Renal Crónico/fisiopatología , Fallo Renal Crónico/terapia , Síndrome Nefrótico/etiología , Pronóstico , Proteinuria/etiología , Inducción de Remisión , Factores de RiesgoRESUMEN
BACKGROUND: Predictors of treatment resistance and relapse have not been well described in antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis. OBJECTIVE: To identify clinical, pathologic, and serologic predictors of treatment resistance and relapse in a community-based cohort of patients with ANCA-associated vasculitis. DESIGN: Cohort of patients identified at or near the time of biopsy diagnosis and followed as clinically indicated. SETTING: The Glomerular Disease Collaborative Network. PATIENTS: 350 patients who received a new diagnosis of ANCA-associated vasculitis between 1985 and 2003 and were followed for a median of 49 months. MEASUREMENTS: Patients were categorized according to whether they had antiproteinase-3 (anti-PR3) antibodies or antimyeloperoxidase (anti-MPO) antibodies. Organ involvement was determined by biopsy or by well-defined clinical criteria. Treatment resistance was defined as progressive decline in kidney function with active urine sediment or the persistence or appearance of extrarenal manifestations. Relapse was defined as the time to the resurgence of vasculitic symptoms. RESULTS: Treatment resistance affected 23% of 334 treated patients and was associated with female sex, black ethnicity, and presentation with severe kidney disease (odds ratio per serum creatinine elevation of 100 micromol/L [1.13 mg/dL], 1.28 [95% CI, 1.16 to 1.39]). The following factors were associated with relapse in 258 (77%) patients who attained remission: seropositivity for anti-PR3 antibodies (hazard ratio, 1.87 [CI, 1.11 to 3.14]) and disease of the lung (hazard ratio, 1.71 [CI, 1.04 to 2.81]) or upper respiratory tract (hazard ratio, 1.73 [CI, 1.04 to 2.88]). Relapses occurred in 26% of patients with no risk factors versus 73% of patients with all 3 risk factors (hazard ratio, 3.7 [CI, 1.4 to 9.7]). Among 143 patients attaining remission who subsequently stopped all immunosuppressant therapy, relapse rates were similar for those who had received cyclophosphamide therapy for 6 months or less (34%) compared with those treated for a longer duration (35%), even after adjusting for risk factors for relapse (hazard ratio, 1.41 [CI, 0.80 to 2.50]). LIMITATIONS: The cohort mostly included patients with biopsy-proven kidney disease. Patients were not followed with uniform treatment protocols, and only limited information about their clinical course before diagnosis was available. CONCLUSIONS: Female or black patients, or those with severe kidney disease, may be resistant to initial treatment more often than other patients with ANCA-associated small-vessel vasculitis. Increased risk for relapse appears to be related to the presence of lung or upper airway disease and anti-PR3 antibody seropositivity.
Asunto(s)
Corticoesteroides/uso terapéutico , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Ciclofosfamida/uso terapéutico , Inmunosupresores/uso terapéutico , Vasculitis/tratamiento farmacológico , Vasculitis/inmunología , Adulto , Anciano , Biopsia , Progresión de la Enfermedad , Femenino , Humanos , Fallo Renal Crónico/etiología , Fallo Renal Crónico/patología , Fallo Renal Crónico/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Recurrencia , Factores de Riesgo , Factores de Tiempo , Insuficiencia del Tratamiento , Vasculitis/patología , Vasculitis/fisiopatologíaRESUMEN
BACKGROUND: Acute renal failure (ARF) in the setting of end-stage liver disease has a dismal prognosis without liver transplantation. Renal replacement therapy (RRT) is a common bridge to liver transplant despite a paucity of supportive data. We investigated our single-center patient population to determine efficacy of RRT in liver transplant candidates with ARF. METHODS: We identified 102 liver transplant candidates receiving RRT for ARF between April 30, 1999 and January 31, 2004. Patients that had initiated RRT intra- or postoperatively or received outpatient hemodialysis or peritoneal dialysis prior to admission were excluded. Survival to liver transplant, short-term mortality following liver transplant, and selected clinical characteristics were examined. RESULTS: Of patients who received RRT, 35% survived to liver transplant or discharge. Mortality was 94% in patients not receiving a liver and was associated with a higher Acute Physiological and Chronic Health Evaluation (APACHE) II, lower mean arterial pressure, and the use of continuous renal replacement therapy (CRRT). Patients receiving CRRT had greater severity of illness than those on hemodialysis. The 1-year mortality of patients initiating RRT prior to liver transplant was 30% versus 9.7% for all other liver recipients (P < 0.0045). CONCLUSION: RRT is justifiable for liver transplant candidates with ARF. Though mortality was high, a substantial percentage (31%) of patients survived to liver transplant. Postoperative mortality is increased compared with all other liver transplant recipients, but is acceptable considering the near-universal mortality without transplantation.