RESUMO
ANCA vasculitis is an autoimmune disease with increased expression of the autoantigen genes, myeloperoxidase (MPO) and proteinase 3 (PRTN3), but the origin and significance of expression is less distinct. To clarify this, we measured MPO and PRTN3 messenger RNA in monocytes, normal-density neutrophils, and in enriched leukocytes from peripheral blood mononuclear cells. Increased autoantigen gene expression was detected in normal-density neutrophils and enriched leukocytes from patients during active disease compared to healthy individuals, with the largest difference in enriched leukocytes. RNA-seq of enriched leukocytes comparing active-remission pairs identified a gene signature for low-density neutrophils. Cell sorting revealed low-density neutrophils contained mature and immature neutrophils depending on the presence or absence of CD10. Both populations contributed to autoantigen expression but the frequency of immature cells in low-density neutrophils did not correlate with low-density neutrophil MPO or PRTN3 expression. Low-density neutrophils were refractory to MPO-ANCA induced oxidative burst, suggesting an alternative role for low-density neutrophils in ANCA vasculitis pathogenesis. In contrast, normal-density neutrophils were activated by MPO-ANCA and monoclonal anti-PR3 antibody. Normal-density neutrophil activation correlated with MPO and PRTN3 mRNA. Increased autoantigen gene expression originating from the mature low-density and normal-density neutrophils suggests transcriptional dysregulation is a hallmark of ANCA vasculitis. Thus, the correlation between autoantigen gene expression and antibody-mediated normal-density neutrophil activation connects autoantigen gene expression with disease pathogenesis.
Assuntos
Anticorpos Anticitoplasma de Neutrófilos , Neutrófilos , Autoantígenos/genética , Expressão Gênica , Humanos , Leucócitos Mononucleares , Mieloblastina , Ativação de Neutrófilo , Peroxidase/genéticaRESUMO
RATIONALE & OBJECTIVES: Glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A (IgA) nephropathy, share clinical presentations, yet result from multiple biological mechanisms. Challenges to identifying underlying mechanisms, biomarkers, and new therapies include the rarity of each diagnosis and slow progression, often requiring decades to measure the effectiveness of interventions to prevent end-stage kidney disease (ESKD) or death. STUDY DESIGN: Multicenter prospective cohort study. SETTING & PARTICIPANTS: Cure Glomerulonephropathy (CureGN) will enroll 2,400 children and adults with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (including IgA vasculitis) and a first diagnostic kidney biopsy within 5 years. Patients with ESKD and those with secondary causes of glomerular disease are excluded. EXPOSURES: Clinical data, including medical history, medications, family history, and patient-reported outcomes, are obtained, along with a digital archive of kidney biopsy images and blood and urine specimens at study visits aligned with clinical care 1 to 4 times per year. OUTCOMES: Patients are followed up for changes in estimated glomerular filtration rate, disease activity, ESKD, and death and for nonrenal complications of disease and treatment, including infection, malignancy, cardiovascular, and thromboembolic events. ANALYTICAL APPROACH: The study design supports multiple longitudinal analyses leveraging the diverse data domains of CureGN and its ancillary program. At 2,400 patients and an average of 2 years' initial follow-up, CureGN has 80% power to detect an HR of 1.4 to 1.9 for proteinuria remission and a mean difference of 2.1 to 3.0mL/min/1.73m2 in estimated glomerular filtration rate per year. LIMITATIONS: Current follow-up can only detect large differences in ESKD and death outcomes. CONCLUSIONS: Study infrastructure will support a broad range of scientific approaches to identify mechanistically distinct subgroups, identify accurate biomarkers of disease activity and progression, delineate disease-specific treatment targets, and inform future therapeutic trials. CureGN is expected to be among the largest prospective studies of children and adults with glomerular disease, with a broad goal to lessen disease burden and improve outcomes.
Assuntos
Glomerulonefrite por IGA/patologia , Glomerulonefrite Membranosa/patologia , Glomerulosclerose Segmentar e Focal/patologia , Falência Renal Crônica/prevenção & controle , Nefrose Lipoide/patologia , Centros Médicos Acadêmicos , Adolescente , Adulto , Fatores Etários , Biópsia por Agulha , Criança , Diagnóstico Diferencial , Progressão da Doença , Feminino , Glomerulonefrite/mortalidade , Glomerulonefrite/patologia , Glomerulonefrite/terapia , Glomerulonefrite por IGA/mortalidade , Glomerulonefrite por IGA/terapia , Glomerulonefrite Membranosa/mortalidade , Glomerulonefrite Membranosa/terapia , Glomerulosclerose Segmentar e Focal/mortalidade , Glomerulosclerose Segmentar e Focal/terapia , Humanos , Imuno-Histoquímica , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Nefrose Lipoide/mortalidade , Nefrose Lipoide/terapia , Prognóstico , Estudos Prospectivos , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Análise de Sobrevida , Adulto JovemRESUMO
Background: In anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, antigen specificity varies between myeloperoxidase (MPO) and proteinase 3 (PR3). This has been reported to vary in relation to age, gender, geography and extrarenal manifestations. However, studies are difficult to compare as criteria for inclusion vary. The aim of this study was to investigate the relationship between ANCA serotype, latitude, ultraviolet (UV) radiation levels, age, gender and renal function at diagnosis in a large study with uniform inclusion criteria. Methods: Patients with biopsy-proven ANCA-associated glomerulonephritis were identified from regional or nationwide registries in 14 centres in Norway, Sweden, the UK, the Czech Republic, Croatia, Italy and the USA during the period 2000-13. UV radiation levels for 2000-13 in Europe were obtained from the Swedish Meteorological and Hydrological Institute. Results: A total of 1408 patients (45.2% PR3-ANCA) were included in the study. In univariable analysis, PR3-ANCA was significantly associated with male gender {odds ratio [OR] 2.12 [95% confidence interval (CI) 1.71-2.62]}, younger age [OR per year 0.97 (95% CI 0.96-0.98)] and higher glomerular filtration rate [OR per mL/min 1.01 (95% CI 1.01-1.02); P < 0.001] at diagnosis but not with latitude or UV radiation. In multivariable logistic regression analysis, latitude and UV radiation also became significant, with higher odds for PR3-ANCA positivity at northern latitudes/lower UV radiation levels. However, the latitudinal difference in MPO:PR3 ratio is smaller than differences previously reported concerning microscopic polyangiitis and granulomatosis with polyangiitis. Conclusions: The ratio between PR3-ANCA and MPO-ANCA varies in glomerulonephritis with respect to age, gender, renal function and geographic latitude/UV radiation levels.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/epidemiologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Glomerulonefrite/imunologia , Mieloblastina/imunologia , Peroxidase/imunologia , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Especificidade de Anticorpos , Biópsia , República Tcheca/epidemiologia , Demografia , Feminino , Geografia , Glomerulonefrite/sangue , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Sistema de Registros , Sorogrupo , Suécia/epidemiologia , Reino Unido/epidemiologia , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Intravenous pulse methylprednisolone (MP) is commonly included in the management of severe ANCA associated vasculitis (AAV) despite limited evidence of benefit. We aimed to evaluate outcomes in patients who had, or had not received MP, along with standard therapy for remission induction in severe AAV. METHODS: We retrospectively studied 114 consecutive patients from five centres in Europe and the United States with a new diagnosis of severe AAV (creatinine > 500 µmol/L or dialysis dependency) and that received standard therapy (plasma exchange, cyclophosphamide and high-dose oral corticosteroids) for remission induction with or without pulse MP between 2000 and 2013. We evaluated survival, renal recovery, relapses, and adverse events over the first 12 months. RESULTS: Fifty-two patients received pulse MP in addition to standard therapy compared to 62 patients that did not. There was no difference in survival, renal recovery or relapses. Treatment with MP associated with higher risk of infection during the first 3 months (hazard ratio (HR) 2.7, 95%CI [1.4-5.3], p = 0.004) and higher incidence of diabetes (HR 6.33 [1.94-20.63], p = 0.002), after adjustment for confounding factors. CONCLUSIONS: The results of this study suggest that addition of pulse intravenous MP to standard therapy for remission induction in severe AAV may not confer clinical benefit and may be associated with more episodes of infection and higher incidence of diabetes.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Diabetes Mellitus , Infecções , Metilprednisolona , Pulsoterapia/métodos , Indução de Remissão/métodos , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/epidemiologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/terapia , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etiologia , Feminino , Humanos , Imunossupressores/uso terapêutico , Infecções/epidemiologia , Infecções/etiologia , Testes de Função Renal/métodos , Masculino , Metilprednisolona/administração & dosagem , Metilprednisolona/efeitos adversos , Pessoa de Meia-Idade , Avaliação de Processos e Resultados em Cuidados de Saúde , Troca Plasmática/estatística & dados numéricos , Diálise Renal/estatística & dados numéricos , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de DoençaRESUMO
ANCA-associated vasculitis is an autoimmune condition characterized by vascular inflammation and organ damage. Pharmacologically induced remission of this condition is complicated by relapses. Potential triggers of relapse are immunologic challenges and environmental insults, both of which associate with changes in epigenetic silencing modifications. Altered histone modifications implicated in gene silencing associate with aberrant autoantigen expression. To establish a link between DNA methylation, a model epigenetic gene silencing modification, and autoantigen gene expression and disease status in ANCA-associated vasculitis, we measured gene-specific DNA methylation of the autoantigen genes myeloperoxidase (MPO) and proteinase 3 (PRTN3) in leukocytes of patients with ANCA-associated vasculitis observed longitudinally (n=82) and of healthy controls (n=32). Patients with active disease demonstrated hypomethylation of MPO and PRTN3 and increased expression of the autoantigens; in remission, DNA methylation generally increased. Longitudinal analysis revealed that patients with ANCA-associated vasculitis could be divided into two groups, on the basis of whether DNA methylation increased or decreased from active disease to remission. In patients with increased DNA methylation, MPO and PRTN3 expression correlated with DNA methylation. Kaplan-Meier estimate of relapse revealed patients with increased DNA methylation at the PRTN3 promoter had a significantly greater probability of a relapse-free period (P<0.001), independent of ANCA serotype. Patients with decreased DNA methylation at the PRTN3 promoter had a greater risk of relapse (hazard ratio, 4.55; 95% confidence interval, 2.09 to 9.91). Thus, changes in the DNA methylation status of the PRTN3 promoter may predict the likelihood of stable remission and explain autoantigen gene regulation.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/genética , Autoantígenos/genética , Metilação de DNA , Mieloblastina/genética , Peroxidase/genética , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de RemissãoRESUMO
BACKGROUND: Fibrillary glomerulonephritis is characterized by randomly arranged fibrils, approximately 20 nm in diameter by electron microscopy. Patients present with proteinuria, hematuria and kidney insufficiency, and about half of the reported patients progress to end-stage kidney disease within 4 years. The dependence of patient characteristics and outcomes on race has not been explored. In this study, we describe a cohort of patients with fibrillary glomerulonephritis and compare their clinical characteristics and outcomes with those of patients previously described. METHODS: The University of North Carolina (UNC) Nephropathology Database was used to retrospectively identify patients diagnosed with fibrillary glomerulonephritis between 1985 and 2015. Of these patients, those treated at UNC were selected. Their demographic and clinical characteristics - including signs and symptoms, comorbidities, laboratory values, treatments and outcomes - were compared with those of patients described earlier. RESULTS: Among the 287 patients identified, 42 were treated at the UNC Kidney Center. When compared to earlier cohorts, a higher frequency of black race, hepatitis C virus (HCV) infection and use of hemodialysis were noted in both black and HCV-positive patients. Autoimmune diseases, infections and malignancies were frequently observed, present in over half of all cases. CONCLUSION: According to this study, fibrillary glomerulonephritis represents a secondary glomerular disease process (associated with autoimmune disease, infection or malignancy) in many cases and hence screening is essential. As the screening for comorbidities increased over time, more underlying causes were identified. We noted a high frequency of HCV among black patients, suggesting a possible causative association. Treatment of underlying disease is essential for patients for the best outcome.
Assuntos
Glomerulonefrite/etnologia , Glomerulonefrite/terapia , Falência Renal Crônica/etnologia , Falência Renal Crônica/terapia , Negro ou Afro-Americano , Idoso , Biópsia , Feminino , Glomerulonefrite/complicações , Humanos , Rim/patologia , Falência Renal Crônica/complicações , Glomérulos Renais/patologia , Masculino , Pessoa de Meia-Idade , North Carolina , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , UniversidadesRESUMO
Here we conducted a retrospective study to examine the risk of cardiovascular events (CVEs) relative to that of end-stage renal disease (ESRD) in patients with primary membranous nephropathy, in a discovery cohort of 404 patients. The cumulative incidence of CVEs was estimated in the setting of the competing risk of ESRD with risk factors for CVEs assessed by multivariable survival analysis. The observed cumulative incidences of CVEs were 4.4%, 5.4%, 8.2%, and 8.8% at 1, 2, 3, and 5 years respectively in the primary membranous nephropathy cohort. In the first 2 years after diagnosis, the risk for CVEs was similar to that of ESRD in the entire cohort, but exceeded it among patients with preserved renal function. Accounting for traditional risk factors and renal function, the severity of nephrosis at the time of the event (hazard ratio 2.1, 95% confidence interval 1.1 to 4.3) was a significant independent risk factor of CVEs. The incidence and risk factors of CVEs were affirmed in an external validation cohort of 557 patients with primary membranous nephropathy. Thus early in the course of disease, patients with primary membranous nephropathy have an increased risk of CVEs commensurate to, or exceeding that of ESRD. Hence, reduction of CVEs should be considered as a therapeutic outcome measure and focus of intervention in primary membranous nephropathy.
Assuntos
Doenças Cardiovasculares/epidemiologia , Glomerulonefrite Membranosa/epidemiologia , Falência Renal Crônica/epidemiologia , Adulto , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Feminino , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/mortalidade , Glomerulonefrite Membranosa/fisiopatologia , Humanos , Incidência , Rim/fisiopatologia , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/mortalidade , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , North Carolina/epidemiologia , Ontário/epidemiologia , Prognóstico , Modelos de Riscos Proporcionais , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores de TempoRESUMO
BACKGROUND: Patients with end-stage renal disease (ESRD) receiving dialysis have poor health-related quality of life. Physical symptoms are highly prevalent among dialysis-dependent patients and play important roles in health-related quality of life. A range of symptom assessment tools have been used in dialysis-dependent patients, but there has been no previous systematic assessment of the existing symptom measures' content, validity, and reliability. STUDY DESIGN: Systematic review of the literature. SETTINGS & POPULATION: Patients with ESRD on maintenance dialysis therapy. SELECTION CRITERIA FOR STUDIES: Instruments with 3 or more physical symptoms previously used in dialysis-dependent patients and evidence of validity or reliability testing. INTERVENTION: Patient-reported physical symptom assessment instrument. OUTCOMES: Instrument symptom-related content, validity, and reliability. RESULTS: From 3,148 screened abstracts, 89 full-text articles were eligible for review. After article exclusion and further article identification by reference reviews, 58 articles on 23 symptom assessment instruments with documented reliability or validity testing were identified. Of the assessment instruments, 43.5% were generic and 56.5% were ESRD specific. Symptoms most frequently assessed were fatigue, shortness of breath, insomnia, nausea and vomiting, and appetite. Instruments varied widely in respondent time burden, recall period, and symptom attributes. Few instruments considered recall periods less than 2 weeks and few assessed a range of symptom attributes. Psychometric testing was completed for congruent validity (70%), known-group validity (25%), responsiveness (30%), internal consistency (78%), and test-retest reliability (65%). Content validity was assessed in dialysis populations in 57% of the 23 instruments. LIMITATIONS: Consideration of physical symptoms only and exclusion of single symptom-focused instruments. CONCLUSIONS: The number of available instruments focused exclusively on physical symptoms in dialysis patients is limited. Few symptom-containing instruments have short recall periods, assess diverse symptom attributes, and have undergone comprehensive psychometric testing. Improved symptom-focused assessment tools are needed to improve symptom evaluation and symptom responsiveness to intervention among dialysis-dependent patients.
Assuntos
Falência Renal Crônica/psicologia , Falência Renal Crônica/terapia , Avaliação de Resultados da Assistência ao Paciente , Qualidade de Vida/psicologia , Diálise Renal/psicologia , Autorrelato , Humanos , Falência Renal Crônica/diagnóstico , Diálise Renal/efeitos adversosRESUMO
BACKGROUND: Rituximab has been used in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) since 2003. Our objective was to describe outcomes and adverse events following rituximab since that time in an inception cohort. METHODS: Patients with AAV (diagnosed 1991-2012) who received rituximab (n = 120) were evaluated and incidence per person-year (PPY) with 95% confidence interval was calculated for relapse and infections. Time to remission and relapse by number of rituximab infusions given per treatment course (≤2 versus >2) and by ever having been exposed to cyclophosphamide were compared using Kaplan-Meier curves. Rituximab-treated patients were characterized in comparison with AAV patients treated with cyclophosphamide but not exposed to rituximab (n = 351) using Fisher's exact or rank tests. RESULTS: Rituximab resulted in 86% achieving remission and 41% having a subsequent relapse in a median of 19 months (range 9-29). Time to remission and relapse were similar between rituximab infusion courses (≤2 versus >2; remission P = 0.86 and relapse P = 0.78, respectively). Incidence of relapse was 0.22 PPY (0.14, 0.31) and of severe infection was 0.12 PPY (0.08, 0.24). Time to relapse was shorter in those never exposed to cyclophosphamide (n = 20): 50% by 8 months versus 50% by 24 and 30 months for those with prior or concurrent exposure to cyclophosphamide (n = 100). Compared with those who never received rituximab, rituximab-treated patients were younger (P < 0.001), more likely to have granulomatosis with polyangiitis (P = 0.001) and had more upper airway (P = 0.01) and less kidney involvement (P = 0.007). CONCLUSIONS: Rituximab is beneficial when prescribed outside of a trial setting. Response to treatment and relapse is similar regardless of infusion number. Rituximab without cyclophosphamide may result in a shorter time to relapse supporting combination of these therapies.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Anticorpos Monoclonais Murinos/uso terapêutico , Imunossupressores/uso terapêutico , Adulto , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/mortalidade , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Estudos de Coortes , Ciclofosfamida/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Indução de Remissão , Rituximab , Taxa de SobrevidaRESUMO
BACKGROUND: Disease control in anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) with immunosuppression is effective but burdened by adverse events, especially infections. The study goal was to evaluate risks and types of infections in patients with AAV. METHODS: Biopsy-proven AAV patients (diagnosed 1/1991-6/2011) followed in an inception cohort were evaluated for adverse events. Severe infections (requiring intravenous antibiotics, intensive care unit, or causing death) were recorded. Infection number was grouped as none, 1-2 or ≥3. Cox regression was used to estimate hazard ratios with 95% confidence intervals. RESULTS: A total of 489 patients (median age 59; 47% female, 55% myeloperoxidase-ANCA) were followed for 2.8 years (median). At 1, 2 and 5 years cumulative incidence of infection was 51, 58 and 65% and severe infection was 22, 23 and 26%. Pulmonary and upper respiratory infections were most common (42 and 30% ever experienced each, respectively), highest in the first 3 months. Staphylococcus aureus was most frequently seen among positive cultures (41%, 78 S. aureus/192 total positive cultures), and only one Pneumocystis jiroveci pneumonia (6 weeks into treatment). All-cause death in 12 months was associated with infections (% deaths: 0 infections 3%; 1-2 infections 10%, ≥3 infections 13%, P = 0.002). Controlling for age, sex and kidney function, patients with severe infections were 4.2 times more likely to die within 12 months (95% CI 2.0-8.7; P = 0.001). CONCLUSIONS: More infections increase the risk of a severe infection which increases risk of all-cause mortality. Respiratory and S. aureus infections are dominant. Targeted prophylactic therapy could decrease morbidity.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Imunossupressores/efeitos adversos , Rim/fisiologia , Peroxidase/imunologia , Infecções Estafilocócicas/microbiologia , Adulto , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Incidência , Rim/efeitos dos fármacos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , North Carolina/epidemiologia , Prognóstico , Infecções Estafilocócicas/induzido quimicamente , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/mortalidade , Staphylococcus aureus/isolamento & purificação , Taxa de SobrevidaRESUMO
Primary membranous nephropathy is associated with increased risk of venous thromboembolic events, which are inversely correlated with serum albumin levels. To evaluate the potential benefit of prophylactic anticoagulation (venous thromboembolic events prevented) relative to the risk (major bleeds), we constructed a Markov decision model. The venous thromboembolic event risk according to serum albumin was obtained from an inception cohort of 898 patients with primary membranous nephropathy. Risk estimates of hemorrhage were obtained from a systematic literature review. Benefit-to-risk ratios were predicted according to bleeding risk and serum albumin. This ratio increased with worsening hypoalbuminemia from 4.5:1 for an albumin under 3 g/dl to 13.1:1 for an albumin under 2 g/dl in patients at low bleeding risk. Patients at intermediate bleeding risk with an albumin under 2 g/dl have a moderately favorable benefit-to-risk ratio (under 5:1). Patients at high bleeding risk are unlikely to benefit from prophylactic anticoagulation regardless of albuminemia. Probabilistic sensitivity analysis, to account for uncertainty in risk estimates, confirmed these trends. From these data, we constructed a tool to estimate the likelihood of benefit based on an individual's bleeding risk profile, serum albumin level, and acceptable benefit-to-risk ratio (www.gntools.com). This tool provides an approach to the decision of prophylactic anticoagulation personalized to the individual's needs and adaptable to dynamic changes in health status and risk profile.
Assuntos
Anticoagulantes/uso terapêutico , Técnicas de Apoio para a Decisão , Glomerulonefrite Membranosa/tratamento farmacológico , Seleção de Pacientes , Tromboembolia Venosa/prevenção & controle , Idoso , Anticoagulantes/efeitos adversos , Árvores de Decisões , Feminino , Glomerulonefrite Membranosa/complicações , Glomerulonefrite Membranosa/diagnóstico , Hemorragia/induzido quimicamente , Humanos , Hipoalbuminemia/complicações , Funções Verossimilhança , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Método de Monte Carlo , Medicina de Precisão , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Incerteza , Tromboembolia Venosa/etiologiaRESUMO
BACKGROUND: The utility of genetic testing in sporadic focal segmental glomerulosclerosis (FSGS) is unclear. We sought to determine the frequency of podocyte-related gene mutations in a heterogeneous population of adults and children with biopsy-proven FSGS. METHODS: The prevalence of pathogenic mutations in five genes (NPHS2, TRPC6, ACTN4, INF2 and PLCE1) and of APOL1 risk alleles (G1 and G2) was ascertained in children and adults diagnosed between 1984 and 2011 with FSGS by renal biopsy. Clinical data were extracted from medical records. RESULTS: A total of 65 patients (28 children, 37 adults) with sporadic FSGS were identified (34 females, 31 males), with a mean age of 25 ± 16 years (range from 3 to 62 years). The majority of patients were African American (39 African American, 21 White and 2 Hispanic). We identified biallelic pathogenic NPHS2 mutations in 2 of 28 (7.1%) children, both of whom were of non-Hispanic Caucasian background. A homozygous NPHS2 p.R138Q/p.R138Q mutation was detected in a 5-year-old Caucasian female. Two compound heterozygous NPHS2 mutations p.R138Q/p.R229Q were identified in a 7-year-old Caucasian male patient. One novel, potentially pathogenic non-synonymous variant in INF2 was identified in an African American patient. The proportion of African Americans with two APOL1 risk alleles was 69.2%. CONCLUSIONS: This study delineates a role for genetic testing for NPHS2 in children with biopsy-proven sporadic FSGS. Further studies which specify clinical and pathological details of patients will help further define whether there are specific populations that warrant systematic testing of other podocyte-related genes in sporadic FSGS.
Assuntos
DNA/genética , Glomerulosclerose Segmentar e Focal/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Mutação , Podócitos/patologia , Adolescente , Adulto , Biópsia , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Testes Genéticos , Glomerulosclerose Segmentar e Focal/metabolismo , Glomerulosclerose Segmentar e Focal/patologia , Heterozigoto , Homozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Podócitos/metabolismo , Estudos Retrospectivos , Adulto JovemRESUMO
Individuals with lupus nephritis (LN) are at high risk of adverse maternal and fetal outcomes in pregnancy. Outside of pregnancy, proliferative lesions on kidney biopsies are associated with disease progression, but these have not been consistently associated with increased risk in pregnancy. This retrospective, single-center study examines how histologic findings, the timing from kidney biopsy to pregnancy, and the clinical features in the first trimester are associated with preterm birth among individuals with LN. Among 35 deliveries in 31 women, the mean gestational age at delivery was 33.8 weeks. The presence of a urine protein-to-creatinine ratio >0.5 g/g in the first trimester was associated with preterm delivery (81% vs. 36%, p = 0.04). Preterm birth was more common in individuals with glomerular crescents on biopsy (89% in those with >20% crescents vs. 50% in those with <20%, p = 0.06). A pregnancy occurring within 2 years after a kidney biopsy was more likely to result in preterm birth than if the biopsy was performed more than 2 years prior to conception (82% vs. 23%, p = 0.01). The time from diagnostic biopsy may be a surrogate for disease activity, and a 2-year delay from biopsy might allow sufficient time to achieve disease remission. Overall, these data could aid family planning discussions and promote preconception disease optimization for patients and their providers.
RESUMO
The role of stressors, insect bites, and infections on disease relapse of ANCA vasculitis has yet to be entirely explored, with limited retrospective studies focused on disease onset from small participant cohorts. Our study analyzes longitudinal survey data from 2011-2022 to evaluate this perspective from a large ANCA vasculitis cohort. We collected surveys every three to six months to obtain information on self-reported psychological stressors and significant life events, insect bites, and infections throughout clinical disease. We defined cohorts as those who relapsed (Relapse Cohort) and controls as those who did not relapse (Remission Cohort) during the study period. Survey responses were retrospectively reviewed during a 15-month timeframe prior to relapse or during 15 months of remission and categorized by type of stress event, insect bite, and infections at every available 3-month interval. There were no significant differences in stress and insect bites between the relapse and remission cohorts. Patients who relapsed reported more frequent upper respiratory infections and other infections, such as those affecting the skin and eyes, but there were no significant differences in the incidence of pulmonary or urinary infections compared to the remission cohort. There was a significant difference in reported upper respiratory infections 9 to 15 months prior to the relapse date, indicating a remote history of infections as a potentially significant physical stressor that may contribute to disease relapse. More frequent patient-reported infections, specifically upper respiratory infections, may contribute to patient vulnerability to relapse. Counseling and close monitoring of patients after infectious symptoms could aid in earlier detection of disease flares. Future studies are essential to further understand the importance of distal risk factors and how they impact relapse.
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Introduction: Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), 2 major clinicopathologic variants of antineutrophil cytoplasmic autoantibody (ANCA) vasculitides, are mostly associated with proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA, respectively. Less is known regarding the uncommon forms of ANCA vasculitis, PR3-ANCA MPA and MPO-ANCA GPA. Methods: In this cohort study we detailed the clinical presentation and outcome of patients with PR3-ANCA MPA and MPO-ANCA GPA from the Glomerular Disease Collaborative Network (GDCN) inception cohort. Baseline clinical manifestations, relapses, end-stage kidney disease (ESKD), and survival were compared within MPA cases by PR3-ANCA (n = 116) versus MPO-ANCA (n = 173) and within GPA cases by PR3-ANCA (n = 108) versus MPO-ANCA (n = 43). Fisher's exact test and Wilcoxon two sample test were used for comparisons. Proportional hazards models were used to evaluate the development of relapses, ESKD, and death. Results: Patients with PR3-ANCA MPA were younger (53 years vs. 62 years, P = 0.0007) and had increased prevalence of joint involvement (56% vs. 40%, P = 0.0115) and ear, nose, and throat (ENT) involvement (44% vs. 26%, P = 0.002) than MPO-ANCA MPA. Relapses, ESKD, and survival were similar between both MPA subsets. Within the GPA group, patients with MPO-ANCA GPA were older (61 years vs. 46 years, P = 0.0007) and more likely female (56% vs. 35%, P = 0.027) than PR3-ANCA GPA patients. MPO-ANCA GPA was also characterized by less prevalent ENT manifestations (58% vs. 77%, P = 0.028) and neurologic manifestations (5% vs. 25%, P = 0.0029), and increased ESKD and mortality. Conclusions: PR3-ANCA MPA and MPO-ANCA GPA are clinicopathologically distinct subsets of ANCA vasculitis that differ from MPO-ANCA MPA and PR3-ANCA GPA. Although the impact of these differences on the clinical management and outcome warrants further evaluation, these results support the recommendation of including both the phenotypic diagnosis and ANCA serotype in the diagnosis of ANCA vasculitis.
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Individuals receiving long-term hemodialysis are at increased risk of developing cardiovascular disease (CVD). Traditional cardiovascular risk factors do not fully explain the high CVD risk in this population. During hemodialysis, blood interacts with the biomaterials of the hemodialysis circuit. This interaction can activate the complement system and the factor XII-driven contact system. FXII activation triggers both the intrinsic pathway of coagulation and the kallikrein-kinin pathway, resulting in thrombin and bradykinin production, respectively. The complement system plays a key role in the innate immune response, but also contributes to the pathogenesis of numerous disease states. Components of the complement pathway, including mannose binding lectin and C3, are associated with CVD risk in people with end-stage kidney disease (ESKD). Both the complement system and the factor XII-driven contact coagulation system mediate proinflammatory and procoagulant responses that could contribute to or accelerate CVD in hemodialysis recipents. This review summarizes what is already known about hemodialysis-mediated activation of the complement system and in particular the coagulation contact system, emphasizing the potential role these systems play in the identification of new biomarkers for CVD risk stratification and the development of potential therapeutic targets or innovative therapies that decrease CVD risk in ESKD patients.
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INTRODUCTION: Lupus nephritis (LN) is an independent risk factor for venous thromboembolism (VTE). The risk of VTE has not been analyzed by International Society of Nephrology/Renal Pathology Society or World Health Organization LN class. Study goals were to measure VTE incidence in an LN patient cohort, to evaluate associations between VTE and LN class, and to investigate factors modifying associations between VTE and LN class. METHODS: A retrospective analysis was performed using Glomerular Disease Collaborative Network data. Image-confirmed VTE was compared between patients with any LN class V lesion and patients with only LN class III or IV. Logistic regression was used to calculate odds ratios and 95% confidence intervals. Effect modification was assessed between main effect and covariates. RESULTS: Our cohort consisted of 534 LN patients, 310 (58%) with class III/IV and 224 (42%) with class V with or without class III/IV, including 106 with class V alone. The VTE incidence was 62 of 534 (11.6%). The odds of VTE were not significantly different between patients with class III/IV and class V in adjusted analyses (odds ratio [OR] = 0.82, 95% confidence interval [CI] = 0.45-1.48). An age interaction was observed (P = 0.009), with increased odds of VTE with class III/IV diagnosed at a younger age (2.75, 0.90-8.41 estimated at age 16 years) and decreased odds with class III/IV diagnosed at an older age (0.23, 0.07-0.72 estimated at age 46 years), compared to class V. CONCLUSIONS: The VTE incidence was similar among patients with LN classes III/IV and V, suggesting that VTE risk is not limited to class V-related nephrotic syndrome and that age may modulate LN class-specific VTE risk.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Anticorpos Monoclonais Murinos/uso terapêutico , Antirreumáticos/uso terapêutico , Linfócitos B/metabolismo , Antígenos CD5/metabolismo , Adulto , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Recidiva , Indução de Remissão , Medição de Risco , RituximabRESUMO
BACKGROUND: In primary membranous nephropathy (MN), partial remission (PR) (≥50% reduction of proteinuria to <3.5 g/d) is associated with a greater risk of relapse and end-stage kidney disease (ESKD) compared with complete remission (CR). We aimed to determine factors associated with relapse or renal failure in patients who attain the standard definition of PR. METHODS: We captured PR, CR, relapse, and the composite of doubling of serum creatinine or ESKD in a cohort of 267 patients with MN, nephrotic syndrome, and >12 months of follow-up. Characteristics at the time of PR associated with the composite outcome or relapse were evaluated using a time-to-event analysis. RESULTS: A total of 192 patients attained PR and 86 attained CR. Serum albumin at PR (hazard ratio [HR]: 1.58 per 0.5 g/dl decrease from 4.0 g/dl; 95% confidence interval [CI]: 1.03-2.43) and duration of nephrotic proteinuria (HR: 1.01 per month increase; 95% CI: 1.00-1.03) were independent risk factors for the composite endpoint. Serum albumin at PR was associated with an increased risk of relapse (HR: 1.58 per 0.5 g/dl decrease below 4.0 g/dl; 95% CI: 1.24-2.01). A cutoff for serum albumin ≤3.5 g/dl at PR performed best in predicting relapse and composite outcome. CONCLUSIONS: Patients with serum albumin >3.5 g/dl at PR have decreased risk of composite outcome or relapse compared with PR with low albumin. A definition of PR that includes normalization of serum albumin may be a more robust surrogate endpoint in MN than the traditional definition of PR.