RESUMO
Mechanisms for the generation of anti-dsDNA autoantibodies are still not completely elucidated. One theory states that dsDNA interacts for mimicry with antibodies raised versus other antigens but molecular features for mimicry are unknown. Here we show that, at physiological acid-base balance, anti-Annexin A1 binds IgG2 dsDNA in a competitive and dose-dependent way with Annexin A1 and that the competition between the two molecules is null at pH 9. On the other hand, these findings also show that dsDNA and Annexin A1 interact with their respective antibodies on a strictly pH-dependent basis: in both cases, the binding was minimal at pH 4 and maximal at pH9-10. The anionic charge of dsDNA is mainly conferred by the numerous phosphatidic residues. The epitope binding site of Annexin A1 for anti-Annexin A1 IgG2 was here characterized as a string of 34 amino acids at the NH2 terminus, 10 of which are anionic. Circulating levels of anti-dsDNA and anti-Annexin A1 IgG2 antibodies were strongly correlated in patients with systemic lupus erythematosus (n 496) and lupus nephritis (n 425) stratified for age, sex, etc. These results show that dsDNA competes with Annexin A1 for the binding with anti-Annexin A1 IgG2 on a dose and charged mediated base, being able to display an inhibition up to 75%. This study provides the first demonstration that dsDNA may interact with antibodies raised versus other anionic molecules (anti-Annexin A1 IgG2) because of charge mimicry and this interaction may contribute to anti-dsDNA antibodies generation.
Assuntos
Anexina A1 , Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Humanos , Anticorpos Antinucleares , Autoanticorpos , Imunoglobulina G , Anexina A1/metabolismo , DNARESUMO
OBJECTIVES: We aimed to identify the rates and predictors of chronic damage accrual and mortality in lupus nephritis (LN). METHODS: We retrospectively measured SLICC/ACR Damage Index (SDI) in biopsy proven active LN with at least 5 years follow-up. We searched for the predictors of first SDI increase and death at univariate and multivariate regression analysis. Then, we considered clinical/biochemical/histological features at diagnosis, corticosteroids dose and proportion of follow-up in complete renal remission. RESULTS: 187 patients (91.4% females, age 28.1 years, 95.7% Caucasians) were included. After a median follow-up of 18.6 years, 26 patients (13.9%) died, 116 (62%) accrued damage. SDI annual rate has significantly reduced over the last decades (from a mean of 0.14±0.17 in 1970-1985, to 0.09±0.21 in 1986-2001, to 0.07±0.1 in 2002-2019; p=0.0032). SDI increases occurred more frequently in renal (22.5%), ocular (18.2%), cardiovascular, neuropsychiatric (13.4% both) and malignancy (12.8%) domains. First SDI increase free survival was 73.3%, 59.8%, 49.9% and 38% at 5,10,15 and 20 years. At multivariate analysis, hypertension (HR:1.699, CI:1.126-2.457, p=0.011), presentation with acute renal dysfunction (HR:1.587,CI:1.082-2.327, p=0.018) and average prednisone dose >5mg/day (HR:3.378, CI:1.984-5.751, p<0.0001) independently predicted damage. Achievement of complete renal remission (HR:0.993, CI:0.987-0.999, p<0.039) reduced the risk of damage. Age (HR:1.063, CI:1.027-1.099, p=0.0004), hypertension (HR:3.096, CI:1.211-7.912, p=0.019), and no immunosuppressors as maintenance therapy (HR:4.168, CI:1.212-14.336, p=0.024) predicted mortality at multivariate analysis. CONCLUSIONS: Besides arterial hypertension, presentation with acute renal dysfunction and corticosteroids dose predict SDI increase in LN, while achieving renal remission prevents damage. Aggressive therapy to induce remission in the acute phases of LN and low corticosteroids dose in maintenance therapy may prevent the increase of chronic damage.
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Hipertensão , Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Corticosteroides/uso terapêutico , Adulto , Feminino , Humanos , Rim/patologia , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , Masculino , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
Clinical Trial registry name and registration number: Zeus study, NCT02403115.
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Nefropatias , Nefrite Lúpica , Humanos , Anticorpos , RimRESUMO
Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease with a wide range of clinical expressions. The kidney is often affected, usually within 5 years of the onset of SLE, and lupus nephropathy (LN) carries a high risk for increased morbidity. The clinical heterogeneity of the disease is accompanied by complex disturbances affecting the immune system with inflammation and tissue damage due to loss of tolerance to nuclear antigens and the deposition of immune complexes in tissues. Several studies have reported that in human SLE, there is an important role of the Type-I-interferons (INF) system suggested by the upregulation of INF-inducible genes observed in serial gene expression microarray studies. This review aims to describe the transduction pathways of Type-I-interferons, in particular INFα, and its immune-regulatory function in the pathogenesis of SLE and, in particular, in LN. In addition, recent novelties concerning biologic therapy in LN will be discussed.
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Interferon Tipo I , Lúpus Eritematoso Sistêmico , Humanos , Interferon-alfa/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/genética , Interferon Tipo I/metabolismo , Complexo Antígeno-Anticorpo , Antígenos NuclearesRESUMO
OBJECTIVES: Serum anti-dsDNA and anti-nucleosome IgGs have been proposed as signatures for SLE and LN in limited numbers of patients. We sought to show higher sensitivity and specificity of the same antibodies with the IgG2 isotype and included IgG2 antibodies vs specific intracellular antigens in the analysis. METHODS: A total of 1052 SLE patients with (n = 479) and without (n = 573) LN, recruited at different times from the beginning of symptoms, were included in the study. Patients with primary APS (PAPS, n = 24), RA (RA, n = 24) and UCTD (UCTD, n = 96) were analysed for comparison. Anti-nucleosome (dsDNA, Histone2A, Histone3), anti-intracellular antigens (ENO1), anti-annexin A1 and anti-C1q IgG2 were determined by non-commercial techniques. RESULTS: The presence in the serum of the IgG2 panel was highly discriminatory for SLE/LN vs healthy subjects. Serum levels of anti-dsDNA and anti-C1q IgG2 were more sensitive than those of IgGs (Farr radioimmunoassay/commercial assays) in identifying SLE patients at low-medium increments. Of more importance, serum positivity for anti-ENO1 and anti-H2A IgG2 discriminated between LN and SLE (ROC T0-12 months), and high levels at T0-1 month were detected in 63% and 67%, respectively, of LN, vs 3% and 3%, respectively, of SLE patients; serum positivity for each of these was correlated with high SLEDAI values. Minor differences existed between LN/SLE and the other rheumatologic conditions. CONCLUSION: Nephritogenic IgG2 antibodies represent a specific signature of SLE/LN, with a few overlaps with other rheumatologic conditions. High levels of anti-ENO1 and anti-H2A IgG2 correlated with SLE activity indexes and were discriminatory between SLE patients limited to the renal complication and other SLE patients. TRIAL REGISTRATION: The Zeus study was registered at https://clinicaltrials.gov, NCT02403115.
Assuntos
Anticorpos Antinucleares/imunologia , Imunoglobulina G/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Adolescente , Adulto , Anexina A1/imunologia , Especificidade de Anticorpos , Síndrome Antifosfolipídica/imunologia , Artrite Reumatoide/imunologia , Biomarcadores Tumorais/imunologia , Complemento C1q/imunologia , Estudos Transversais , DNA/imunologia , Proteínas de Ligação a DNA/imunologia , Feminino , Histonas/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Nucleossomos/imunologia , Fosfopiruvato Hidratase/imunologia , Proteínas Supressoras de Tumor/imunologia , Doenças do Tecido Conjuntivo Indiferenciado/imunologia , Adulto JovemRESUMO
OBJECTIVES: Circulating anti-ENO1 and anti-H2A IgG2 have been identified as specific signatures of LN in a cross-over approach. We sought to show whether the same antibodies identify selected population of patients with LN with potentially different clinical outcomes. METHODS: Here we report the prospective analysis over 36 months of circulating IgG2 levels in patients with newly diagnosed LN (n=91) and SLE (n=31) and in other patients with SLE recruited within 2 years from diagnosis (n=99). Anti-podocyte (ENO1), anti-nucleosome (DNA, histone 2 A, histone 3) and anti-circulating proteins (C1q, AnnexinA1-ANXA1) IgG2 antibodies were determined by home-made techniques. RESULTS: LN patients were the main focus of the study. Anti-ENO1, anti-H2A and anti-ANXA1 IgG2 decreased in parallel to proteinuria and normalized within 12 months in the majority of patients while anti-dsDNA IgG2 remained high over the 36 months. Anti-ENO1 and anti-H2A had the highest association with proteinuria (Heat Map) and identified the highest number of patients with high proteinuria (68% and 71% respectively) and/or with reduced estimated glomerula filtration rate (eGFR) (58% for both antibodies) compared with 23% and 17% of anti-dsDNA (agreement analysis). Anti-ENO1 positive LN patients had higher proteinuria than negative patients at T0 and presented the maximal decrement within 12 months. CONCLUSIONS: Anti-ENO1, anti-H2A and anti-ANXA1 antibodies were associated with high proteinuria in LN patients and Anti-ENO1 also presented the maximal reduction within 12 months that paralleled the decrease of proteinuria. Anti-dsDNA were not associated with renal outcome parameters. New IgG2 antibody signatures should be utilized as tracers of personalized therapies in LN. TRIAL REGISTRATION: The Zeus study was registered at https://clinicaltrials.gov (study number: NCT02403115).
Assuntos
Imunoglobulina G/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Adulto , Anexina A1/imunologia , Anticorpos Antinucleares/imunologia , Autoanticorpos/imunologia , Biomarcadores Tumorais/imunologia , Complemento C1q/imunologia , DNA/imunologia , Proteínas de Ligação a DNA/imunologia , Progressão da Doença , Feminino , Histonas/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Nucleossomos/imunologia , Fosfopiruvato Hidratase/imunologia , Estudos Prospectivos , Proteínas Supressoras de Tumor/imunologiaRESUMO
Due to complex comorbidity, high infectious complication rates, an elevated risk of relapsing for primary renal disease, as well as inferior recipient and allograft survivals, individuals with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAVs) are often considered as poor transplant candidates. Although several aspects of recurrent and de novo AAVs remain unclear, recent evidence suggests that kidney transplantation (KT) represents the best option, which is also the case for this particular subgroup of patients. Special counselling and individualized approaches are strongly recommended at the time of enlistment and during the entire post-transplant follow-up. Current strategies include avoiding transplantation within one year of complete clinical remission and thoroughly assessing the recipient for early signs of renal or systemic vasculitis. The main clinical manifestations of allograft AAV are impaired kidney function, proteinuria, and hematuria with ANCA positivity in most cases. Mixed results have been obtained using high-dose steroids, mycophenolate mofetil, or cyclophosphamide. The aim of the present review was to summarize the available literature on AAVs in KT, particularly focusing on de novo pauci-immune glomerulonephritis.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Transplante de Rim , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Anticorpos Anticitoplasma de Neutrófilos , Humanos , Rim , ProteinúriaRESUMO
OBJECTIVES: Short-term predictive endpoints of chronic kidney disease (CKD) are needed in lupus nephritis (LN). We tested response to therapy at 1 year. METHODS: We considered patients with LN who underwent renal biopsy followed by induction therapy between January 1970 and December 2016. LN was assessed using the International Society of Nephrology/Renal Pathology Society (2003) criteria and the National Institute of Health (NIH) activity and chronicity index. The renal outcome was CKD. Response was defined according to EULAR/European League Against Rheumatism/European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations: complete: proteinuria <0.5 g/24 hours, (near) normal estimated glomerular filtration rate (eGFR); partial: ≥50% proteinuria reduction to subnephrotic levels, (near) normal eGFR; and no response: all the other cases. Logistic regression analysis was employed for 12-month response and Cox regression for CKD prediction. RESULTS: We studied 381 patients (90.5% Caucasians). After 12-month therapy, 58%, 26% and 16% of patients achieved complete, partial and no response, respectively, according to EULAR/ERA-EDTA. During a median follow-up of 10.7 (IQR: 4.97-18.80) years, 53 patients developed CKD. At 15 years, CKD-free survival rate was 95.2%, 87.6% and 55.4% in patients with complete, partial and no response at 12 months, respectively (p<0.0001). CKD-free survival rates did not differ between complete and partial responders (p=0.067). Serum creatinine (HR: 1.485, 95% CI 1.276 to 1.625), eGFR (HR 0.967, 95% CI 0.957 to 0.977) and proteinuria at 12 months (HR 1.234, 95% CI 1.111 to 1.379) were associated with CKD, yet no reliable cut-offs were identified on the receiver operating characteristic curve. In multivariable analysis, no EULAR/ERA-EDTA response at 12 months (HR 5.165, 95% CI 2.770 to 7.628), low C4 (HR 1.053, 95% CI 1.019 to 1.089) and persistent arterial hypertension (HR 3.154, 95% CI 1.500 to 4.547) independently predicted CKD. CONCLUSIONS: Lack of EULAR/ERA-EDTA response at 12 months predicts CKD.
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Nefrite Lúpica/complicações , Nefrite Lúpica/tratamento farmacológico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia , Adulto , Feminino , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do TratamentoRESUMO
Lupus nephritis (LN) is a frequent and severe manifestation of SLE. Along the decades, the epidemiology of LN and its clinical presentation have been changing. However, even though retrospective cohort studies report a decreased mortality rate and an improvement in the disease prognosis, the percentage of patients progressing into end stage renal disease (ESRD) keeps steady despite the improvements in therapeutic strategies. Current in-use medications have been available for decades now, yet over the years, regimens for optimizing their efficacy and minimizing toxicity have been developed. Therapeutic research is now moving towards the direction of precision medicine and several new drugs, targeting selectively different pathogenetic pathways, are currently under evaluation with promising results. In this review, we address the main changes and persistent unmet needs in LN management throughout the past decades, with a focus on prognosis and upcoming treatments.
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Nefrite Lúpica/diagnóstico , Progressão da Doença , Humanos , Nefrite Lúpica/classificação , Nefrite Lúpica/patologia , Nefrite Lúpica/terapia , Prognóstico , Recidiva , Indução de Remissão , Fatores de RiscoRESUMO
RATIONALE & OBJECTIVE: Idiopathic retroperitoneal fibrosis (IRF) is a rare disorder of unknown cause. Medical therapy can induce remission, but disease relapses are common. This study sought to characterize long-term outcomes of IRF and the factors associated with disease recurrences. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Retrospective analysis of 50 patients with IRF prospectively followed up for 8.9 (IQR, 4.7-12.7) years at a tertiary-care referral center. EXPOSURES: Demographic, clinical, treatment, and laboratory parameters, including measures of autoimmunity. OUTCOME: Disease relapse. ANALYTICAL APPROACH: Proportional hazards analysis for the subdistribution of competing risks. RESULTS: 49 patients received medical treatment and 35 underwent interventional procedures. All patients experienced a clinical response (defined as regression of disease-related symptoms and hydronephrosis, and decrease in the maximal transverse diameter of the retroperitoneal mass on computed tomography of >50%), 44 of whom responded within 1 year. The remaining 6 responded over a median of 2.95 years after starting therapy. 40 patients were alive at last observation, 1 receiving maintenance dialysis and 15 with estimated glomerular filtration rate < 60mL/min/1.73m2. Patient survival at 5, 10, and 15 years was 95%, 84%, and 68%, respectively. 19 (38%) patients had at least 1 relapse (occurring a median of 5.19 years after starting therapy), defined as an increase in serum creatinine level of at least 30% or recurrence/development of hydronephrosis and ≥20% increase in the maximal transverse diameter of the retroperitoneal mass on computed tomography. Cumulative incidences of relapse at 5, 10, and 15 years were 21%, 41%, and 48%, respectively. Baseline antinuclear antibody positivity and male sex were associated with relapse (subdistribution hazard ratios [sHRs] of 5.35 [95% CI, 2.15-13.27] and 4.94 [95% CI, 1.32-18.57], respectively), while higher corticosteroid therapy dosage at 1 year (sHR for relapse per 1-mg/d greater dosage, 0.91 [95% CI, 0.84-0.98]) and treatment with prednisone alone or with tamoxifen (sHR for relapse of 0.25 [95% CI, 0.07-0.85] vs other therapies) were associated with lower rate of relapse. LIMITATIONS: Small sample size and variable approaches to therapy. CONCLUSIONS: IRF relapses were common and were experienced more frequently by male patients. Corticosteroids alone or with tamoxifen were associated with a lower rate of relapse. The strong association of antinuclear antibody positivity with relapse supports the hypothesis of an autoimmune pathogenesis of IRF.
Assuntos
Hidronefrose/terapia , Prednisolona/uso terapêutico , Fibrose Retroperitoneal/tratamento farmacológico , Fibrose Retroperitoneal/epidemiologia , Tomografia Computadorizada por Raios X/métodos , Fatores Etários , Idoso , Análise de Variância , Estudos de Coortes , Feminino , Humanos , Hidronefrose/diagnóstico por imagem , Hidronefrose/etiologia , Imunossupressores/uso terapêutico , Incidência , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Doenças Raras , Recidiva , Diálise Renal/métodos , Fibrose Retroperitoneal/complicações , Fibrose Retroperitoneal/diagnóstico por imagem , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Análise de Sobrevida , Centros de Atenção Terciária , Resultado do TratamentoRESUMO
BACKGROUND: There is little information about very long-term outcomes of kidney allograft recipients exposed to calcineurin inhibitors. METHODS: In this single-centre retrospective study with 20-year follow-up, we analyzed data from 644 patients who underwent primary renal transplantation between 1983 and 1993. Participants were treated with a cyclosporine-based immunosuppressive scheme and had allograft function at 1 year. RESULTS: After 20 years, 15.2% patients died, 39.7% experienced allograft loss, 26.8% were alive with a functioning transplant, and 18.2% were lost to follow-up. Cardiovascular disease (30.8%), malignancy (26.6%) and infection (17.0%) were the main causes of death. Age, new-onset proteinuria > 1 g/day, major acute cardiovascular event (MACE), and malignancy were independent predictors of mortality at time-dependent multivariate analysis. Chronic rejection (63.3%), recurrent glomerulonephritis (14.0%), and nonspecific interstitial fibrosis/tubular atrophy (13.2%) were the leading cause of allograft loss. Basal disease, hepatitis C, difference between 1 year and nadir serum creatinine, new-onset proteinuria > 1 g/day, and MACE were independent predictors of transplant failure. Among patients with 20-year allograft function, we recorded the following complications: hypertension (85%), malignancy (13%), diabetes (9%), and cardiovascular disease (9%). Median serum creatinine and proteinuria were 1.4 mg/dL and 0.6 g/day, respectively. CONCLUSIONS: Prolonged use of cyclosporine may expose to several dose-related adverse events and may contribute to the development of allograft dysfunction but it does not necessarily cause relentless, progressive transplant failure if patients are carefully and consistently monitored during the follow-up.
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Inibidores de Calcineurina/efeitos adversos , Ciclosporina/efeitos adversos , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Adulto , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/mortalidade , Humanos , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Falha de TratamentoRESUMO
Twenty-yr patient and death-censored graft survival of 348 kidney transplant recipients with primary glomerulonephritis (GN) and of 696 matched controls were 82.2% in GN patients and 75% in controls (p = 0.037) and 49.5% and 54%, respectively (p = 0.013). GN patients had a higher incidence of graft failure than controls even considering death as a competing risk (p = 0.004). In the GN group, graft survival of deceased and of living donor recipients was similar. At multivariate analysis, GN as primary disease (RR: 1.47), delayed graft function recovery (RR: 2.34), acute rejection (RR: 2.36), and any PRA positivity (RR: 1.01) were predictive of graft loss. GN recurred in 85 of 348 grafts (24.4%), and 43 were lost for recurrence. In non-recurrent patients, graft survival at 20 yr was significantly better than in recurrent patients (59.4% vs. 24.4%, p = 0.000), but not different from that of controls (59.4 vs. 54%, p = 0.9). At multivariate analysis, young age at transplantation (RR: 0.97), shorter duration of dialysis (RR: 1.05 per each dialysis year), and graft from living donors (RR: 1.668) were independent predictors of recurrence. Patients with primary GN have reduced graft survival in comparison with controls, and this is mainly due to recurrence of original disease. However, the most frequent recurrence in living recipients does not compromise graft survival.
Assuntos
Glomerulonefrite/complicações , Rejeição de Enxerto/mortalidade , Sobrevivência de Enxerto/fisiologia , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias/mortalidade , Adulto , Aloenxertos , Estudos de Casos e Controles , Feminino , Seguimentos , Taxa de Filtração Glomerular , Glomerulonefrite/cirurgia , Rejeição de Enxerto/etiologia , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Prognóstico , Recidiva , Diálise Renal , Estudos Retrospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
Deposition of autoantibodies in glomeruli is a key factor in the development of lupus nephritis (LN). For a long time, anti-dsDNA and anti-C1q antibodies were thought to be the main cause of the kidney damage. However, recent studies have shown that the list of autoantibidies that have renal tropism and deposit in the kidney in LN is increasing and the link between anti-dsDNA and renal pathology is weak due to potential confounders. Aspecific bindings of dsDNA with cationic antibodies and of anti-dsDNA with several renal antigens such as actinin, laminin, entactin, and annexinA2 raised doubts about the specific target of these antibodies in the kidney. Moreover, the isotype of anti-dsDNA in SLE and LN has never received adequate interest until the recent observation that IgG2 are preponderant over IgG1, IgG3 and IgG4. Based on the above background, recent studies investigated the involvement of anti-dsDNA IgG2 and of other antibodies in LN. It was concluded that circulating anti-dsDNA IgG2 levels do not distinguish between LN versus non-renal SLE, and, in patients with LN, their levels do not change over time. Circulating levels of other antibodies such as anti-ENO1 and anti-H2 IgG2 were, instead, higher in LN vs non-renal SLE at the time of diagnosis and decreased following therapies. Finally, new classes of renal antibodies that potentially modify the anti-inflammatory response in the kidney are emerging as new co-actors in the pathogenetic scenario. They have been defined as 'second wave antibodies' for the link with detoxifying mechanisms limiting the oxidative stress in glomeruli that are classically stimulated in a second phase of inflammation. These findings have important clinical implications that may modify the laboratory approach to LN. Serum levels of anti-ENO1 and anti-H2 IgG2 should be measured in the follow up of patients for designing the length of therapies and identify those patients who respond to treatments. Anti-SOD2 could help to monitor and potentiate the anti-inflammatory response in the kidney.
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Autoanticorpos , Nefrite Lúpica , Nefrite Lúpica/imunologia , Nefrite Lúpica/diagnóstico , Humanos , Autoanticorpos/imunologia , Autoanticorpos/sangue , Animais , Anticorpos Antinucleares/imunologia , Anticorpos Antinucleares/sangue , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Autoantígenos/imunologiaRESUMO
Background: A renewed interest for activity and chronicity indices as predictors of lupus nephritis (LN) outcome has emerged. Revised National Institutes of Health activity and chronicity indices have been proposed to classify LN lesions, but they should be validated by future studies. The aims of this study were (1) to detect the histologic features associated with the development of kidney function impairment (KFI), and (2) to identify the best clinical-histologic model to predict KFI at time of kidney biopsy. Methods: Patients with LN who had more than ten glomeruli per kidney biopsy specimen were admitted to the study. Univariate and multivariate logistic regression and Cox proportional hazards models were used to investigate whether activity and chronicity indices could predict KFI development. Results: Among 203 participants with LN followed for 14 years, correlations were found between the activity index, and its components, and clinical-laboratory signs of active LN at baseline. The chronicity index was correlated with serum creatinine. Thus, serum creatinine was significantly and directly correlated with both activity and chronicity indices. In the multivariate analysis, glomerulosclerosis (OR, 3.05; 95% CI, 1.17 to 7.91; P=0.02) and fibrous crescents (OR, 6.84; 95% CI, 3.22 to 14.52; P<0.001) associated with either moderate/severe tubular atrophy (OR, 3.17; 95% CI, 1.04 to 9.64; P=0.04), or with interstitial fibrosis (OR, 2.36; 95% CI, 1.05 to 5.32; P=0.04), predicted KFI. Considering both clinical and histologic features, serum creatinine (OR, 1.68; 95% CI, 1.31 to 2.15; P<0.001), arterial hypertension (OR, 4.64; 95% CI, 1.90 to 11.32; P<0.001), glomerulosclerosis (OR, 2.12; 95% CI, 1.00 to 4.50; P=0.05), and fibrous crescents (OR, 5.18; 95% CI, 2.43 to 11.04; P<0.001) independently predicted KFI. Older age (P<0.001) and longer delay between clinical onset of LN and kidney biopsy (P<0.001) were significantly correlated with baseline chronicity index. Conclusions: The chronicity index and its components, but not the activity index, were significantly associated with an impairment of kidney function. The Cox model showed that serum creatinine, arterial hypertension, chronic glomerular lesions, and delay in kidney biopsy predicted KFI. These data reinforce the importance of timely kidney biopsy in LN.
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Nefrite Lúpica , Biópsia , Creatinina , Humanos , Rim/patologia , Glomérulos Renais/patologia , Nefrite Lúpica/diagnóstico , Estados UnidosRESUMO
OBJECTIVE: To investigate second kidney biopsy as predictor of end-stage kidney disease (ESKD) in active lupus nephritis (LN). METHODS: Patients with biopsy-proven LN (International Society of Nephrology/Renal Pathology Society 2003) who had undergone a second kidney biopsy between January 1990 and December 2018 were included. Clinical and histological findings at first and at second biopsy were analysed with Cox proportional hazard models to predict ESKD, defined as start of kidney replacement therapy. Survival curves were calculated with Kaplan-Meier method. RESULTS: Ninety-two patients with LN were included, 87% females, mean follow-up 17.9±10.1 years. Reasons for second kidney biopsy encompassed nephritic flares (n=28, 30.4%), proteinuric flares (n=46, 50%) or lack of renal response (n=18, 19.5%). Class switch from first biopsy occurred in 50.5% of cases, mainly from non-proliferative towards proliferative classes. Class IV remained stable in over 50% of cases. Twenty-five patients (27.2%) developed ESKD, mostly belonging to the nephritic flare group (17/28, 60.7%). Independent predictors of ESKD at second biopsy were activity index (AI; (HR 95% CI) 1.20 (1.03 to 1.41), p=0.022), chronicity index (CI; 1.41 (1.09 to 1.82), p=0.008) and 24h-proteinuria (1.22 (1.04 to 1.42), p=0.013). AI≥2 (log-rank p=0.031), CI >4 (log-rank p=0.001) or proteinuria ≥3.5 g/day (log-rank=0.009) identified thresholds for higher ESKD risk. In a subgroup analysis, glomerular activity and tubular chronicity mostly accounted for AI and CI association with ESKD. No histological or laboratory predictors emerged at first biopsy (95% CI): AI: 0.88 to 1.19; CI: 0.66 to 1.20; proteinuria 0.85 to 1.08. CONCLUSIONS: Findings at second but not at first kidney biopsy in patients with persistently active or relapsing LN inform about ESKD development in a long-term follow-up.
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Falência Renal Crônica , Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Biópsia , Feminino , Humanos , Rim/patologia , Falência Renal Crônica/complicações , Falência Renal Crônica/patologia , Lúpus Eritematoso Sistêmico/complicações , Nefrite Lúpica/patologia , Masculino , Proteinúria/complicações , Proteinúria/patologia , Estudos RetrospectivosRESUMO
BACKGROUND: Central venous catheter use is rising in chronic and acute hemodialysis. Catheter-related bloodstream infections are a major complication of central venous catheter use. This article examines clinical factors associated with catheter-related bloodstream infections incidence. METHODS: In this retrospective, single-center study, 413 patients undergoing extracorporeal treatments between 1 February 2014 and 31 January 2017 with 560 central venous catheters were recruited. Clinical parameters, such as gender, age, kidney disease status, diabetes, immunosuppression, and vintage dialysis, were collected at study entry. An incidence rate ratio (95% confidence interval) was calculated to assess the association between catheter-related bloodstream infections incidence rate and each clinical variable/central venous catheter type. Significant associations at the univariate analyses were investigated with multivariate Cox models. RESULTS: During a cumulative time of 66,686 catheter-days, 54 catheter-related bloodstream infections (incidence rate: 0.81) events occurred. Gram negative bacteria were more frequent in patients with age < 80 years (16 (36%) vs. 0, p = 0.02). At the univariate analyses, male sex (incidence rate ratio: 1.9 (1.1-3.5), p = 0.03), age < 80 years (incidence rate ratio: 2.4 (1.1-5.5), p = 0.016) and acute kidney injury (incidence rate ratio: 5.6 (3.1-10), p < 0.0001) were associated with higher catheter-related bloodstream infections incidence rate. Compared with tunneled jugular central venous catheter, higher catheter-related bloodstream infections incidence rate was associated with non-tunneled jugular (incidence rate ratio: 6.45 (2.99-13.56), p < 0.0001) and non-tunneled femoral (incidence rate ratio: 12.90 (5.87-27.61), p < 0.0001) central venous catheter use; tunneled femoral central venous catheter was associated with higher non-significant incidence rate (incidence rate ratio: 2.45 (0.93-5.85), p = 0.07). The multivariate analyses showed that acute kidney injury (hazard ratio: 3.03 (1.38-6.67), p = 0.006), non-tunneled (hazard ratio: 3.11 (1.30-7.41), p = 0.01) and femoral (hazard ratio: 2.63 (1.36-5.07), p = 0.004) central venous catheter were associated with higher catheter-related bloodstream infections incidence rate. CONCLUSION: Central venous catheter characteristics and acute kidney injury are independently associated with higher catheter-related bloodstream infections rate.
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Infecções Relacionadas a Cateter/epidemiologia , Cateterismo Venoso Central/efeitos adversos , Cateteres de Demora/efeitos adversos , Cateteres Venosos Centrais/efeitos adversos , Diálise Renal , Injúria Renal Aguda/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Infecções Relacionadas a Cateter/diagnóstico , Infecções Relacionadas a Cateter/microbiologia , Cateterismo Venoso Central/instrumentação , Feminino , Unidades Hospitalares , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Nefrologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
COVID-19 is a life-threatening infection among elderly patients, comorbid patients, or transplanted patients. Lombardy (region of Italy), accounts for 786,324 cases as of 21 April 2021. We retrospectively describe our single Centre experience in 82 adult kidney-transplant patients with COVID-19 infection during two pandemic outbreaks: 27 (first outbreak) and 65 (second outbreak). Thirty-seven patients were hospitalized (HP) and sixty-five were home managed (HM). Infection presented with fever (80%), cough (51%), and dyspnea (33%). HP were older (60 ± 11 vs. 50 ± 14 years, p = 0.001), had more severe respiratory symptoms (dyspnea 62.1%, p < 0.0001-cough 67% p = 0.008), and a longer length of disease (30 ± 28 vs. 21 ± 10, p = 0.04). The incidence of acute kidney injury (AKI) was 29.7% (p < 0.0001). Steroid dosage was increased in 66% of patients (p = 0.0003), while calcineurin inhibitors were reduced by up to one third in 45% of cases, p < 0.0001. Eleven patients died (13%). HM patients recovered completely without sequelae. In the overall cohort, AKI development (p = 0.006 OR 50.4 CI 95% 3.0-836) and age (p = 0.04 OR 1.1 CI 95% 1.0-1.2) were the most important factors influencing the probability of death during the infection. Although we report a relatively low incidence of infection (5.1%) the incidence of death is almost four times higher than it is in the general population.
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In 32-kidney transplanted patients (KTxps), the safety and the effects on BMD and mineral metabolism (MM) of one-year treatment with denosumab (DB) were studied. Femoral and vertebral BMD and T-score, FRAX score and vertebral fractures (sVF) before (T0) and after 12 months (T12) of treatment were measured. MM, renal parameters, hypocalcemic episodes (HpCa), urinary tract infections (UTI), major graft and KTxps outcomes were monitored. The cohort was composed mainly of females, n = 21. We had 29 KTxps on steroid therapy and 22 KTxps on vitamin D supplementation. At T0, 25 and 7 KTxps had femoral osteoporosis (F-OPS) and osteopenia (F-OPS), respectively. Twenty-three and six KTxps had vertebral osteoporosis (V-OPS) and osteopenia (V-OPS), respectively. Seventeen KTxps had sVF. At T12, T-score increased at femoral and vertebral sites (p = 0.05, p = 0.008). The prevalence of F-OPS and V-OPS reduced from 78% to 69% and from 72% to 50%, respectively. Twenty-five KTxps ameliorated FRAX score and two KTxps had novel sVF. At T12, a slight reduction of Ca was present, without HpCa. Four KTxps had UTI. No graft rejections, loss of graft or deaths were reported. Our preliminary results show a good efficacy and safety of DB in KTxps. Longer and randomized studies involving more KTxps might elucidate the possible primary role of DB in the treatment of bone disorders in KTxps.
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BACKGROUND: The ideal long-term maintenance therapy of Lupus Nephritis (LN) is still a matter of debate. The present study was aimed at comparing the efficacy/safety profile of cyclosporine (CsA), mycophenolate mofetil (MMF) and azathioprine (AZA) in long-term maintenance therapy of LN. METHODS: We performed a retrospective study of patients with biopsy-proven active LN. After induction therapy, all patients received maintenance therapy with CsA, MMF or AZA based on medical decision. Primary endpoint was complete renal remission (CRR) after 8 years (defined as proteinuria < 0.5 g/24 h, eGFR > 60 ml/min/1.73 mq); secondary endpoints were: CRR after 1 year, renal and extrarenal flares, progression of chronic kidney disease (CKD stage 3 or above) and side-effects. RESULTS: Out of 106 patients, 34 received CsA, 36 MMF and 36 AZA. Clinical and histological characteristics at start of induction therapy were comparable among groups. At start of maintenance therapy, CsA patients had significantly higher proteinuria (P = 0.004) or nephrotic syndrome (P = 0.024) and significantly lower CRR (23.5% vs 55.5% on MMF and 41.7% on AZA, P = 0.024). At one year, CRR was similar in the three groups (79.4% on CsA, 63.8% on MMF, 58.3% on AZA, P = 0.2). At 8 years, the primary endpoint was achieved by 79.4% of CsA vs 83.3% of MMF and 77.8% of AZA patients (P = 0.83); 24 h proteinuria, serum creatinine, eGFR were similar. CKD stage 3 or above developed in 8.8% of CsA, in 8.3% of MMF and in 8.3% of AZA patients (P = 0.92). Flares-free survival curves and incidence of side-effects were not different. CONCLUSIONS: This is the first study comparing CsA, MMF and AZA on long-term LN maintenance therapy. All treatments had similar efficacy in achieving and maintaining CRR, despite more severe baseline clinical features in patients treated with CsA.
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Nefrite Lúpica , Ácido Micofenólico , Azatioprina/efeitos adversos , Ciclosporina/efeitos adversos , Seguimentos , Humanos , Imunossupressores/efeitos adversos , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/tratamento farmacológico , Ácido Micofenólico/efeitos adversos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Objective: The long-term outcome of children born to SLE mothers still represents a controversial topic in literature, with some studies reporting a possible increased prevalence of different neurologic and psychiatric diseases (NPD), including neurodevelopmental disorders (ND), and in particular learning disorders (LD). Different risk factors have been advocated, such as the in utero exposure to auto-antibodies and drugs, particularly Azathioprine (AZA). Methods: A case-control study was designed to compare pregnancies treated with AZA (cases) with those not treated with AZA (controls). All the pregnancies had been prospectively followed in two Italian centers. The match was based upon renal involvement, antiphospholipid (aPL) status, maternal age at pregnancy (±5 years) and child's age at the time of the study (±2 years). SLE mothers were interviewed by a telephone survey, particularly focused on the presence of a certified NPD in their children ≥6 years of age. Results: Twenty-seven cases and 65 controls were similar in terms of demographic, immunological and clinical features, except for a higher rate of SLE flares during pregnancy in cases (22.2% vs. 10.8%, p:0.191). The 92 children had a mean age of 14.0 years at the time of the survey; 11 had at least one NPD (12.0%). The frequency of each single NPD was similar to that of the general pediatric population and no association was found with either the in utero exposure to AZA, or other specific factors (auto-antibodies, disease activity, obstetric complications, prematurity). Conclusion: The long-term neuropsychiatric outcome of the children born to SLE mothers did not show neither an increased frequency of NPD as compared to the general pediatric population nor a specific pattern of NPD. The in utero exposure to AZA was not associated with the development of NPD in this case-control study of prospectively-followed pregnancies. NPD are complex conditions and large prospective studies are needed to capture the wide range of variables that may contribute to their development in the offspring of SLE women.