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[This corrects the article DOI: 10.1016/j.ekir.2024.01.016.].
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Introduction: This retrospective study on patients with biopsy-proven lupus nephritis (LN) aimed to assess the probability of sustained clinical remission (sCR) and to investigate sCR effects on disease flares and impaired kidney function (IKF). Methods: sCR was defined as clinical-Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) = 0 and estimated glomerular filtration rate (eGFR) >60 ml/min per 1.73 m2 lasting ≥1 year; IKF: eGFR <60 ml/min per 1.73 m2 for >3 months. We analyzed the probability of achieving and maintaining sCR, and the yearly risk of flare. Cox models were used to identify predictors of sCR and IKF with variables analyzed as time-dependent covariates when appropriate. Results: Of 303 patients followed-up with for 14.8 (interquartile range: 9.8-22) years, 257 (84.8%) achieved sCR. The probability of achieving sCR progressively increased over time reaching 90% at 15 years. Baseline age (hazard ratio [HR]: 1.017; 95% confidence interval [CI]: 0.005-1.029; P = 0.004), hydroxychloroquine intake (HR: 1.385; 95% CI: 1.051-1.825; P = 0.021), and absence of arterial hypertension (HR: 0.699; 95% CI: 0.532-0.921; P = 0.011) were independent predictors of sCR. Among patients who achieved sCR, 142 (55.3%) developed a lupus flare after a median time of 3.6 (2.3-5.9) years. In the remaining 115 patients, sCR persisted for 9.5 (5.8-14.5) years. The probability of sCR to persist at 15 years was 38%. SLE flare risk decreased to 10%, 5%, and 2% in patients with sCR lasting <5, 5 to 10, and >10 years, respectively. At the last observation, 57 patients (18.81%) had IKF. sCR achievement (HR: 0.18, P < 0.001) and its duration (HR: 0.83, P < 0.001) were protective against IKF. Conclusion: sCR is an achievable target in LN management and protects against IKF. The longer the sCR, the higher the chance of its persistence and the lower the risk of SLE flares.
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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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Autoanticuerpos , Nefritis Lúpica , Nefritis Lúpica/inmunología , Nefritis Lúpica/diagnóstico , Humanos , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Animales , Anticuerpos Antinucleares/inmunología , Anticuerpos Antinucleares/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangre , Autoantígenos/inmunologíaRESUMEN
Background: The prevalence of atrial fibrillation (AF) in end stage kidney disease (ESKD) patients undergoing dialysis is high, however, the high risk of bleeding often hampers with a correct anticoagulation in ESKD patients with AF, despite high thromboembolic risk. Left atrial appendage (LAA) occlusion is a anticoagulation (OAT) for thromboembolism prevention in AF populations with high hemorrhagic risk. Methods and Results: The purpose of the study was to evaluate the efficacy and safety of LAA occlusion in a cohort of dialysis patients undergoing the procedure (LAA occlusion cohort, n = 106), in comparison with two other ESKD cohorts, one taking warfarin (Warfarin cohort, n = 114) and the other without anticoagulation therapy (No-OAT cohort, n = 148). After a median follow-up of 4 years, a Cox regression model, adjusted for possible confounding factors, showed that the hazard ratios (HRs) of thromboembolic events in the LAA occlusion cohort were 0.19 (95%CI 0.04-0.96; p = 0.045) and 0.16 (95%CI 0.04-0.66; p = 0.011) as compared with Warfarin and No-OAT cohorts, respectively. The HR of bleeding in the LAA occlusion cohort was 0.37 (95%CI 0.16-0.83; p = 0.017) compared to Warfarin cohort, while there were no significant differences between the LAA occlusion and the No-OAT cohort (HR 0.51; 95%CI 0.23-1.12; p = 0.094). Adjusted Cox regression models showed lower mortality in patients undergoing LAA occlusion as compared with both the Warfarin cohort (HR 0.60; 95%CI 0.38-0.94; p = 0.027) and no-OAT cohort (HR 0.52; 95%CI 0.34-0.78; p = 0.002). Thromboembolic events in the LAA occlusion cohort were lower than expected according to the CHA2DS2VASc score (1.7 [95%CI 0.3-3.0] vs 6.7 events per 100 person/years, p < 0.001). Conclusion: In ESKD patients with AF, LAA occlusion is safe and effective and is associated with reduced mortality compared with OAT or no therapy.
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Idiopathic membranous nephropathy (IMN) is a pathologically defined disorder of the glomerulus, primarily responsible for nephrotic syndromes (NS) in nondiabetic adults. The underlying molecular mechanisms are still not completely clarified. To explore possible molecular and functional signatures, an optimised mass spectrometry (MS) method based on next-generation data-independent acquisition combined with ion-mobility was applied to serum of patients affected by IMN (n = 15) or by other glomerulopathies (PN) (n = 15). The statistical comparison highlighted a panel of 57 de-regulated proteins with a significant increase in lipoprotein-related proteins (APOC1, APOB, APOA1, APOL1 and LCAT) and a substantial quantitative alteration of key serpins (including A4, D1, A7, A6, F2, F1 and 1) possibly associated with IMN or NS and podocyte stress. A critical dysregulation in metabolisms of lipids (e.g., VLDL assembly and clearance) likely to be related to known hyperlipidemia in IMN, along with involvement of non-classical complement pathways and a putative enrolment of ficolin-2 in sustaining the activation of the lectin-mediated complement system have been pinpointed. Moreover, mannose receptor CD206 (MRC1-down in IMN) and biotinidase (BTD-up in IMN) are able alone to accurately distinguish IMN vs. PN. To conclude, our work provides key proteomic insights into the IMN complexity, opening the way to an efficient stratification of MN patients.
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Glomerulonefritis Membranosa , Síndrome Nefrótico , Adulto , Humanos , Proteoma , Proteómica , Glomérulos Renales/metabolismo , Apolipoproteína L1RESUMEN
The prevalence and clinical significance of anti-neutrophil cytoplasmic antibodies [ANCAs] in patients with lupus nephritis [LN] is not fully elucidated. Our aim was to determine whether LN patients with ANCA positivity had different clinicopathological features and outcomes compared to ANCA-negative patients. METHODS: Among our LN patients we retrospectively selected those who underwent ANCA testing the day of the kidney biopsy and before the start of induction treatment. Clinical/histopathological features at kidney biopsy and renal outcome of ANCA-positive patients were compared with those of ANCA-negative subjects. RESULTS: We included 116 Caucasian LN patients in the study; 16 patients [13.8%] were ANCA-positive. At kidney biopsy, ANCA-positive patients presented more frequently with an acute nephritic syndrome than ANCA-negative ones; the difference however does not reach statistical significance [44 vs. 25%, p = 0.13]. At histological evaluation, proliferative classes [100% vs 73%; p = 0.02], class IV [68.8% vs 33%; p < 0.01] and necrotizing tuft lesions [27 vs 7%, p = 0.04] were more frequent, and the activity index was higher [10 vs 7; p = 0.03] in ANCA-positive than in ANCA-negative patients. Despite worse histological features, after a 10-year observation period, there were no significant differences in the number of patients with chronic kidney function impairment (defined as eGFR < 60 mL/min per 1.73 m2) between the ANCA-positive and negative groups [24.2 vs 26.6%, p = 0.9]. This could be the result of the more aggressive therapy, with rituximab plus cyclophosphamide, that ANCA-positive patients received more frequently than ANCA-negative ones [25 vs. 1.3%, p < 0.01]. CONCLUSIONS: ANCA-positive LN patients frequently have histological markers of severe activity (proliferative classes and high activity index) that require timely diagnosis and aggressive therapy to limit the development of irreversible chronic kidney damage.
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Nefritis Lúpica , Humanos , Nefritis Lúpica/diagnóstico , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/epidemiología , Anticuerpos Anticitoplasma de Neutrófilos , Estudios Retrospectivos , Relevancia Clínica , PrevalenciaRESUMEN
OBJECTIVES: Antineutrophil cytoplasmic antibody (ANCA) may appear in the course of rheumatic diseases (RD) but the kidney involvement is very rare and the prognosis poorly defined. METHODS: We retrospectively identified patients with RD among 153 patients with ANCA glomerulonephritis (ANCA-GN). Their clinical/histological presentation and outcome were compared with that of primitive ANCA-GN patients (1:4) matched for sex, age, ANCA type and follow-up. RESULTS: Nine patients (5.9%) were included: three had rheumatoid arthritis, two systemic sclerosis, two psoriatic arthritis, one ankylosing spondylitis and one seronegative spondylarthritis. Seven patients were MPO positive, two PR3 positive. ANCA-GN developed 74 months after RD with microscopic haematuria and acute kidney dysfunction in all but two patients. After 68-month follow-up, four patients (44.4%) achieved response to therapy defined as eGFR >60/min/1,73 m2 or stable, no microscopic haematuria and negative ANCA. At ANCA-GN diagnosis, serum creatinine and C-reactive protein were significantly lower in RD-ANCA-GN (2.38 vs. 3.34mg/dl, p=0.05 and 2.3mg/dl vs. 7.2mg/dl; p=0.05, respectively) while haemoglobin was higher (12.3g/dl vs. 9.3g/dl p<0.01) than in the 36 primitive ANCA-GN patients of control group. At kidney biopsy, focal forms were more frequent in RD patients (44.45% vs. 18.75%, p=0.11). The treatment between the two groups was not significantly different. At last observation, the percentage of patients with ESKD was lower in RD than in controls (11.1%vs. 30.5%; p=0.23). CONCLUSIONS: Patients with RD seem to develop ANCA-GN with less severe clinical/histological kidney involvement, and better long-term kidney survival than primitive ANCA-GN. This is probably due to the strict monitoring of RD patients that allows a prompter ANCA-GN diagnosis and treatment.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Glomerulonefritis , Enfermedades Reumáticas , Humanos , Anticuerpos Anticitoplasma de Neutrófilos , Hematuria/etiología , Estudios Retrospectivos , Riñón/patología , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológicoRESUMEN
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.
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Anexina A1 , Lupus Eritematoso Sistémico , Nefritis Lúpica , Humanos , Anticuerpos Antinucleares , Autoanticuerpos , Inmunoglobulina G , Anexina A1/metabolismo , ADNRESUMEN
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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Fallo Renal Crónico , Lupus Eritematoso Sistémico , Nefritis Lúpica , Biopsia , Femenino , Humanos , Riñón/patología , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/patología , Lupus Eritematoso Sistémico/complicaciones , Nefritis Lúpica/patología , Masculino , Proteinuria/complicaciones , Proteinuria/patología , Estudios RetrospectivosRESUMEN
The podocyte injury, and consequent proteinuria, that characterize the pathology of idiopathic membranous nephropathy (IMN) is mediated by an autoimmune reaction against podocyte antigens. In particular, the activation of pathways leading to abundant renal deposits of complement is likely to involve the binding of mannose-binding lectin (MBL) to aberrant glycans on immunoglobulins. To obtain a landscape of circulatory IgG Fc glycosylation characterizing this disease, we conducted a systematic N-glycan profiling study of IgG1, 2, and 4 by mass spectrometry. The cohort included 57 IMN patients, a pathological control group with nephrotic syndrome (PN) (n = 20), and 88 healthy control subjects. The effect of sex and age was assessed in all groups and controlled by rigorous matching. Several IgG Fc glycan traits were found to be associated with IMN. Interestingly, among them, only IgG4-related results were specific for IMN and not for PN. Hypo-galactosylation of IgG4, already shown for IMN, was observed to occur in the absence of core fucose, in line with a probable increase of pro-inflammatory IgG. In addition, elevated levels of fucosylated IgG4, along with low levels of hybrid-type glycans, were detected. Some of these IgG4 alterations are likely to be more pronounced in high PLA2R (phospholipase A2 receptor) patients. IgG Fc glycosylation patterns associated with IMN warrant further studies of their role in disease mechanisms and may eventually enrich the diagnostic spectrum regarding patient stratification.
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Glomerulonefritis Membranosa , Síndrome Nefrótico , Podocitos , Autoanticuerpos , Femenino , Glomerulonefritis Membranosa/patología , Humanos , Inmunoglobulina G , Riñón/metabolismo , Masculino , Síndrome Nefrótico/metabolismo , Podocitos/patologíaRESUMEN
Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a rare autoimmune disease characterized by medium and small vessels inflammation. Cardiac vasculitic involvement is one of the most severe manifestations with a significant impact on patients' long-term prognosis: anyway, a specific therapeutic approach for heart involvement in EGPA has not been explored yet. Current regimen consists of a long-term therapy with high dose of glucocorticoids, causing the well-known related-adverse events; immunosuppressive drugs are used in patients with severe manifestations, with some limitations. New therapeutic approaches are needed for patients with refractory disease or contraindications to conventional therapies. The quest for the ideal therapy is going toward a more and more personalized approach: on the one hand, efforts are made to use already existing therapies in the most appropriate way; on the other hand, new insights into EGPA pathogenesis allow the discovery of new targets, as demonstrated by mepolizumab and rituximab, targeting eosinophils, and B-cell compartments. This review summarizes the emerging therapies used in EGPA, focusing on the most recent studies on biologics and analyzing their efficacy and safety.
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Clinical Trial registry name and registration number: Zeus study, NCT02403115.
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Enfermedades Renales , Nefritis Lúpica , Humanos , Anticuerpos , RiñónRESUMEN
OBJECTIVES: Fabry disease (FD) is an X-linked lysosomal storage disorder, resulting from a deficiency of the enzyme α-galactosidase A, responsible for breaking down glycolipids such as globotriaosylceramide and its deacylated derivative, globotriaosylsphingosine (LysoGb3). Here, we compare the levels of LysoGb3 in dried blood spots (DBS) and plasma in patients with classic and late-onset phenotypes. METHODS: LysoGb3 measurements were performed in 104 FD patients, 39 males and 65 females. Venous blood was collected. A portion was spotted onto filter paper and another portion separated to obtain plasma. The LysoGb3 concentrations in DBS and plasma were determined by highly sensitive electrospray ionization liquid chromatography tandem mass spectrometry. Agreement between different matrices was assessed using linear regression and Bland Altman analysis. RESULTS: The method on DBS was validated by evaluating its precision, accuracy, matrix effect, recovery, and stability. The analytical performances were verified by comparison of a total of 104 paired DBS and plasma samples from as many FD patients (representing 46 GLA variants). There was a strong correlation between plasma and the corresponding DBS LysoGb3 concentrations, with few exceptions. Discrepancies were observed in anemic patients with typically low hematocrit levels compared to the normal range. CONCLUSIONS: The method proved to be efficient for the rapid analysis of LysoGb3. DBS provides a convenient, sensitive, and reproducible method for measuring LysoGb3 levels for diagnosis, initial phenotypic assignment, and therapeutic monitoring in patients with FD.
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Enfermedad de Fabry , Esfingolípidos , Biomarcadores , Pruebas con Sangre Seca , Enfermedad de Fabry/diagnóstico , Femenino , Glucolípidos , Humanos , Masculino , alfa-Galactosidasa/genéticaRESUMEN
The formation of neutrophil extracellular traps (NETs) is a strategy utilized by neutrophils for capturing infective agents. Extracellular traps consist in a physical net made of DNA and intracellular proteins externalized from neutrophils, where bacteria and viruses are entrapped and killed by proteolysis. A complex series of events contributes to achieving NET formation: signaling from infectious triggers comes first, followed by decondensation of chromatin and extrusion of the nucleosome components (DNA, histones) from the nucleus and, after cell membrane breakdown, outside the cell. NETs are composed of either DNA or nucleosome proteins and hundreds of cytoplasm proteins, a part of which undergo post-translational modification during the steps leading to NETs. There is a thin balance between the production and the removal of circulating NETs from blood where digestion of DNA by circulating DNases 1 and IL3 has a critical role. A delay in NET removal may have consequences for autoimmunity. Recent studies have shown that circulating NET levels are increased in systemic lupus erythematosus (SLE) for a functional block of NET removal mediated by anti-DNase antibodies or, in rare cases, by DNase IL3 mutations. In SLE, the persistence in circulation of NETs signifies elevated concentrations of either free DNA/nucleosome components and oxidized proteins that, in some cases, are recognized as non-self and presented to B-cells by Toll-like receptor 9 (TLR9). In this way, it is activated as an immunologic response, leading to the formation of IgG2 auto-antibody. Monitoring serum NET levels represents a potential new way to herald the development of renal lesions and has clinical implications. Modulating the balance between NET formation and removal is one of the objectives of basic research that are aimed to design new drugs for SLE. Clinical Trial Registration Number: The Zeus study was registered at https://clinicaltrials.gov (study number: NCT02403115).
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Takayasu Arteritis (TAK) is a large-vessel vasculitis that preferentially involves the aorta and its primary branches. Cardiac involvement is frequent in TAK and is a major determinant of the patient's outcome. Glucocorticoids (GC) are the mainstay of therapy for TAK, with high doses of GC effective to induce remission. However, relapses are common and lead to repeated and prolonged GC treatments with high risk of related adverse events. Potential GC toxicity is a major concern, especially because patients with TAK are young and need to be treated for several years, often for the whole life. Conventional immunosuppressive drugs are used in patients with severe manifestations but present some limitations. New therapeutic approaches are needed for patients with refractory disease or contraindications to conventional therapies. Fortunately, major progress has been made in understanding TAK pathogenesis, leading to the development of targeted biotherapies. In particular, IL-6 and TNF-α pathways seems to be the most promising therapeutic targets, with emerging data on Tocilizumab and TNF inhibitors. On the other hand, new insights on JAK-Inhibitors, Rituximab, Ustekinumab and Abatacept have been explored in recent studies. This review summarizes the emerging therapies used in TAK, focusing on the most recent studies on biologics and analyzing their efficacy and safety.
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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.
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Anticuerpos Antinucleares/inmunología , Inmunoglobulina G/inmunología , Lupus Eritematoso Sistémico/inmunología , Nefritis Lúpica/inmunología , Adolescente , Adulto , Anexina A1/inmunología , Especificidad de Anticuerpos , Síndrome Antifosfolípido/inmunología , Artritis Reumatoide/inmunología , Biomarcadores de Tumor/inmunología , Complemento C1q/inmunología , Estudios Transversales , ADN/inmunología , Proteínas de Unión al ADN/inmunología , Femenino , Histonas/inmunología , Humanos , Masculino , Persona de Mediana Edad , Nucleosomas/inmunología , Fosfopiruvato Hidratasa/inmunología , Proteínas Supresoras de Tumor/inmunología , Enfermedades Indiferenciadas del Tejido Conectivo/inmunología , Adulto JovenRESUMEN
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).
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Inmunoglobulina G/inmunología , Lupus Eritematoso Sistémico/inmunología , Nefritis Lúpica/inmunología , Adulto , Anexina A1/inmunología , Anticuerpos Antinucleares/inmunología , Autoanticuerpos/inmunología , Biomarcadores de Tumor/inmunología , Complemento C1q/inmunología , ADN/inmunología , Proteínas de Unión al ADN/inmunología , Progresión de la Enfermedad , Femenino , Histonas/inmunología , Humanos , Masculino , Persona de Mediana Edad , Nucleosomas/inmunología , Fosfopiruvato Hidratasa/inmunología , Estudios Prospectivos , Proteínas Supresoras de Tumor/inmunologíaRESUMEN
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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Nefritis Lúpica/complicaciones , Nefritis Lúpica/tratamiento farmacológico , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/etiología , Adulto , Femenino , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Pronóstico , Resultado del TratamientoRESUMEN
BACKGROUND: Belimumab (Benlysta) is currently approved for the treatment of active Lupus despite standard therapy. Few data are available on the efficacy of this drug in lupus nephritis (LN). METHODS: 17 LN female followed in two Nephrology Italian Unit received belimumab for a median period of 36 months (range 6-42 months). The indications were: arthralgia in 3 patients, cutaneous manifestations in 2, residual proteinuria in 8, and the need to reduce steroids for severe side effects in 4. Of interest, 1 patient started therapy during Peritoneal Dialysis and continued after kidney transplantation due to non-responsive arthralgias. RESULTS: Arthralgia and skin manifestations resolved in all patients. Proteinuria normalized in three patients and stabilized in all but one of the others. Steroids were indefinitely stopped in six patients (35%) and reduced to around 40% of the basal dosage in the other patients. During belimumab therapy, three extrarenal and one renal SLE flares were diagnosed accounting for a rate of renal flares of 0.02/patient/year. No major adverse events leading to therapy withdrawal occurred. CLINICAL CASE: Arthralgia resolved, immunological parameters improved and prednisone could be reduced within few months in the patient who started belimumab during peritoneal dialysis. After kidney transplantation belimumab was stopped but due to arthralgias unresponsive to standard immunosuppressive therapy it was restarted with success. CONCLUSIONS: Belimumab allows the achievement of complete response together with the withdrawal or the reduction of corticosteroids in almost all our patients. Of interest its satisfactory use in a patient in peritoneal dialysis and after kidney transplantation.
Asunto(s)
Lupus Eritematoso Sistémico , Nefritis Lúpica , Anticuerpos Monoclonales Humanizados , Femenino , Glucocorticoides/efectos adversos , Humanos , Inmunosupresores/efectos adversos , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Nefritis Lúpica/tratamiento farmacológico , Diálisis Renal , Resultado del TratamientoRESUMEN
Rapidly progressive glomerulonephritis (RPGN) is mainly caused by anti-glomerular basement membrane (GBM) antibody-mediated glomerulonephritis, immune-complex or anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides and leads to rapid loss of renal function. Detection of ANCA and autoantibodies (autoAbs) to GBM and dsDNA enables early diagnosis and appropriate treatment of RPGN aiding in preventing end-stage renal disease.Determination of ANCA on neutrophils (ANCA) as well as autoAbs to myeloperoxidase (MPO-ANCA), proteinase 3 (PR3-ANCA), GBM, and dsDNA was performed by the novel multiplex CytoBead technology combining cell- and microbead-based autoAb analyses by automated indirect immunofluorescence (IIF). Forty patients with granulomatosis with polyangiitis (GPA), 48 with microscopic polyangiitis (MPA), 2 with eosinophilic GPA, 42 with systemic lupus erythematosus (SLE), 43 with Goodpasture syndrome (GPS), 57 with infectious diseases (INF), and 55 healthy subjects (HS) were analyzed and findings compared with classical single testing.The CytoBead assay revealed for GPA, MPA, GPS, and SLE the following diagnostic sensitivities and for HS and INF the corresponding specificities: PR3-ANCA, 85.0% and 100.0%; MPO-ANCA, 77.1% and 99.1%; anti-GBM autoAb, 88.4% and 96.4%; anti-dsDNA autoAb, 83.3% and 97.3%; ANCA, 91.1% and 99.1%, respectively. Agreement with classical enzyme-linked immunosorbent assay and IIF was very good for anti-GBM autoAb, MPO-ANCA, PR3-ANCA, and ANCA, respectively. Anti-dsDNA autoAb comparative analysis demonstrated fair agreement only and a significant difference (Pâ=â0.0001).The CytoBead technology provides a unique multiplex reaction environment for simultaneous RPGN-specific autoAb testing. CytoBead RPGN assay is a promising alternative to time-consuming single parameter analysis and, thus, is well suited for emergency situations.