RESUMO
The complement system, an important part of the innate system, is known to play a central role in many immune mediated kidney diseases. All parts of the complement system including the classical, alternative, and mannose-binding lectin pathways have been implicated in complement-mediated kidney injury. Although complement components are thought to be mainly synthesized in the liver and activated in the circulation, emerging data suggest that complement is synthesized and activated inside the kidney leading to direct injury. Urinary complement biomarkers are likely a better reflection of inflammation within the kidneys as compared to traditional serum complement biomarkers which may be influenced by systemic inflammation. In addition, urinary complement biomarkers have the advantage of being non-invasive and easily accessible. With the rise of therapies targeting the complement pathways, there is a critical need to better understand the role of complement in kidney diseases and to develop reliable and non-invasive biomarkers to assess disease activity, predict treatment response and guide therapeutic interventions. In this review, we summarized the current knowledge on urinary complement biomarkers of kidney diseases due to immune complex deposition (lupus nephritis, primary membranous nephropathy, IgA nephropathy) and due to activation of the alternative pathway (C3 glomerulopathy, thrombotic microangiography, ANCA-associated vasculitis). We also address the limitations of current research and propose future directions for the discovery of urinary complement biomarkers.
Assuntos
Biomarcadores , Proteínas do Sistema Complemento , Nefropatias , Humanos , Biomarcadores/urina , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/urina , Proteínas do Sistema Complemento/metabolismo , Nefropatias/urina , Nefropatias/imunologia , Nefropatias/diagnóstico , Animais , Ativação do ComplementoRESUMO
OBJECTIVE: Extramusculoskeletal manifestations of spondyloarthritis (SpA) may precede the development of articular features. Patients seen in ophthalmology, dermatology, and gastroenterology clinics with uveitis, psoriasis, or inflammatory bowel disease (IBD) may have undiagnosed SpA. We set out to identify and evaluate screening tools for SpA in patients with psoriasis, uveitis, and IBD and determine factors that influence the performance of these instruments. METHODS: This scoping review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase, and Web of Science were searched from inception to January 2022. RESULTS: We identified 13 screening tools for psoriatic arthritis, 2 SpA screening tools for uveitis, and 3 SpA screening tools for IBD. All screening tools were patient-oriented questionnaires except for the Dublin Uveitis Evaluation Tool, a physician-applied algorithm. The questionnaires varied in length, scoring method, cutoff score, and spectrum of included SpA features. Average completion time was less than five minutes. Across the three patient populations, the sensitivities and specificities of these screening tools were comparable in the primary validation cohorts. Sensitivities and specificities were generally lower in secondary validation studies, with marked variability among cohorts. CONCLUSION: Our results highlight the heterogeneity and limitations of existing SpA screening tools. Although these tools show promise for use within a specific target population, none are generalizable to all patients with extramusculoskeletal manifestations at risk of SpA. Future studies should explore the utility of a generic patient-oriented SpA screening tool that can be applied to patients with psoriasis, uveitis, or IBD; is easy to use and comprehend; and captures all clinical domains of SpA.
Assuntos
Doenças Inflamatórias Intestinais , Psoríase , Espondilartrite , Uveíte , Humanos , Uveíte/diagnóstico , Uveíte/etiologia , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/diagnóstico , Psoríase/diagnóstico , Psoríase/complicações , Espondilartrite/diagnóstico , Espondilartrite/complicações , Inquéritos e Questionários , Programas de Rastreamento/métodos , Valor Preditivo dos Testes , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Intrarenal complement activation has been implicated in the pathogenesis of tubulointerstitial fibrosis in lupus nephritis (LN) based on prior animal studies. The assembly of the membrane attack complex (MAC) by complement C5b to C9 on the cell membrane leads to cytotoxic pores and cell lysis, while CD59 inhibits MAC formation by preventing C9 from joining the complex. We hypothesize that complement activation and imbalance between complement activation and inhibition, as defined by increased production of individual complement components and uncontrolled MAC activation relative to CD59 inhibition, are associated with interstitial fibrosis and tubular atrophy (IFTA) in LN and correlate with the key mediators of kidney fibrosis- transforming growth factor receptors beta (TGFRß), platelet-derived growth factor beta (PDGFß) and platelet-derived growth factor receptor beta (PDGFRß). METHODS: We included urine samples from 46 adults and pediatric biopsy-proven lupus nephritis patients who underwent clinically indicated kidney biopsies between 2010 and 2019. We compared individual urinary complement components and the urinary C9-to-CD59 ratio between LN patients with moderate/severe IFTA and none/mild IFTA. IFTA was defined as none/mild (<25% of interstitium affected) versus moderate/severe (≥ 25% of interstitium affected). Proteomics analysis was performed using mass spectrometry (Orbitrap Fusion Lumos, Thermo Scientific) and processed by the Proteome Discoverer. Urinary complement proteins enriched in LN patients with moderate/severe IFTA were correlated with serum creatinine, TGFßR1, TGFßR2, PDGFß, and PDGFRß. RESULTS: Of the 46 LN patients included in the study, 41 (89.1%) were women, 20 (43.5%) self-identified as Hispanic or Latino, and 26 (56.5%) self-identified as Black or African American. Ten of the 46 (21.7%) LN patients had moderate/severe IFTA on kidney biopsy. LN patients with moderate/severe IFTA had an increased urinary C9-to-CD59 ratio [median 0.91 (0.83-1.05) vs 0.81 (0.76-0.91), p=0.01]. Urinary C3 and CFI levels in LN patients with moderate/severe IFTA were higher compared to those with none/mild IFTA [C3 median (IQR) 24.4(23.5-25.5) vs. 20.2 (18.5-22.2), p= 0.02], [CFI medium (IQR) 28.8 (21.8-30.6) vs. 20.4 (18.5-22.9), p=0.01]. Complement C9, CD59, C3 and CFI correlated with TGFßR1, PDGFß, and PDGFRß, while C9, CD59 and C3 correlated with TGFßR2. CONCLUSION: This study is one of the first to compare the urinary complement profile in LN patients with moderate/severe IFTA and none/mild IFTA in human tissues. This study identified C3, CFI, and C9-to-CD59 ratio as potential markers of tubulointerstitial fibrosis in LN.
Assuntos
Nefrite Lúpica , Adulto , Animais , Humanos , Feminino , Criança , Masculino , Nefrite Lúpica/patologia , Proteômica , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Ativação do Complemento , Fibrose , AtrofiaRESUMO
Hypocomplementemia urticarial vasculitis syndrome (HUVS) is a rare form of systemic vasculitis which is characterized by the presence of urticaria and hypocomplementemia. The presence of recurrent and chronic urticarial rash is the dominant clinical finding in HUVS. Other manifestations including angioedema, arthritis, gastrointestinal symptoms, ocular inflammation, pulmonary involvement, renal involvement, and central nervous system involvement are also seen. Although the pathophysiology of HUVS is yet to be fully understood, it has been demonstrated that immune complex-mediated injury is the predominant mechanism responsible for severe systemic manifestations; a mechanism of injury similar to systemic lupus erythematosus (SLE). HUVS shared many clinicopathological features with SLE and it is prudent to question whether HUVS is a separate disease entity or SLE in evolution. Herein we present a case of a male patient who was diagnosed with SLE a year after being diagnosed with HUVS.
RESUMO
Adult-onset Still's disease (AOSD) is a rare autoinflammatory disease that typically presents with a triad of fever, evanescent rash, and arthritis. There is often a delay in diagnosis of AOSD due to its nonspecific clinical presentation, which may mimic other infectious, rheumatological disorders, and malignancies. Corticosteroids have been the cornerstone for the management of AOSD for the past many years. However, with the expanding understanding of its pathogenesis, novel therapeutic options targeting various cytokines are being increasingly recognized. Herein, we present a case of AOSD that was successfully treated with tocilizumab, a monoclonal antibody against the interleukin-6 (IL-6) receptor. For the purpose of this article, we also conducted a literature search to review the current therapeutic options available for the treatment of AOSD.
RESUMO
BACKGROUND: With increasing workload and dismal working conditions, healthcare professionals (HCPs) in India often suffer from burnout. Understanding the extent of these problems and the contributing factors is necessary to build a healthy workforce capable of serving the society. The purpose of this study was to systematically review and analyze: 1) the prevalence of burnout among HCPs in India and 2) the factors associated with burnout in this population. METHODS: A systematic search of MEDLINE and EMBASE, from the inception of these databases to October 2019, was conducted using keywords. The search results were screened to identify studies evaluating burnout among HCPs in India using a standard burnout tool. Using a random effect model, the pooled prevalence of burnout was estimated using Maslach Burnout Inventory (MBI) in three domains: emotional exhaustion (EE), depersonalization (DP), and personal accomplishment (PA). Risk factors for burnout were assessed qualitatively. RESULTS: A total of 15 studies assessing burnout in 3845 Indian HCPs were identified. The pooled prevalence of burnout was 24% in the EE domain, 27% in the DP domain, and 23% in the PA domain. Younger age, female gender, unmarried status, and difficult working conditions were associated with increased risk of burnout. CONCLUSION: Burnout is highly prevalent among Indian HCPs, with close to one-fourth of them suffering from burnout. A number of personal and professional factors are associated with burnout, and these should be considered while developing solutions to tackle burnout.