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ANCA-associated vasculitides (AAV) comprise granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis. All forms may involve different organ systems, yet kidney and lung involvement are common and fatal in many cases. Here, we aimed to determine the predictive value of pulmonary disease manifestation and individual CT findings in AAV patients. Available CT scans and clinical information on mortality, renal outcomes, occurrence of relapses and damage scores were analysed retrospectively from a tertiary rheumatology center in Germany. We included a total of 94 AAV patients (49 with GPA, 41 with MPA). Forty-four patients had lung involvement with available CT scans, 70.5% of which with GPA and 72.7% with renal involvement. Nodule formation and cavities were more frequent among GPA patients, whereas ground-glass opacities (GGO), ILD and pleural effusion were observed predominantly in MPA patients. Over a median follow-up of 37 months, GPA patients had a slightly higher overall mortality, whereas end-stage kidney failure rates were significantly increased in MPA patients. Relapse frequencies were comparable between both entities. The presence of GGO and pleural effusion were associated with higher relapse rates, whereas nodules were negatively correlated with relapses. Notably, RTX-treated patients had less infections as compared to individuals under different therapies. Our data demonstrate the outstanding importance of characteristic CT patterns in AAV diagnosis assessment. Especially certain CT patterns including GGO and pleura effusion may help to identify patients who are at higher risk for relapsing disease.
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In everyday clinical practice, immunologically mediated systemic vasculitides are among the rare diseases, meaning that basic knowledge of major symptoms and indicative laboratory findings is crucial for the inclusion of these complex clinical entities in differential diagnostic considerations. For many years, systemic vasculitides have been classified according to the primarily affected vessel size, distinguishing large, medium-sized, and small vessels. Pain is very often one of the main complaints of these diseases, be it, for example, the temporally accentuated headache in giant cell arteritis, the early morning myalgias in the shoulder and hip girdle in polymyalgia rheumatica, or the mononeuritis multiplex in eosinophilic granulomatosis with polyangiitis. General symptoms such as fever, weight loss, and night sweats are often accompanied by greatly increased parameters of inflammation. In addition, organ-specific symptoms and/or laboratory abnormalities may provide crucial information. These include ENT symptoms, pulmonary or skin manifestations, as well as signs of renal involvement, such as peripheral edema, rise in blood pressure, hematuria, proteinuria, or a rapid loss of kidney function. If there is reasonable suspicion of disease, patients should be transferred to specialized centers with an interdisciplinary team. In most cases, an immunosuppressive therapy regimen is required, although in recent years the path towards avoiding high glucocorticoid doses with many side effects has been paved by the use of novel therapies.
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Síndrome de Churg-Strauss , Granulomatosis con Poliangitis , Humanos , Granulomatosis con Poliangitis/diagnóstico , Granulomatosis con Poliangitis/terapia , CefaleaRESUMEN
The mechanisms underlying Parkinson's disease (PD) etiology are only partially understood despite intensive research conducted in the field. Recent evidence suggests that early neurodevelopmental defects might play a role in cellular susceptibility to neurodegeneration. To study the early developmental contribution of GBA mutations in PD we used patient-derived iPSCs carrying a heterozygous N370S mutation in the GBA gene. Patient-specific midbrain organoids displayed GBA-PD relevant phenotypes such as reduction of GCase activity, autophagy impairment, and mitochondrial dysfunction. Genome-scale metabolic (GEM) modeling predicted changes in lipid metabolism which were validated with lipidomics analysis, showing significant differences in the lipidome of GBA-PD. In addition, patient-specific midbrain organoids exhibited a decrease in the number and complexity of dopaminergic neurons. This was accompanied by an increase in the neural progenitor population showing signs of oxidative stress-induced damage and premature cellular senescence. These results provide insights into how GBA mutations may lead to neurodevelopmental defects thereby predisposing to PD pathology.
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Organoids are emerging in vitro models of human physiology. Neural models require the evaluation of functional activity of single cells and networks, which is commonly measured by microelectrode arrays. The characteristics of organoids clash with existing in vitro or in vivo microelectrode arrays. With inspiration from implantable mesh electronics and growth of organoids on polymer scaffolds, we fabricated suspended hammock-like mesh microelectrode arrays for neural organoids. We have demonstrated the growth of organoids enveloping these meshes and the culture of organoids on meshes for up to one year. Furthermore, we present proof-of-principle recordings of spontaneous electrical activity across the volume of an organoid. Our concept enables a new class of microelectrode arrays for in vitro models of three-dimensional electrically active tissue.
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Técnicas Biosensibles , Mallas Quirúrgicas , Humanos , Microelectrodos , Organoides , Electrofisiología/métodosRESUMEN
PURPOSE: Osteoarthritis (OA) patients demonstrated higher Osteopontin (OPN) plasma, serum, and synovial fluid concentrations than healthy individuals. In the present study, we aimed to investigate whether OPN could be used as a diagnostic or prognostic marker for OA symptom/disease severity. METHODS: Using Web of Science, PubMed, Scopus, and Embase, we conducted a systematic review and meta-analysis of studies that measured OPN levels in OA patients' plasma, serum, or synovial fluid. After setting the eligibility criteria, data extraction, and quality assessment of the identified studies, we performed statistical analysis using Revman 5.4 and Open Meta analyst. RESULTS: OPN has been found to be associated with advanced knee joint damage in OA patients. In addition, higher expression of OPN is thought to be associated with disease progression. Nevertheless, further studies should examine the role of other markers of chronic bone damage, such as leptin and sclerostin. This systematic review and meta-analysis included 14 studies with a total of 776 cases and 530 controls. OPN was significantly elevated in osteoarthritis patients' plasma, serum, and synovial fluid samples, with significant heterogeneity between studies. CONCLUSION: We recommend that OPN plasma and synovial fluid levels be measured as a diagnostic and prognostic marker to determine the severity of OA symptoms.
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Osteoartritis , Osteopontina , Humanos , Osteopontina/metabolismo , Osteoartritis/diagnóstico , Osteoartritis/metabolismo , Líquido Sinovial/metabolismo , Biomarcadores/metabolismo , Huesos/metabolismoRESUMEN
BACKGROUND: A dysregulated 'gut-kidney axis' may contribute to immunoglobulin A nephropathy (IgAN). We studied whether IgAN patients have disturbed intestinal permeability. METHODS: In a prospective, cross sectional, pilot study we assessed intestinal permeability in 35 IgAN patients, 18 patients with non-IgAN glomerulonephritides (GNs) and 19 healthy controls. After an overnight fast, trial participants ingested a multi-sugar solution and samples were obtained from 0 to 2, 2 to 5- and 5 to 24-h urine portions. Urinary sugar concentrations were quantified using isocratic ion-exchange high performance liquid chromatography. Indices of small intestinal permeability (0-2-h lactulose/L-rhamnose (L/R) ratio), distal small intestinal and proximal colonic permeability (2-5-h sucralose/erythritol (S/E) ratio) and colonic permeability (5-24-h sucralose/erythritol (S/E) ratio) were evaluated. Associations between groups and indices of intestinal permeability were investigated by a linear mixed model. RESULTS: Small intestinal permeability (0-2 h L/R-ratio) was significantly increased in patients with glomerular diseases versus healthy controls. More precisely, increased small intestinal permeability was exclusively noted in non-IgAN GN patients, whereas IgAN patients exhibited a trend towards elevated small intestinal permeability. In total, 54% of patients with IgAN and 67% of non-IgAN GN patients had increased small intestinal permeability. Neither distal small intestinal and proximal colonic permeability nor colonic gut permeability indices (i.e., 2-5 h and 5-24 h S/E ratios) were significantly different between controls and any of the GN patient groups. CONCLUSION: The present single center pilot study suggests that disturbed intestinal permeability is common in patients with glomerular diseases and is not specific for IgAN. TRIAL REGISTRATION NUMBER: German Clinical Trials Register DRKS00021533, Date: 24.04.2020.
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Glomerulonefritis por IGA , Humanos , Estudios Prospectivos , Estudios Transversales , Proyectos Piloto , Ramnosa , Permeabilidad , EritritolRESUMEN
Immunoglobulin A (IgA) mediates mucosal responses to food antigens and the intestinal microbiome and is involved in susceptibility to mucosal pathogens, celiac disease, inflammatory bowel disease, and IgA nephropathy. We performed a genome-wide association study of serum IgA levels in 41,263 individuals of diverse ancestries and identified 20 genome-wide significant loci, including 9 known and 11 novel loci. Co-localization analyses with expression QTLs prioritized candidate genes for 14 of 20 significant loci. Most loci encoded genes that produced immune defects and IgA abnormalities when genetically manipulated in mice. We also observed positive genetic correlations of serum IgA levels with IgA nephropathy, type 2 diabetes, and body mass index, and negative correlations with celiac disease, inflammatory bowel disease, and several infections. Mendelian randomization supported elevated serum IgA as a causal factor in IgA nephropathy. African ancestry was consistently associated with higher serum IgA levels and greater frequency of IgA-increasing alleles compared to other ancestries. Our findings provide novel insights into the genetic regulation of IgA levels and its potential role in human disease.
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Enfermedad Celíaca , Diabetes Mellitus Tipo 2 , Glomerulonefritis por IGA , Enfermedades Inflamatorias del Intestino , Humanos , Ratones , Animales , Glomerulonefritis por IGA/genética , Glomerulonefritis por IGA/complicaciones , Estudio de Asociación del Genoma Completo , Enfermedad Celíaca/genética , Predisposición Genética a la Enfermedad , Diabetes Mellitus Tipo 2/complicaciones , Inmunoglobulina A/genética , Riñón/metabolismoRESUMEN
Assessing the prognosis is essential in chronic diseases, such as IgA nephropathy. The 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend the "International IgAN Prediction Tool" (available at www.qxmd.com) for this. The key limitation was that the tool was only validated at the time of the kidney biopsy. An improved algorithm is now described, which allows assessing the prognosis at 1 or 2 years after biopsy. Herein, we review the strengths, limitations, and potential clinical usefulness of this new prediction tool.
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Glomerulonefritis por IGA , Fallo Renal Crónico , Biopsia , Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis por IGA/patología , Glomerulonefritis por IGA/terapia , Humanos , Riñón/patología , Fallo Renal Crónico/patología , PronósticoRESUMEN
T helper cells aid B cells with the production of antibodies and thus play a central role in disease development of systemic lupus erythematosus (SLE). Numerous T helper cell abnormalities have been described in SLE patients that contribute to disease pathophysiology and provide suitable targets for therapeutic intervention. In addition, T effector cell also play a less well-defined role in SLE. This review focusses on underlying molecular mechanisms of different T cell alterations in SLE.
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Lupus Eritematoso Sistémico , Linfocitos B , Humanos , Linfocitos T Colaboradores-Inductores , Linfocitos T ReguladoresRESUMEN
Several studies have pointed to retinal involvement in COVID-19, yet many questions remain regarding the ability of SARS-CoV-2 to infect and replicate in retinal cells and its effects on the retina. Here, we have used human pluripotent stem cell-derived retinal organoids to study retinal infection by SARS-CoV-2. Indeed, SARS-CoV-2 can infect and replicate in retinal organoids, as it is shown to infect different retinal lineages, such as retinal ganglion cells and photoreceptors. SARS-CoV-2 infection of retinal organoids also induces the expression of several inflammatory genes, such as interleukin 33, a gene associated with acute COVID-19 and retinal degeneration. Finally, we show that the use of antibodies to block ACE2 significantly reduces SARS-CoV-2 infection of retinal organoids, indicating that SARS-CoV-2 infects retinal cells in an ACE2-dependent manner. These results suggest a retinal involvement in COVID-19 and emphasize the need to monitor retinal pathologies as potential sequelae of "long COVID."
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COVID-19 , Enzima Convertidora de Angiotensina 2 , COVID-19/complicaciones , Humanos , Organoides/metabolismo , Retina , Células Ganglionares de la Retina , SARS-CoV-2 , Síndrome Post Agudo de COVID-19RESUMEN
Parkinson's disease (PD) is a neurodegenerative disease with unknown cause in the majority of patients, who are therefore considered "idiopathic" (IPD). PD predominantly affects dopaminergic neurons in the substantia nigra pars compacta (SNpc), yet the pathology is not limited to this cell type. Advancing age is considered the main risk factor for the development of IPD and greatly influences the function of microglia, the immune cells of the brain. With increasing age, microglia become dysfunctional and release pro-inflammatory factors into the extracellular space, which promote neuronal cell death. Accordingly, neuroinflammation has also been described as a feature of PD. So far, studies exploring inflammatory pathways in IPD patient samples have primarily focused on blood-derived immune cells or brain sections, but rarely investigated patient microglia in vitro. Accordingly, we decided to explore the contribution of microglia to IPD in a comparative manner using, both, iPSC-derived cultures and postmortem tissue. Our meta-analysis of published RNAseq datasets indicated an upregulation of IL10 and IL1B in nigral tissue from IPD patients. We observed increased expression levels of these cytokines in microglia compared to neurons using our single-cell midbrain atlas. Moreover, IL10 and IL1B were upregulated in IPD compared to control microglia. Next, to validate these findings in vitro, we generated IPD patient microglia from iPSCs using an established differentiation protocol. IPD microglia were more readily primed as indicated by elevated IL1B and IL10 gene expression and higher mRNA and protein levels of NLRP3 after LPS treatment. In addition, IPD microglia had higher phagocytic capacity under basal conditions-a phenotype that was further exacerbated upon stimulation with LPS, suggesting an aberrant microglial function. Our results demonstrate the significance of microglia as the key player in the neuroinflammation process in IPD. While our study highlights the importance of microglia-mediated inflammatory signaling in IPD, further investigations will be needed to explore particular disease mechanisms in these cells.
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IgA nephropathy (IgAN) is the most common type of glomerulonephritis in Asia and the Western world. In most patients, it follows an asymptomatic to oligosymptomatic course and GFR loss, if any, is slow. The mainstay of therapy therefore is optimized supportive care, i.e., measures that lower blood pressure, reduce proteinuria, minimize lifestyle risk factors, and otherwise help to reduce non-specific insults to the kidneys. The value of immunosuppression has become controversial and if at all, systemic high-dose corticosteroid therapy should be considered for a few months taking into account patient characteristics that would caution against or preclude such therapy. In addition, adverse events related to corticosteroid therapy markedly increase as GFR declines. Beyond corticosteroids, there is little evidence that any additional immunosuppression is helpful, with the exception of mycophenolate mofetil in patients of Asian descent. A considerable number of clinical trials ranging from enteric coated budesonide to blockade of B-cell function to complement inhibitors are currently ongoing and will hopefully allow a more targeted therapy of high-risk patients with progressive IgAN in the future.
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Glomerulonefritis por IGA , Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis por IGA/tratamiento farmacológico , Glomerulonefritis por IGA/etiología , Humanos , Terapia de Inmunosupresión , Inmunosupresores/efectos adversos , Riñón , Proteinuria/inducido químicamente , Proteinuria/tratamiento farmacológicoRESUMEN
In COVID-19, guidelines recommend a urinalysis on hospital admission as SARS-CoV-2 renal tropism, post-mortem, was associated with disease severity and mortality. Following the hypothesis from our pilot study, we now validate an algorithm harnessing urinalysis to predict the outcome and the need for ICU resources on admission to hospital. Patients were screened for urinalysis, serum albumin (SA) and antithrombin III activity (AT-III) obtained prospectively on admission. The risk for an unfavorable course was categorized as (1) "low", (2) "intermediate" or (3) "high", depending on (1) normal urinalysis, (2) abnormal urinalysis with SA ≥ 2 g/dL and AT-III ≥ 70%, or (3) abnormal urinalysis with SA or AT-III abnormality. Time to ICU admission or death served as the primary endpoint. Among 223 screened patients, 145 were eligible for enrollment, 43 falling into the low, 84 intermediate, and 18 into high-risk categories. An abnormal urinalysis significantly elevated the risk for ICU admission or death (63.7% vs. 27.9%; HR 2.6; 95%-CI 1.4 to 4.9; p = 0.0020) and was 100% in the high-risk group. Having an abnormal urinalysis was associated with mortality, a need for mechanical ventilation, extra-corporeal membrane oxygenation or renal replacement therapy. In conclusion, our data confirm that COVID-19-associated urine abnormalities on admission predict disease aggravation and the need for ICU (ClinicalTrials.gov number NCT04347824).
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Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease worldwide and since its first description extensive research has identified a number of key central pathogenetic contributors, including genetic, immunological and environmental factors. Along with its multifaceted pathophysiology, the clinical presentation of IgAN varies, ranging from mild forms with only minor urinary findings and preserved renal function to cases that rapidly progress to end-stage renal disease. Because of this, early identification of patients at risk for a progressive course is urgently needed. The search for valid and easily accessible biomarkers showed urinary Dickkopf-3 as a promising candidate to predict the course of kidney function. In addition, a recently established IgAN risk prediction tool derived from an international cohort of IgAN patients allows estimation of the risk of a 50% loss of kidney function over several years upon diagnosis. This might serve as a significant tool to individually predict the course of renal function by combining biometric, clinical, histological and treatment information at the time of diagnosis. Today there is no doubt that a comprehensive supportive treatment regimen is the main pillar for all IgAN patients. The value of an additional immunosuppressive treatment in IgAN patients at risk for disease progression is less clear. Early risk stratification and individualized therapies would be desirable for IgAN patients to facilitate the choice of treatment strategies, which is still a matter of ongoing discussion.
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Glomerulonefritis por IGA , Estudios de Cohortes , Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis por IGA/tratamiento farmacológico , Humanos , Inmunoglobulina A , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/etiología , Glomérulos Renales , Medicina de PrecisiónRESUMEN
ABSTRACT: Chronic renal replacement therapy by either a kidney transplant (KTX) or hemodialysis (HD) predisposes patients to an increased risk for adverse outcomes of COVID-19. However, details on this interaction remain incomplete. To provide further characterization, we undertook a retrospective observational cohort analysis of the majority of the hemodialysis and renal transplant population affected by the first regional outbreak of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) in Germany. In a region of 250,000 inhabitants we identified a total of 21 cases with SARS-CoV-2 among 100 KTX and 260 HD patients, that is, 7 KTX with COVID-19, 14 HD with COVID-19, and 3 HD with asymptomatic carrier status. As a first observation, KTX recipients exhibited trends for a higher mortality (43 vs 18%) and a higher proportion of acute respiratory distress syndrome (ARDS) (57 vs 27%) when compared to their HD counterparts. As a novel finding, development of ARDS was significantly associated with the time spent on previous renal replacement therapy (RRT), defined as the composite of dialysis time and time on the transplant (non-ARDS 4.3 vs ARDS 10.6âyears, Pâ=â.016). Multivariate logistic regression analysis showed an OR of 1.7 per year of RRT. The association remained robust when analysis was confined to KTX patients (5.1 vs 13.2âyears, Pâ=â.002) or when correlating the time spent on a renal transplant alone (Pâ=â.038). Similarly, longer RRT correlated with death vs survival (Pâ=â.0002). In conclusion our data suggest renal replacement vintage as a novel risk factor for COVID-19-associated ARDS and death. The findings should be validated by larger cohorts.
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COVID-19/epidemiología , Fallo Renal Crónico/epidemiología , Trasplante de Riñón/mortalidad , Diálisis Renal/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , COVID-19/mortalidad , Femenino , Alemania/epidemiología , Humanos , Fallo Renal Crónico/terapia , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2RESUMEN
BACKGROUND: Inhibitors of the renin-angiotensin system (RAS) are cornerstones of supportive therapy in patients with IgA nephropathy (IgAN). We analyzed the effects of single versus dual RAS blockaQueryde during our randomized STOP-IgAN trial. METHODS: STOP-IgAN participants with available successive information on their RAS treatment regimen and renal outcomes during the randomized 3-year trial phase were stratified post hoc into two groups, i.e. patients under continuous single or dual RAS blocker therapy over the entire 3 years of the trial phase. Primary and secondary STOP-IgAN trial endpoints, i.e. frequencies of full clinical remission, eGFR-loss ≥ 15 and ≥ 30 ml/min/1.73 m2 and ESRD onset, were analyzed by logistic regression and linear mixed effects models. RESULTS: Among the 112 patients included in the present analysis, 82 (73%) were maintained on single and 30 (27%) on dual RAS inhibitor therapy throughout the trial. Neither RAS blocker strategy significantly affected full clinical remission, eGFR-loss rates, onset of ESRD. Proteinuria moderately increased in patients under dual RAS blockade by 0.1 g/g creatinine during the 3-year trial phase. This was particularly evident in patients without additional immunosuppression during the randomized trial phase, where proteinuria increased by 0.2 g/g creatinine in the dual RAS blockade group. In contrast, proteinuria decreased in patients under single RAS blocker therapy by 0.3 g/g creatinine. The course of eGFR remained stable and did not differ between the RAS treatment strategies. CONCLUSION: In the STOP-IgAN cohort, neither RAS blocker regimen altered renal outcomes. Patients on dual RAS blockade even exhibited higher proteinuria over the 3-year trial phase.