Autoantibodies against laminin-521 are pathogenic in anti-glomerular basement membrane disease.

Anti-glomerular basement membrane (anti-GBM) disease is an organ-specific autoimmune disorder characterized by autoantibodies against GBM components. Evidence from human inherited kidney diseases and animal models suggests that the α, ß, and γ chains of laminin-521 are all essential for maintaining the glomerular filtration barrier. We previously demonstrated that laminin-521 is a novel autoantigen within the GBM and that autoantibodies to laminin-521 are present in about one-third of patients. In the present study, we investigated the pathogenicity of autoantibodies against laminin-521 with clinical and animal studies. Herein, a rare case of anti-GBM disease was reported with circulating autoantibodies binding to laminin-521 but not to the NC1 domains of α1-α5(IV) collagen. Immunoblot identified circulating IgG from this patient bound laminin α5 and γ1 chains. A decrease in antibody levels was associated with improved clinical presentation after plasmapheresis and immunosuppressive treatments. Furthermore, immunization with laminin-521 in female Wistar-Kyoto rats induced crescentic glomerulonephritis with linear IgG deposits along the GBM, complement activation along with infiltration of T cells and macrophages. Lung hemorrhage occurred in 75.0% of the rats and was identified by the presence of erythrocyte infiltrates and hemosiderin-laden macrophages in the lung tissue. Sera and kidney-eluted antibodies from rats immunized with laminin-521 demonstrated specific IgG binding to laminin-521 but not to human α3(IV)NC1, while the opposite was observed in human α3(IV)NC1-immunized rats. Thus, our patient data and animal studies imply a possible independent pathogenic role of autoantibodies against laminin-521 in the development of anti-GBM disease.

Autoimmunity in Anti-Glomerular Basement Membrane Disease: A Review of Mechanisms and Prospects for Immunotherapy.

Anti-glomerular basement membrane (anti-GBM) disease is an organ-specific autoimmune disorder characterized by autoantibodies against the glomerular and alveolar basement membranes, leading to rapidly progressive glomerulonephritis and severe alveolar hemorrhage. The noncollagenous domain of the α3 chain of type IV collagen, α3(IV)NC1, contains the main target autoantigen in this disease. Epitope mapping studies of α3(IV)NC1 have identified several nephritogenic epitopes and critical residues that bind to autoantibodies and trigger anti-GBM disease. The discovery of novel target antigens has revealed the heterogeneous nature of this disease. In addition, both epitope spreading and mimicry have been implicated in the pathogenesis of anti-GBM disease. Epitope spreading refers to the development of autoimmunity to new autoepitopes, thus worsening disease progression, whereas epitope mimicry, which occurs via sharing of critical residues with microbial peptides, can initiate autoimmunity. An understanding of these autoimmune responses may open opportunities to explore potential new therapeutic approaches for this disease. We review how current advances in epitope mapping, identification of novel autoantigens, and the phenomena of epitope spreading and mimicry have heightened the understanding of autoimmunity in the pathogenesis of anti-GBM disease, and we discuss prospects for immunotherapy.

Epidemiology, clinical features, risk factors, and outcomes in anti-glomerular basement membrane disease: A systematic review and meta-analysis.

Anti-glomerular basement membrane (GBM) disease is a small-vessel vasculitis that represents the most aggressive form of autoimmune glomerulonephritis. The study aimed to investigate the prevalence, clinical characteristics, risk factors, and outcomes of anti-GBM disease through a systematic review and meta-analysis involving 47 studies with 2830 patients. The overall incidence of anti-GBM disease ranged from 0.60 to 1.79 per million population per annum. In rapidly progressive glomerulonephritis and crescentic glomerulonephritis, the pooled incidence rates were 8.0% and 12.8%, respectively. The pooled prevalence rates of anti-GBM antibodies, antineutrophil cytoplasmic antibodies (ANCA), and lung hemorrhage were 88.8%, 27.4%, and 32.6%, respectively. Patients with combined ANCA positivity demonstrated a prognosis comparable to those patients with only anti-GBM antibodies, though with differing clinical features. The pooled one-year patient and kidney survival rates were 76.2% and 30.2%, respectively. Kidney function on diagnosis and normal glomeruli percentage were identified as strong prognostic factors. This study represents the first comprehensive meta-analysis on anti-GBM disease, providing insights into its management. However, caution is warranted in interpreting some results due to the observational nature of the included studies and high heterogeneity.

Evaluation of the Risk Prediction Models in Predicting Kidney Outcomes in Antiglomerular Basement Membrane Disease.

Introduction: A previous study showed that the renal risk score (RRS) was transferrable to antiglomerular basement membrane (anti-GBM) disease and proposed a risk stratification according to the need of renal replacement therapy (RRT) and the percentage of normal glomeruli (N). Herein, we analyzed the risk factors associated with kidney outcomes in patients with biopsy-proven anti-GBM disease and evaluated these 2 prognosis systems. Methods: A total of 120 patients with biopsy-proven anti-GBM disease with complete clinicopathologic and outcome data were analyzed. Results: The median time to kidney biopsy was 41 days (interquartile range [IQR]: 22-63 days). RRT and N were the only independent predictors of end-stage kidney disease (ESKD). Patients with N ≥10% were more likely to achieve ESKD-free outcomes, even in the subcohort of patients who underwent posttreatment biopsies (P < 0.001). N and serum creatinine at presentation (cut-off values 750 µmol/l and 1300 µmol/l) were 2 independent factors for predicting kidney recovery. The RRS and the risk stratification tool exhibited predictive value for ESKD and could be transferred to patients with kidney biopsy following treatment (Harrell's C statistic [C] = 0.738 and C = 0.817, respectively). However, a cross-over of outcomes among groups was observed in the risk stratification tool in long-term follow-up, when patients with RRT and N ≥10% achieved better kidney outcomes than those without RRT but N <10%. Conclusion: Normal glomeruli percentage, even posttreatment, was a strong indicator for kidney outcomes, especially on long-term prognosis. Serum creatinine is a predictor for kidney recovery, independent of biopsy findings. The risk stratification tool for kidney survival was transferrable to patients with anti-GBM disease with biopsy following treatment in our cohort; however, this needs further validations for long-term outcomes.

High cut-off membranes in patients requiring renal replacement therapy: a systematic review and meta-analysis.

BACKGROUND: Whether high cut-off (HCO) membranes are more effective than high-flux (HF) membranes in patients requiring renal replacement therapy (RRT) remains controversial. The aim of this systematic review was to investigate the efficacy of HCO membranes regarding the clearance of inflammation-related mediators, ß2-microglobulin and urea; albumin loss; and all-cause mortality in patients requiring RRT. METHODS: We searched all relevant studies on PubMed, Embase, Web of Science, the Cochrane Library, and China National Knowledge Infrastructure, with no language or publication year restrictions. Two reviewers independently selected studies and extracted data using a prespecified extraction instrument. Only randomized controlled trials (RCTs) were included. Summary estimates of standardized mean differences (SMDs) or weighted mean differences (WMDs) and risk ratios (RRs) were obtained by fixed-effects or random-effects models. Sensitivity analyses and subgroup analyses were performed to determine the source of heterogeneity. RESULTS: Nineteen RCTs involving 710 participants were included in this systematic review. Compared with HF membranes, HCO membranes were more effective in reducing the plasma level of interleukin-6 (IL-6) (SMD -0.25, 95% confidence interval (CI) -0.48 to -0.01, P   =  0.04, I2  = 63.8%); however, no difference was observed in the clearance of tumor necrosis factor-α (TNF-α) (SMD 0.03, 95% CI -0.27 to 0.33, P  = 0.84, I2  = 4.3%), IL-10 (SMD 0.22, 95% CI -0.12 to 0.55, P  = 0.21, I2  = 0.0%), or urea (WMD -0.27, 95% CI -2.77 to 2.23, P  = 0.83, I2  = 19.6%). In addition, a more significant reduction ratio of ß 2 -microglobulin (WMD 14.8, 95% CI 3.78 to 25.82, P  = 0.01, I2  = 88.3%) and a more obvious loss of albumin (WMD -0.25, 95% CI -0.35 to -0.16, P  < 0.01, I2  = 40.8%) could be observed with the treatment of HCO membranes. For all-cause mortality, there was no difference between the two groups (risk ratio [RR] 1.10, 95% CI 0.87 to 1.40, P  = 0.43, I2  = 0.0%). CONCLUSIONS: Compared with HF membranes, HCO membranes might have additional benefits on the clearance of IL-6 and ß 2-microglobulin but not on TNF-α, IL-10, and urea. Albumin loss is more serious with the treatment of HCO membranes. There was no difference in all-cause mortality between HCO and HF membranes. Further larger high-quality RCTs are needed to strengthen the effects of HCO membranes.

The Prevalence and Characteristics of Circulating IgA Anti-Glomerular Basement Membrane Autoantibodies in Anti-Glomerular Basement Membrane Disease.

Introduction: In some cases, immunoglobulin (IgA)-mediated antiglomerular basement membrane (anti-GBM) disease has been reported. Whether circulating IgA anti-GBM antibodies affect the clinico-pathologic characteristics and outcome of typical anti-GBM disease deserves further study. Methods: Circulating IgA anti-α3(IV)NC1 antibodies were examined by enzyme-linked immunosorbent assay (ELISA) using recombinant human α3(IV)NC1 as solid phase antigens in 107 patients with anti-GBM disease and 115 controls. Clinical, pathological, and follow-up data of patients were retrospectively analyzed. Results: Circulating IgA anti-α3(IV)NC1 antibodies were found in 18.7% (20/107) of patients with anti-GBM disease but were not detected in healthy controls or in patients with other glomerular diseases. The positivity of circulating IgA anti-α3(IV)NC1 antibodies was not associated with whether the patient was with combined IgA nephropathy or other glomerulonephritis. Kidney immunofluorescence showed no statistical difference in IgA deposition between patients with circulating IgA anti-α3(IV)NC1 antibodies and patients without (30.0% vs. 40.4%, P = 0.725). The titers of circulating immunoglobulin G (IgG) anti-α3(IV)NC1 antibodies in patients with circulating IgA anti-α3(IV)NC1 antibodies were significantly higher than those without (200 [183.3, 200] vs. 161 [85.5, 200] U/ml, P = 0.005). There were no significant differences in kidney outcome and mortality between the 2 groups. Conclusion: Circulating IgA anti-α3(IV)NC1 antibodies occurred in 18.7% (20/107) of patients with anti-GBM in our center and were specific to anti-GBM disease. Patients with circulating IgA anti-α3(IV)NC1 antibodies showed a higher levels of serum IgG anti-α3(IV)NC1 antibodies than those without.

Application of extracorporeal therapies in critically ill COVID-19 patients.

The coronavirus disease 2019 (COVID-19) pandemic is a major public health event caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has spread widely all over the world. A high proportion of patients become severely or critically ill, and suffer high mortality due to respiratory failure and multiple organ dysfunction. Therefore, providing timely and effective treatment for critically ill patients is essential to reduce overall mortality. Convalescent plasma therapy and pharmacological treatments, such as aerosol inhalation of interferon-α (IFN-α), corticosteroids, and tocilizumab, have all been applied in clinical practice; however, their effects remain controversial. Recent studies have shown that extracorporeal therapies might have a potential role in treating critically ill COVID-19 patients. In this review, we examine the application of continuous renal replacement therapy (CRRT), therapeutic plasma exchange (TPE), hemoadsorption (HA), extracorporeal membrane oxygenation (ECMO), and extracorporeal carbon dioxide removal (ECCO2R) in critically ill COVID-19 patients to provide support for the further diagnosis and treatment of COVID-19.

Sacubitril/valsartan in chronic kidney disease: From pharmacological mechanism to clinical application.

Chronic kidney disease (CKD) is an irreversible, progressive disease characterized by persistent kidney damage, and significantly increased risks of cardiovascular event. However, therapeutic strategies to prevent or slow the progression of CKD remain limited. Sacubitril/valsartan (LCZ696), the representative of the first novel angiotensin receptor-neprilysin inhibitor, has been incorporated into clinical practice guidelines for improving outcomes as a milestone in patients with heart failure. Considering the complex and close relationship between CKD and heart failure, LCZ696 may be beneficial in the treatment of CKD. This review summarizes the pharmacological mechanism and clinical application of LCZ696 in patients with CKD, including its effect on cardiovascular risk and renal outcome, together with potential adverse events. Additionally, due to the influence of serum creatinine and estimated glomerular filtration rate on LCZ696 in patients with heart failure, we also discussed the effects of LCZ696 in patients with advanced CKD and end-stage renal disease. It should be noted that, current clinical studies on LCZ696 are mostly carried out in patients with heart failure, and renal indicators are selected as secondary outcomes. Therefore, more researches should be conducted in patients with CKD alone in the future, to determine the efficacy and safety of LCZ696 in patients with CKD.

Sleep disorders in Alzheimer's disease: the predictive roles and potential mechanisms.

Sleep disorders are common in patients with Alzheimer's disease, and can even occur in patients with amnestic mild cognitive impairment, which appears before Alzheimer's disease. Sleep disorders further impair cognitive function and accelerate the accumulation of amyloid-ß and tau in patients with Alzheimer's disease. At present, sleep disorders are considered as a risk factor for, and may be a predictor of, Alzheimer's disease development. Given that sleep disorders are encountered in other types of dementia and psychiatric conditions, sleep-related biomarkers to predict Alzheimer's disease need to have high specificity and sensitivity. Here, we summarize the major Alzheimer's disease-specific sleep changes, including abnormal non-rapid eye movement sleep, sleep fragmentation, and sleep-disordered breathing, and describe their ability to predict the onset of Alzheimer's disease at its earliest stages. Understanding the mechanisms underlying these sleep changes is also crucial if we are to clarify the role of sleep in Alzheimer's disease. This paper therefore explores some potential mechanisms that may contribute to sleep disorders, including dysregulation of the orexinergic, glutamatergic, and γ-aminobutyric acid systems and the circadian rhythm, together with amyloid-ß accumulation. This review could provide a theoretical basis for the development of drugs to treat Alzheimer's disease based on sleep disorders in future work.

Pharmacological Treatment of Vascular Dementia: A Molecular Mechanism Perspective.

Vascular dementia (VaD) is a neurodegenerative disease, with cognitive dysfunction attributable to cerebrovascular factors. At present, it is the second most frequently occurring type of dementia in older adults (after Alzheimer's disease). The underlying etiology of VaD has not been completely elucidated, which limits its management. Currently, there are no approved standard treatments for VaD. The drugs used in VaD are only suitable for symptomatic treatment and cannot prevent or reduce the occurrence and progression of VaD. This review summarizes the current status of pharmacological treatment for VaD, from the perspective of the molecular mechanisms specified in various pathogenic hypotheses, including oxidative stress, the central cholinergic system, neuroinflammation, neuronal apoptosis, and synaptic plasticity. As VaD is a chronic cerebrovascular disease with multifactorial etiology, combined therapy, targeting multiple pathophysiological factors, may be the future trend in VaD.

Harmine inhibits the proliferation and migration of glioblastoma cells via the FAK/AKT pathway.

AIMS: Glioblastoma is one of the most invasive tumors of the central nervous system, and has a high degree of malignancy and poor prognosis. Harmine, an active ingredient extracted from perennial herbs, has been reported to have obvious antitumor effects on various tumors. However, the effects of harmine on glioblastoma growth remain unknown. We here explored the effects of harmine on glioblastoma and its underlying molecular mechanisms related to tumorigenesis. MATERIALS AND METHODS: CCK-8 and immunofluorescent assay were performed to measure anti-proliferative effect of harmine on U251-MG and U373-MG cells. Wound healing assay was performed to measure the effects of harmine on cell migration. qRT-PCR and western blot were performed to detect the protein/gene expression. BALB/c nude mice bearing U251-MG xenografts was used to measure the effects of harmine on the growth of glioblastoma in vivo. KEY FINDINGS: Harmine treatment significantly suppressed the proliferation of U251-MG and U373-MG cells in a dose and time-dependent way. Mechanistically, harmine reduced the basal and EGF-enhanced the phosphorylation level of FAK and AKT. Moreover, harmine inhibited the cell viability of U251-MG and U373-MG cells by downregulating the phosphorylation of the FAK/AKT pathway. Besides, harmine significantly suppressed the migration of U251-MG cells by suppressing the expression of MMP2, MMP9 and VEGF. Subsequently, orthotopic xenograft models revealed that harmine treatment dramatically inhibited the growth of glioblastoma in vivo. SIGNIFICANCE: In conclusion, these results suggest that harmine suppresses the proliferation and migration of U251-MG and U373-MG cells by inhibiting the FAK/AKT signaling pathway. Our findings elucidate harmine could be a promising drug for glioblastoma therapy.

[Advances in the role of autoantibodies in diabetic nephropathy: Review].

Diabetic nephropathy (DN) is the most common cause of global end-stage renal disease (ESRD) and is one of the leading causes of mortality in patients with type 1 and type 2 diabetes. Recent studies have found that autoimmunity is closely related to the occurrence and development of DN, especially the autoantibodies which play a crucial role in the pathogenesis of DN. Currently, autoantibodies found in the serum of DN patients mainly include G-protein coupled receptor autoantibodies, pancreatic autoantibodies and autoantibodies related to endothelial cell damage. In the special environment of diabetes, high glucose (HG) can stimulate the production of a variety of autoantibodies, which can mediate the damage of renal function via different mechanisms and affect the progression of DN. Therefore, it is important to explore the role of autoantibodies in the pathogenesis of DN.

Exploring the bi-directional relationship between autophagy and Alzheimer's disease.

Alzheimer's disease (AD) is characterized by ß-amyloid (Aß) deposition and Tau phosphorylation, in which its pathogenesis has not been cleared so far. The metabolism of Aß and Tau is critically affected by the autophagy. Abnormal autophagy is thought to be involved in the pathogenesis of AD, regulating autophagy may become a new strategy for AD treatment. In the early stage of AD, the presence of Aß and Tau can induce autophagy to promote their clearance by means of mTOR-dependent and independent manners. As AD progress, the autophagy goes aberrant. As a result, Aß and Tau generate continually, which aggravates both autophagy dysfunction and AD. Besides, several related genes and proteins of AD can also adapt autophagy to make an effect on the AD development. There seems to be a bi-directional relationship between AD pathology and autophagy. At present, this article reviews this relationship from these aspects: (a) the signaling pathways of regulating autophagy; (b) the relationships between the autophagy and the processing of Aß; (c) Aß and Tau cause autophagy dysfunction; (d) normal autophagy promotes the clearance of Aß and Tau; (e) the relationships between the autophagy and both genes and proteins related to AD: TFEB, miRNAs, Beclin-1, Presenilin, and Nrf2; and (f) the small molecules regulating autophagy on AD therapy. All of the above may help to further elucidate the pathogenesis of AD and provide a theoretical basis for clinical treatment of AD.

Outcome of lung cancer patients with acute respiratory failure requiring mechanical ventilation.

To assess the weaning outcome of lung cancer patients with acute respiratory failure (ARF) requiring mechanical ventilation, we retrospectively analyzed the database of the respiratory intensive care unit at a university-affiliated tertiary care hospital. Charts were reviewed for cancer status, biochemistries before respiratory failure, causes of respiratory failure, acute physiology and chronic health evaluation (APACHE) III score, ventilatory settings, data recorded during spontaneous breathing, duration of ventilator days, and weaning outcome. Ninety-five consecutive respiratory failure events in 81 patients were recorded from January 1, 1995 through June 30, 1999. Twenty-six episodes ended with successful weaning (27.4%). Age, gender, and cancer status did not affect the weaning outcome. Serum albumin level, APACHE III score, highest fractional inspired O2 (FiO2) and highest positive end-expiratory pressure, organ failure, ability to shift to partial ventilatory support, and duration of mechanical ventilation could significantly influence the weaning outcome statistically. The overall hospital mortality rate was 85.2%. Our results suggested that lung cancer patients with ARF will have a better chance to wean if the initial APACHE III score was less than 70, use of FiO2 never exceeded 0.6, or less than 2 additional organ systems failed during the treatment course.