Search Results (233)

Mitochondrial dysfunction and macrophage dysregulation are well recognized as significant contributors to the pathogenesis of autoimmune diseases. However, the detailed mechanisms connecting these two factors remain poorly understood. This study hypothesizes that low but chronic interferon-gamma (IFN-γ) plays a critical role in these processes. To explore this, we utilized ARE-Del mice, a model characterized by sustained low-level IFN-γ expression and lupus nephritis (LN)-like symptoms. Age- and tissue-dependent gene expression analyses in ARE-Del mice revealed significant suppression of mitochondrial complex I components and activities, particularly in the kidneys. The genotype-dependent suppression of mitochondrial complex I indicates early disruption, which leads to macrophage dysfunction. Notably, remission restored gene expression of mitochondrial complex I and macrophage dysfunction in isolated renal macrophages from NZB/W lupus-prone mice. These findings suggest that chronic low-level IFN-γ disrupts mitochondrial complex I activity in macrophages, highlighting its role in the early pathogenesis of autoimmune diseases like lupus nephritis. This provides new insights into the molecular interactions underlying autoimmune pathogenesis and suggests potential targets for therapeutic intervention. Full article

Background: Anti-ETAR (endothelin A receptor) antibodies and anti-CXCR3 (C-X-C motif chemokine receptor 3) antibodies are types of non-HLA (human leukocyte antigens) antibodies that could have some influence on the course of glomerulonephritis. The authors aimed to study the influence of these antibodies’ levels on the course of specific glomerulonephritis types. Methods: We evaluated the anti-ETAR and anti-CXCR3 antibody levels in the serum of patients with membranous nephropathy (n = 18), focal and segmental glomerulosclerosis (FSGS) (n = 25), systemic lupus erythematosus (n = 17), IgA nephropathy (n = 14), mesangiocapillary glomerulonephritis (n = 6), anti-neutrophil cytoplasmic antibodies (c-ANCA) vasculitis (n = 40), and perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) vasculitis (n = 16), and we compared their levels with the control group (n = 22). Next, we observed the patients’ clinical parameters (serum creatinine, albumin, total protein) for 2 years and checked the correlation of the clinical course markers with basic receptor antibody level. Results: Our results indicate lower anti-ETAR antibody levels in patients with FSGS and IgA nephropathy compared to the control group. Both types of antibodies correlated with creatinine levels after 2 years of observation in IgA nephropathy. Both types of antibodies seemed to negatively influence the total protein and albumin levels in systemic lupus erythematosus. Conclusions: This prospective observation showed that anti-ETAR and anti-CXCR 3 antibody levels are connected with the course of IgA nephropathy and lupus nephritis. Full article

Historically, oxidants have been considered mechanisms of glomerulonephritis, but a direct cause–effect correlation has never been demonstrated. Several findings in the experimental model of autoimmune conditions with renal manifestations point to the up-regulation of an oxidant/anti-oxidant system after the initial deposition of autoantibodies in glomeruli. Traces of oxidants in glomeruli cannot be directly measured for their rapid metabolism, while indirect proof of their implications is derived from the observation that Superoxide Oxidase 2 (SOD2) is generated by podocytes after autoimmune stress. The up-regulation of other anti-oxidant systems takes place as well. Here, we discuss the concept that a second wave of antibodies targeting SOD2 is generated in autoimmune glomerulonephritis and may negatively influence the clinical outcome. Circulating and renal deposits of anti-SOD2 antibodies have been detected in patients with membranous nephropathy and lupus nephritis, two main examples of autoimmune disease of the kidney, which correlate with the clinical outcome. The presence of anti-SOD2 antibodies in circulation and in the kidney has been interpreted as a mechanism which modifies the normal tissue response to oxidative stress. Overall, these findings repropose the role of the oxidant/anti-oxidant balance in autoimmune glomerulonephritis. The same conclusion on the oxidant/anti-oxidant balance may be proposed in renal transplant. Patients receiving a renal graft may develop antibodies specific for Glutathione Synthetase (GST), which modulates the amount of GST disposable for rapid scavenging of reactive oxygen species (ROS). The presence of anti-GST antibodies in serum is a major cause of rejection. The perspective is to utilize molecules with known anti-oxidant effects to modulate the anti-oxidative response in autoimmune pathology of the kidney. A lot of molecules with known anti-oxidant effects can be utilized, many of which have already been proven effective in animal models of autoimmune glomerulonephritis. Many molecules with anti-oxidant activity are natural products; in some cases, they are constituents of diets. Owing to the simplicity of these drugs and the absence of important adverse effects, many anti-oxidants could be directly utilized in human beings. Full article

Background/Objectives: Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE), involving immune complex deposition in the kidneys. While renal biopsy is the diagnostic gold standard, its invasiveness limits frequent use, driving the need for non-invasive urinary biomarkers to monitor disease progression and response to treatment. This study aimed to identify and validate urinary biomarkers for LN. Methods: Data from 10 LN-related omics databases, including urine, PBMCs, and kidney tissue, were analyzed. Differentially expressed proteins (DEPs) and genes (DEGs) were identified, and candidate biomarkers were validated via ELISA in an independent cohort of 87 urine samples. Results: We identified 78 biomarkers, with 14 overlapping across transcriptomic categories. Novel urinary biomarkers, including SERPING1, SLPI, and CD48, were validated. Urinary CD163, VCAM1, and ALCAM levels showed significant differences between LN and healthy controls, while urinary immune complexes (ICx) demonstrated superior diagnostic performance, with urinary ALCAM-ICx and CCL21-ICx achieving the highest AUC values. Conclusions: Our findings highlight the potential of urinary immune complexes and antigens as non-invasive biomarkers for LN. ALCAM, CD163, and SERPING1-ICx, in particular, were found as promising candidates for a urinary biomarker panel to aid in the diagnosis and monitoring of LN. Full article

Background/Objectives: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the abnormal activation of autoreactive T and B cells, autoantibody production, complement activation, and immune-complex deposition, resulting in tissue damage. However, data on immunologic disturbances in SLE, particularly regarding flares, are scarce. Methods: We investigated 35 patients with SLE: 12 (34.3%) with disease exacerbation (SLE disease activity index [SLEDAI] ≥ 5 points) and 23 (65.7%) in remission (SLEDAI < 5 points). All patients met the 2019 EULAR/ACR SLE criteria. Flow cytometry was used to identify B cell subsets, including memory B cells. Results: In the whole patient group, SLEDAI was positively related to the percentage of transitional/regulatory B cells (r = 0.38, p = 0.034). Some lymphocyte subsets correlated with complement levels, e.g., the percentage of naïve and memory B cells showed associations with C3c complement (r = 0.43, p = 0.018 and r = −0.45, p = 0.016, respectively). Furthermore, regarding inflammatory markers, we found associations between C-reactive protein and the percentage of plasmablasts (r = 0.40, p = 0.026) and plasmocytes (r = 0.44, p = 0.017). Finally, the percentage of plasmablasts correlated with SLE duration (r = 0.42, p = 0.016). In the follow-up analysis, during a median observation of 5 years, 5 out of the initially 23 inactive SLE patients developed a disease flare. They were characterized by longer disease duration stated in the beginning compared to patients who remained in remission (p = 0.019). Conclusions: Our study highlights significant associations between various B cell subsets and SLE disease activity. A more personalized approach to indicate patients with SLE at a higher risk of lupus flares is crucial for better management. Full article

Introduction: Invasive aspergillosis (IA) is an opportunistic fungal infection that typically occurs in the immunocompromised host and is associated with severe morbidity and mortality. Myocardial abscess formation is seldomly described. Detailed Case Description: We present a case of IA with purulent myocarditis. The patient was on long-term high-dose corticosteroid and mycophenolate mofetil therapy for severe lupus nephritis. After multiple visits to his general practitioner and nephrologist for general malaise, he was admitted to our hospital with visual complaints. Within several days, he developed atrial fibrillation, respiratory insufficiency, and, finally, a decreased level of consciousness. After admission to the intensive care unit, the broncho alveolar lavage (BAL) fluid galactomannan (GM) index was normal, but the serum GM index was severely elevated. Despite initiation of antifungal therapy, the patient passed away shortly thereafter. Autopsy revealed massive intracranial hemorrhage and disseminated IA affecting the lungs, brain, and myocardium, with macroscopic myocardial abscess formation. Discussion: This classic case of diagnostic uncertainty illustrates how invasive fungal infections can progress to disseminated disease while showing nonspecific symptoms only. It emphasizes the importance of vigilance for opportunistic fungal infections in a growing category of immunocompromised patients. Conclusion: Clinicians should have a low threshold of suspicion for fungal infections in patients on combination immunosuppressive medication, such as high-dose corticosteroid therapy in combination with T-cell inhibitors like MMF. Full article

Background: Since the introduction of the SLICC criteria in 2012, biopsy-proven lupus nephritis (LN) has been the only independent diagnostic criterion for systemic lupus erythematosus (SLE). This was reaffirmed by the EULAR/ACR in 2019, emphasizing the importance of renal biopsy in LN. However, the current classification lacks specific histopathological criteria for defining LN. This study describes the histological findings of patients with LN, compares them with those of other glomerular diseases, and evaluates their diagnostic accuracy in a large Latin American population. Methods: This retrospective cohort included 731 kidney biopsies from two distinct academic centers. The patients were divided into two groups as follows: a LN group and a control group comprising patients with membranous nephropathy, IgA nephropathy, membranoproliferative glomerulonephritis, pauci-immune glomerulonephritis, and proliferative glomerulonephritis. Sensitivity and specificity analyses were conducted for various histopathological features. Results: We identified the following five features strongly correlated with LN: mesangial proliferation, subendothelial deposits, C1q staining ≥1+, dominant IgG, and ≥4 positive immunofluorescence elements. Combined, these features yielded an area under the ROC curve of 0.94 (95% CI: 0.91–0.95). These results were validated in a diverse population. In membranous nephropathy, histological features such as mesangial deposits, C1q positivity, and ≥4 positive immunofluorescence elements effectively distinguished class V LN from non-lupus membranous nephropathy, with an area under the ROC curve of 0.85 (95% CI: 0.76–0.93). Conclusions: The combination of mesangial proliferation, subendothelial deposits, C1q staining ≥1+, dominant IgG, and ≥4 positive immunofluorescence elements offer good accuracy for diagnosing renal involvement in SLE in a large Latin American population. In the absence of pathognomonic features, combined criteria are valuable diagnostic tools, particularly when other SLE criteria are lacking. Full article

Autoimmune glomerulonephritis is a homogeneous area of renal pathology with clinical relevance in terms of its numerical impact and difficulties in its treatment. Systemic lupus erythematosus/lupus nephritis and membranous nephropathy are the two most frequent autoimmune conditions with clinical relevance. They are characterized by glomerular deposition of circulating autoantibodies that recognize glomerular antigens. Technologies for studying renal tissue and circulating antibodies have evolved over the years and have culminated with the direct analysis of antigen–antibody complexes in renal bioptic fragments. Initial studies utilized renal microdissection to obtain glomerular tissue. Obtaining immunoprecipitates after partial proteolysis of renal tissue is a recent evolution that eliminates the need for tissue microdissection. New technologies based on ‘super-resolution microscopy’ have added the possibility of a direct analysis of the interaction between circulating autoantibodies and their target antigens in glomeruli. Peptide and protein arrays represent the new frontier for identifying new autoantibodies in circulation. Peptide arrays consist of 7.5 million aligned peptides with 16 amino acids each, which cover the whole human proteome; protein arrays utilize, instead, a chip containing structured proteins, with 26.000 overall. An example of the application of the peptide array is the discovery in membranous nephropathy of many new circulating autoantibodies including formin-like-1, a protein of podosomes that is implicated in macrophage movements. Studies that utilize protein arrays are now in progress and will soon be published. The contribution of new technologies is expected to be relevant for extending our knowledge of the mechanisms involved in the pathogenesis of several autoimmune conditions. They may also add significant tools in clinical settings and modify the therapeutic handling of conditions that are not considered to be autoimmune. Full article

Background/Objectives: Leflunomide, an isoxazole immunosuppressant, is widely used in the treatment of diseases such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA) as well as lupus nephritis (LN). In recent years, clinical data have shown that some patients have obvious weight loss, liver injury, and other serious adverse reactions after taking leflunomide. However, the causes and mechanisms by which leflunomide reduces weight are unclear. Methods: Therefore, we used a mouse animal model to administer leflunomide, and we observed that the weight of mice in the leflunomide experimental group was significantly reduced (p < 0.01). In this animal experiment, a metabolomic method was used to analyze the livers of the mice in the experimental group and found that the main difference in terms of metabolic pathways was in the metabolism of aromatic amino acids, and it was confirmed that leflunomide can inhibit the limitations of phenylalanine, tyrosine, and tryptophan biosynthesis. Results: Our study revealed that leflunomide inhibited the activity of DAHPS in the gut microbiota, disrupting the metabolism of phenylalanine, tyrosine, and tryptophan, as well as the metabolism of carbohydrates and lipids. Leflunomide also increased endoplasmic reticulum stress by activating the PERK pathway, thereby promoting CHOP expression and increasing apoptosis-induced liver damage. Conclusions: These effects may be related to the observed weight loss induced by leflunomide. Full article

Lupus nephritis (LN) is a severe form of systemic lupus erythematosus (SLE), characterized by inflammation in the renal glomeruli and tubules. Previous research has demonstrated that dihydroartemisinin (DHA) can reduce inflammatory damage in LN mouse models. Oxymatrine, which has similar biological properties to DHA, may also provide therapeutic benefits. This study aims to investigate the effects of oxymatrine on LN using a murine model and examines its molecular mechanisms through an analysis of microarray datasets from LN patients. The analysis identified differentially expressed genes (DEGs) in renal tissues, regulated by the transcription factor Yin Yang 1 (YY1), which was found to be significantly upregulated in LN patient kidneys. The results indicate that oxymatrine targets the YY1/IL-6/STAT3 signaling pathway. In cell models simulating renal inflammation, oxymatrine reduced YY1 expression and inhibited the secretion of inflammatory factors (IFs), thereby diminishing inflammation. YY1 is crucial in modulating IFs’ secretion and contributing to LN pathogenesis. Additionally, oxymatrine’s interaction with YY1, leading to its downregulation, appears to be a key mechanism in alleviating LN symptoms. These findings support oxymatrine as a promising therapeutic agent for LN, offering new avenues for treating this autoimmune kidney disorder. Full article

Background: Percutaneous ultrasound-guided renal biopsy (PRB) is a key element for diagnosis and management of several renal pathologies. We aimed to lay out the experience of our pediatric nephrology unit performing PRBs. The rationale and findings of these biopsies, safety issues and considerations of the extracted data are going to be analyzed. Methods: A retrospective study was conducted from 2008 to 2023 based on the review of the medical records of pediatric patients who underwent PRBs. In total, 216 kidney biopsies in 206 patients were performed: 115 (53.2%) during the 2008–2015 period and 101 (46.8%) during the 2016–2023 period. Results: The most frequent clinical indication for PRBs was nephritic syndrome followed by nephrotic syndrome, observed in 84 (40.8%) and 72 (34.9%) patients, respectively. The predominant diagnosis was minimal change disease (MCD) (23.3%), followed by focal segmental glomerulosclerosis (FSGS) (15%) equal to lupus nephritis (LN) (15%), and immunoglobulin A nepropathy (10.2%). Minor complications, such as subcapsular hematomas were observed in approximately 15% of patients while no therapeutic intervention was needed. Conclusions: This report is the first review of pathohistological data covering a pediatric population over a 15-year period in Greece and one of the largest in southeastern Europe, especially in the Balkan region. The main indication for a PRB was nephritic syndrome; however, MCD was the main histological diagnosis. This study emphasis the fact that PRBs constitute a safe and reliable method of diagnostic approach to kidney diseases in childhood and offers important information on therapeutic approaches as well as the prognosis of these patients. Full article

Systemic lupus erythematosus (SLE) is an autoimmune disease affecting multiple organs, with lupus nephritis (LN) occurring in 40–50% of SLE patients. Despite advances in diagnosis and treatment, LN remains a major cause of morbidity and mortality, with 10–20% of patients progressing to end-stage renal disease (ESRD). While knowledge of LN’s pathogenesis has improved, mechanisms of renal recovery are still largely unexplored. Neuropilin-1 (NRP-1), a transmembrane receptor expressed in renal tissue, has emerged as a promising biomarker for assessing renal recovery in LN. This study evaluates and correlates longitudinal levels of NRP-1 with kidney histology using an NZB/W F1 mouse model of LN. A total of 30 mice were used, with 15 receiving intravenous cyclophosphamide (CYC) and 15 being untreated. NRP-1 levels were measured in urine and serum, and kidney samples were taken from a subgroup of mice for histological evaluation. The results demonstrated a progressive increase in renal and urinary NRP-1 expression, particularly notable at weeks 26 and 32. Urinary NRP-1 levels above 34.40 ng/mL were strong predictors of favorable renal response, showing 100% sensitivity and 88% specificity. These findings indicate a robust correlation between urinary NRP-1 levels and renal histological recovery, underscoring the potential of NRP-1 as a valuable biomarker for assessing renal response in LN. This study demonstrates that renal production of NRP-1 is linked to histological recovery and establishes a foundation for future research into the role of NRP-1 in lupus kidney recovery. Full article

Epitope spreading is a critical mechanism driving the progression of autoimmune glomerulonephritis. This phenomenon, where immune responses broaden from a single epitope to encompass additional targets, contributes to the complexity and severity of diseases such as membranous nephropathy (MN), lupus nephritis (LN), and ANCA-associated vasculitis (AAV). In MN, intramolecular spreading within the phospholipase A2 receptor correlates with a worse prognosis, while LN exemplifies both intra- and intermolecular spreading, exacerbating renal involvement. Similarly, ANCA reactivity in AAV highlights the destructive potential of epitope diversification. Understanding these immunological cascades reveals therapeutic opportunities—targeting early epitope spreading could curb disease progression. Despite promising insights, the clinical utility of epitope spreading as a prognostic tool remains debated. This review provides a complete overview of the current evidence, exploring the dual-edged nature of epitope spreading, the intricate immune mechanisms behind it, and its therapeutic implications. By elucidating these dynamics, we aim to pave the way for more precise, targeted interventions in autoimmune glomerular diseases. Full article

Systemic lupus erythematosus (SLE) is an autoimmune disorder that often leads to kidney injury, known as lupus nephritis (LN). Although renal biopsy is the primary way to diagnose LN, it is invasive and not practical for regular monitoring. As an alternative, several groups have proposed urinary extracellular vesicles (uEVs) as potential biomarkers for LN, as recent studies have shown their significance in reflecting kidney-related diseases. As a result, we developed a flow cytometry approach that allowed us to determine that LN patients exhibited a significantly higher total uEV concentration compared to SLE patients without kidney involvement. Additionally, an analysis of different-sized uEV subsets revealed that microvesicles ranging from 0.3 to 0.5 μm showed the most promise for distinguishing LN. These findings indicate that evaluating uEV concentration and size distribution could be a valuable diagnostic and monitoring tool for LN, pending further validation in more comprehensive studies. Full article

Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which kidney involvement, so-called lupus nephritis (LN), is common and one of the most severe manifestations. Oxidative stress (OS) may play a role in the pathogenesis of LN through the exacerbation of inflammation and immune cell dysfunction/dysregulation. Nuclear factor erythroid 2-related factor 2 (Nrf2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the NFE2L2 gene and is regarded as a central regulator of the antioxidative response. Nrf2-activating compounds have been shown to alleviate oxidative stress in cells and tissues of lupus-prone mice. Although the precise mechanisms of Nrf2 activation on the immune system in SLE remain to be elucidated, Nrf2-activating compounds are considered novel therapeutical options to suppress OS and thereby might alleviate disease activity in SLE, especially in LN. This review therefore summarizes the role of the Nrf2 signaling pathway in the pathogenesis of SLE with LN and describes compounds modulating this pathway as potential additional clinical interventions. Full article