Objective: This study aimed to identify clinical and laboratory predictors of kidney involvement and disease relapse in pediatric patients with IgA vasculitis (Immunoglobulin A vasculitis, IgAV). Materials and Methods: A retrospective cohort study was conducted on 173 children diagnosed with IgAV at the Children's Clinical Hospital of the Medical University of Warsaw between 2018 and 2022. Patients were categorized into groups based on renal involvement (IgAVN+ vs. IgAVN-) and disease recurrence. The analysis included demographic data, clinical manifestations, allergy history, presence of infection, duration of hospitalization, relapse occurrence, the interval between the first and second hospitalization, and laboratory markers. Results: Renal involvement was observed in 42% of cases, while disease recurrence occurred in 9.25% of patients. IgAVN+ patients were older, had longer hospital stays, and more frequently exhibited gastrointestinal symptoms, consistent with previous research. A history of allergic conditions was more prevalent in both the IgAVN+ and recurrence groups. An increase in IgA levels over time was associated with a higher risk of nephropathic development. Patients with recurrences had higher IgM levels and an elevated neutrophil-to-lymphocyte ratio (NLR) (p = 0.07). In the ROC (Receiver Operating Characteristic) analysis, a cutoff value of 1.67 for NLR (AUC 0.71; p = 0.0002; sensitivity 0.87; specificity 0.58) was identified as a risk factor for disease recurrence. Conclusions: Older age at disease onset, gastrointestinal involvement, and allergies are associated with renal involvement in pediatric IgAV. Immune dysregulation, reflected by elevated NLR and IgM, may contribute to disease recurrence. It is important to monitor changes in IgA levels over time, as an increase in IgA concentration is a risk factor for the development of nephropathy. Additionally, calculating the NLR is recommended, as it may indicate the probability of disease recurrence.

The 21st International Vasculitis Workshop, held in Barcelona, Spain, from April 7 to 10, 2024, highlighted advances in pediatric vasculitis, focusing on a holistic, multidisciplinary approach. Common childhood vasculitides, including IgA Vasculitis (IgAV) and Kawasaki Disease (KD), were discussed. The Ankara 2008 criteria for IgAV, endorsed by EULAR and PReS, were evaluated for their performance in adults, showing high sensitivity but necessitating further refinement for improved specificity. Studies on genetic associations, such as Human Leukocyte Antigen (HLA) polymorphisms in IgAV, and biomarkers like S100A8/A9, HMGB1, and RAGE, were presented. Kawasaki disease research included novel anti-apolipoprotein A-2 antibodies, showing promise in reducing coronary arteritis. Monogenic vasculitides, such as deficiency of ADA2, were addressed with new consensus-driven recommendations. The workshop underscored the importance of continued research and tailored therapeutic strategies to improve outcomes in pediatric vasculitis, paving the way for advancements in diagnosis, management, and understanding of these complex diseases.

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.

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.

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.

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.

Vasculitis in children represents a diverse group of diseases characterized by inflammation of blood vessels, which can lead to significant morbidity if not promptly recognized and managed. This review explores the epidemiology, pathophysiology, classification, and management of key pediatric vasculitides. Classification based on vessel size aids in diagnosis and treatment. Understanding these conditions" clinical features and therapeutic options is critical for improving pediatric patient outcomes and preventing long-term complications. Continued research is essential for refining treatment strategies and enhancing patient care.

Of the primary vasculitis pediatricians are familiar with, Kawasaki disease and IgA vasculitis are the most common. The other large, medium and small vessel vasculitis are seldom seen in practice. Though rare, early diagnosis and appropriate management is critical for the best outcome. Primary vasculitis in the pediatric age group have several differential diagnoses which range from infections to monogenic causes such as deficiency of Adenosine Deaminase -2. Each child, therefore, needs a careful systematic approach.

IgA vasculitis (IgAV) is considered a systemic form of IgA nephropathy (IgAN). The two diseases share similar geographic and ethnic distribution, along with common variants in genetic association studies. The pathophysiology of IgAN and IgA vasculitis nephritis (IgAVN) can be explained by the four-hit hypothesis. Key molecules involved at each step in both diseases were evaluated as diagnostic and prognostic biomarkers with many common factors, most prominently serum galactose-deficient IgA1. On kidney biopsy, the two diseases are indistinguishable, and the established histological Oxford classification for IgAN will soon be validated for IgAVN. Chronic lesions (segmental glomerulosclerosis and tubular atrophy / interstitial fibrosis) seem more frequent in IgAN, while proliferative lesions (endocapillary hypercellularity and crescents) are more frequent in IgAVN, which could explain the worse IgAN renal prognosis. Due to characteristic skin rash, IgAVN patients are diagnosed precociously. Conversely, the frequent absence of overt clinical signs in IgAN leads to a delayed diagnostic kidney biopsy in the disease evolution, which explains the chronic pathologic lesions. From a therapeutic perspective, while impressive advances have been made in recent years for IgAN, there is a glaring lack of evidence-based guidelines for the treatment of IgAVN. Large therapeutic clinical studies are required, and future IgAN trials should include IgAVN.

Endothelial cell injury is a hallmark of IgA vasculitis (IgAV), possibly associated with various factors, including oxidative stress. Certain single nucleotide polymorphisms (SNPs) of glutathione S-transferases (GST) genes have been shown to increase susceptibility to oxidative stress. The objective of our study was to evaluate the gene polymorphisms of GSTM1, GSTT1, GSTP1, and GSTA1 in patients with IgAV. DNA was extracted from the blood of 124 children with IgAV and 168 age-matched healthy controls. A higher frequency of the GSTM1 null genotype was observed in patients with gastrointestinal (GI) system involvement compared to those without GI system involvement (51.5% vs. 28.6%, p = 0.011). Additionally, the GSTM1 null genotype was less prevalent (30.8% vs. 69.2%, p = 0.032), while the GSTP1 Val/Val genotype was significantly more prevalent in patients who developed urogenital complications (scrotal swelling) during the course of the disease (60% vs. 40%, p = 0.039). This study is the first to suggest an association between GSTM1 and GSTP1 polymorphisms and various phenotypes observed during the clinical course of IgAV in the pediatric population. However, it was performed on a national and likely single ethnic cohort, too small for definitive conclusions, so larger studies are needed to confirm this association.

Palpable purpura, gastrointestinal symptoms, joint involvement, and renal disease characterize immunoglobulin A vasculitis (IgAV). Renal involvement ranging from mild proteinuria to severe nephritic or nephrotic syndrome highlights the importance of monitoring kidney function in patients with IgAV. Recognizing these key features is crucial for early diagnosis and appropriate management to prevent long-term complications related to kidney disease. However, the pathogenesis of IgAV remains unclear. Disease mechanisms involve various factors, including the interplay of aberrantly glycosylated IgA, anti-endothelial cell antibodies, and neutrophils following infection triggers, which are the main pathogenic mechanisms of IgAV. Insights from cases of IgAV related to Coronavirus disease 2019 have offered additional understanding of the connection between infection and IgAV pathogenesis. This review provides a valuable resource for healthcare professionals and rheumatology researchers seeking a better understanding of the clinical features and pathophysiology of IgAV.

Immunoglobulin A (IgA) vasculitis with intussusception is acute and severe vasculitis combined with acute abdomen in children. The diagnosis of the disease depends on the results of imaging examinations, and its treatment mainly includes enema and surgery. The literature summarized the detailed diagnosis and treatment data in previous literature reports.

We described the clinical manifestations, ultrasonic features, and treatment of patients admitted to a single center and reviewed previous literature regarding cases with detailed clinical data in the PubMed database within the past 20 years.

The review included 36 patients, including 22 boys and 14 girls. A total of 32 patients were diagnosed using ultrasound (88.9%). The main sites of intussusception were the ileum and ileocolon in 16 (44.4%) and 11 (30.6%) cases, respectively. Thirteen patients (36.1%) were treated with enema, with 6 responding to the treatment. 26 patients (72.2%) underwent surgical treatment. Patients with ileal intussusception were more likely to be treated with surgery than those with colonic intussusception (P < .05). The single-center clinical data of 23 patients showed that there was no significant difference in laboratory test findings between patients with and without surgical treatment (P > .05). Patients with long insertion lengths were more likely to require surgery and resection (P < .05).

Ultrasonography is the first-line investigation for diagnosis. The main sites of intussusception were ileum and ileocolon. The length of intubation was related to surgery; treatment is according to the intussusception site. Air enema is not suitable for intussusception of the small intestine.

Renal injury often occurs as a complication in autoimmune diseases such as systemic lupus erythematosus (SLE). It is estimated that a minimum of 20% SLE patients develop lupus nephritis, a condition that can be fatal when the pathology progresses to end-stage renal disease. Studies in animal models showed that incidence of immune cell infiltrates in the kidney was linked to pathological injury and correlated with severe lupus nephritis. Thus, preventing immune cell infiltration into the kidney is a potential approach to impede the progression to an end-stage disease. A requirement to investigate the role of kidney-infiltrating leukocytes is the development of reproducible and efficient protocols for purification and characterization of immune cells in kidney samples. This chapter describes a detailed methodology that discriminates tissue-resident leukocytes from blood-circulating cells that are found in kidney. Our protocol was designed to maximize cell viability and to reduce variability among samples, with a combination of intravascular staining and magnetic bead separation for leukocyte enrichment. Experiments included as example were performed with FcγRIIb[KO] mice, a well-characterized murine model of SLE. We identified T cells and macrophages as the primary leukocyte subsets infiltrating into the kidney during severe nephritis, and we extensively characterized them phenotypically by flow cytometry.

The pathogenesis of IgAV, the most common systemic vasculitis in childhood, appears to be complex and requires further elucidation. We aimed to investigate the potential role of galactose-deficient immunoglobulin A1 (Gd-IgA1), high-mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE) and protocadherin 1 (PCDH1) in the pathogenesis of IgAV. Our prospective study enrolled 86 patients with IgAV and 70 controls. HMGB1, RAGE, Gd-IgA1 and PCDH1 in serum and urine were determined by the enzyme-linked immunosorbent assay (ELISA) method at the onset of the disease and after a six-month interval in patients and once in the control group. Serum concentrations of HMGB1, RAGE and PCDH1 and urinary concentrations of HMGB1, RAGE, Gd-IgA1 and PCDH1 were significantly higher in patients with IgAV than in the control group (p < 0.001). Concentrations of HMGB1 (5573 pg/mL vs. 3477 pg/mL vs. 1088 pg/mL, p < 0.001) and RAGE (309 pg/mL vs. 302.4 pg/mL vs. 201.3 pg/mL, p = 0.012) in the serum of patients remained significantly elevated when the disease onset was compared with the six-month follow-up interval, and thus could be a potential marker of disease activity. Urinary concentration of HMGB1 measured in the follow-up period was higher in patients with nephritis compared to IgAV without nephritis (270.9 (146.7-542.7) ng/mmol vs. 133.2 (85.9-318.6) ng/mmol, p = 0.049) and significantly positively correlated with the urine albumine to creatinine ratio (τ = 0.184, p < 0.05), the number of erythrocytes in urine samples (τ = 0.193, p < 0.05) and with the outcome of nephritis (τ = 0.287, p < 0.05); therefore, HMGB1 could be a potential tool for monitoring patients with IgAV who develop nephritis. Taken together, our results imply a possible interplay of Gd-IgA1, HMGB1, RAGE and PCDH1 in the development of IgAV. The identification of sensitive biomarkers in IgAV may provide disease prevention and future therapeutics.

Autoimmune diseases (AIDs) arise from a breakdown in immunological self-tolerance, wherein the adaptive immune system mistakenly attacks healthy cells, tissues and organs. AIDs impose excessive treatment costs and currently rely on non-specific and universal immunosuppression, which only offer symptomatic relief without addressing the underlying causes. AIDs are driven by autoantigens, targeting the autoantigens holds great promise in transforming the treatment of these diseases. To achieve this goal, a comprehensive understanding of the pathogenic mechanisms underlying different AIDs and the identification of specific autoantigens are critical. In this review, we categorize AIDs based on their underlying causes and compile information on autoantigens implicated in each disease, providing a roadmap for the development of novel immunotherapy regimens. We will focus on type 1 diabetes (T1D), which is an autoimmune disease characterized by irreversible destruction of insulin-producing β cells in the Langerhans islets of the pancreas. We will discuss insulin as possible autoantigen of T1D and its role in T1D pathogenesis. Finally, we will review current treatments of TID and propose a potentially effective immunotherapy targeting autoantigens.

S100A8/A9 protein is a well-known marker of disease activity or severity in many autoimmune and autoinflammatory diseases, but there have not been many studies about the role of S100A8/A9 in IgA vasculitis (IgAV). The aim of our study was to evaluate S100A8/A9 as a possible biomarker of activity in IgAV. We measured the serum levels of S100A8/A9 in pediatric patients with IgA vasculitis at the onset of the disease, after three months, and after six months. We compared these levels between patients with active disease, remission, and a control group, and assessed their correlation with disease activity and other markers of inflammation. Patients with active disease had significantly higher levels of serum S100A8/A9 (median ± SD) than those in the control group at the beginning of the disease (5740 ± 3157 ng/mL vs. 1447 ± 858.3 ng/mL; p < 0.0001), but also three months and six months after disease onset (p < 0.001). There was a positive correlation between S100A8/A9 serum levels and disease activity (p = 0.0003). Patients with active disease had significantly higher levels of S100A8/A9 than those in remission three months after disease onset (p = 0.0260). There was a correlation between S100A8/A9 and C-reactive protein, the C3 component of complement, ferritin, and fibrinogen. Serum levels of S100A8/A9 were also higher in patients with greater skin areas covered with rash. We demonstrated that serum levels of S100A8/A9 correlated well with disease activity and other biomarkers of inflammation in children with IgAV. According to our results, serum S100A8/A9 may be a good indicator of active disease in IgAV.

We investigated the polarisation of CD68+ macrophages and perforin and granulysin distributions in kidney lymphocyte subsets of children with IgA vasculitis nephritis (IgAVN). Pro-inflammatory macrophage (M)1 (CD68/iNOS) or regulatory M2 (CD68/arginase-1) polarisation; spatial arrangement of macrophages and lymphocytes; and perforin and granulysin distribution in CD3+ and CD56+ cells were visulaised using double-labelled immunofluorescence. In contrast to the tubules, iNOS+ cells were more abundant than the arginase-1+ cells in the glomeruli. CD68+ macrophage numbers fluctuated in the glomeruli and were mostly labelled with iNOS. CD68+/arginase-1+ cells are abundant in the tubules. CD56+ cells, enclosed by CD68+ cells, were more abundant in the glomeruli than in the tubuli, and co-expressed NKp44. The glomerular and interstitial/intratubular CD56+ cells express perforin and granulysin, respectively. The CD3+ cells did not express perforin, while a minority expressed granulysin. Innate immunity, represented by M1 macrophages and CD56+ cells rich in perforin and granulysin, plays a pivotal role in the acute phase of IgAVN.

Studies concerning the genetic background of IgA vasculitis (IgAV), a small-vessel vasculitis occurring predominantly in childhood, have confirmed that the HLA-DRB1 gene showed a strong association with disease susceptibility. The objective was to investigate human leukocyte antigen (HLA) polymorphisms among Croatian patients with IgAV and their influence on disease susceptibility and clinical heterogeneity. Thus, 130 children with IgAV and 202 unrelated healthy individuals were enrolled in the study. Genomic DNA was extracted from whole peripheral blood, and HLA-A, -B, -DRB1 and -DQB1 gene polymorphism analysis was performed. HLA-A*03 (21.4% vs. 12.38%, p = 0.0092), HLA-B*37 (2.9% vs. 0.2%, p = 0.0054) and HLA-DRB1*12 (3.1% vs. 0.7%, p = 0.0216) alleles were significantly more frequent in IgAV patients than in controls. High-resolution typing revealed significantly higher frequency of HLA-DRB1*10:01 and -DRB1*11:03 among IgAV patients with gastrointestinal manifestations of the disease in comparison to controls (p = 0.0021 and p = 0.0301, respectively), while HLA-DRB1*14:01P occurred significantly more often in the group of patients who developed nephritis during the course of the disease (17.5% vs. 4.5%, p = 0.0006). Our results demonstrated that there is an association of HLA-A*03, HLA-B*37 and HLA-DRB1*12 alleles with susceptibility to IgAV in the examined Croatian pediatric population. Studies which aim to determine the HLA profile may contribute to the elucidation of the genetic background of autoimmune diseases, including IgAV.

Immunoglobulin-A vasculitis (IgAV) is an inflammatory disease that affects small blood vessels. This study was performed to identify an association between protein tyrosine phosphatase non-receptor type 22 (PTPN22) + 788G > A (rs33996649), transforming growth factor-beta (TGF-β) -509C > T (rs18004069), interleukin 1-beta (IL-1β) -511C > T (rs16944), interleukin 5 (IL-5) -746C/T (rs2069812), and angiotensin-converting enzyme (ACE) I/D (rs4646994) gene polymorphisms, susceptibility to IgAV, as well as the mRNA levels of IL-1β, IL-1β, and TGF-β.

A total of 53 patients with IgAV and 50 healthy controls were enrolled. PTPN22, TGF-β, IL-1β, ACE gene polymorphisms, ACE gene I/D polymorphisms, and mRNA expression levels were analyzed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, allele-specific PCR, and real-time PCR with TaqMan kits, respectively.

PTPN22, TGF-β, IL-1β, IL-5, and ACE variants showed no genotype or allele differences between patients with IgAV and controls. Increased levels of IL-1β and TGF-β mRNA expressions were observed in patients with IgAV (p < 0.001). Patients with the IL-1β AG genotype showed significantly increased amounts of arthritis than patients with non-AG (p = 0.004). Age at disease onset was found to be significantly different in patients with IgAV according to the presence of TGF-β TT genotype (p = 0.047).

Polymorphisms in PTPN22, TGF-β, IL-5, IL-1β, and ACE genes are unlikely to confer susceptibility to IgAV. However, the presence of the AG genotype of IL-1β is associated with susceptibility to IgAV-related arthritis. This is the first study to report a significant increase in serum mRNA levels of IL-1β and TGF-β in IgAV patients, supporting a susceptibility to IgAV in childhood.

The clinical spectrum of immunoglobulin A vasculitis nephritis (IgAVN) ranges from the relatively common transitory microscopic hematuria and/or low-grade proteinuria to nephritic or nephrotic syndrome, rapidly progressive glomerulonephritis, or even renal failure. Clinical and experimental studies have shown a multifactor pathogenesis: Infection triggers, impaired glycosylation of IgA1, complement activation, Toll-like-receptor activation and B cell proliferation. This knowledge can identify IgAVN patients at a greater risk for adverse outcome and increase the evidence for treatment recommendations.

IgA vasculitis (IgAV) is a small vessel vasculitis that is more common in childhood. Very limited evidence exists on patients who experience an atypical disease course. The aim of this study was to describe a cohort of children diagnosed with recurrent or persisting IgAV to identify any themes associated with their disease course and areas of unmet needs.

A single centre retrospective study of children diagnosed with recurrent or persisting IgAV at Alder Hey Children's Hospital (Liverpool, UK). Clinical data, including features at presentation and during follow up, potential triggers, abnormal laboratory and histology results, treatment and outcome at last clinical review were retrospectively collected. Key themes were identified.

A total of 13 children met the inclusion criteria (recurrent disease, n = 4; persisting disease, n = 9). Median age at first presentation was 10.2 years [2.6-15.5], female:male ratio 1.2:1. Children in the atypical cohort were significantly older than a larger cohort of children who followed a non-complicated disease course (median age 5.5 years (range [0.6-16.7], p = 0.003)). All children re-presented with a purpuric rash (either recurring or persisting), accompanied by joint involvement in 92% of patients (12/13). Disease-modifying anti-rheumatic drugs (DMARDs) were used in 8/13 (62%) children. The median time from first presentation to diagnosis of atypical disease was 18.4 months [5.3-150.8] and the time from first presentation to treatment was 24.1 months [1.8-95.4]. Use of corticosteroids was significantly higher in children with renal involvement (p = 0.026). During follow up, 8/13 (62%) children were admitted at least once, whilst 10/13 (77%) had re-presented at least once to the emergency department. Five (38%) children were referred to psychology services and 7 (54%) children reported feelings of frustration.

This series describes some characteristics of a small cohort of children with atypical IgAV. It also identifies unmet needs in children with atypical IgAV, which includes delays in diagnosis and lengthy waits for treatment, lack of high-quality evidence regarding treatment choices and a high unrecognised disease burden. Further research is needed to study this subgroup of children as evidence is lacking.

Several histologic classifications are used in the evaluation of IgA vasculitis nephritis (IgAVN), however, to date, no studies have determined which one has the strongest association with the severity of IgAVN and, as a consequence, its outcomes.

Patients included in the study were diagnosed with IgAV and IgAVN in seven tertiary university medical centers in Croatia, Italy and Israel. The International Study of Kidney Disease in Children (ISKDC), Haas, Oxford, and Semiquantitative classification (SQC) classifications were used in the analysis and description of renal biopsy. Time from biopsy to outcome evaluation was a statistically significant factor in outcome prediction that was used to define the base model, and was a covariate in all the tested models.

Sixty-seven patients were included in this study. The SQC classification proved to be the best one in outcome prediction, followed by the Oxford classification. The ISKDC and Haas classifications could not predict renal outcome. The Oxford parameters for mesangial hypercellularity and tubular atrophy, as well as the SQC parameters for cellular crescents showed an independent statistically significant contribution to outcome prediction. High level of twenty-four hour protein excretion was associated with a higher grade in the Oxford, SQC and ISKDC classifications. Endocapillary proliferation was positively associated with the Pediatric Vasculitis Activity Score (PVAS) at diagnosis, while tubular atrophy was negatively associated.

The SQC, followed by the Oxford classification were found to provide the best classifications of renal biopsy analysis in patients to predict the outcome in patients with IgAVN. Cellular crescents, mesangial hypercellularity and tubular atrophy showed significant contributions, indicating that active and chronic variables should be included in the estimation.

IgA vasculitis (IgAV) or Henoch-Schönlein purpura (HSP) is the most common vasculitis in children, and nephritis (IgAVN or HSPN) is the most important and only chronic manifestation of the disease. Despite this, there are no diagnostic criteria and we rely on the European League Against Rheumatism/Paediatric Rheumatology International Trials Organization/Paediatric Rheumatology European Society-endorsed Ankara 2008 classification criteria in our daily practice. Basic investigations that should be done in every patient with IgAVN include blood pressure measurement, estimated glomerular filtration rate and urinalysis. Kidney biopsy is still the gold standard for the diagnosis of IgAVN since noninvasive confirmation of nephritis is still pending. According to the Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) recommendations, the first-line treatment for with mild forms of IgAVN is oral glucocorticoids, for patients with moderate IgAVN parenterally administrated glucocorticoids in pulsed doses, while initial treatment for patients with the most severe forms of IgAVN include pulsed doses of glucocorticoids in combination with intravenous cyclophosphamide pulses. New therapeutic options are currently being tested, aiming to reduce the production of galactose-deficient IgA₁ and autoantibodies or suppress the alternative or lectin complement pathway and blocking mesangial cell activation.