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The kidney is often the target of immune system dysregulation in the context of primary or systemic disease. In particular, the glomerulus represents the anatomical entity most frequently involved, generally as the expression of inflammatory cell invasion or circulant or in situ immune-complex deposition. Glomerulonephritis is the most common clini...
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... recent decades, major advances have been made as regards our understanding of the pathogenesis of some pediatric forms of GN ( Table 1). n Hypocomplementemic forms represent a wide spectrum of diseases ranging from acute (post-infectious GN) to severe forms of C3 glomerulopathies. ...Context 2
... the other hand, the new histological classifications have concretely contributed to a better understanding of patient prognosis and therefore to more tailored therapies. The most recent classifications of GN, which include histological, immunological, genetic and clinical aspects (biomarkers) are a direct consequence of the better understanding of the pathophysiological mechanisms underlying these pathologies ( Table 1). This is also true for GN secondary to systemic diseases, such as Systemic Lupus Erytematosus (SLE), for which diagnostic criteria, histological classification, clinical and histological prognostic factors, specific biomarkers and therapeutic approaches have changed substantially over the last 10 years. ...Context 3
... is also true for GN secondary to systemic diseases, such as Systemic Lupus Erytematosus (SLE), for which diagnostic criteria, histological classification, clinical and histological prognostic factors, specific biomarkers and therapeutic approaches have changed substantially over the last 10 years. In this review, we update the current understanding of the etiologic events and genetic factors involved in the pathogenesis of pediatric immunologically mediated primitive forms of GN, together with the clinical spectrum and prognosis ( Table 1). Possible new therapeutic targets are also briefly discussed. ...Context 4
... the chronic forms were classified as type I, type II and type III membrano-proliferative GN (MPGN), according to the position of the deposits on electron microscopy (EM) (subendothelial, intramembranous, and sub-epithelial). Following a better understanding of the pathogenetic mechanisms involved (Table 1), there has been a reclassification. Types I and III MPGN, which exhibit deposits of IgG and C3 on immunofluorescence (IF), are now considered as MPGN caused by IC (IC-MPGN), while type II MPGN, also known as dense deposit disease (DDD), and all the forms with isolated/predominant C3 IF-deposits, are considered as C3G (Figure 1). ...Citations
... The glomerulus is a central kidney compartment that is commonly affected by autoimmune and inflammatory diseases, whereas tubules are rarely affected by these conditions (104). IgA nephropathy (IgAN) is the predominant form of primary glomerulonephritis; 25-50% of IgAN patients develop end-stage renal disease within 20 years of diagnosis (105). ...
The immune system and the kidneys are closely related. Immune components mediate acute kidney disease and are crucial to the progression of chronic kidney disease. Beyond its pathogenic functions, the immune system supports immunological homeostasis in healthy kidneys. The kidneys help maintain immune equilibrium by removing metabolic waste products and toxins, thereby limiting local and systemic inflammation. In this review, we describe the close relationship between the immune system and the kidneys. We discuss how the imbalance in the immune response can be deleterious to the kidneys and how immunomodulation can be important in preventing end-stage renal disease. In addition, recent tools such as in silico platforms and kidney organoids can help unveil the relationship between immune cells and kidney homeostasis.
Expected final online publication date for the Annual Review of Immunology, Volume 42 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... The glomerulus is a central kidney compartment that is commonly affected by autoimmune and inflammatory diseases, whereas tubules are rarely affected by these conditions (104). IgA nephropathy (IgAN) is the predominant form of primary glomerulonephritis; 25-50% of IgAN patients develop end-stage renal disease within 20 years of diagnosis (105). ...
The immune system and the kidneys are closely related. Immune components mediate acute kidney disease and are crucial to the progression of chronic kidney disease. Beyond its pathogenic functions, the immune system supports immunological homeostasis in healthy kidneys. The kidneys help maintain immune equilibrium by removing metabolic waste products and toxins, thereby limiting local and systemic inflammation. In this review, we describe the close relationship between the immune system and the kidneys. We discuss how the imbalance in the immune response can be deleterious to the kidneys and how immunomodulation can be important in preventing end-stage renal disease. In addition, recent tools such as in silico platforms and kidney organoids can help unveil the relationship between immune cells and kidney homeostasis. 207 ,. • · �-Review in Advance first posted on January 11, 2024. (Changes may still occur before final publication.) Annu. Rev. Immunol. 2024.42. Downloaded from www.annualreviews.org Access provided by WIB6097-Johannes Gutenberg University of Mainz on 01/12/24. For personal use only.
... Immunopathology, clinical symptoms, and morphological abnormalities are all factors that go into classifying glomeruli disorders [33]. To classify the glomeruli diseases, these objects need to be detected first. ...
Context: Analyzing digital pathology images is necessary to draw diagnostic conclusions by investigating tissue patterns and cellular morphology. However, manual evaluation can be time-consuming, expensive, and prone to inter- and intra-observer variability. Objective: To assist pathologists using computerized solutions, automated tissue structure detection and segmentation must be proposed. Furthermore, generating pixel-level object annotations for histopathology images is expensive and time-consuming. As a result, detection models with bounding box labels may be a feasible solution. Design: This paper studies. YOLO-v4 (You-Only-Look-Once), a real-time object detector for microscopic images. YOLO uses a single neural network to predict several bounding boxes and class probabilities for objects of interest. YOLO can enhance detection performance by training on whole slide images. YOLO-v4 has been used in this paper. for glomeruli detection in human kidney images. Multiple experiments have been designed and conducted based on different training data of two public datasets and a private dataset from the University of Michigan for fine-tuning the model. The model was tested on the private dataset from the University of Michigan, serving as an external validation of two different stains, namely hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS). Results: Average specificity and sensitivity for all experiments, and comparison of existing segmentation methods on the same datasets are discussed. Conclusions: Automated glomeruli detection in human kidney images is possible using modern AI models. The design and validation for different stains still depends on variability of public multi-stain datasets.
... Glomerulonephritis is also classified on the basis of their clinical presentation and histopathological findings. 16 It became clear that patients with immunological complex GN displayed a diversity of histologic characteristics once renal biopsy was implemented into clinical practice. The first pathologic classification of lupus nephritis was developed in 1974 under by World Health Organization in an effort to standardize definitions and improve communication. ...
Background: This study was conducted to determine pattern (spectrum) of renal diseases on basis of renal biopsy in a tertiary care hospital in Islamabad. Methodology: This retrospective observational study was conducted at Nephrology department of Pakistan Institute of Medical Sciences Islamabad from February 2012 to April 2020. Results of all biopsies done during this period were analyzed to determine the prevalence of different renal diseases on basis of histopathology and immunofluorescence. Results: There were 254 kidney biopsy samples studied during the course of study. Out of total 254 patients 133 (52.4%) were male and 121 (47.6%) were female. Mean age of participants was 34.47±7.67 years (Range:15-60 years). Primary glomerulonephritis and secondary glomerulonephritis was found in 169 (66.5%) and 48 (18.9%) respectively, while tubulo-interstitial disease was reported in 37 (14.6%) of the total biopsies. Among 169 biopsies that showed primary GN, IgA Nephropathy (IgAN) was the most common in 16% of the biopsies, followed by membranous GN in 15.4% while membranoproliferative GN (MPGN) was seen in 13.6%, and focal and segmental glomerulosclerosis (FSGS) was seen in 13% of primary GN. Among 48 biopsies with secondary GN, lupus nephritis (LN) was found to be most common in 83.3% followed by amyloidosis in 6.3%. Among 37 biopsies having tubulo-interstitial disease, acute tubular nephritis (ATN) and renal cortical necrosis was seen in 29.7% each followed by tubulo-interstitial nephritis in 18.9% and acute interstitial nephritis (AIN) was seen in 16.2%. Conclusion: This study shows that primary GN is the most common finding on renal biopsy. Among them IgA Nephropathy is the commonest lesion followed by membranous nephropathy, MPGN and FSGS. Among secondary GN, Lupus Nephritis is the commonest lesion. Key words: Glomerulonephritis, Renal Biopsy, Renal Disease, Renal histopathology
... Antiestreptolisina O (ASLO) es un anticuerpo producido contra la exotoxina estreptolisina O, sintetizada por la bacteria Streptococcus pyogenes y liberada al torrente sanguíneo durante la infección, ya sea a nivel del tracto respiratorio, piel y tejidos blandos, entre otros órganos (9). La unión ASLO con la estreptolisina O, constituyen inmunocomplejos circulantes, que suelen depositarse en el glomérulo, desencadenando glomerulonefritis, pudiendo incrementar otros trastornos cardiovasculares en la infancia (10). ...
Objetivo: Establecer asociación entre los niveles séricos de biomarcadores inmunológicos con el riesgo cardiovascular en adultos jóvenes. Metodología: Estudio descriptivo de corte trasversal que empleó 130 estudiantes de dos instituciones universitarias en las ciudades de Barranquilla y Santa Marta, Colombia, 55 de género masculino y 75 femenino, con edad promedio de 19,49 años. Los niveles de biomarcadores séricos Antiestreptolisina O (ASLO), Proteína C Reactiva (PCR) y Factor Reumatoide (RF), fueron determinados mediante el método de precipitación de partículas en látex, mientras que el riesgo cardiovascular se estableció mediante la escala Framinghan, ajustada según edad. Resultados: Para los niveles de riesgo cardiovascular por género, el resultado comparativo demostró mayor riesgo alto en el género masculino (38,1%), comparado con el género femenino (24%), mientras que el riesgo máximo reflejó paridad en ambos géneros (20% para el masculino y 21,3% el femenino); niveles elevados de ASLO se relacionan con riesgo cardiovascular elevado en el 29,97% de los individuos analizados; mientras que la PCR y Factor Reumático presentaron niveles variables en cualquier grado de riesgo cardiovascular. Conclusión: El presente estudio demostró que no existe una clara asociación estadística entre los niveles de ASLO, PCR y RF con el riesgo cardiovascular, como sí lo evidencian los del colesterol HDL, en la población estudiada.
... La presencia de un síndrome nefrítico que curse concomitantemente o que se presente inmediatamente después de una infección viral, especialmente del tracto respiratorio superior, obliga a hacer el diagnóstico diferencial con nefropatía IgA, siendo esta la glomerulonefritis primaria más frecuente en todas las edades, pero aquí el hallazgo diferenciador es el complemento sérico, que en esta enfermedad generalmente es normal (16) y en la paciente estaba disminuido. Adicionalmente, los estudios de autoinmunidad y de otras infecciones fueron negativos. ...
... Tanto la paciente descrita, como los casos similares encontrados, tuvieron una evolución clínica favorable sin deterioro de la función renal y resolución de la hipertensión, por lo que no hubo necesidad de realizar biopsia renal en la fase aguda de la enfermedad; sin embargo, la paciente debe continuar en seguimiento de la función renal (16) . ...
La mononucleosis infecciosa es un síndrome clínico de causa viral que generalmente tiene un curso benigno y autolimitado, caracterizado por fiebre, faringoamigdalitis y adenomegalias generalizadas, siendo la afectación de órganos o sistemas algo inusual. Se presenta el caso de una niña de ocho años con un síndrome mononucleósico por virus de Epstein-Barr y Citomegalovirus, con un síndrome nefrítico agudo hipocomplementémico secundario, sin deterioro de la función renal y evolución clínica favorable. La ausencia de un período de latencia entre el proceso infeccioso y la aparición de los síntomas de síndrome nefrítico, es un elemento clave en el diagnóstico diferencial con el síndrome nefrítico agudo postestreptocócico, que es la causa más común en niños.
... The pathogenesis of AAV is multifactorial and genetic/epigenetic factors interact with different external triggers. Dysregulation of B cells and lack of balance between T helpers and T effectors lead to the production of ANCA (anti-neutrophil cytoplasmic antibody), activation of neutrophils, and further damage of vessel walls with the late multiorgan consequences [66]. The relevant biologic agents, preliminarily described in case reports, then evaluated in several clinical trials enrolling adult and (in some projects) also pediatric and adolescent patients, include rituximab (anti-B CD 20 moab), infliximab (anti-TNFα moab), etanercept (TNFα-receptor blocker), abatacept (CTLA-4 Ig Fc fusion protein), alemtuzumab (humanized anti-CD52 moab) and tocilizumab (anti-IL6 moab) [67]. ...
Therapy of immune-mediated kidney diseases has evolved during recent decades from the non-specific use of corticosteroids and antiproliferative agents (like cyclophosphamide or azathioprine), towards the use of more specific drugs with measurable pharmacokinetics, like calcineurin inhibitors (cyclosporine A and tacrolimus) and mycophenolate mofetil, to the treatment with biologic drugs targeting detailed specific receptors, like rituximab, eculizumab or abatacept. Moreover, the data coming from a molecular science revealed that several drugs, which have been previously used exclusively to modify the upregulated adaptive immune system, may also exert a local effect on the kidney microstructure and ameliorate the functional instability of podocytes, reducing the leak of protein into the urinary space. The innate immune system also became a target of new therapies, as its specific role in different kidney diseases has been de novo defined. Current therapy of several immune kidney diseases may now be personalized, based on the detailed diagnostic procedures, including molecular tests. However, in most cases there is still a space for standard therapies based on variable protocols including usage of steroids with the steroid-sparing agents. They are used as a first-line treatment, while modern biologic agents are selected as further steps in cases of lack of the efficacy or toxicity of the basic therapies. In several clinical settings, the biologic drugs are effective as the add-on therapy.
... This final fibrous stage is unlikely to respond to immunosuppressive therapy and has a high risk of ESKD. 1,13,14 Types of Crescentic Glomerulonephritis: Three mechanisms of glomerular injury are known that can result in activation of podocytes and epithelial proliferation to form crescents. Type-I: Anti-GBM (Goodpasture syndrome)constitutes circulating antibodies IgG directed against the non-collagenous domain of alpha-3 chain of type IV collagen, present in the GBM and/or alveolar basement membrane. ...
... IC mediated RPGN is the most common and severe form, particularly in children with PIGN, IgA nephropathy/vasculitis and LN. 14 ...
... Ten percent of patients with GPA or MPA may have ANCA-negative GN limited to the kidneys and are taken under this spectrum with similar clinical features, biopsy findings and prognosis. 13,14 The histological classification: focal (50% normal glomeruli), crescentic (>50% cellular crescents), sclerotic (>50% sclerotic glomeruli) and mixed (any other combination) has significant prognostic value. Validation studies have confirmed the predictive value of this system in adults and in children. ...
Rapidly progressive glomerulonephritis (RPGN), characterized by a rapid development of nephritis with loss of kidney function in days or weeks, is typically associated histologically, with crescents in most glomeruli; and is a challenging problem, particularly in low resource settings. RPGN is a diagnostic and therapeutic emergency requiring prompt evaluation and treatment to prevent poor outcomes. Histopathologically, RPGN consists of four major categories, anti-glomerular basement membrane (GBM) disease, immune complex mediated, pauci-immune disorders and idiopathic /overlap disorders. Clinical manifestations include gross hematuria, proteinuria, oliguria, hypertension and edema. Diagnostic evaluation, including renal function tests, electrolytes, urinalysis/microscopy and serology including (anti GBM antibody, antineutrophil cytoplasmic antibody (ANCA)) starts simultaneously with management. An urgent renal biopsy is required to allow specific pathologic diagnosis as well as to assess disease activity and chronicity to guide specific treatment.
The current guidelines for management of pediatric RPGN are adopted from adult experience and consist of induction and maintenance therapy. Aggressive combination immunosuppression has markedly improved outcomes, however, nephrotic syndrome, severe acute kidney injury requiring dialysis, presence of fibrous crescents and chronicity are predictors of poor renal survival. RPGN associated post infectious glomerulonephritis (PIGN) usually has good prognosis in children without immunosuppression whereas immune-complex-mediated GN and lupus nephritis (LN) are associated with poor prognosis with development of end stage kidney disease (ESKD) in more than 50% and 30% respectively.
Given the need for prompt diagnosis and urgent treatment to avoid devastating outcomes, we conducted a review of the latest evidence in RPGN management to help formulate clinical practice guidance for children in our setting.
Information sources and search strategy: The search strategy was performed in the digital databases of PubMed, Cochrane Library, google scholar, from their inception dates to December 2020. Three investigators independently performed a systematic search using the following search terms “Rapidly progressive glomerulonephritis” “children” “crescentic glomerulonephritis” “management” at the same time, backtracking search for references of related literature.
... Cases of dual ANCA and anti-GBM antibody positivity are widely reported (17% of reported cases in children) and it has been suggested that the initial presence of ANCA may be the trigger responsible for exposing the epitope in the alpha-3 chain [8]. Dual positivity is associated with a poorer prognosis, and thus, early, aggressive treatment is recommended [18]. Patients may also present with features overlapping with membranous nephropathy at a higher rate than would be expected by chance and atypical presentations of this disease are reported [19]. ...
Anti-glomerular basement membrane disease (Anti-GBM), previously known as Goodpasture syndrome, is an extremely rare cause of rapidly progressive glomerulonephritis and chronic kidney disease stage 5 (CKD5) in children. It is associated with acute pulmonary haemorrhage and it has a poor prognosis. It is classified as an autoimmune, small-vessel vasculitis caused by autoantibody formation against the alpha-3 chain in type IV collagen found in the glomerular basement membrane. Evidence of anti-GBM antibodies in serum or histologically are required for diagnosis. Treatment in children is based on very limited adult data and often involves the use of acute apheresis to rapidly remove circulating factors coupled with intensive immunosuppression such as cyclophosphamide and intravenous corticosteroids. There is also an emerging role for the use of biologic agents such as B cell depletion. The evidence base in children with anti-GBM disease is extremely limited. Multi-centre international collaboration is required to provide insight into this disease, better describe its prognosis and work towards improving outcomes. This review article summarises the key features of this disease in children, highlights treatment options and considers areas of unmet need.
