Version May 2024
INTRODUCTION — Glomerulonephritis (GN) generally presents as a constellation of findings that include hematuria, proteinuria, edema, and, often, hypertension [1]. GN is caused by a number of disorders that are all characterized by glomerular injury accompanied by inflammation. In some cases, GN may progress to kidney failure.
The pathogenesis and etiology of GN in children will be reviewed here. The approach to evaluating a child with GN is discussed separately. (See "Glomerular disease: Evaluation in children".)
PATHOGENESIS — Although the pathogenesis is not fully understood, available evidence suggests that most cases of GN are due to an autoimmune response, which is modified by genetic factors, to a variety of different etiologic agents including infectious agents [2,3]. The immunologic response, in turn, activates a number of biologic processes (eg, complement activation, leukocyte recruitment, and release of growth factors and cytokines) that result in glomerular inflammation and injury [4,5]. GN may be isolated to the kidney (primary GN) or be a component of a systemic disorder (secondary GN) (table 1).
The immunologic mechanisms involved in the pathogenesis of GN are briefly reviewed here and are discussed in greater detail separately. (See "Mechanisms of immune injury of the glomerulus".)
Immunologic damage — Humoral (also referred to T helper cell 2-regulated) immune response to a variety of inciting agents results in immunoglobulin (Ig) deposition and complement activation within the glomeruli (figure 1). In glomerular diseases that are primarily due to immunologic injury, immune complex deposition is an active process caused by in situ binding of antibodies to antigens localized within the glomeruli. The antigens may be structural glomeruli components, such as the Goodpasture antigen located in the glomerular basement membrane (GBM) in the non-collagenous domain of the alpha-3 chain of type IV collagen [6].
Alternatively, the antigens may be trapped or deposited within the glomerulus, including self-antigens such as chromatin components in lupus nephritis, neutrophil antigens in antineutrophil cytoplasmic autoantibody (ANCA) GN, IgA in IgA nephropathy, or exogenous antigens due to infectious agents such as bacteria (Streptococcus, Staphylococcus), viruses (hepatitis B), or tumor antigens [7]. These in situ-formed immune complexes may enlarge if there is further immune response consisting of polyclonal B-cell activation, which induces the formation of different antibodies. These include rheumatic factors IgM, anti-IgG, or anti-idiotypic antibodies that bind to these complexes. Autoantibodies to complement factors can induce C3 GN through complement activation.
Another possible mechanism for immune complex deposition is the passive process of trapping circulating immune complexes within the glomeruli. Although this process has been studied in animal models (serum sickness disease), it appears to be less commonly seen in human GN than in situ glomerular immune complex formation.
GN that is due to antibody formation requires the presence of T lymphocytes. CD4+T lymphocytes specific for nephritogenic autoantigens (proteinase-3, myeloperoxidase, Goodpasture antigen) are present in the circulation of patients with granulomatosis with polyangiitis or anti-GBM (Goodpasture) disease [8,9]. T lymphocytes may also cause GN in the absence of antibodies, as demonstrated in experimental animal models [10,11]. Although the mechanism for this cellular-mediated immunity is less well defined in humans, it appears to involve activation of both T cell lymphocytes and macrophages, particularly in rapidly progressive (crescentic) GN (RPGN). (See "Mechanisms of glomerular crescent formation", section on 'Macrophages' and "Mechanisms of glomerular crescent formation", section on 'T cells'.)
Secondary processes — The primary immunologic pathologic process activates the following systems that contribute to the inflammatory response and glomerular damage (figure 1). (See "Mechanisms of immune injury of the glomerulus", section on 'Inflammatory mechanisms of glomerular injury'.)
●Complement system – The humoral immunologic response activates the classic complement pathway [12]. In some kidney disorders (eg, membranoproliferative type II and poststreptococcal GN), the alternative pathway is activated. Complement activation results in generation of chemotactic and chemokinetic peptides (C3a, C5a, and C3b) that attract white cells to the site of injury and formation of the membrane attack complex (C5b-C9), which may cause direct injury to glomerular cells [13] and results in the release of cytokines, reactive oxygen species (ROS), prostaglandins, and cell apoptosis [14]. (See "Overview and clinical assessment of the complement system", section on 'Introduction'.)
●Coagulation system – In patients with RPGN, direct injury to the endothelial cells activates the coagulation cascade. This results in thrombi formation and fibrin deposition that are important components in the formation of crescents. (See "Mechanisms of glomerular crescent formation", section on 'Initiating events' and "Mechanisms of glomerular crescent formation".)
●Leukocyte recruitment – A constant feature of GN is the glomerular infiltration of leukocytes (neutrophils, monocytes, and macrophages), which are sequentially recruited to the glomeruli by the coordinated release of chemoattractants (eg, C3a, C5a, and CXC chemokines). When activated, these cells generate ROS (such as hydrogen peroxide), lysosomal enzymes (which damage endothelial cells, the GBM, and the mesangium), and growth factors (which induce fibrin deposition, cell proliferation, and crescent formation). As in patients with granulomatosis with polyangiitis, who have kidney involvement, pathogenesis is due to adherence to renal endothelial cells and release proteases, ROS, and inflammatory cytokines, resulting in glomerular injury. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Cytokine profiles and functions of CD4+ T helper cell subsets' and "Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis", section on 'Role of endothelial cells'.)
●Glomerular cells – Injury to the glomerular endothelial and mesangial cells result in cell proliferation and adhesion molecule expression and the production and release of vasoactive molecules (endothelin and nitric oxide), cytokines, ROS, growth factors, and prostaglandins.
●Growth factors and cytokines – Many growth factors and cytokines (eg, interleukins) are produced by glomerular cells and by inflammatory cells. These small peptides bind to specific cell surface receptors and may either promote or prevent kidney injury.
•Growth factors such as platelet-derived growth factor, transforming growth factor-beta, and vascular endothelial growth factor have important roles in glomerular injury involving glomerular cell proliferation, extracellular matrix deposition, and sclerosis.
•Interleukins (IL) are known to play an important role in the inflammatory response. IL-1, IL-8, and IL-18 have a proinflammatory action in GN [15]. IL-1 induces mesangial cell proliferation and promotes the synthesis of several substances. IL-8 is produced by mesangial cells and is a chemoattractant for granulocytes.
ETIOLOGIC CLASSIFICATION — Because the differential diagnosis for GN is broad, using a classification schema is helpful to narrow the causes of childhood GN in a systematic manner. The etiology of GN can be classified by the following methods:
●Clinical presentation
●Histopathology
The preferred etiologic approach is to use the clinical presentation schema because the histopathologic method requires a biopsy sample.
Clinical presentation — Children with GN can present in several scenarios, as discussed in the following sections. Each clinical presentation includes different kidney diseases. In addition, several glomerular disorders may be included in one or more clinical presentation (eg, IgA nephropathy). A presumptive clinical diagnosis is made based on the presentation, presence of extrarenal findings, family history, and laboratory testing including urinalysis. Histologic confirmation is made by kidney biopsy. (See "Glomerular disease: Evaluation in children".)
Acute nephritic syndrome — Acute nephritic syndrome typically presents as the sudden onset of hematuria (either gross or microscopic) with proteinuria, decreased glomerular filtration rate, and retention of sodium and water, which usually results in an elevated blood pressure and edema.
In children, the most common cause of acute nephritic syndrome is poststreptococcal GN [16-18]. Acute GN (GN) also has been associated with other infectious agents (table 2). Other causes of acute nephritic syndrome include other GN (eg, IgA vasculitis [IgAV; Henoch-Schönlein purpura (HSP)], nephritis associated with subacute bacterial endocarditis, and shunt nephritis). (See "Poststreptococcal glomerulonephritis" and "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis", section on 'Kidney disease' and "Kidney disease in the setting of infective endocarditis or an infected ventriculoatrial shunt", section on 'Clinical features and kidney biopsy findings'.)
In addition, several causes of chronic GN may present as acute nephritic syndrome and may be initially indistinguishable clinically from acute disorders. These chronic conditions include primary GN (eg, IgA nephropathy and membranoproliferative GN [MPGN]) and secondary GN (eg, lupus nephritis). (See "IgA nephropathy: Clinical features and diagnosis" and "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis" and "Lupus nephritis: Diagnosis and classification".)
Rapidly progressive glomerulonephritis — Rapidly progressive GN (RPGN) is a clinical syndrome manifested by features of subacute nephritic syndrome with a progressive loss of kidney function over a comparatively short period of time (days, weeks, or months). It is characterized morphologically by extensive crescent formation (picture 1A-D).
RPGN occurs rarely in children. Causes of pediatric RPGN include [19]:
●Primary GN – IgA nephropathy, MPGN, and anti-glomerular basement membrane (GBM) disease
●Secondary GN – Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, lupus nephritis, poststreptococcal GN, IgAV (HSP) nephritis
Early diagnosis with kidney biopsy and serologic testing as well as early initiation of appropriate therapy are essential to minimize the degree of irreversible kidney injury. Empiric therapy may be started in patients with severe disease, particularly if either kidney biopsy or interpretation of the biopsy will be delayed. However, despite aggressive treatment, approximately one-half of the affected children will develop end-stage kidney disease.
The clinical manifestations, diagnosis, and treatment of RPGN are discussed separately. (See "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis".)
Recurrent macroscopic hematuria — Recurrent macroscopic hematuria in children is commonly caused by IgA nephropathy, which often occurs one or two days after an upper respiratory infection. (See "IgA nephropathy: Clinical features and diagnosis", section on 'Clinical features'.)
Recurrent macroscopic hematuria may also be seen in children with Alport syndrome. (See "Clinical manifestations, diagnosis, and treatment of Alport syndrome (hereditary nephritis)", section on 'Kidney manifestations'.)
Chronic glomerulonephritis — Patients who present with chronic GN may have few overt symptoms, and asymptomatic hematuria or proteinuria discovered on routine urinalysis may be the only presenting sign. In addition, causes of chronic GN may present as acute nephritic syndrome and may be initially indistinguishable clinically from acute disorders.
In some cases, patients are diagnosed in a late stage of disease and present with hypertension, kidney impairment, and proteinuria with or without hematuria. The kidney biopsy at this stage may only demonstrate nonspecific and nondiagnostic findings of fibrosis, glomerular sclerosis, and tubular atrophy on light microscopy. Immunofluorescence microscopy may be more helpful in making a diagnosis.
Chronic GN that presents in childhood includes both primary GN (eg, MPGN, IgA nephropathy, and anti-GBM disease) and secondary GN (eg, lupus nephritis and ANCA-associated vasculitis).
Histopathology — A kidney biopsy may be needed to determine the histologic etiology of GN or confirm the diagnosis. In some cases, the diagnosis can be made clinically and a biopsy is not required (eg, poststreptococcal GN). Histopathology also allows to diagnose active lesions potentially reversible with therapeutic interventions or chronic and irreversible lesions.
The histopathologic evaluation consists of the following:
●Light microscopy
●Immunofluorescence examination
●Electron microscopy
Light microscopy — The light microscopic findings generally are not specific, as the same morphological pattern may be produced by a number of different diseases. As an example, MPGN can be caused by a variety of systemic immune complex diseases, including infective endocarditis or hepatitis C viruses, or can be a primary idiopathic disorder. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis".)
In addition, a specific disease may present with several different histologic patterns. As an example, lupus nephritis can present as six different histologic patterns on kidney biopsy. (See "Lupus nephritis: Diagnosis and classification".)
●Minimal mesangial lupus nephritis (class I)
●Mesangial proliferative lupus nephritis (class II)
●Focal lupus nephritis (class III)
●Diffuse lupus nephritis (class IV)
●Membranous lupus nephropathy (class V)
●Advanced sclerosing lupus nephritis (class VI)
Despite the diagnostic limitation of light microscopy, it is a generally useful tool because histologic findings often correlate with the clinical status and prognosis of the patient. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)
●Diffuse proliferative GN is associated with inflammatory lesions in most or all of the glomeruli. Patients may have significant and serious clinical findings, including nephrotic range proteinuria, edema, hypertension, and impaired kidney function.
●Focal GN is associated with inflammatory lesions in less than one-half of the glomeruli. In contrast with diffuse proliferative GN, patients with focal involvement generally do not have serious clinical findings and have a better prognosis.
Immunofluorescence microscopy — Immunofluorescence microscopy demonstrates the pattern of immunoglobulin and complement glomerular deposition, which is helpful in identifying specific kidney disorders among the different causes of GN (algorithm 1).
●Linear deposition of IgG along the GBM is diagnostic for anti-GBM GN.
●Granular deposits are characteristic of immune complex diseases. The pattern of deposition is based on the immunosera used (eg, anti-IgG, anti-IgA, anti-C3) and is used to diagnose specific GN, as demonstrated by the following examples:
•IgA deposition greater than IgG deposition in the mesangium is characteristic for either IgA nephropathy or IgAV (HSP) nephritis (picture 2).
•IgG and C3 deposition that is on the external side of the GBM is characteristic of poststreptococcal GN (picture 3), whereas IgG and C3 deposition found along the GBM and mesangium are seen in MPGN types I and III (picture 4).
•IgG, mainly IgG1 and IgG3, together with IgA, IgM, C3, C4, and C1q, also called full house, is highly suggestive of lupus nephritis.
•Deposits that only contain C3 without IgG along the glomerular, tubular, and Bowman's capsule basement membranes, and the mesangium is characteristic of dense deposit disease (MPGN type II) and C3 glomerulopathy [20,21]. (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis".)
●Absence of immunoglobulins is characteristic of pauci-immune GN that is seen in patients with ANCA-associated vasculitis [22]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis", section on 'Histopathology'.)
Electron microscopy — Electron microscopy may be useful in confirming or making a specific diagnosis of an underlying kidney disorder. As an example, electron microscopy demonstrates the characteristic subepithelial "humps" seen in patients with poststreptococcal GN (picture 5). (See "Poststreptococcal glomerulonephritis".)
SPECIFIC DISORDERS — Specific glomerulonephritides in children are divided into primary GN [23] (disease process isolated to the kidney) or secondary GN (kidney disease is a component of a systemic disorder), and many are discussed individually elsewhere (table 1).
Primary glomerulonephritis
●Membranoproliferative GN (MPGN) (see "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis")
●IgA nephropathy (see "IgA nephropathy: Clinical features and diagnosis")
●Anti-glomerular basement membrane (GBM) disease (see "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis")
●Idiopathic crescentic GN (see "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis")
Secondary glomerulonephritis
●Poststreptococcal GN (see "Poststreptococcal glomerulonephritis")
●IgA vasculitis (Henoch-Schönlein purpura [HSP]) (see "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis" and "IgA vasculitis (Henoch-Schönlein purpura): Kidney manifestations")
●Systemic lupus erythematosus nephritis (see "Lupus nephritis: Diagnosis and classification")
●Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (see "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis")
●Nephritis associated with infective endocarditis (see "Infective endocarditis in children", section on 'Complications')
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Glomerular disease (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Overview – Glomerulonephritis (GN) generally presents as a constellation of findings that include hematuria, proteinuria, edema, and, often, hypertension. It is caused by a number of disorders that are all characterized by glomerular injury accompanied by inflammation. (See 'Clinical presentation' above.)
●Pathogenesis – The pathogenesis of GN is not fully understood. Currently available data suggest that most cases of GN are due to an immunologic response to a variety of different etiologic agents. The immunologic response, in turn, activates a number of biologic processes (eg, complement activation, leukocyte recruitment, and release of growth factors and cytokines), which result in glomerular inflammation and injury. (See 'Pathogenesis' above.)
●Classification – Because the differential diagnosis for GN is broad, using a classification schema is helpful to narrow the causes of GN in a systematic manner. The etiology of GN in children can be classified by its clinical presentation (acute GN, rapidly progressive GN [RPGN], recurrent macroscopic hematuria, and chronic GN) or by histopathology. The histologic findings are based on light, immunofluorescence, and electron microscopy. (See 'Etiologic classification' above.)
●Specific disorders – GN may be isolated to the kidney (primary GN) or be a component of a systemic disorder (secondary GN) (table 1). Specific causes of GN in children are discussed in separate reviews. (See 'Specific disorders' above.)
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