Mechanisms of immune injury of the glomerulus

INTRODUCTION — Most forms of glomerulonephritis (GN) are thought to be immune-mediated [1,2], but in the majority of cases the inciting etiologic agents remain elusive. GN can be induced by infections, such as poststreptococcal and hepatitis C virus-induced cryoglobulinemic GN, and there are a few examples of drug-induced [3] and cancer-associated GN [4]:

●(See "Group A streptococcus: Virulence factors and pathogenic mechanisms".)

●(See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis".)

●(See "Overview of kidney disease in patients with cancer", section on 'Paraneoplastic glomerular diseases'.)

The immunopathogenesis of GN is complex and may be the result of a "perfect storm" of genetics and unfavorable environmental conditions. Genetic factors clearly predispose certain individuals to develop immune responses that can lead to GN [5-7]. Glomerular injury is usually mediated by the actions of multiple elements of both the innate and the adaptive immune systems, resulting in diverse clinical and pathologic manifestations [8]. A schematic depiction of the relationship among immune events, effector cells, mediator release, and eventual glomerular injury is shown in the figure (figure 1).

The complex nature of GN is well illustrated by immunoglobulin A (IgA) nephropathy. This disease results from a defect of IgA glycosylation, which may be associated with the production of autoantibodies directed against the deglycosylated hinge regions of IgA. Environmental factors such as gluten-containing food or microbiota play a critical role in the development of the disease in part by stimulating IgA production in gut-associated plasma cells [9]. Deglycosylated IgA may bind to receptors on the surface of macrophages or mesangial cells leading to deposits in the mesangium. Subsequently, deglycosylated IgA in the mesangium may act as a planted antigen and form the core of an immune complex containing anti-glycan autoantibodies and activated complement components [10]. Genetics may modulate each step of the pathogenesis, including defective glycosylation, the immune response to altered IgA, response to infection through innate immunity, and complement activation [11,12]. (See "IgA nephropathy: Pathogenesis".)

This topic will review the immune events that occur after antigen exposure and that lead to immune complex formation in glomeruli, T cell-mediated glomerular injury, and the glomerular response to immune injury and the mediators that are involved.

COMPONENTS OF THE NEPHRITOGENIC IMMUNE RESPONSE — The nephritogenic immune response includes both humoral and cellular components. The humoral immune responses are the result of B cell activation and maturation into plasma cells, which can lead to immunoglobulin deposition and complement activation in glomeruli. The T helper cell (Th)1-regulated or Th17-regulated cellular immune response contributes to the infiltration of circulating mononuclear inflammatory cells (including lymphocytes and macrophages) into glomeruli and to crescent formation. (See "The adaptive cellular immune response: T cells and cytokines" and "Mechanisms of glomerular crescent formation", section on 'T cells'.)

This section will review the roles of humoral immunity and cellular immunity in the pathogenesis of glomerular disease. General mechanisms of humoral and cellular immunity are discussed elsewhere:

●(See "The adaptive humoral immune response".)

●(See "The adaptive cellular immune response: T cells and cytokines".)

Humoral immunity — Most glomerular diseases are characterized by the formation of immune complexes that contain immunoglobulins and complement components, which suggests that the humoral immune response is the principal cause of injury. Examples include postinfectious glomerulonephritis (GN), IgA nephropathy, anti-glomerular basement membrane (GBM) antibody disease, lupus nephritis, membranous nephropathy (MN), immune complex-mediated membranoproliferative GN, and several causes of rapidly progressive (crescentic) GN.

Immune deposits form in the glomerulus either actively because the target antigen(s) is localized predominantly in the glomerulus or, less commonly, passively because of the role of the glomerulus in filtration. Antibodies that induce glomerular immune deposits may be directed against the following antigens:

●Normal constituents of the glomerulus, such as the non-collagenous domain of the alpha-3 chain of type IV collagen in anti-GBM disease [13,14]; M-type phospholipase A2 receptor (PLA2R), thrombospondin type-1 domain-containing 7A (THSD7A), neural epidermal growth factor-like 1 protein (NELL-1), neutral endopeptidase (NEP), semaphorin 3B, and protocadherins 7 or FAT1 on the podocyte in MN [15-21]; and nephrin in the slit diaphragm in minimal change disease [22].

•(See "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis".)

•(See "Membranous nephropathy: Pathogenesis and etiology".)

•(See "Minimal change disease: Etiology, clinical features, and diagnosis in adults".)

●Nonrenal self-antigens that become localized to glomeruli, such as DNA nucleosome complexes in lupus nephritis, myeloperoxidase (MPO) or proteinase 3 (PR3) in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, or abnormally glycosylated IgA in IgA nephropathy [23-25]. These non-glomerular endogenous antigens localize in glomeruli because of passive trapping often via spontaneous aggregation or by interaction with negatively charged sites on the glomerular capillary wall. Circulating nonrenal self-antigens can also bind to receptors located in the mesangium (eg, transferrin receptor for IgA1) [26]. Antigens can be "planted" in the glomerulus followed by antibody binding to form immune complexes (known as in situ immune complex formation), or they may be passively trapped as components of immune complexes formed in the circulation:

•(See "Lupus nephritis: Diagnosis and classification", section on 'Pathogenesis'.)

•(See "Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis".)

•(See "IgA nephropathy: Pathogenesis", section on 'IgA1 O-glycosylation'.)

●Exogenous antigens or immune aggregates that localize in glomerular capillaries via charge affinity for glomerular structures, passive trapping, or local precipitation of macromolecular aggregates. Cationic bovine serum albumin in early childhood MN and HCV antigen-containing cryoglobulins in hepatitis C virus-associated membranoproliferative GN are two examples [27,28]:

•(See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'Infections'.)

•(See "Overview of kidney disease associated with hepatitis C virus infection", section on 'Membranoproliferative glomerulonephritis without cryoglobulins'.)

Humoral immunity against a target antigen does not necessarily indicate pathogenicity. Autoantibodies to MPO, PR3, and the GBM are present in asymptomatic individuals [29], and anti-PLA2R antibodies can precede the development of MN by months or years [30,31]. (See 'Other determinants of glomerular injury' below.)

Cellular immunity — Strong evidence exists for a primary role for mononuclear cells, particularly lymphocytes and macrophages in the absence of antibody deposition, in causing glomerular injury in diseases such as minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and crescentic GN. In addition, some evidence supports a role for both platelets and T cells, including specific T cell subsets, in glomerular pathology [32].

IMMUNE MECHANISMS OF GLOMERULAR INJURY — There are two immune mechanisms of glomerular injury: inflammatory and noninflammatory [1]:

●Inflammatory injury (glomerulonephritis [GN]) is characterized by glomerular infiltration by hematopoietic cells such as neutrophils and macrophages and/or proliferation of resident glomerular cells. These effector cells may induce thrombosis, necrosis, and crescent formation which, if extensive, can result in rapidly progressive GN (see 'Inflammatory mechanisms of glomerular injury' below). The major clinical features of GN are:

•An active urinary sediment including hematuria, often with some of the red blood cells having a dysmorphic or abnormal appearance (picture 1 and picture 2), with or without red blood cell casts (picture 3), and leukocyturia

•Varying degrees of proteinuria, ranging from mild to the nephrotic range

•Reduced glomerular filtration rate that depends upon the severity of the disease

Common causes of immune-mediated GN include IgA nephropathy, lupus nephritis, and postinfectious or infection-related GN. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

●Noninflammatory lesions resulting from immune injury usually target the glomerular podocyte (picture 4) and are associated with ultrastructural and major functional changes in the glomerulus that result in an increase in glomerular permeability to albumin and other proteins. (See 'Noninflammatory mechanisms of immune glomerular injury' below.)

The major clinical features of noninflammatory glomerular lesions are proteinuria and the nephrotic syndrome, with little or no hematuria and no red blood cell casts. Common causes of immune-mediated nephrotic syndrome without inflammatory changes are minimal change disease (MCD) and membranous nephropathy (MN). (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

Importance of the site of glomerular injury — A major determinant of whether the patient presents with GN and an active urine sediment (nephritic syndrome) or with proteinuria and little or no hematuria (nephrotic syndrome) is the site of glomerular injury.

Three major types of resident glomerular cells (visceral epithelial cells [podocytes], endothelial cells, and mesangial cells (picture 4)) populate the glomerular tuft, and parietal epithelial cells (PECs) line the inside of the glomerular (Bowman's) capsule:

●Glomerular endothelial and mesangial cells come into direct contact with circulating factors like complement and inflammatory cells including neutrophils, macrophages, natural killer (NK) cells, and T cells. Immune complexes that form or deposit in the mesangial matrix or subendothelial space often result in glomerular inflammation and the nephritic syndrome. (See 'Inflammatory mechanisms of glomerular injury' below.)

●Glomerular visceral epithelial cells, or podocytes, are the major barrier that restricts the filtration of negatively charged or large (>60 kDa) plasma proteins. Injury to podocytes leads to massive proteinuria and is often associated with the nephrotic syndrome. As podocytes are separated from the circulation by the glomerular basement membrane (GBM), subepithelial immune deposits that target podocytes seldom produce glomerular inflammation, and therefore there is little or no hematuria and no red blood cell casts. (See 'Noninflammatory mechanisms of immune glomerular injury' below.)

●Glomerular parietal epithelial cells (PECs) cover the inner aspect of Bowman's capsule and contribute to crescent formation. While podocytes are thought to be terminally differentiated, experimental data indicate that glomerular PECs make up a component of crescents and can replenish damaged podocytes [33-36]. (See "Mechanisms of glomerular crescent formation", section on 'Glomerular parietal epithelial cells'.)

Other determinants of glomerular injury — In addition to the site of glomerular injury, a number of other factors can contribute to glomerular injury. These include:

●The biologic properties of the immunoglobulins that form the deposits. As an example, complement-fixing immunoglobulin G (IgG) subtypes, such as IgG1 and IgG3, cause more inflammation than immunoglobulins that activate complement poorly, such as IgA and IgG4 [17].

●The mechanism by which the deposits are formed. Antigen-antibody interactions that take place within the glomerulus (in situ immune complex formation) result in local complement activation and are much more nephritogenic than passive trapping of similar complexes preformed in the circulation [37,38].

●The amount of immune deposit formation. The greater the quantity of immune deposits, the greater the degree of tissue injury.

●The nature of the epitope(s) recognized. Pathogenic antibodies against linear epitopes on the Goodpasture antigen have been associated with kidney injury [39], and an epitope motif has been identified in a mutual B and T cell epitope [40]. Certain myeloperoxidase (MPO) epitopes have been found to be specific for active antineutrophil cytoplasmic antibody (ANCA) disease, while others remain present during remission or are also present in healthy individuals [41,42]. These findings partly explain the lack of correlation between MPO-ANCA titers and active disease. There is accumulating evidence that intra-molecular spreading is a key event in the development of pathogenicity and disease severity in anti-GBM disease [43], ANCA disease [41,42], and phospholipase A2 receptor (PLA2R)-related MN [44].

Independent of how or where immune deposits form in glomeruli, there is evidence that immunoglobulins alone may induce significant tissue injury. Antibodies directed against some components of the podocyte slit diaphragm (such as nephrin) can induce proteinuria without inflammation [22,45]. One finding that supports the pathogenicity of anti-nephrin antibodies has been described in patients with congenital nephrotic syndrome of the Finnish type (CNF), which is associated with mutations in the gene for nephrin [46]. When children with CNF undergo kidney transplantation, they may develop nephritogenic antibodies to the transplanted nephrin neo-antigen with recurrent nephrotic syndrome [47,48]. In experimental and human MN, nephritogenic antibodies most likely behave as bifunctional molecules activating complement and altering the function of the target antigen [17,49,50]. (See "Congenital nephrotic syndrome", section on 'Congenital Nephrotic Syndrome of Finnish type'.)

Glomerular injury usually results from the activation of effector cells and the release of a variety of inflammatory mediators (figure 1). These mediators include products of complement activation, such as C5a and C5b-9, that are induced by antibodies (see "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis"); oxidants and proteases released by both inflammatory and resident glomerular cells; and a variety of other cytokines, chemokines, growth factors, and vasoactive agents [1,51].

Glomerular injury can also result from the absence of certain mediators. As an example, complement factor H (CFH) is a negative regulator of the alternative pathway of complement. In mice, CFH deficiency leads to uncontrolled C3 activation and spontaneous kidney disease similar to C3 glomerulopathy [52]. In humans, a familial form of C3 glomerulopathy has been described in patients of Cypriot origin who have a mutation in the gene for complement factor H-related protein 5. This mutation increases the ability of complement factor H-related protein 5 to bind factor H, thereby preventing factor H from regulating C3 [53]. The localization of glomerular C3 deposits may be influenced by activity of the complement regulatory protein type 1 (CR1) at the surface of podocytes [54]. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'CFHR5 nephropathy'.)

Conversely, in IgA nephropathy, genome-wide association studies have identified deletion of complement factor-related genes 1 and 3 as protective against the disease. Because the corresponding gene products compete with factor H, it has been hypothesized that the absence of these genes could lead to more potent inhibition of complement by factor H [12]. Higher serum factor H-related protein (FHR)-5 levels were associated with a lack of response to immunosuppression, the presence of endocapillary hypercellularity, and histology scores of disease severity (the Oxford Classification MEST score) [55]. (See "IgA nephropathy: Pathogenesis", section on 'Complement activation'.)

Several immune mechanisms can be present simultaneously (eg, both anti–GBM and ANCA). Over 60 percent of patients with anti-GBM disease have autoantibodies directed against linear peptides of MPO heavy chain [56]. Circulating antibodies against aberrant glycosylated MPO have been detected in one-half of the patients with anti-GBM disease without MPO-ANCA [57].

INFLAMMATORY MECHANISMS OF GLOMERULAR INJURY — When immune complexes form in the glomerulus, they often provoke a cellular inflammatory response. Inflammation-inducing immune deposits can be seen in the following sites:

●Glomerular basement membrane (GBM), as occurs in anti-GBM antibody disease (picture 5).

●Capillary wall adjacent to the endothelial cells (subendothelial deposits), as occurs in class III or IV lupus nephritis and membranoproliferative glomerulonephritis (GN) (picture 6 and picture 7).

●Mesangium, as occurs in IgA nephropathy and lupus nephritis (picture 8 and picture 9). (See 'Importance of the site of glomerular injury' above.)

Subendothelial and mesangial deposits initiate multiple inflammatory processes, including complement activation, procoagulant activity, cytokine growth factor release, and chemoattractant generation. Copious antibody deposition is often seen in patients with autoimmune or infection-associated GN but is not always required for the development of severe inflammation as can be seen in antineutrophil cytoplasmic antibody (ANCA)-associated GN (pauci-immune GN) (picture 5) or C3 glomerulopathy.

Severe GN of any cause can induce crescent formation (picture 10), which is typically associated with rapidly progressive GN. The mechanisms underlying crescent formation are discussed elsewhere. (See "Mechanisms of glomerular crescent formation" and "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis".)

By contrast, immune complexes that deposit in the capillary wall adjacent to the podocytes (subepithelial deposits) do not generate an inflammatory response, since the immune deposits are separated from the systemic circulation by the GBM (picture 11). (See 'Noninflammatory mechanisms of immune glomerular injury' below and "Membranous nephropathy: Clinical manifestations and diagnosis", section on 'Pathology'.)

The following sections describe the roles of the major mediators and effector cells in inflammatory types of GN. These include complement and other humoral mediators, which can promote the infiltration of circulating inflammatory cells such as neutrophils, macrophages, natural killer (NK) cells, T cells, and platelets. In addition, there may be proliferation of resident glomerular cells, particularly mesangial cells and parietal epithelial cells.

Complement and other humoral mediators — The importance of complement activation, complement regulatory proteins, and other humoral mediators such as macrophage inhibitory factor (MIF), chemokines, and cytokines can be illustrated by the following observations [58-60]:

●Generation of the chemotactic factor C5a, a protein fragment released from complement component C5, is particularly important in antibody-induced glomerular inflammation [61]. C5a is involved in the recruitment of inflammatory cells, such as neutrophils, eosinophils, monocytes, and T lymphocytes, and in the activation of phagocytic cells, release of granule-based enzymes, and generation of oxidants, all of which can contribute to tissue injury.

In ANCA-induced glomerulonephritides, which include granulomatosis with polyangiitis and microscopic polyangiitis, neutrophil activation and the GN are mediated by the C5a receptor [62]. C5a receptor (CD88) blockade protects against myeloperoxidase (MPO)-ANCA GN in mice [63], and randomized control trials in humans with ANCA vasculitis have shown that C5a receptor inhibition was effective in ameliorating GN and could replace high-dose glucocorticoid therapy [64,65].

●Immune complex-mediated GN is significantly ameliorated in transgenic mice that over express a complement inhibitor in plasma and in mice in which the genes for the complement components C3 and C4 have been deleted [66]. Similarly, anti-GBM disease is made worse by the absence of complement regulatory proteins [67,68].

●The membrane attack complex (C5b-9) mediates injury to mesangial cells (eg, in IgA nephropathy and lupus nephritis) and endothelial cells (eg, in lupus nephritis and C3 glomerulopathy) [69]. (See "IgA nephropathy: Pathogenesis", section on 'Complement activation'.)

●Disorders of alternative complement pathway regulation are also associated with GN. The term C3 glomerulopathy has been proposed for this group of glomerular disorders, which are mostly caused by mutations in or autoantibodies to complement regulatory proteins (CFH, CFI) or by autoantibodies that stabilize the C3 convertase, also known as C3 nephritic factor [70]. Regulators of the alternate pathway are in development and show promise as therapeutic options for patients with C3 glomerulopathy or atypical HUS [71-74].

•(See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis", section on 'Pathogenesis'.)

•(See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'C3 glomerulonephritis'.)

Genetic and immune abnormalities of the alternative complement pathway have also been associated with "atypical postinfectious GN" with persisting symptoms and progression to end-stage kidney disease (ESKD); such patients likely have C3 GN [75].

●Immune complex-mediated GN and the associated inflammatory cell infiltration are, in some experimental settings, significantly reduced by the administration of an antibody directed against MIF, which is a proinflammatory cytokine [76].

●Deficiency or antagonism of chemokines (such as monocyte chemoattractant protein [MCP]-1 and Regulated on Activation Normal T cell Expressed and Secreted [RANTES]) and/or chemokine receptors (including CCR2 and CCR5) helps to prevent GN in animal models [77-80]. Conversely, expression of the chemokine CXCR1 may be associated with recruitment of neutrophils to the glomerular tuft in human GN [81].

Circulating inflammatory cells

Neutrophils — Neutrophils are present in kidney biopsies from patients with poststreptococcal GN (picture 12 and picture 13), membranoproliferative GN, IgA vasculitis (Henoch-Schönlein purpura), lupus nephritis, and some forms of crescentic GN [32]. (See "Poststreptococcal glomerulonephritis", section on 'Light microscopy' and "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis".)

Neutrophil localization in glomerular capillaries is dependent upon the generation of chemotactic factors within and around an inflammatory focus. The most prominent chemoattractants are C5a (derived from the activation of complement) and several chemokines, such as interleukin (IL)-8, which can be bound to endothelial cells via heparan sulfate proteoglycans [59,66,82-85].

Multiphoton microscopy has showed that neutrophils and monocytes normally traffic through glomerular capillaries for only a few minutes but are retained in the presence of glomerular inflammation [86]. During the period of retention, neutrophils either remained static or crawled through the glomerular vasculature. In response to immune complex deposition, the retained neutrophils generated oxidants in inflamed glomeruli.

Once attracted to glomeruli, neutrophil localization is mediated by the interaction between adhesion molecules expressed on glomerular endothelial cells (eg, selectins, integrins [CD11/CD18], and Ig-like molecules such as intercellular adhesion molecule-1 [ICAM-1]) and their corresponding ligands on neutrophils [59,82,87]. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".)

At the site of immune complex formation, neutrophils phagocytose the immune complex aggregates, become activated, and undergo a respiratory burst that generates reactive oxygen species. Hydrogen peroxide is the principal neutrophil-derived oxidant that mediates glomerular injury via interactions with both another neutrophil-derived cationic enzyme, MPO, which also localizes in glomeruli because of its positive charge, and with halides to form hypohalous acids, which halogenate the glomerular capillary wall.

Neutrophils also store cationic serine proteases, such as elastase and cathepsin G, within azurophilic granules. The activation of neutrophils in glomeruli causes the extracellular release of these proteins, which degrade elements of the glomerular capillary wall.

In addition, in some forms of GN, such as ANCA-associated GN and lupus nephritis, neutrophils generate neutrophil extracellular traps (NETs). NETs are web-like structures of histones decorated with proteases, peptides, and enzymes that are also likely to be injurious [88]. NET-associated extracellular histones cause toll-like receptor 2/4 (TLR-2/4)-dependent vascular necrosis in severe experimental GN [89].

Role in ANCA-associated vasculitis — In addition to their general role in GN, neutrophils are also involved in the pathogenesis of ANCA-associated granulomatosis with polyangiitis and microscopic polyangiitis. Proteinase 3 (PR3) and MPO are cationic proteases localized in the primary granules of neutrophils and are displayed on the neutrophil cell surface in response to certain cytokines. At the cell surface, they are accessible to antibodies directed against PR3 or MPO, which are involved in the pathogenesis of glomerular injury.

●(See "Overview of and approach to the vasculitides in adults", section on 'Small-vessel vasculitis'.)

●(See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Disease associations'.)

●(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)

Intravenous injection of anti-MPO antibodies in mice leads to activation of MPO, resulting in capillary localization, the release of oxidants and proteases, and a crescentic GN that closely mimics the histologic findings in humans with ANCA-associated vasculitis [90]. By contrast, inhibition of MPO activity [91] or depletion of circulating neutrophils resulted in complete protection against anti-MPO antibody-induced disease [90]. Other animal studies showed that the ANCA-neutrophil interaction also activates complement [92], which led to the development of the C5a-receptor antagonist avacopan for treatment of ANCA-associated vasculitis [65,66]. (See "Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis", section on 'Neutrophil priming and activation'.)

In summary, the importance of neutrophil-mediated glomerular injury is supported by many observations in animal models, including beneficial effects of both neutrophil depletion and interference with adhesion molecule function, and studies utilizing inhibitors or animals genetically deficient in neutrophil enzymes [82,90,91].

Macrophages — Macrophages are prominent constituents of several glomerular lesions, particularly those that exhibit crescent formation [51,93]. (See "Mechanisms of glomerular crescent formation" and "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis", section on 'Types of crescentic GN'.)

Macrophages and patrolling monocytes localize to glomeruli via interactions with both deposited immunoglobulins (through Fc receptors) and several chemokines, including macrophage chemoattractant protein 1, macrophage inflammatory protein 1-alpha (MIP-1-alpha), RANTES, leukocyte-derived matrix metalloproteinase-9 (MMP-9), and CX₃CR1 [94-97].

Unlike neutrophils, macrophages are also readily recruited by lymphocyte-derived molecules, such as MIF, that result from the interaction between specifically sensitized T cells and intraglomerular antigens [98]. In addition, monocytes also localize in the glomeruli via interaction with leukocyte adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), alpha-4-beta-2 integrins and with osteopontin [97,99,100]. Endothelial Lutheran (Lu) blood group antigens and basal cell adhesion molecule (BCAM) proteins may also play an important role by promoting alpha-4-beta-1 integrin-mediated adhesion of monocytes and macrophages in experimental crescentic GN [101].

Macrophages can adopt proinflammatory (M1) or antiinflammatory (M2) phenotypes, although these phenotypes exist on a continuum [102]. These phenotypes are plastic in vivo, with macrophages responding to cues in the microenvironment. Early pauci-immune necrotizing GN is characterized by a selective localization of CD163⁺M2 macrophages at sites of glomerular fibrinoid necrosis and in normal-appearing glomeruli [103].

The importance of macrophages in mediating glomerular injury has been demonstrated by the beneficial effect of interventions such as macrophage depletion, inhibition of MIF, and inhibition of granulocyte-macrophage colony-stimulating factor (GM-CSF) [58,76,94,98]. As an example, the protective effect of the absence of GM-CSF has been demonstrated in GM-CSF-negative mice which, after the induction of anti-GBM antibody disease, had less infiltration of monocytes than wild-type mice and were protected from crescentic glomerular injury [94]. In crescentic GN, macrophages also contribute to the progression from acute inflammation to chronic fibrosis [104]. (See "Mechanisms of glomerular crescent formation", section on 'Macrophages'.)

In summary, macrophages can serve as effector cells when glomerular injury is triggered by either humoral or cell-mediated immune responses. Macrophages are presumed to be the principal effector cells in inflammatory glomerular lesions induced by sensitized T cells in the absence of antibody [105]. Like neutrophils (see 'Neutrophils' above), macrophages may generate oxidants and proteases. However, they can also release tissue factor, which initiates fibrin deposition and crescent formation, and transforming growth factor (TGF)-beta, which leads to the synthesis of extracellular matrix and the eventual development of glomerular sclerosis.

T cells — T cells are rarely conspicuous in glomerular lesions but can be detected, particularly in diseases that are primarily mediated by macrophages, such as crescentic GN [1,32,51]. (See 'Macrophages' above.)

Although there is experimental evidence that glomerular injury can be induced by systemic T cells in the absence of antibody deposition, there is little evidence that glomerular T cells alone are nephritogenic, with the exception of permeability factors derived from T cells [99,106] (see 'Glomerular permeability factors' below). T cell-mediated injury occurs primarily via the release of chemokines and the recruitment of macrophages, which subsequently function as effector cells (figure 2) [107].

T helper 17 cells — There is increasing evidence supporting the role of T helper 17 (Th17) cells in some forms of GN [1,108]. These cells are called Th17 cells because they produce members of the interleukin (IL)-17 cytokine family. Expansion of Th17 cells is driven by IL-23, and the IL-23/Th17 axis is important in various models of experimental GN [109-113].

Th17 cells also promote autoimmune anti-MPO-mediated GN through the secretion of IL-17a.

The immunodominant MPO T cell epitope at amino acid positions 409-428 has been identified and shown to be recognized by CD4-positive T cells [114]. ANCA-activated neutrophils induce glomerular injury and also lodge MPO in glomeruli, allowing the autoreactive anti-MPO CD4-positive cells to induce delayed-type hypersensitivity-like necrotizing GN [114].

Furthermore, mice deficient in IL-17a were protected from anti-MPO-mediated GN and had reduced accumulation of renal macrophages and lower renal expression of mRNA for the monocyte-attracting chemokine CCL5 [112]. These observations suggest that IL-17a may be a therapeutic target for this disease.

Regulatory T cells — While effector T cells, such as the Th17 cells discussed above, potentiate glomerular injury, regulatory T cells (Tregs) have been reported to ameliorate injury and promote tolerance [115-117]. Tregs have been reported to suppress innate and adaptive immune responses in the kidney and have been reported to be abnormal in number or function in several forms of GN [118].

Platelets — Platelets are prominent in several glomerular lesions, primarily those that involve intraglomerular thrombosis as seen in antiphospholipid antibody syndrome and thrombotic microangiopathies.

●(See "Antiphospholipid syndrome and the kidney".)

●(See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)".)

●(See "Lupus nephritis: Diagnosis and classification", section on 'Vascular lesions'.)

In addition to their role in thrombotic processes involving endothelial cell injury, platelets also release a number of products that participate in and augment glomerular injury including vasoactive, mitogenic, and chemotactic substances. The following are some of the relationships that have been reported:

●Platelet-derived factors such as platelet-activating factor and platelet factor 4 enhance both glomerular permeability to proteins and immune complex deposition [119,120].

●Platelet-derived growth factor (PDGF) contributes to mesangial cell proliferation [121], and transforming growth factor beta (TGF-beta) contributes to mesangial sclerosis.

●Platelets contribute to leukocyte recruitment and are themselves recruited to the inflamed glomerulus via a platelet alpha-IIb beta-3 integrin/GPVI collagen receptor-dependent pathway [122].

●Platelets contribute to neutrophil-mediated glomerular injury via non-chemotactic mechanisms [123].

Activation and/or proliferation of resident glomerular cells — There are four different types of resident glomerular cells: endothelial cells, podocytes and parietal epithelial cells, and mesangial cells (picture 4). The importance of the close and concerted interaction among the four different cellular components of the glomerulus is already apparent during embryonic development and remains paramount even in adults, including in disease states [124].

Glomerular endothelial cell injury — Glomerular endothelial cells appear to be the principal targets of injury in several diseases, such as hemolytic uremic syndrome, preeclamptic toxemia of pregnancy, and some forms of vasculitis [125].

●(See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'Histopathology of TMA'.)

●(See "Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis", section on 'Role of endothelial cells'.)

●(See "Preeclampsia: Clinical features and diagnosis".)

Glomerular endothelial cell injury can induce phenotype change (expression of adhesion molecules), release of vasoactive agents (endothelin, nitric oxide), and conversion to a prothrombotic state [126,127]. These changes lead to cell proliferation, apoptosis, detachment, leukocyte adhesion, and, most importantly, thrombosis [126].

Glomerular mesangial cell injury — Glomerular mesangial cell injury is seen in diseases in which the mesangium is involved. This most commonly occurs with immune deposit formation in the mesangium, a finding observed in IgA nephropathy, lupus nephritis, and other disorders [128,129].

●(See "IgA nephropathy: Pathogenesis".)

●(See "Lupus nephritis: Diagnosis and classification".)

●(See "IgA vasculitis (Henoch-Schönlein purpura): Kidney manifestations", section on 'Evaluation and diagnosis'.)

Glomerular mesangial cells can be readily cultured and studied in vitro. Such studies have identified a long list of mediators that can activate mesangial cells [130-137]. These include:

●Cytokines, such as interleukin (IL)-1, tumor necrosis factor (TNF), and TWEAK, a cytokine of the TNF family

●Growth factors, such as platelet-derived growth factor (PDGF), transforming growth factor (TGF)-beta, vascular endothelial growth factor (VEGF), connective tissue growth factor (CTGF), and fibroblast growth factor-2 (FGF-2)

●C5b-9, the complement membrane attack complex

●Immune complexes

●Reactive oxygen species

The mesangial response to injury is characterized by alterations in cell cycle proteins that favor cell proliferation, phenotype change (to an actin-positive myofibroblast), extracellular matrix production, and/or apoptosis. Many of these effects involve agonist interaction with specific receptors on the mesangial cell, including IgA receptors, transferrin receptors, and toll-like receptors [138-142]. In addition, transglutaminase 2 is involved in a process of auto-amplification of IgA binding. The potential importance of this effect was demonstrated in a mouse model of IgA nephropathy in which mesangial IgA deposits were markedly reduced in the absence of transglutaminase 2 [140].

Platelet-derived growth factor (PDGF) appears to be the principal mediator of mesangial cell migration and proliferation in glomerular disease [131,136], an effect that may be magnified by hypoxia [132]. In addition, receptors for PDGF are upregulated in GN [143], and antagonism of PDGF prevented scarring in an animal model of GN [134].

Mesangial cell proliferation is associated with increased expression of cyclin-dependent kinases and reduced expression of cyclin kinase inhibitors, such as P21 and P27 [133]. Mesangial cell proliferation is an essential precursor to subsequent mesangial matrix expansion and sclerosis, due primarily to the actions of TGF-beta and CTGF [144]. Increased prostanoid synthesis, possibly modulated by TGF-beta, may also have a role in this process [145].

Activated mesangial cells produce chemokines and cytokines, which act on mesangial cells themselves and on other resident glomerular cells or leukocytes. These cells, in turn, secrete mediators that act on mesangial cells, forming a paracrine loop [129].

Therapeutic interventions that target mesangial cell proliferation or matrix production may ameliorate both acute and chronic forms of glomerular injury in those disorders in which these features are prominent [128,131].

Glomerular parietal epithelial cell injury — Glomerular parietal epithelial cells (PECs) are different from podocytes, which are glomerular visceral epithelial cells (picture 4) [34,146]. A major pathogenic role of glomerular PECs appears to be in crescent formation. Mouse models of GN that target the initial injury to the glomerular endothelial cells and/or the GBM showed that subsequent glomerular PEC proliferation led to a marked increase in cell number within crescents [147]. Plasma components can contribute to glomerular PEC proliferation, but consistent evidence is available only for fibrin-induced activation of glomerular PEC proliferation [148,149].

Glomerular PECs also may provide a reservoir for the replenishment of damaged podocytes [34-36,146]; however this appears to be the case particularly in very young and juvenile kidneys [35]. MicroRNA-193a regulates the transdifferentiation of human parietal epithelial cells toward a podocyte phenotype [150].

Podocytes — Lineage tracing and cell-specific marker studies in mice have shown that dedifferentiated podocytes populate early glomerular crescents and proliferate, thereby contributing to the cellular mass [151,152]. This proliferation is at least in part due to the repression of the cyclin-dependent kinase inhibitor p57Kip2, which normally maintains podocyte quiescence, by expression of microRNA (miRNA)-92a in podocytes of mice and patients with crescentic GN. Podocyte-specific ablation or inhibition of miR-92a in mice prevented glomerular injury by enabling p57Kip2 expression [153].

Podocytes may also contribute to crescent formation by release of soluble factors. Podocytes of mice and humans with crescentic GN have increased expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF), which, in mice increases phosphorylation of the EGFR/ErbB1 receptor. In HB-EGF-deficient mice, EGFR was not activated in glomeruli and disease was ameliorated. In addition, podocyte-specific deletion or pharmacological inhibition of EGFR in mice alleviated the severity of injury even when started after the induction of experimental GN [154]. There are also counteracting mechanisms that can increase the resistance of glomeruli to crescentic GN; the nuclear factor erythroid 2-related factor (NRF2) drives podocyte-specific expression of peroxisome proliferator-activated receptor gamma, which in turn prevents podocyte injury. NRF2 deficiency markedly aggravates the course of crescentic GN [155]. Podocyte injury may also contribute to PEC proliferation and crescent formation due to reduced expression of Krüppel-like factor 4, a zinc-finger transcription factor that is essential for maintaining podocyte homeostasis and PEC quiescence [156,157].

●(See "Mechanisms of glomerular crescent formation", section on 'Glomerular parietal epithelial cells'.)

●(See "Mechanisms of glomerular crescent formation", section on 'Coagulation proteins'.)

Another example of the interplay between different glomerular cell types may help explain the presence of severe proteinuria in diseases primarily affecting the mesangium, such as IgA nephropathy. Mesangial expansion places stress on individual podocytes by requiring that they cover a more extensive surface of the glomerular capillary wall, which leads to foot process effacement, alteration of filtration slits, focal detachment of intact podocytes, and proteinuria [158,159]. This podocyte depletion, in turn, is also a forerunner of segmental sclerosis. (See "Focal segmental glomerulosclerosis: Pathogenesis".)

NONINFLAMMATORY MECHANISMS OF IMMUNE GLOMERULAR INJURY — Noninflammatory mechanisms of immune glomerular injury typically lead to proteinuria and, if sufficiently severe, to the nephrotic syndrome, without the pathologic or clinical features observed with the inflammatory mechanisms of glomerular injury described in the preceding section. There is usually little or no hematuria and no red cell casts with this type of immune glomerular injury.

The most common causes of noninflammatory immune glomerular injury are minimal change disease (MCD, also called minimal change nephrotic syndrome), primary focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN). These disorders are characterized by dramatic increases in glomerular permeability because the principal target of injury is the podocyte (picture 4), and the diseases are classified among the podocytopathies.

●(See "Minimal change disease: Etiology, clinical features, and diagnosis in adults".)

●(See "Focal segmental glomerulosclerosis: Clinical features and diagnosis".)

●(See "Membranous nephropathy: Pathogenesis and etiology".)

●(See "Biology of glomerular podocytes".)

Pathogenic agents in podocytopathies of immune origin — A number of immune mediators can directly induce sufficient podocyte dysfunction to result in proteinuria without inflammation. These include T cell-derived factors, vasoactive agents, complement C5b-9 (the membrane attack complex), and cytokines such as interleukin (IL)-13 and cardiotrophin-like cytokine factor 1 [160-162].

These pathogenetic agents are not involved in secondary FSGS resulting from an adaptive response to glomerular hypertrophy and hyperfiltration or from scarring due to previous injury, as with healed lesions of lupus nephritis or vasculitis. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Pathogenesis of secondary FSGS'.)

Genetic disease is another cause of FSGS that most often presents in infancy and childhood and is usually resistant to glucocorticoid therapy.

●(See "Focal segmental glomerulosclerosis: Genetic causes".)

●(See "Steroid-resistant nephrotic syndrome in children: Etiology", section on 'Genetic variants'.)

Glomerular permeability factors — With MCD and primary FSGS, the existence of a circulating permeability factor is postulated based upon the following clinical observations:

●Rapid recurrence of MCD or primary FSGS in normal kidneys transplanted into some patients with these disorders [163] (see "Kidney transplantation in adults: Focal segmental glomerulosclerosis in the transplanted kidney")

●Rapid disease resolution when MCD and FSGS kidneys are placed in a normal environment [164,165]

●The ability of serum from some patients with primary FSGS who develop recurrent disease to increase the albumin permeability of isolated normal glomeruli in vitro [166]

●Transmission from mother to child of glomerular permeability factors, such as soluble urokinase-type plasminogen activator receptor (suPAR, also called soluble urokinase receptor) [167,168]

Additional support for a role for permeability factors in some podocytopathies is provided by findings in animal models of glomerular disease:

●In rodents, the administration of an unidentified permeability factor derived from T cells of patients with active MCD, or administration of stem cells from patients with active MCD or primary FSGS, produces significant proteinuria in association with minimal glomerular abnormalities [106,169].

●Overexpression of interleukin (IL)-13, a cytokine that is upregulated in T cells of children with glucocorticoid-sensitive nephrotic syndrome in relapse, causes proteinuria and foot process effacement in rats [170,171]. (See "Minimal change disease: Etiology, clinical features, and diagnosis in adults", section on 'Glomerular permeability factor'.)

●Podocyte secretion of abnormally sialylated angiopoietin-like 4 protein (Angptl4) may play an important role in the pathogenesis of MCD [172]. Experimental data show that overproduction of this protein in podocytes causes binding of the protein to the glomerular basement membrane (GBM), nephrotic-range proteinuria, and diffuse effacement of foot processes as seen in MCD in humans [173].

●Non-immunoglobulin proteins derived from the plasma of patients with primary FSGS who developed recurrent nephrotic syndrome after kidney transplantation increase urinary albumin excretion in rats [174].

The identity of permeability factors in humans with nephrotic syndrome is not known. Current in vitro assays are crude and experimental, and correlations with clinical activity have been inconsistent. Most studies have been performed in patients with MCD and primary FSGS, but such factors have also been reported in other disorders of glomerular permeability [175,176].

Mechanisms of increased glomerular permeability — The mechanisms by which non-immunoglobulin permeability factors act on the podocyte to cause marked increases in glomerular permeability are unknown. At least two mechanisms have been proposed:

●Alterations in slit diaphragm structure and function since antibodies specific for slit diaphragm proteins increase glomerular permeability [45,175,177]

●Interference with podocyte attachment to the GBM [178]

Both circulating suPAR and Angptl4 released from podocytes may act as glomerular permeability factors.

Possible role of suPAR — In mouse models, proteinuria can be induced by overexpression of suPAR in glomerular visceral epithelial cells (podocytes) and by the administration of suPAR [179]. Circulating suPAR activates podocyte beta-3 integrin in both native and grafted kidneys, causing foot process effacement, proteinuria, and a FSGS-like glomerulopathy [179].

However, the role of suPAR as a permeability factor in humans with FSGS is controversial for at least two reasons:

●Patients with primary FSGS due to a podocin gene (NPHS2) mutation have higher suPAR levels than those without a mutation, but recurrence of FSGS occurs less frequently than in patients with non-genetic primary FSGS [180].

●Plasma suPAR levels do not reliably and consistently distinguish primary from secondary FSGS [181,182].

●Administration of recombinant soluble urokinase receptor does not consistently induce podocyte alterations and proteinuria in mice [183].

Thus, questions remain as to the association of elevated suPAR with specific, anatomically defined subsets of FSGS and to the prognostic value of suPAR in patients with FSGS [184,185]. A possible explanation for the different findings is that the available assays may not measure the correct form of suPAR (eg, free, glycosylated, low-molecular-weight fraction, etc) [186,187]. Bone marrow-derived immature myeloid cells appear to be a main source of circulating suPAR contributing to proteinuric kidney disease [188]. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'suPAR'.)

Possible role of angiopoietin-like 4 protein — Podocyte secretion of angiopoietin-like 4 protein (Angptl4) may play an important role in the pathogenesis of MCD [172,173]. Overproduction of Angptl4 in podocytes causes binding of the protein to the GBM, nephrotic-range proteinuria (more than 500-fold increase in albuminuria), and diffuse effacement of foot processes as seen in MCD in humans (picture 14) [172,173]. By contrast, transgenic expression of Angptl4 in adipose tissue results in increased circulating Angptl4 levels but no proteinuria [172].

Defective sialylation of Angptl4 appears to be involved in the increase in glomerular permeability [172,173]. In a rat study, administration of a sialic acid precursor increased the sialylation of Angptl4 and reduced proteinuria by more than 40 percent [172].

The glomerular expression of Angptl4 is glucocorticoid sensitive [172]. This is consistent with the efficacy of glucocorticoid therapy in patients with MCD. However, these results are challenged by absent or minimal Angptl4 staining in kidney tissue from MCD patients in relapse and lack of increased Angptl4 expression in human podocytes cultured with sera from MCD patients in relapse compared with remission [189].

●(See "Minimal change disease: Treatment in adults", section on 'Choice of initial therapy'.)

●(See "Treatment of idiopathic nephrotic syndrome in children".)

Possible role of anti-nephrin antibodies — Despite the absence of typical glomerular deposits of immunoglobulin, patients with glucocorticoid-dependent and frequently relapsing nephrotic syndrome (MCD and primary FSGS) may remit when treated with anti-CD20 antibodies (eg, rituximab or other B cell-targeting antibodies), suggesting an autoantibody-mediated mode of podocyte injury. This was supported by the finding of circulating anti-nephrin autoantibodies in a subset of patients with active MCD accompanied by podocyte-associated punctate IgG on kidney biopsy [22]. (See "Minimal change disease: Etiology, clinical features, and diagnosis in adults", section on 'Role of B cells'.)

Complement membrane attack complex in membranous nephropathy — The complement membrane attack complex, C5b-9, is an established mediator of noninflammatory, experimental immune injury. In MN, the development of subepithelial immune deposits of IgG (usually IgG4 subclass) (picture 11), C3, and C5b-9 induces large increases in glomerular protein permeability and proteinuria without significant inflammatory disease [190-192].

An understanding of the mechanisms that underlie MN has evolved largely from studies of the Heymann nephritis model of MN in rats, which is indistinguishable pathologically, immunopathologically, and functionally from MN in humans [193]. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Mechanisms of podocyte injury'.)

In Heymann nephritis (a model of MN), subepithelial deposits develop as a consequence of IgG antibody binding in situ to megalin, a protein located in the clathrin-coated pits of podocytes [194]. A second protein, called receptor-associated protein, binds to megalin and is also a target antigen [195,196]. These two proteins comprise the Heymann nephritis antigenic complex (HNAC) [195,196]. However, megalin is not responsible for human MN, since it is not found in human podocytes or in the subepithelial deposits [194].

The major antigen in primary MN in humans is the phospholipase A2 receptor (PLA2R) with circulating anti-PLA2R antibodies being present in approximately 80 percent of affected patients [15]. In addition, the severity of the clinical disease often correlates with the plasma concentration of anti-PLA2R antibodies. It has been difficult to establish the pathogenicity of human anti-PLA2R autoantibodies by adoptive transfer to experimental animals because they lack podocyte PLA2R. A transgenic mouse line expressing murine PLA2R1 (mPLA2R1) did develop MN-like lesions after injection with rabbit-derived anti-mPLA2R1 [197], and transfer of human anti-THSD7A did produce subepithelial immune deposits containing human IgG and the target antigen as well as proteinuria when injected into mice [50]. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Phospholipase A2 receptor'.)

Mechanisms of complement activation — Studies of the pathogenesis of primary MN have shed light on the molecular mechanisms of complement activation [198]. IgG4 is the predominant IgG subclass deposited in glomeruli in primary MN which, as noted in the preceding section, is most often due to antibodies directed against the PLA2R. (See "Membranous nephropathy: Clinical manifestations and diagnosis", section on 'Features distinguishing primary and secondary MN'.)

IgG4 does not activate the classical complement pathway as evidenced by the lack of C1q staining in primary MN [199]. However, both the mannose-binding lectin pathway and the alternative pathway are activated in most patients with primary MN [199]. Moreover, aberrantly-glycosylated anti-PLA2R-positive IgG autoantibodies from patients with MN were able to bind and activate the complement lectin pathway and injure PLA2R-expressing podocytes via the C5b-9 complex and C3a and C5a receptor-induced proteolysis [200]. These findings likely explain the abundance of complement deposits in primary MN but do not necessarily account for all cases. In a subset of patients with mannose-binding lectin deficiency (approximately 10 percent of the normal population), only the alternative pathway is activated, which fits with the absence of C4d deposits in these patients [201]. (See "Complement pathways", section on 'Lectin pathway'.)

Mechanisms of C5b-9-mediated injury — As the immune aggregates are formed, they are capped and shed from the podocyte surface to form discrete subepithelial deposits, similar to the findings in MN in humans (picture 11); in addition, complement is activated with C3 and C5b-C9 (the membrane attack complex) usually being constituents of the deposits [202]. Complement activation probably requires simultaneous inactivation of complement regulatory proteins, some of them, such as CR1, being expressed by the podocyte [191,194]. (See "Overview and clinical assessment of the complement system", section on 'Alternative pathway activation'.)

Unlike the antigen-antibody complexes that are shed from the cell surface, C5b-9 inserts into the podocyte membrane and is then transported across the cell and extruded into the urinary space, resulting in elevated levels of C5b-9 in the urine [203-205].

C5b-9 is thought to be the principal mediator of altered glomerular barrier function in MN since selective depletion or genetic absence of any terminal complement component greatly reduces the ability of antibodies to induce proteinuria in the intact animal, an isolated perfused kidney, or an isolated glomerulus [1,206]. A similar mechanism is thought to occur in humans based upon the following observations: the virtual identity of the histologic lesions in rats and humans; the presence of C3 and C5b-9 in subepithelial deposits in both rats and humans; and the selective increase in C5b-9 excretion in the urine in patients with active MN [204,205].

The mechanisms involved in the sublytic effects of C5b-9 on podocytes that lead to proteinuria primarily involve the production of hydrogen peroxide [190,207]. C5b-9 also has other effects:

●It increases the expression of transforming growth factor (TGF)-beta-2, TGF-beta-3, and TGF receptors, leading to overproduction of extracellular matrix that results in thickening of the GBM (picture 15) and "spike" formation (picture 16) [190,207].

●It induces endoplasmic reticulum (ER) stress and activates the unfolded protein response and autophagy, which can repair the ER-induced damage and may protect the podocyte from the sublytic effect of C5b-9 [208-211].

●It leads to podocyte apoptosis, detachment, and excretion in the urine, as well as DNA damage and alterations in cell cycle proteins that favor hypertrophy over proliferation and podocytopenia [190,207].

●It disrupts and dislocates the podocyte slit diaphragm by dissociating nephrin from the actin cytoskeleton [206,212].

●In addition to initiating the formation of C5b-9, cleavage of C3 and C5 produces C3a and C5a that engage the C3aR1 and C5aR1 receptors on podocytes to induce cysteine and aspartic proteinases that cause the proteolysis of synaptopodin and NEPH1, two essential podocyte proteins [200].

In the absence of effective therapy, these changes contribute to eventual glomerular sclerosis. On the other hand, C5b-9 may also limit complement-induced injury by enhancing the ubiquitin-proteasome system, which results in accelerated removal of damaged proteins [213].

Despite its usual pathogenic role, C5b-9 does not appear to be mandatory for the development of MN. This was demonstrated in a study of passive Heymann nephritis in C6-deficient rats [214]. MN with IgG and C3 deposition and proteinuria similar to that in normal rats occurred despite the absence of C5b-9 formation. Subepithelial immune deposits induced in mice by injecting serum of patients with anti-THSD7A were not accompanied by C3 deposition [50].

Potential mechanisms for disruption of glomerular integrity in this setting might involve the direct effect of autoantibody interaction with the target antigens PLA2R or THSD7A as shown for antibodies to another podocyte antigen, neutral endopeptidase, involved in the neonatal alloimmune form of MN [17]. As an example, MN patient serum containing anti-PLA2R antibodies interferes with the adhesion to collagen of cells expressing PLA2R [215], and anti-THSD7A antibodies cause cytoskeletal rearrangement and detachment of cells expressing THSD7A [50]. (See "Membranous nephropathy: Pathogenesis and etiology".)

SUMMARY

●Overview – Glomerulonephritis (GN) results from immunologic mechanisms. The etiologic agents in human GN are largely unknown with the exception of infection-related forms of disease, such as beta-hemolytic streptococci in poststreptococcal GN, hepatitis C virus in cryoglobulinemic membranoproliferative GN, and hepatitis B virus in some cases of membranous nephropathy (MN). It is likely that most precipitating factors, such as infections, cancer, drug exposures, or toxin exposures, initiate similar immune responses that result in GN via shared common pathways. The nature of the immune responses which lead to GN and the individuals who develop them are strongly influenced by genetic factors. (See 'Introduction' above.)

●Components of the immune response – The nephritogenic immune response includes both humoral and cellular components. The humoral immune response leads to immunoglobulin deposition and complement activation in glomeruli. The cellular, Th1- or Th17-regulated immune response contributes to both the infiltration of circulating mononuclear inflammatory cells (including lymphocytes and macrophages) into glomeruli and to necrotizing GN and crescent formation. (See 'Humoral immunity' above and 'Cellular immunity' above.)

●Immune mechanisms of glomerular injury – Both inflammatory and noninflammatory mechanisms are involved in glomerular injury (see 'Immune mechanisms of glomerular injury' above):

•Inflammatory injury is characterized by glomerular hypercellularity that results from infiltrating hematopoietic cells (such as neutrophils and macrophages) and/or proliferating glomerular cells. These effector cells induce other abnormalities, such as thrombosis, necrosis, and crescent formation which, if extensive, can result in rapidly progressive GN. The major clinical features of GN are hematuria and occasional leukocyturia, often with some of the red blood cells having a dysmorphic appearance (picture 1 and picture 2), with or without red blood cell casts (picture 3); varying degrees of proteinuria, ranging from mild to the nephrotic range; and, depending upon disease severity, a normal or reduced glomerular filtration rate. The major mediators and effector cells of the cellular inflammatory response are discussed above. (See 'Inflammatory mechanisms of glomerular injury' above.)

•Noninflammatory lesions resulting from immune injury usually involve the glomerular podocyte (picture 4) and are associated with a major functional change in the glomerulus that results in an increase in glomerular permeability to albumin and other proteins. The major clinical features of noninflammatory glomerular lesions are proteinuria and the nephrotic syndrome, with little or no hematuria and no red blood cell casts. A number of immune mediators can directly induce sufficient podocyte dysfunction to result in nephrotic-range proteinuria without inflammation. (See 'Noninflammatory mechanisms of immune glomerular injury' above.)

●Importance of site of glomerular injury – The major determinant of whether the patient has an inflammatory injury (GN) presenting with an active urine sediment (nephritic syndrome) or a noninflammatory injury presenting with proteinuria and little or no hematuria (nephrotic syndrome) is the site of glomerular injury. Glomerular endothelial and mesangial cells are in contact with circulating factors (eg, complement) or inflammatory cells (eg, neutrophils, macrophages, and T cells), and injury to these cells typically produces an inflammatory injury. By contrast, glomerular epithelial cells (visceral and parietal) are separated from the circulation by the GBM. Thus, glomerular injury primarily involving the podocytes is commonly associated with little or no activation of circulating inflammatory cells. (See 'Importance of the site of glomerular injury' above.)

●Other determinants of injury – A number of other factors can contribute to glomerular injury, including the biologic properties of immunoglobulins that form the immune deposits, whether immune deposits are formed in situ or trapped as preformed circulating immune complexes, the amount of immune deposit formation, the nature of the epitope(s), and the diffusion of the immune response (epitope spreading). (See 'Other determinants of glomerular injury' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges William G Couser, MD, and Pierre Ronco, MD, PhD, who contributed to earlier versions of this topic review.