ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Mechanisms of glomerular crescent formation

Mechanisms of glomerular crescent formation
Literature review current through: Jan 2024.
This topic last updated: Mar 23, 2022.

INTRODUCTION AND DEFINITION — Cellular glomerular crescents are defined as two or more layers of proliferating cells in Bowman's space (picture 1 and picture 2) and are a hallmark of inflammatory glomerulonephritis and a histologic marker of severe glomerular injury. Crescents can be circumferential or segmental. In general, the severity of the kidney failure and other clinical manifestations of glomerulonephritis (eg, hypertension, edema) correlates with the percentage of glomeruli that exhibit crescents [1-6]. The duration and potential reversibility of the underlying disease correspond with the relative predominance of cellular or fibrous components in the crescents. (See 'Course of crescents' below.)

Crescentic glomerulonephritis is typically associated with the syndrome of rapidly progressive glomerulonephritis, which can occur in most forms of inflammatory glomerular injury, including postinfectious glomerulonephritis, immunoglobulin A (IgA) nephropathy, lupus nephritis, renal vasculitis, membranoproliferative glomerulonephritis, and anti-glomerular basement membrane (GBM) disease. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

This topic will review the mechanisms of glomerular crescent formation. The classification, clinical presentation, evaluation, diagnosis, and treatment of crescentic glomerulonephritis, as well as the mechanisms and pathogenesis of glomerular injury, are discussed elsewhere. (See "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis" and "Mechanisms of immune injury of the glomerulus".)

INITIATING EVENTS — Glomerular crescent formation appears to represent a nonspecific response to severe injury to the glomerular capillary wall [5]. The initiating event is the development of physical gaps (also called rents or holes) in the glomerular capillary wall, glomerular basement membrane, and Bowman's capsule (picture 2 and picture 3) [7,8]. These gaps permit the entry into Bowman's space of coagulation factors, which lead to fibrin formation (due to conversion of fibrinogen to fibrin polymers and delayed fibrinolysis) and cellular elements (such as monocytes and lymphocytes), both of which promote crescent formation (picture 3) [5,9]. Although the precise mechanism by which these gaps in the glomerular basement membrane (GBM) appear in humans is unclear, it seems likely that a variety of upstream immune mechanisms are involved, including the deposition of autoantibodies and immune complexes, the activation of complement, and the recruitment of inflammatory cells [10].

Based upon experimental studies in murine species, crescent formation is believed to be primarily mediated by a T helper 1 (Th1) nephritogenic immune response involving CD4+ T cells, macrophages, and fibrin as effectors of cell-mediated immunity [11]. Th17 CD4 effector cells also appear to play an important role [12,13] with a potential cytokine-chemokine-driven cross-regulation of Th1 and Th17 subpopulations [14]. Recruitment of Th1 cells is controlled by regulatory T cells [15], including Treg1 cells characterized by activation of the transcription factor Tbet, which optimizes the capacity to downregulate Th1 responses by induction of chemokine receptor CXCR3 [16]. Nephritogenic Th17 cells are controlled by STAT3-dependent Treg17 cells expressing the chemokine receptor CCR6 [17]. Although the study of mouse models is informative, pathogenesis may be different in humans. (See "The adaptive cellular immune response: T cells and cytokines".)

FORMATION AND COMPOSITION — Disruption of the integrity of the glomerular capillary wall with severe glomerular injury initiates a series of events that can result in crescent formation (figure 1 and picture 4). These factors, which are discussed in detail in the following sections, include:

Rents in the glomerular capillary wall and glomerular basement membrane allow circulating cells, mostly monocytes and T cells, inflammatory mediators, and plasma proteins, particularly coagulation proteins (such as fibrinogen), to pass through the capillary wall and basement membrane and into Bowman's space.

The contents in Bowman's space can enter the interstitium, via disruption of Bowman's capsule, contributing to periglomerular inflammation. In addition, periglomerular CD8+ T cells can migrate through breaches in Bowman's capsule to participate in crescent formation [18].

Crescent formation results from the subsequent participation of coagulation factors, particularly partially or fully polymerized fibrin; tissue factor, which promotes fibrin deposition; and several different cell types, including macrophages, dendritic cells, glomerular parietal epithelial cells, glomerular visceral epithelial cells (podocytes), kidney progenitor cells, and interstitial fibroblasts.

In addition, limited data from experimental studies have identified other factors that may contribute to crescent formation:

Stimulation of toll-like receptor 4 (TLR4) or 9 (TLR9) can promote the development of crescentic glomerulonephritis by effects on both the adaptive and innate immune response [19,20]. TLR4 has a crucial direct effect on kidney cells.

Genetically determined differences in both glomerular and bone marrow-derived cells can influence individual susceptibility to crescent formation [21,22].

Complement — The role of complement in initiating glomerular inflammation has been recognized for many years, mainly from work in experimental models. More recently, there has been increasing appreciation of the importance of complement in human glomerulonephritis [23]. Complement can be activated by:

Deposition of antibodies, as in anti-glomerular basement membrane (GBM) disease. (See "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Pathogenesis'.)

Immune complexes, as in lupus nephritis and IgA nephropathy. (See "Lupus nephritis: Diagnosis and classification", section on 'Pathogenesis' and "IgA nephropathy: Pathogenesis", section on 'Complement activation'.)

Activated neutrophils, as in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis. (See "Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis", section on 'Activation of the alternative complement pathway'.)

Dysregulation of normal control mechanisms, as in C3 glomerulopathy. (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis", section on 'Pathogenesis'.)

The extent to which complement contributes directly to crescent formation in these types of glomerulonephritis is not clear. However, complement inhibition has been successful in ANCA-associated vasculitis [24] and is being evaluated in clinical trials in other forms of glomerulonephritis.

Coagulation proteins — A central feature of crescent formation is the presence in Bowman's space of coagulation factors that lead to the cross-linking of fibrin and a deficiency in fibrinolytic mechanisms, both of which can facilitate fibrin deposition (picture 5). The importance of fibrin is illustrated by the findings in animal models that defibrination can prevent [25] or reverse crescent formation [26].

Tissue factor, tissue factor pathway inhibitor, thrombin, and the plasminogen/plasmin system are procoagulant/fibrinolytic molecules that are central to this process.

Tissue factor — The primary stimulus to fibrin deposition in crescent formation appears to be tissue factor, which binds to and activates factor VII [27]. Tissue factor is derived from endothelial cells, glomerular visceral epithelial cells (podocytes), and macrophages [27,28]. In addition, macrophage-derived interleukin (IL)-1 and tumor necrosis factor (TNF) stimulate tissue factor production by glomerular endothelial cells [29].

In early glomerulonephritis, tissue factor expression appears to derive from intrinsic glomerular cells; later, it primarily originates from macrophages [27]. (See 'Glomerular visceral epithelial cells (podocytes)' below and 'Macrophages' below.)

Tissue factor pathway inhibitor — Accompanying the increase in tissue factor activity is an early reduction in tissue factor pathway inhibitor (TFPI), which also favors fibrin deposition [30]. This early response is followed by enhancement of TFPI expression in later stage disease, chronically inhibiting the deposition of fibrin [30,31]. A similar effect can be induced by the administration of recombinant TFPI which, in experimental crescentic glomerulonephritis, reduces both fibrin deposition and crescent formation [30].

Thrombin — An important role for thrombin in crescent formation was suggested in a mouse model in which hirudin, a selective thrombin antagonist, or the absence of protease-activated receptor 1, a cellular thrombin receptor, significantly reduced both glomerular crescent formation and macrophage and T-cell infiltration [32]. (See 'Macrophages' below and 'T cells' below.)

Plasminogen/plasmin system — The plasminogen/plasmin system plays a central role in fibrinolysis and the resolution of glomerular crescents. In experimental and human crescentic glomerulonephritis, there is decreased fibrinolytic activity due to both a reduction in tissue-type plasminogen activator and an increase in plasminogen activator inhibitor-1 (PAI-1) [33-35]. The end result is that extraglomerular fibrin cross-linking occurs in Bowman's space. Fibrin is a potent chemotactic factor that also helps recruit macrophages into the glomeruli [36]. (See 'Macrophages' below.)

Protease-activated receptor-2 (PAR-2), which is a cellular receptor in glomerular cells and macrophages, aggravates experimental crescentic glomerulonephritis due to both augmentation of kidney PAI-1 expression and inhibition of matrix metalloproteinase-9 activity [37]. By contrast, mice lacking PAR-2 have reductions in PAI-1 activity, fibrin deposition, and crescent formation [37].

Macrophages — Macrophages play a central role in the formation of glomerular crescents since both tissue factor expression and fibrin deposition are macrophage-dependent phenomena [38]. In an experimental model of anti-GBM antibody-induced glomerulonephritis, macrophages accounted for 42 percent of cells in early crescents and 64 to 71 percent of cells in advanced cellular or fibrocellular crescents [39].

Macrophages in the glomeruli presumably derive from the circulation and also probably enter from the periglomerular interstitium via gaps in Bowman's capsule. These gaps may be caused by inflammatory processes similar to those that result in rupture of the glomerular basement membrane (picture 3) [7,8] and/or by cell-mediated mechanisms [40,41]. (See 'Initiating events' above.)

Localization of macrophages to the glomeruli in crescentic glomerulonephritis involves multiple chemoattractants. These include:

The C-C chemokines macrophage chemoattractant protein-1 (MCP-1), macrophage migration inhibitory factor (MIF), macrophage inflammatory protein-1-alpha (MIP-1-alpha), and osteopontin [42-45]. Expression of chemokine receptor 2B (CCR2B), which is the receptor for MCP-1, may be particularly important [46].

Adhesion molecules, such as vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, and CD44, which are all expressed on glomerular parietal epithelial cells [47,48].

Kidney cell-derived granulocyte-macrophage colony stimulating factor (GM-CSF) may increase expression of VCAM-1, MCP-1, and IL-1 beta, thereby promoting crescent formation [49].

Once localized to Bowman's space, activated macrophages contribute to crescent formation by proliferating and by releasing the following molecules:

Tissue factor. (See 'Tissue factor' above.)

IL-1 and TNF upregulate adhesion molecule expression, stimulate cell proliferation, and recruit more macrophages [39]. Selective blockade of IL-1 with IL-1 receptor antagonists [50] or of TNF with anti-TNF antibodies or soluble TNF receptors markedly reduces crescent formation in experimental models [51,52]. In contrast to the macrophage origin of most inflammatory mediators, some evidence suggests that the principal source of TNF may be intrinsic kidney cells [53].

Transforming growth factor (TGF)-beta may play an important role in both disease activity and the transition from cellular to fibrocellular and fibrous crescents since it is a potent stimulus to the production of collagen I [54]. With respect to disease activity, TGF-beta signaling appears to play an important role in the development and progression of crescentic glomerulonephritis [55]. Further support comes from a study of 15 patients with crescentic glomerulonephritis in which higher urinary TGF-beta levels were associated with a lower likelihood of response to immunosuppressive therapy, possibly reflecting more severe disease [56].

With respect to the development of fibrotic disease, an important role for TGF-beta was suggested in a rat model of glomerulonephritis in which administration of a chimeric soluble TGF receptor that binds to and inhibits the actions of TGF-beta reduced extracellular matrix accumulation in the glomeruli [57]. A reduction in extracellular matrix accumulation has also been demonstrated in other studies by inhibiting TGF-beta expression [58] or activity [59].

The mannose receptor, a pattern recognition receptor implicated in the uptake of endogenous and microbial ligands, is upregulated on activated macrophages. Mannose receptor-deficient mice were protected from crescentic glomerulonephritis in a mouse nephrotoxic nephritis model despite humoral and T-cell responses similar to those of wild-type mice [60]. These data suggest that blocking the receptor might provide a more specific approach than broad-based immunosuppressive therapy.

Depletion of CCR2+ inflammatory monocytes in a mouse model of vasculitis reduces macrophage infiltration and ameliorates glomerular necrosis and crescent formation [61].

Several studies in patients with crescentic glomerulonephritis found increased glomerular expression of matrix metalloproteinases (MMP)-2, -3, -9, and -11 and tissue inhibitor of metalloproteinases (TIMP)-1, which correlated with cellular crescents and disease activity [62,63]. In experimental studies, MMP-9 protects against experimental crescentic glomerulonephritis through its fibrinolytic activity [37,64].

Macrophages contribute to kidney dysfunction and tissue damage in established crescentic glomerulonephritis as it progresses from the acute inflammatory to a chronic fibrotic phase [65]. However, the ability of macrophages to change function over time creates challenges for a macrophage-targeted therapeutic intervention [66]. Classic examples of resident macrophage plasticity include the maturation of kidney dendritic cells to educate T-lymphocytes and the polarization of kidney macrophages to M1 or M2 functional phenotypes in response to environmental cues. Bone marrow-derived or resident macrophages display biphasic expression of proinflammatory and reparative factors in response to injury.

Genetics of macrophage-associated damage — Considerable advances have been made in the genetic susceptibility of macrophage activation in rat anti-GBM nephritis. Wistar Kyoto (WKY) rats develop crescentic, necrotizing glomerulonephritis after immunization with GBM, or following administration of nephrotoxic serum, whereas Lewis (LEW) rats, which share the same MHC, do not [67]. Two major crescentic glomerulonephritis loci have been identified in these animals, specifically CRGN1 and CRGN2 [68]. These loci contribute exclusively to circulating cell-related glomerular injury by regulating macrophage infiltration and activation.

Predisposition at CRGN1 is accounted for by copy number polymorphisms in Fc gamma receptor III (FCGR3), an activating Fc receptor for IgG expressed at the surface of macrophages [69]. The FCGR3-related sequence (FCGR3-rs) is a novel rat-specific Fc receptor with a cytoplasmic domain 6 amino acids longer than its paralogue, FCGR3. The FRCR3-rs gene is deleted from the WKY rat genome, and this deletion is associated with enhanced macrophage activity in this strain. FCGR3-rs may act to inhibit FCGR3-mediated signaling and phagocytosis, and this could be considered a novel mechanism in the modulation of Fc receptor-mediated cell activation in autoimmune diseases [70]. Binding of antibody or immune complexes to Fc receptors activates intracellular signal transduction pathways, including spleen tyrosine kinase (SYK), leading to the production of inflammatory cytokines. A SYK inhibitor was shown to reduce the severity of established nephrotoxic nephritis and experimental autoimmune glomerulonephritis in WKY rats [71,72].

The second locus, CRGN2, contains the activator protein-1 (AP-1) transcription factor JUND, which is markedly overexpressed in WKY macrophages and glomeruli and behaves as a primary regulator of oxidative stress and IL-1 beta synthesis in these cells [73,74]. JUND knockdown in rat and human primary macrophages reduces macrophage activity and cytokine secretion, indicating conservation of JUND function in macrophage activation in rats and humans, and suggesting in vivo inhibition of JUND as a possible new therapeutic strategy for diseases characterized by inflammation and macrophage activation. Macrophage levels of purinergic receptor P2X 7 (P2RX7), a ligand-gated cation channel involved in IL-1 beta and IL-18 processing and release, are also genetically determined and control NLRP3 (a member of the nucleotide-binding oligomerization-like receptor family) inflammasome activation pathway and susceptibility to anti-GBM nephritis [75].

Dendritic cells — Dendritic cells are an important component of the kidney mononuclear phagocyte system and, like macrophages, can be pro- or antiinflammatory. Their depletion at an early stage of nephrotoxic glomerulonephritis induces exacerbation of the disease, while their depletion at a later stage leads to attenuation [76]. The CD11b+ subset of dendritic cells promotes crescentic glomerulonephritis, whereas the smaller population of CD103+ dendritic cells protects from glomerulonephritis by promoting Treg accumulation [77]. Within the kidney, specific paracrine factors released from kidney parenchymal cells, such as IL-10, damage-associated molecular patterns (DAMPs), or apoptotic bodies, initiate or augment this phenotypic reprogramming [78].

T cells — T cells are found in Bowman's space and in crescents [40,79]. Localization of T helper cells to the glomeruli may involve a variety of factors. These include traditional chemoattractants (such as monocyte chemoattractant protein [MCP] and macrophage inflammatory protein [MIP]-1-alpha), certain cytokines (such as IL-12p40 and IL-18), mast cells, and costimulatory ligands on macrophages and non-lymphoid cells (such as CD80 and CD86) [80-82]. Some of these cytokines may also stimulate production of proinflammatory cytokines such as interferon-gamma and TNF [80]. There is also evidence for the role of cytotoxic CD8+ T cells from murine models of ANCA-induced crescentic glomerulonephritis [83]. In some circumstances, CD8+ cells may migrate through breaches in Bowman's capsule to access the glomerulus [18].

The role of T cells in glomerular injury may be related to antigen recognition and macrophage recruitment via the release of factors such as MIF and interferon-gamma [11,84]. In addition, a possible role for voltage-gated potassium channel Kv1.3, which is expressed on effector memory T cells, was proposed in a rat model of anti-GBM crescentic glomerulonephritis [85]. Kv1.3 channels were also expressed on some macrophages and in the glomeruli. Administration of a Kv1.3 blocker was associated with fewer crescents and less proteinuria than in rats given the vehicle alone. Further evidence for the importance of T cells in glomerulonephritis comes from studies demonstrating the benefit of inducing mucosal tolerance in models of both anti-GBM antibody- and ANCA-induced experimental nephritis [86,87].

Glomerular parietal epithelial cells — Glomerular parietal epithelial cells are significant constituents of crescents [88,89]. Parietal epithelial cell dysfunction plays a key role in the development of crescents, at least in some experimental models [90]. Unlike glomerular visceral epithelial cells (podocytes), which are normally terminally differentiated cells with little proliferative capacity (see 'Glomerular visceral epithelial cells (podocytes)' below), glomerular parietal epithelial cells can and do proliferate, presumably in response to growth factors, such as platelet-derived growth factor and fibroblast growth factor-2 (basic fibroblast growth factor) [36]. Studies performed in a mouse model using genetic tagging of glomerular parietal epithelial cells demonstrated the significant contribution of these cells to crescent formation [89]. In addition, mice deficient in CD44 (a marker of parietal epithelial cells) are partly protected from crescentic glomerulonephritis [91]. There is also a requirement for the tetraspanin CD9 in migration and proliferation of parietal epithelial cells in murine models of crescentic glomerulonephritis [92].

Since glomerular parietal epithelial cells are not major sources of procoagulant molecules or growth factors, they may not be as important as macrophages and interstitial fibroblasts (as described above) in determining the course and consequences of crescent formation. However, glomerular parietal epithelial cells can undergo dedifferentiation and become macrophage-like inflammatory effector cells and may be the primary cells producing type I collagen [93,94].

Glomerular visceral epithelial cells (podocytes) — Glomerular visceral epithelial cells (podocytes) (figure 2) were considered to be terminally differentiated cells and had not been regarded as participants in crescent formation. However, lineage tagging experiments showed that new podocytes could be recruited from glomerular parietal epithelial cells through differentiation and proliferation [95]. Evidence supporting the contribution of podocytes to crescent formation was provided by studies in murine models of and humans with anti-GBM antibody disease in which podocytes adhered to both the glomerular basement membrane and the parietal basement membrane, forming podocyte bridges between the glomerular tuft and Bowman's capsule [96-98]. It has been suggested that podocyte bridging may be an important event that occurs early in the development of crescentic glomerulonephritis [96].

Podocytes also populate crescents [97,98] and may undergo epithelial mesenchymal transformation to contribute to crescent formation, particularly in early disease [98,99]. The following observations provide support for these findings:

Nestin, a marker for the metanephric blastema that gives rise to podocytes, has been identified in crescents of kidney biopsies from patients with crescentic glomerulonephritis [100].

Genetically tagged podocytes are an important component of cellular crescents in a murine model of anti-GBM antibody disease [97].

In mice, selective deletion of the Von Hippel-Lindau gene in glomeruli leads to clinical evidence of glomerulonephritis and spontaneous formation of crescent-like structures that are composed primarily of podocytes [101].

De novo induction of heparin-binding epidermal growth factor-like growth factor (HB-EGF) has been demonstrated in podocytes in both mice and humans with crescentic glomerulonephritis [102]. In addition, deficiency or conditional deletion of the epidermal growth factor receptor (EGFR) gene from podocytes of mice alleviates the severity of anti-GBM nephritis, suggesting an autocrine loop that involves induction of HB-EGF in podocytes [102].

De novo expression of HB-EGF in podocytes is also found in crescentic glomerulonephritis in humans [102,103]. This observation raises the possibility of new therapies since EGFR inhibitors (eg, cetuximab, panitumumab) are clinically available for use in selected patients with cancer.

MicroRNA-92a (miR-92a) is enriched in podocytes of patients and mice with crescentic glomerulonephritis and targets the cyclin-dependent kinase inhibitor p57Kip2. Podocyte-specific deletion of miR-92a, or administration of antimiR-92a, ameliorates crescentic glomerulonephritis in mice [104].

Kidney progenitor cells — Kidney progenitor cells localized in Bowman's capsule are capable of regenerating podocytes. These cells are identified by stem cell markers CD133 and CD24 and are in various stages of differentiation. Different types of progenitor cells seem to be located at the vascular and urinary poles, [105]. Data obtained in human crescentic glomerulonephritis suggest that crescent formation may primarily result from dysregulated proliferation of kidney progenitor cells in response to the injured podocyte [106]. Podocyte loss, perhaps due to a failure of replenishment of podocytes by parietal epithelial cells, has been reported in both experimental crescentic glomerulonephritis and ANCA-associated vasculitis [107,108].

Interstitial fibroblasts — In some models of experimental crescentic glomerulonephritis, interstitial fibroblasts are the second most prominent cell type after macrophages [7,8]. These cells are believed to enter Bowman's space from the periglomerular interstitium through gaps in Bowman's capsule. In the crescent, the fibroblast is a major source of interstitial collagen, which characterizes the transition from cellular to fibrous crescents. Fibroblast proliferation is thought to be growth factor-dependent, probably involving basic fibroblast growth factor (also called fibroblast growth factor-2) [36,109].

COURSE OF CRESCENTS — The presence of crescents does not necessarily predict irreversible glomerular damage. In IgA nephropathy, for example, there may be crescents in a small proportion of glomeruli (usually less than 25 percent) during episodes of gross hematuria and acute worsening of kidney function, but the lesions resolve in most patients with little or no scarring [110-112]. This lack of progression occurs when the crescents are predominantly cellular, without a significant fibroblast or collagen component. In a rat model of anti-glomerular basement membrane (GBM) disease, treatment with an inhibitor of spleen tyrosine kinase (SYK) can result in reversal of crescents, demonstrating that this is possible [72]. (See "IgA nephropathy: Treatment and prognosis", section on 'IgA nephropathy with rapidly progressive (crescentic) glomerulonephritis'.)

Whether crescents progress or resolve may depend upon the integrity of Bowman's capsule and the cellular composition of the crescent. Production of interstitial collagen and progression to fibrous crescents are more common when capsular rupture occurs and fibroblasts and macrophages are prominent in Bowman's space [36]. (See 'Interstitial fibroblasts' above and 'Macrophages' above.)

Although the presence of fibrous crescents generally correlates with glomerular sclerosis, there is no evidence that events in the crescents cause injury to the glomerular capillaries. As an example, defibrination abolishes crescent formation in animal models without improving kidney function [25,26]. Thus, crescent formation appears to be a consequence, not a cause, of severe glomerular injury (see 'Initiating events' above). However, there is increasing evidence that large crescents may occlude the outlet from Bowman's capsule to the proximal tubule to produce "atubular glomeruli" with subsequent degeneration of both glomeruli and tubules [113,114].

The treatment and prognosis of the kidney disease varies with disease severity and the cause of the glomerulonephritis. These issues are discussed in detail elsewhere. (See "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis", section on 'Treatment'.)

SUMMARY

Definition – Cellular glomerular crescents are defined as two or more layers of proliferating cells in Bowman's space (picture 1 and picture 2) and are a hallmark of inflammatory glomerulonephritis and a histologic marker of severe glomerular injury. In general, the severity of the kidney failure and other clinical manifestations of glomerulonephritis (eg, hypertension, edema) correlates with the percentage of glomeruli that exhibit crescents. Crescentic glomerulonephritis is typically associated with the syndrome of rapidly progressive glomerulonephritis. (See 'Introduction and definition' above.)

Initiating events – Glomerular crescent formation appears to represent a nonspecific response to severe injury to the glomerular capillary wall. The initiating event is the development of physical gaps (also called rents or holes) in the glomerular capillary wall, glomerular basement membrane, and Bowman's capsule (picture 2 and picture 3). (See 'Initiating events' above.)

Formation and composition of crescents – Rents in the glomerular capillary wall and glomerular basement membrane allow circulating cells, mostly monocytes and T cells, inflammatory mediators, and plasma proteins, particularly coagulation proteins, to pass through the capillary wall and basement membrane and into Bowman's space. The contents in Bowman's space can enter the interstitium, contributing to periglomerular inflammation (figure 1 and picture 4). Crescent formation results from the participation of these factors (see 'Formation and composition' above):

Complement (see 'Complement' above)

Coagulation factors, particularly fibrin and tissue factor (see 'Coagulation proteins' above)

Macrophages (see 'Macrophages' above)

Dendritic cells (see 'Dendritic cells' above)

T cells (see 'T cells' above)

Glomerular parietal epithelial cells (see 'Glomerular parietal epithelial cells' above)

Glomerular visceral epithelial cells (podocytes) (see 'Glomerular visceral epithelial cells (podocytes)' above)

Kidney progenitor cells (see 'Kidney progenitor cells' above)

Interstitial fibroblasts (see 'Interstitial fibroblasts' above)

Course of crescents – The presence of crescents does not necessarily predict irreversible glomerular damage. The potential reversibility of the injury corresponds in part with the relative predominance of cellular versus fibrous components in the crescents. (See 'Course of crescents' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Pierre Ronco, MD, PhD, who contributed to an earlier version of this topic review.

  1. Nikolic-Paterson DJ, Atkins RC. The role of macrophages in glomerulonephritis. Nephrol Dial Transplant 2001; 16 Suppl 5:3.
  2. Morrin PA, Hinglais N, Nabarra B, Kreis H. Rapidly progressive glomerulonephritis. A clinical and pathologic study. Am J Med 1978; 65:446.
  3. Whitworth JA, Morel-Maroger L, Mignon F, Richet G. The significance of extracapillary proliferation. Clinicopathological review of 60 patients. Nephron 1976; 16:1.
  4. Couser WG. Glomerulonephritis. Lancet 1999; 353:1509.
  5. Jennette JC. Rapidly progressive crescentic glomerulonephritis. Kidney Int 2003; 63:1164.
  6. Singh SK, Jeansson M, Quaggin SE. New insights into the pathogenesis of cellular crescents. Curr Opin Nephrol Hypertens 2011; 20:258.
  7. Lan HY, Nikolic-Paterson DJ, Atkins RC. Involvement of activated periglomerular leukocytes in the rupture of Bowman's capsule and glomerular crescent progression in experimental glomerulonephritis. Lab Invest 1992; 67:743.
  8. Morel-Maroger Striker L, Killen PD, Chi E, Striker GE. The composition of glomerulosclerosis. I. Studies in focal sclerosis, crescentic glomerulonephritis, and membranoproliferative glomerulonephritis. Lab Invest 1984; 51:181.
  9. Bonsib SM. Glomerular basement membrane discontinuities. Scanning electron microscopic study of acellular glomeruli. Am J Pathol 1985; 119:357.
  10. Anguiano L, Kain R, Anders HJ. The glomerular crescent: triggers, evolution, resolution, and implications for therapy. Curr Opin Nephrol Hypertens 2020; 29:302.
  11. Kitching AR, Holdsworth SR, Tipping PG. IFN-gamma mediates crescent formation and cell-mediated immune injury in murine glomerulonephritis. J Am Soc Nephrol 1999; 10:752.
  12. Hopfer H, Holzer J, Hünemörder S, et al. Characterization of the renal CD4+ T-cell response in experimental autoimmune glomerulonephritis. Kidney Int 2012; 82:60.
  13. Summers SA, Steinmetz OM, Li M, et al. Th1 and Th17 cells induce proliferative glomerulonephritis. J Am Soc Nephrol 2009; 20:2518.
  14. Paust HJ, Turner JE, Riedel JH, et al. Chemokines play a critical role in the cross-regulation of Th1 and Th17 immune responses in murine crescentic glomerulonephritis. Kidney Int 2012; 82:72.
  15. Paust HJ, Ostmann A, Erhardt A, et al. Regulatory T cells control the Th1 immune response in murine crescentic glomerulonephritis. Kidney Int 2011; 80:154.
  16. Nosko A, Kluger MA, Diefenhardt P, et al. T-Bet Enhances Regulatory T Cell Fitness and Directs Control of Th1 Responses in Crescentic GN. J Am Soc Nephrol 2017; 28:185.
  17. Kluger MA, Luig M, Wegscheid C, et al. Stat3 programs Th17-specific regulatory T cells to control GN. J Am Soc Nephrol 2014; 25:1291.
  18. Chen A, Lee K, D'Agati VD, et al. Bowman's capsule provides a protective niche for podocytes from cytotoxic CD8+ T cells. J Clin Invest 2018; 128:3413.
  19. Giorgini A, Brown HJ, Sacks SH, Robson MG. Toll-like receptor 4 stimulation triggers crescentic glomerulonephritis by multiple mechanisms including a direct effect on renal cells. Am J Pathol 2010; 177:644.
  20. Summers SA, Steinmetz OM, Ooi JD, et al. Toll-like receptor 9 enhances nephritogenic immunity and glomerular leukocyte recruitment, exacerbating experimental crescentic glomerulonephritis. Am J Pathol 2010; 177:2234.
  21. Smith J, Lai PC, Behmoaras J, et al. Genes expressed by both mesangial cells and bone marrow-derived cells underlie genetic susceptibility to crescentic glomerulonephritis in the rat. J Am Soc Nephrol 2007; 18:1816.
  22. Tipping PG. Crescentic nephritis--is it in your genes? Nephrol Dial Transplant 2008; 23:3065.
  23. Zipfel PF, Wiech T, Gröne HJ, Skerka C. Complement catalyzing glomerular diseases. Cell Tissue Res 2021; 385:355.
  24. Jayne DRW, Merkel PA, Schall TJ, et al. Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med 2021; 384:599.
  25. Naish P, Penn GB, Evans DJ, Peters DK. The effect of defibrination on nephrotoxic serum nephritis in rabbits. Clin Sci 1972; 42:643.
  26. Thomson NM, Moran J, Simpson IJ, Peters DK. Defibrination with ancrod in nephrotoxic nephritis in rabbits. Kidney Int 1976; 10:343.
  27. Tipping PG, Erlich JH, Apostolopoulos J, et al. Glomerular tissue factor expression in crescentic glomerulonephritis. Correlations between antigen, activity, and mRNA. Am J Pathol 1995; 147:1736.
  28. Tipping PG, Holdsworth SR. T cells in glomerulonephritis. Springer Semin Immunopathol 2003; 24:377.
  29. Cunningham MA, Kitching AR, Tipping PG, Holdsworth SR. Fibrin independent proinflammatory effects of tissue factor in experimental crescentic glomerulonephritis. Kidney Int 2004; 66:647.
  30. Erlich JH, Apostolopoulos J, Wun TC, et al. Renal expression of tissue factor pathway inhibitor and evidence for a role in crescentic glomerulonephritis in rabbits. J Clin Invest 1996; 98:325.
  31. Cunningham MA, Ono T, Hewitson TD, et al. Tissue factor pathway inhibitor expression in human crescentic glomerulonephritis. Kidney Int 1999; 55:1311.
  32. Cunningham MA, Rondeau E, Chen X, et al. Protease-activated receptor 1 mediates thrombin-dependent, cell-mediated renal inflammation in crescentic glomerulonephritis. J Exp Med 2000; 191:455.
  33. Kitching AR, Holdsworth SR, Ploplis VA, et al. Plasminogen and plasminogen activators protect against renal injury in crescentic glomerulonephritis. J Exp Med 1997; 185:963.
  34. Kitching AR, Kong YZ, Huang XR, et al. Plasminogen activator inhibitor-1 is a significant determinant of renal injury in experimental crescentic glomerulonephritis. J Am Soc Nephrol 2003; 14:1487.
  35. Rondeau E, Mougenot B, Lacave R, et al. Plasminogen activator inhibitor 1 in renal fibrin deposits of human nephropathies. Clin Nephrol 1990; 33:55.
  36. Atkins RC, Nikolic-Paterson DJ, Song Q, Lan HY. Modulators of crescentic glomerulonephritis. J Am Soc Nephrol 1996; 7:2271.
  37. Moussa L, Apostolopoulos J, Davenport P, et al. Protease-activated receptor-2 augments experimental crescentic glomerulonephritis. Am J Pathol 2007; 171:800.
  38. Tipping PG, Holdsworth SR. The participation of macrophages, glomerular procoagulant activity, and factor VIII in glomerular fibrin deposition. Studies on anti-GBM antibody-induced glomerulonephritis in rabbits. Am J Pathol 1986; 124:10.
  39. Lan HY, Nikolic-Paterson DJ, Mu W, Atkins RC. Local macrophage proliferation in the pathogenesis of glomerular crescent formation in rat anti-glomerular basement membrane (GBM) glomerulonephritis. Clin Exp Immunol 1997; 110:233.
  40. Li HL, Hancock WW, Dowling JP, Atkins RC. Activated (IL-2R+) intraglomerular mononuclear cells in crescentic glomerulonephritis. Kidney Int 1991; 39:793.
  41. Boucher A, Droz D, Adafer E, Noël LH. Relationship between the integrity of Bowman's capsule and the composition of cellular crescents in human crescentic glomerulonephritis. Lab Invest 1987; 56:526.
  42. Lloyd CM, Dorf ME, Proudfoot A, et al. Role of MCP-1 and RANTES in inflammation and progression to fibrosis during murine crescentic nephritis. J Leukoc Biol 1997; 62:676.
  43. Lan HY, Yu XQ, Yang N, et al. De novo glomerular osteopontin expression in rat crescentic glomerulonephritis. Kidney Int 1998; 53:136.
  44. Wada T, Furuichi K, Segawa-Takaeda C, et al. MIP-1alpha and MCP-1 contribute to crescents and interstitial lesions in human crescentic glomerulonephritis. Kidney Int 1999; 56:995.
  45. Hudkins KL, Giachelli CM, Eitner F, et al. Osteopontin expression in human crescentic glomerulonephritis. Kidney Int 2000; 57:105.
  46. Segerer S, Cui Y, Hudkins KL, et al. Expression of the chemokine monocyte chemoattractant protein-1 and its receptor chemokine receptor 2 in human crescentic glomerulonephritis. J Am Soc Nephrol 2000; 11:2231.
  47. Nishikawa K, Guo YJ, Miyasaka M, et al. Antibodies to intercellular adhesion molecule 1/lymphocyte function-associated antigen 1 prevent crescent formation in rat autoimmune glomerulonephritis. J Exp Med 1993; 177:667.
  48. Adler S, Brady HR. Cell adhesion molecules and the glomerulopathies. Am J Med 1999; 107:371.
  49. Timoshanko JR, Kitching AR, Semple TJ, et al. Granulocyte macrophage colony-stimulating factor expression by both renal parenchymal and immune cells mediates murine crescentic glomerulonephritis. J Am Soc Nephrol 2005; 16:2646.
  50. Lan HY, Nikolic-Paterson DJ, Mu W, et al. Interleukin-1 receptor antagonist halts the progression of established crescentic glomerulonephritis in the rat. Kidney Int 1995; 47:1303.
  51. Khan SB, Cook HT, Bhangal G, et al. Antibody blockade of TNF-alpha reduces inflammation and scarring in experimental crescentic glomerulonephritis. Kidney Int 2005; 67:1812.
  52. Lan HY, Yang N, Metz C, et al. TNF-alpha up-regulates renal MIF expression in rat crescentic glomerulonephritis. Mol Med 1997; 3:136.
  53. Timoshanko JR, Sedgwick JD, Holdsworth SR, Tipping PG. Intrinsic renal cells are the major source of tumor necrosis factor contributing to renal injury in murine crescentic glomerulonephritis. J Am Soc Nephrol 2003; 14:1785.
  54. Border WA, Noble NA. Transforming growth factor beta in tissue fibrosis. N Engl J Med 1994; 331:1286.
  55. Song CY, Kim BC, Hong HK, Lee HS. TGF-beta type II receptor deficiency prevents renal injury via decrease in ERK activity in crescentic glomerulonephritis. Kidney Int 2007; 71:882.
  56. Goumenos DS, Kalliakmani P, Tsakas S, et al. Urinary Transforming Growth Factor-beta 1 as a marker of response to immunosuppressive treatment, in patients with crescentic nephritis. BMC Nephrol 2005; 6:16.
  57. Isaka Y, Akagi Y, Kaneda Y, et al. Gene therapy by transforming growth factor beta receptor-IgG Fc chimera blocked glomerular hypertrophy in diabetic nephropathy (abstract). J Am Soc Nephrol 1997; 8:639A.
  58. Isaka Y, Nakamura H, Mizui M, et al. DNAzyme for TGF-beta suppressed extracellular matrix accumulation in experimental glomerulonephritis. Kidney Int 2004; 66:586.
  59. Border WA, Ruoslahti E. Transforming growth factor-beta 1 induces extracellular matrix formation in glomerulonephritis. Cell Differ Dev 1990; 32:425.
  60. Chavele KM, Martinez-Pomares L, Domin J, et al. Mannose receptor interacts with Fc receptors and is critical for the development of crescentic glomerulonephritis in mice. J Clin Invest 2010; 120:1469.
  61. Rousselle A, Kettritz R, Schreiber A. Monocytes Promote Crescent Formation in Anti-Myeloperoxidase Antibody-Induced Glomerulonephritis. Am J Pathol 2017; 187:1908.
  62. Sanders JS, van Goor H, Hanemaaijer R, et al. Renal expression of matrix metalloproteinases in human ANCA-associated glomerulonephritis. Nephrol Dial Transplant 2004; 19:1412.
  63. Nakopoulou L, Lazaris AC, Boletis I, et al. The expression of matrix metalloproteinase-11 protein in various types of glomerulonephritis. Nephrol Dial Transplant 2007; 22:109.
  64. Lelongt B, Bengatta S, Delauche M, et al. Matrix metalloproteinase 9 protects mice from anti-glomerular basement membrane nephritis through its fibrinolytic activity. J Exp Med 2001; 193:793.
  65. Han Y, Ma FY, Tesch GH, et al. Role of macrophages in the fibrotic phase of rat crescentic glomerulonephritis. Am J Physiol Renal Physiol 2013; 304:F1043.
  66. Vielhauer V, Kulkarni O, Reichel CA, Anders HJ. Targeting the recruitment of monocytes and macrophages in renal disease. Semin Nephrol 2010; 30:318.
  67. Reynolds J, Cook PR, Ryan JJ, et al. Segregation of experimental autoimmune glomerulonephritis as a complex genetic trait and exclusion of Col4a3 as a candidate gene. Exp Nephrol 2002; 10:402.
  68. Behmoaras J, Smith J, D'Souza Z, et al. Genetic loci modulate macrophage activity and glomerular damage in experimental glomerulonephritis. J Am Soc Nephrol 2010; 21:1136.
  69. Aitman TJ, Dong R, Vyse TJ, et al. Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 2006; 439:851.
  70. Page TH, D'Souza Z, Nakanishi S, et al. Role of novel rat-specific Fc receptor in macrophage activation associated with crescentic glomerulonephritis. J Biol Chem 2012; 287:5710.
  71. Smith J, McDaid JP, Bhangal G, et al. A spleen tyrosine kinase inhibitor reduces the severity of established glomerulonephritis. J Am Soc Nephrol 2010; 21:231.
  72. McAdoo SP, Reynolds J, Bhangal G, et al. Spleen tyrosine kinase inhibition attenuates autoantibody production and reverses experimental autoimmune GN. J Am Soc Nephrol 2014; 25:2291.
  73. Behmoaras J, Bhangal G, Smith J, et al. Jund is a determinant of macrophage activation and is associated with glomerulonephritis susceptibility. Nat Genet 2008; 40:553.
  74. Hull RP, Srivastava PK, D'Souza Z, et al. Combined ChIP-Seq and transcriptome analysis identifies AP-1/JunD as a primary regulator of oxidative stress and IL-1β synthesis in macrophages. BMC Genomics 2013; 14:92.
  75. Deplano S, Cook HT, Russell R, et al. P2X7 receptor-mediated Nlrp3-inflammasome activation is a genetic determinant of macrophage-dependent crescentic glomerulonephritis. J Leukoc Biol 2013; 93:127.
  76. Hochheiser K, Engel DR, Hammerich L, et al. Kidney Dendritic Cells Become Pathogenic during Crescentic Glomerulonephritis with Proteinuria. J Am Soc Nephrol 2011; 22:306.
  77. Evers BD, Engel DR, Böhner AM, et al. CD103+ Kidney Dendritic Cells Protect against Crescentic GN by Maintaining IL-10-Producing Regulatory T Cells. J Am Soc Nephrol 2016; 27:3368.
  78. Nelson PJ, Rees AJ, Griffin MD, et al. The renal mononuclear phagocytic system. J Am Soc Nephrol 2012; 23:194.
  79. Cunningham MA, Huang XR, Dowling JP, et al. Prominence of cell-mediated immunity effectors in "pauci-immune" glomerulonephritis. J Am Soc Nephrol 1999; 10:499.
  80. Kitching AR, Turner AL, Wilson GR, et al. IL-12p40 and IL-18 in crescentic glomerulonephritis: IL-12p40 is the key Th1-defining cytokine chain, whereas IL-18 promotes local inflammation and leukocyte recruitment. J Am Soc Nephrol 2005; 16:2023.
  81. Odobasic D, Kitching AR, Semple TJ, et al. Glomerular expression of CD80 and CD86 is required for leukocyte accumulation and injury in crescentic glomerulonephritis. J Am Soc Nephrol 2005; 16:2012.
  82. Timoshanko JR, Kitching AR, Semple TJ, et al. A pathogenetic role for mast cells in experimental crescentic glomerulonephritis. J Am Soc Nephrol 2006; 17:150.
  83. Chang J, Eggenhuizen P, O'Sullivan KM, et al. CD8+ T Cells Effect Glomerular Injury in Experimental Anti-Myeloperoxidase GN. J Am Soc Nephrol 2017; 28:47.
  84. Lan HY, Bacher M, Yang N, et al. The pathogenic role of macrophage migration inhibitory factor in immunologically induced kidney disease in the rat. J Exp Med 1997; 185:1455.
  85. Hyodo T, Oda T, Kikuchi Y, et al. Voltage-gated potassium channel Kv1.3 blocker as a potential treatment for rat anti-glomerular basement membrane glomerulonephritis. Am J Physiol Renal Physiol 2010; 299:F1258.
  86. Reynolds J, Abbott DS, Karegli J, et al. Mucosal tolerance induced by an immunodominant peptide from rat alpha3(IV)NC1 in established experimental autoimmune glomerulonephritis. Am J Pathol 2009; 174:2202.
  87. Gan PY, Tan DS, Ooi JD, et al. Myeloperoxidase Peptide-Based Nasal Tolerance in Experimental ANCA-Associated GN. J Am Soc Nephrol 2016; 27:385.
  88. Nitta K, Horita S, Honda K, et al. Glomerular expression of cell-cycle-regulatory proteins in human crescentic glomerulonephritis. Virchows Arch 1999; 435:422.
  89. Smeets B, Uhlig S, Fuss A, et al. Tracing the origin of glomerular extracapillary lesions from parietal epithelial cells. J Am Soc Nephrol 2009; 20:2604.
  90. Wong MN, Tharaux PL, Grahammer F, Puelles VG. Parietal epithelial cell dysfunction in crescentic glomerulonephritis. Cell Tissue Res 2021; 385:345.
  91. Eymael J, Sharma S, Loeven MA, et al. CD44 is required for the pathogenesis of experimental crescentic glomerulonephritis and collapsing focal segmental glomerulosclerosis. Kidney Int 2018; 93:626.
  92. Lazareth H, Henique C, Lenoir O, et al. The tetraspanin CD9 controls migration and proliferation of parietal epithelial cells and glomerular disease progression. Nat Commun 2019; 10:3303.
  93. Shirato I, Asanuma K, Takeda Y, et al. Protein gene product 9.5 is selectively localized in parietal epithelial cells of Bowman's capsule in the rat kidney. J Am Soc Nephrol 2000; 11:2381.
  94. Barisoni L, Nelson PJ. Collapsing glomerulopathy: an inflammatory podocytopathy? Curr Opin Nephrol Hypertens 2007; 16:192.
  95. Appel D, Kershaw DB, Smeets B, et al. Recruitment of podocytes from glomerular parietal epithelial cells. J Am Soc Nephrol 2009; 20:333.
  96. Le Hir M, Keller C, Eschmann V, et al. Podocyte bridges between the tuft and Bowman's capsule: an early event in experimental crescentic glomerulonephritis. J Am Soc Nephrol 2001; 12:2060.
  97. Moeller MJ, Soofi A, Hartmann I, et al. Podocytes populate cellular crescents in a murine model of inflammatory glomerulonephritis. J Am Soc Nephrol 2004; 15:61.
  98. Bariéty J, Bruneval P, Meyrier A, et al. Podocyte involvement in human immune crescentic glomerulonephritis. Kidney Int 2005; 68:1109.
  99. Bariety J, Hill GS, Mandet C, et al. Glomerular epithelial-mesenchymal transdifferentiation in pauci-immune crescentic glomerulonephritis. Nephrol Dial Transplant 2003; 18:1777.
  100. Thorner PS, Ho M, Eremina V, et al. Podocytes contribute to the formation of glomerular crescents. J Am Soc Nephrol 2008; 19:495.
  101. Ding M, Cui S, Li C, et al. Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice. Nat Med 2006; 12:1081.
  102. Bollée G, Flamant M, Schordan S, et al. Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis. Nat Med 2011; 17:1242.
  103. Flamant M, Bollée G, Hénique C, Tharaux PL. Epidermal growth factor: a new therapeutic target in glomerular disease. Nephrol Dial Transplant 2012; 27:1297.
  104. Henique C, Bollée G, Loyer X, et al. Genetic and pharmacological inhibition of microRNA-92a maintains podocyte cell cycle quiescence and limits crescentic glomerulonephritis. Nat Commun 2017; 8:1829.
  105. Ronconi E, Sagrinati C, Angelotti ML, et al. Regeneration of glomerular podocytes by human renal progenitors. J Am Soc Nephrol 2009; 20:322.
  106. Smeets B, Angelotti ML, Rizzo P, et al. Renal progenitor cells contribute to hyperplastic lesions of podocytopathies and crescentic glomerulonephritis. J Am Soc Nephrol 2009; 20:2593.
  107. Puelles VG, Fleck D, Ortz L, et al. Novel 3D analysis using optical tissue clearing documents the evolution of murine rapidly progressive glomerulonephritis. Kidney Int 2019; 96:505.
  108. Zimmermann M, Klaus M, Wong MN, et al. Deep learning-based molecular morphometrics for kidney biopsies. JCI Insight 2021; 6.
  109. Ng YY, Fan JM, Mu W, et al. Glomerular epithelial-myofibroblast transdifferentiation in the evolution of glomerular crescent formation. Nephrol Dial Transplant 1999; 14:2860.
  110. Bennett WM, Kincaid-Smith P. Macroscopic hematuria in mesangial IgA nephropathy: correlation with glomerular crescents and renal dysfunction. Kidney Int 1983; 23:393.
  111. Praga M, Gutierrez-Millet V, Navas JJ, et al. Acute worsening of renal function during episodes of macroscopic hematuria in IgA nephropathy. Kidney Int 1985; 28:69.
  112. Fogazzi GB, Imbasciati E, Moroni G, et al. Reversible acute renal failure from gross haematuria due to glomerulonephritis: not only in IgA nephropathy and not associated with intratubular obstruction. Nephrol Dial Transplant 1995; 10:624.
  113. Kriz W, Hähnel B, Hosser H, et al. Pathways to recovery and loss of nephrons in anti-Thy-1 nephritis. J Am Soc Nephrol 2003; 14:1904.
  114. Chevalier RL, Forbes MS. Generation and evolution of atubular glomeruli in the progression of renal disorders. J Am Soc Nephrol 2008; 19:197.
Topic 3069 Version 16.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟