Official reprint from UpToDate www.uptodate.com ©2015 UpToDate

AuthorPierre Ronco, MD, PhD

Section EditorsRichard J Glassock, MD,MACPFernando C Fervenza, MD,PhD

Deputy EditorJohn P Forman, MD, MSc

Mechanisms of glomerular crescent formation

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2015. | This topic last updated: Jan 22, 2013.

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. In general, the severity of the renal failure

and other clinical manifestations of glomerulonephritis (eg, hypertension, edema) correlates with the percentage of

glomeruli that exhibit crescents [1-5]. 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, IgA

nephropathy, lupus nephritis, renal vasculitis, membranoproliferative glomerulonephritis, and anti-glomerular

basement membrane (GBM) antibody disease. (See "Differential diagnosis and evaluation of glomerular disease",

section on 'Moderate to severe glomerulonephritis'.)

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) [6,7]. 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) [5,8].

Based upon experimental murine studies, 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 [9]. Th17 CD4 effector cells also appear to play an important role [10,11] with a potential cytokine-

chemokine-driven cross-regulation of Th1 and Th17 subpopulations [12]. Recruitment of Th1 is also controlled by

regulatory T cells [13]. (See "T helper subsets: Differentiation and role in disease".)

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. 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

macrophages 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.

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Crescent formation results from the subsequent participation of coagulation factors, particularly fibrin; tissue

factor, which promotes fibrin deposition; and several different cell types, including macrophages, glomerular

parietal epithelial cells, glomerular visceral epithelial cells (podocytes), renal 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 [14,15]. TLR4 has a crucial

direct effect on renal cells.

Genetically determined differences in both glomerular and bone marrow-derived cells can influence individual

susceptibility to crescent formation [16,17].

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 4). The importance of fibrin is illustrated by the findings in animal models that defibrination

can prevent [18] or reverse crescent formation [19].

Tissue factor, tissue factor inhibitor, thrombin, and the plasminogen/plasmin system are procoagulant 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 [20]. Tissue factor is derived from endothelial cells, glomerular visceral

epithelial cells (podocytes), and macrophages [20,21]. In addition, macrophage-derived interleukin-1 and tumor

necrosis factor (TNF) stimulate tissue factor production by glomerular endothelial cells [22].

In early glomerulonephritis, tissue factor expression appears to derive from intrinsic glomerular cells; later, it

primarily originates from macrophages [20]. (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 [23]. This early response is followed by

enhancement of TFPI expression in later stage disease, chronically inhibiting the deposition of fibrin [23,24]. A

similar effect can be induced by the administration of recombinant TFPI which, in experimental crescentic

glomerulonephritis, reduces both fibrin deposition and crescent formation [23].

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 [25]. (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) [26-28]. 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 [29]. (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 renal PAI-1 expression and

inhibition of matrix metalloproteinase-9 activity [30]. In contrast, mice lacking PAR-2 have reductions in PAI activity,

fibrin deposition, and crescent formation [30].

Macrophages — Macrophages play a central role in the formation of glomerular crescents since both tissue factor

expression and fibrin deposition are macrophage-dependent phenomena [31]. In an experimental model of anti-

glomerular basement membrane (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 [32].

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) [6,7] and/or by cell-mediated

mechanisms [33,34]. (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 inhibitory factor (MIF),

macrophage inflammatory protein-1-alpha (MIP-1-alpha), and osteopontin [35-38]. Expression of chemokine

receptor 2B (CCR2B), which is the receptor for MCP-1, may be particularly important [39].

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 [40,41].

Renal cell-derived granulocyte-macrophage colony stimulating factor (GM-CSF) may increase expression of

VCAM-1, MCP-1, and interleukin (IL)-1 beta, thereby promoting crescent formation [42].

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.)

Interleukin (IL)-1 and TNF upregulate adhesion molecule expression, stimulate cell proliferation, and recruit

more macrophages [32]. Selective blockade of IL-1 with IL-1 receptor antagonists [43] or of TNF with anti-

TNF antibodies or soluble TNF receptors markedly reduces crescent formation in experimental models

[44,45]. In contrast to the macrophage origin of most inflammatory mediators, some evidence suggests that

the principal source of TNF may be intrinsic renal cells [46].

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

[47]. With respect to disease activity, TGF-beta signaling appears to play an important role in the

development and progression of crescentic glomerulonephritis [48]. 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 [49].

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 [50]. A reduction

in extracellular matrix accumulation has also been demonstrated in other studies by inhibiting TGF-beta

expression [51] or activity [52].

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 [53]. These data suggest that blocking the receptor might provide a more

specific approach than broad-based immunosuppressive therapy.

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 [54,55]. In experimental studies, MMP-9 protects

against experimental crescentic glomerulonephritis through its fibrinolytic activity [30,56].

T cells — T cells are found in Bowman's space and in crescents [33,57]. 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

interleukin [IL]-12p40 and IL-18), mast cells, and costimulatory ligands on macrophages and non-lymphoid cells

(such as CD80 and CD86) [58-60]. Some of these cytokines may also stimulate production of proinflammatory

cytokines such as interferon-gamma and TNF [58].

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 [9,61]. 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 GBM crescentic

glomerulonephritis [62]. In addition to effector memory T cells, 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.

Glomerular parietal epithelial cells — Glomerular parietal epithelial cells are significant constituents of

crescents [63,64]. 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) [29]. Studies performed in

a mouse model using genetic tagging of glomerular parietal epithelial cells demonstrated the significant contribution

of these cells to crescent formation [64].

Since glomerular parietal epithelial cells are not major sources of procoagulant molecules or growth factors, it is

unlikely that they are 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

dysregulation and become macrophage-like inflammatory effector cells and may be the primary cells producing

type I collagen [65,66].

Glomerular visceral epithelial cells (podocytes) — Glomerular visceral epithelial cells (podocytes) (figure 1)

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 [67]. Evidence supporting the contribution of

podocytes to crescent formation was provided by studies in murine models of and humans with 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 [68-70]. It has been

suggested that podocyte bridging may be an important event that occurs early in the development of crescentic

glomerulonephritis [68].

Podocytes also populate crescents [69,70] and may undergo epithelial mesenchymal transformation to contribute

to crescent formation, particularly in early disease [70,71]. 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 [72].

Genetically tagged podocytes are an important component of cellular crescents in a murine model of anti-

GBM antibody disease [69].

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 [73].

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 [74]. 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 [74].

De novo expression of HB-EGF in podocytes is also found in crescentic glomerulonephritis in humans

[74,75]. This observation raises the possibility of new therapies since EGFR inhibitors (eg, cetuximab,

panitumumab) are clinically available for use in selected patients with cancer.

Renal progenitor cells — Renal 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, [76]. Data

obtained in human crescentic glomerulonephritis suggest that crescent formation may primarily result from

dysregulated proliferation of renal progenitor cells in response to the injured podocyte [77].

Interstitial fibroblasts — In some models of experimental crescentic glomerulonephritis, interstitial fibroblasts are

the second most prominent cell type after macrophages [6,7]. 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) [29,78].

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 renal function, but the lesions resolve

in most patients with little or no scarring [79-81]. This lack of progression occurs when the crescents are

predominantly cellular, without a significant fibroblast or collagen component. (See "Treatment and prognosis of IgA

nephropathy", section on 'Acute kidney injury with gross hematuria'.)

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 [29].

(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 renal function [18,19]. 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 [82,83].

The treatment and prognosis of the renal 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

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 renal 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.)

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.)

Rents in the glomerular capillary wall and glomerular basement membrane allow circulating cells, mostly

macrophages 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. Crescent formation

results from the participation of these factors (see 'Formation and composition' above):

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

Macrophages (see 'Macrophages' 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).

Renal progenitor cells (see 'Renal progenitor cells' above).

Interstitial fibroblasts (see 'Interstitial fibroblasts' above).

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 authors and editors would like to thank Dr. William Couser, who contributed to earlier

versions of this topic review.

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REFERENCES

1. Nikolic-Paterson DJ, Atkins RC. The role of macrophages in glomerulonephritis. Nephrol Dial Transplant2001; 16 Suppl 5:3.

2. Morrin PA, Hinglais N, Nabarra B, Kreis H. Rapidly progressive glomerulonephritis. A clinical and pathologicstudy. 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. Lan HY, Nikolic-Paterson DJ, Atkins RC. Involvement of activated periglomerular leukocytes in the rupture ofBowman's capsule and glomerular crescent progression in experimental glomerulonephritis. Lab Invest 1992;67:743.

7. Morel-Maroger Striker L, Killen PD, Chi E, Striker GE. The composition of glomerulosclerosis. I. Studies infocal sclerosis, crescentic glomerulonephritis, and membranoproliferative glomerulonephritis. Lab Invest 1984;51:181.

8. Bonsib SM. Glomerular basement membrane discontinuities. Scanning electron microscopic study of

acellular glomeruli. Am J Pathol 1985; 119:357.

9. Kitching AR, Holdsworth SR, Tipping PG. IFN-gamma mediates crescent formation and cell-mediatedimmune injury in murine glomerulonephritis. J Am Soc Nephrol 1999; 10:752.

10. Hopfer H, Holzer J, Hünemörder S, et al. Characterization of the renal CD4+ T-cell response in experimentalautoimmune glomerulonephritis. Kidney Int 2012; 82:60.

11. Summers SA, Steinmetz OM, Li M, et al. Th1 and Th17 cells induce proliferative glomerulonephritis. J AmSoc Nephrol 2009; 20:2518.

12. Paust HJ, Turner JE, Riedel JH, et al. Chemokines play a critical role in the cross-regulation of Th1 and Th17immune responses in murine crescentic glomerulonephritis. Kidney Int 2012; 82:72.

13. Paust HJ, Ostmann A, Erhardt A, et al. Regulatory T cells control the Th1 immune response in murinecrescentic glomerulonephritis. Kidney Int 2011; 80:154.

14. Giorgini A, Brown HJ, Sacks SH, Robson MG. Toll-like receptor 4 stimulation triggers crescenticglomerulonephritis by multiple mechanisms including a direct effect on renal cells. Am J Pathol 2010;177:644.

15. Summers SA, Steinmetz OM, Ooi JD, et al. Toll-like receptor 9 enhances nephritogenic immunity andglomerular leukocyte recruitment, exacerbating experimental crescentic glomerulonephritis. Am J Pathol2010; 177:2234.

16. Smith J, Lai PC, Behmoaras J, et al. Genes expressed by both mesangial cells and bone marrow-derivedcells underlie genetic susceptibility to crescentic glomerulonephritis in the rat. J Am Soc Nephrol 2007;18:1816.

17. Tipping PG. Crescentic nephritis--is it in your genes? Nephrol Dial Transplant 2008; 23:3065.

18. Naish P, Penn GB, Evans DJ, Peters DK. The effect of defibrination on nephrotoxic serum nephritis in rabbits.Clin Sci 1972; 42:643.

19. Thomson NM, Moran J, Simpson IJ, Peters DK. Defibrination with ancrod in nephrotoxic nephritis in rabbits.Kidney Int 1976; 10:343.

20. Tipping PG, Erlich JH, Apostolopoulos J, et al. Glomerular tissue factor expression in crescenticglomerulonephritis. Correlations between antigen, activity, and mRNA. Am J Pathol 1995; 147:1736.

21. Tipping PG, Holdsworth SR. T cells in glomerulonephritis. Springer Semin Immunopathol 2003; 24:377.

22. Cunningham MA, Kitching AR, Tipping PG, Holdsworth SR. Fibrin independent proinflammatory effects oftissue factor in experimental crescentic glomerulonephritis. Kidney Int 2004; 66:647.

23. Erlich JH, Apostolopoulos J, Wun TC, et al. Renal expression of tissue factor pathway inhibitor and evidencefor a role in crescentic glomerulonephritis in rabbits. J Clin Invest 1996; 98:325.

24. Cunningham MA, Ono T, Hewitson TD, et al. Tissue factor pathway inhibitor expression in human crescenticglomerulonephritis. Kidney Int 1999; 55:1311.

25. 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.

26. Kitching AR, Holdsworth SR, Ploplis VA, et al. Plasminogen and plasminogen activators protect against renalinjury in crescentic glomerulonephritis. J Exp Med 1997; 185:963.

27. Kitching AR, Kong YZ, Huang XR, et al. Plasminogen activator inhibitor-1 is a significant determinant of renalinjury in experimental crescentic glomerulonephritis. J Am Soc Nephrol 2003; 14:1487.

28. Rondeau E, Mougenot B, Lacave R, et al. Plasminogen activator inhibitor 1 in renal fibrin deposits of humannephropathies. Clin Nephrol 1990; 33:55.

29. Atkins RC, Nikolic-Paterson DJ, Song Q, Lan HY. Modulators of crescentic glomerulonephritis. J Am SocNephrol 1996; 7:2271.

30. Moussa L, Apostolopoulos J, Davenport P, et al. Protease-activated receptor-2 augments experimentalcrescentic glomerulonephritis. Am J Pathol 2007; 171:800.

31. Tipping PG, Holdsworth SR. The participation of macrophages, glomerular procoagulant activity, and factorVIII in glomerular fibrin deposition. Studies on anti-GBM antibody-induced glomerulonephritis in rabbits. Am J

Pathol 1986; 124:10.

32. Lan HY, Nikolic-Paterson DJ, Mu W, Atkins RC. Local macrophage proliferation in the pathogenesis ofglomerular crescent formation in rat anti-glomerular basement membrane (GBM) glomerulonephritis. Clin ExpImmunol 1997; 110:233.

33. Li HL, Hancock WW, Dowling JP, Atkins RC. Activated (IL-2R+) intraglomerular mononuclear cells increscentic glomerulonephritis. Kidney Int 1991; 39:793.

34. Boucher A, Droz D, Adafer E, Noël LH. Relationship between the integrity of Bowman's capsule and thecomposition of cellular crescents in human crescentic glomerulonephritis. Lab Invest 1987; 56:526.

35. Lloyd CM, Dorf ME, Proudfoot A, et al. Role of MCP-1 and RANTES in inflammation and progression tofibrosis during murine crescentic nephritis. J Leukoc Biol 1997; 62:676.

36. Lan HY, Yu XQ, Yang N, et al. De novo glomerular osteopontin expression in rat crescenticglomerulonephritis. Kidney Int 1998; 53:136.

37. Wada T, Furuichi K, Segawa-Takaeda C, et al. MIP-1alpha and MCP-1 contribute to crescents and interstitiallesions in human crescentic glomerulonephritis. Kidney Int 1999; 56:995.

38. Hudkins KL, Giachelli CM, Eitner F, et al. Osteopontin expression in human crescentic glomerulonephritis.Kidney Int 2000; 57:105.

39. Segerer S, Cui Y, Hudkins KL, et al. Expression of the chemokine monocyte chemoattractant protein-1 andits receptor chemokine receptor 2 in human crescentic glomerulonephritis. J Am Soc Nephrol 2000; 11:2231.

40. Nishikawa K, Guo YJ, Miyasaka M, et al. Antibodies to intercellular adhesion molecule 1/lymphocytefunction-associated antigen 1 prevent crescent formation in rat autoimmune glomerulonephritis. J Exp Med1993; 177:667.

41. Adler S, Brady HR. Cell adhesion molecules and the glomerulopathies. Am J Med 1999; 107:371.

42. Timoshanko JR, Kitching AR, Semple TJ, et al. Granulocyte macrophage colony-stimulating factorexpression by both renal parenchymal and immune cells mediates murine crescentic glomerulonephritis. JAm Soc Nephrol 2005; 16:2646.

43. Lan HY, Nikolic-Paterson DJ, Mu W, et al. Interleukin-1 receptor antagonist halts the progression ofestablished crescentic glomerulonephritis in the rat. Kidney Int 1995; 47:1303.

44. Khan SB, Cook HT, Bhangal G, et al. Antibody blockade of TNF-alpha reduces inflammation and scarring inexperimental crescentic glomerulonephritis. Kidney Int 2005; 67:1812.

45. Lan HY, Yang N, Metz C, et al. TNF-alpha up-regulates renal MIF expression in rat crescenticglomerulonephritis. Mol Med 1997; 3:136.

46. Timoshanko JR, Sedgwick JD, Holdsworth SR, Tipping PG. Intrinsic renal cells are the major source of tumornecrosis factor contributing to renal injury in murine crescentic glomerulonephritis. J Am Soc Nephrol 2003;14:1785.

47. Border WA, Noble NA. Transforming growth factor beta in tissue fibrosis. N Engl J Med 1994; 331:1286.

48. Song CY, Kim BC, Hong HK, Lee HS. TGF-beta type II receptor deficiency prevents renal injury via decreasein ERK activity in crescentic glomerulonephritis. Kidney Int 2007; 71:882.

49. Goumenos DS, Kalliakmani P, Tsakas S, et al. Urinary Transforming Growth Factor-beta 1 as a marker ofresponse to immunosuppressive treatment, in patients with crescentic nephritis. BMC Nephrol 2005; 6:16.

50. Isaka Y, Akagi Y, Ando Y, et al. Gene therapy by transforming growth factor-beta receptor-IgG Fc chimerasuppressed extracellular matrix accumulation in experimental glomerulonephritis. Kidney Int 1999; 55:465.

51. Isaka Y, Nakamura H, Mizui M, et al. DNAzyme for TGF-beta suppressed extracellular matrix accumulationin experimental glomerulonephritis. Kidney Int 2004; 66:586.

52. Border WA, Ruoslahti E. Transforming growth factor-beta 1 induces extracellular matrix formation inglomerulonephritis. Cell Differ Dev 1990; 32:425.

53. Chavele KM, Martinez-Pomares L, Domin J, et al. Mannose receptor interacts with Fc receptors and iscritical for the development of crescentic glomerulonephritis in mice. J Clin Invest 2010; 120:1469.

54. 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.

55. Nakopoulou L, Lazaris AC, Boletis I, et al. The expression of matrix metalloproteinase-11 protein in varioustypes of glomerulonephritis. Nephrol Dial Transplant 2007; 22:109.

56. Lelongt B, Bengatta S, Delauche M, et al. Matrix metalloproteinase 9 protects mice from anti-glomerularbasement membrane nephritis through its fibrinolytic activity. J Exp Med 2001; 193:793.

57. 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.

58. Kitching AR, Turner AL, Wilson GR, et al. IL-12p40 and IL-18 in crescentic glomerulonephritis: IL-12p40 is thekey Th1-defining cytokine chain, whereas IL-18 promotes local inflammation and leukocyte recruitment. J AmSoc Nephrol 2005; 16:2023.

59. Odobasic D, Kitching AR, Semple TJ, et al. Glomerular expression of CD80 and CD86 is required forleukocyte accumulation and injury in crescentic glomerulonephritis. J Am Soc Nephrol 2005; 16:2012.

60. Timoshanko JR, Kitching AR, Semple TJ, et al. A pathogenetic role for mast cells in experimental crescenticglomerulonephritis. J Am Soc Nephrol 2006; 17:150.

61. Lan HY, Bacher M, Yang N, et al. The pathogenic role of macrophage migration inhibitory factor inimmunologically induced kidney disease in the rat. J Exp Med 1997; 185:1455.

62. Hyodo T, Oda T, Kikuchi Y, et al. Voltage-gated potassium channel Kv1.3 blocker as a potential treatment forrat anti-glomerular basement membrane glomerulonephritis. Am J Physiol Renal Physiol 2010; 299:F1258.

63. Nitta K, Horita S, Honda K, et al. Glomerular expression of cell-cycle-regulatory proteins in human crescenticglomerulonephritis. Virchows Arch 1999; 435:422.

64. Smeets B, Uhlig S, Fuss A, et al. Tracing the origin of glomerular extracapillary lesions from parietalepithelial cells. J Am Soc Nephrol 2009; 20:2604.

65. Shirato I, Asanuma K, Takeda Y, et al. Protein gene product 9.5 is selectively localized in parietal epithelialcells of Bowman's capsule in the rat kidney. J Am Soc Nephrol 2000; 11:2381.

66. Barisoni L, Nelson PJ. Collapsing glomerulopathy: an inflammatory podocytopathy? Curr Opin NephrolHypertens 2007; 16:192.

67. Appel D, Kershaw DB, Smeets B, et al. Recruitment of podocytes from glomerular parietal epithelial cells. JAm Soc Nephrol 2009; 20:333.

68. Le Hir M, Keller C, Eschmann V, et al. Podocyte bridges between the tuft and Bowman's capsule: an earlyevent in experimental crescentic glomerulonephritis. J Am Soc Nephrol 2001; 12:2060.

69. Moeller MJ, Soofi A, Hartmann I, et al. Podocytes populate cellular crescents in a murine model ofinflammatory glomerulonephritis. J Am Soc Nephrol 2004; 15:61.

70. Bariéty J, Bruneval P, Meyrier A, et al. Podocyte involvement in human immune crescenticglomerulonephritis. Kidney Int 2005; 68:1109.

71. Bariety J, Hill GS, Mandet C, et al. Glomerular epithelial-mesenchymal transdifferentiation in pauci-immunecrescentic glomerulonephritis. Nephrol Dial Transplant 2003; 18:1777.

72. Thorner PS, Ho M, Eremina V, et al. Podocytes contribute to the formation of glomerular crescents. J AmSoc Nephrol 2008; 19:495.

73. Ding M, Cui S, Li C, et al. Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidlyprogressive glomerulonephritis in mice. Nat Med 2006; 12:1081.

74. Bollée G, Flamant M, Schordan S, et al. Epidermal growth factor receptor promotes glomerular injury andrenal failure in rapidly progressive crescentic glomerulonephritis. Nat Med 2011; 17:1242.

75. Flamant M, Bollée G, Hénique C, Tharaux PL. Epidermal growth factor: a new therapeutic target in glomerulardisease. Nephrol Dial Transplant 2012; 27:1297.

76. Ronconi E, Sagrinati C, Angelotti ML, et al. Regeneration of glomerular podocytes by human renalprogenitors. J Am Soc Nephrol 2009; 20:322.

77. Smeets B, Angelotti ML, Rizzo P, et al. Renal progenitor cells contribute to hyperplastic lesions ofpodocytopathies and crescentic glomerulonephritis. J Am Soc Nephrol 2009; 20:2593.

78. Ng YY, Fan JM, Mu W, et al. Glomerular epithelial-myofibroblast transdifferentiation in the evolution ofglomerular crescent formation. Nephrol Dial Transplant 1999; 14:2860.

79. Bennett WM, Kincaid-Smith P. Macroscopic hematuria in mesangial IgA nephropathy: correlation withglomerular crescents and renal dysfunction. Kidney Int 1983; 23:393.

80. Praga M, Gutierrez-Millet V, Navas JJ, et al. Acute worsening of renal function during episodes ofmacroscopic hematuria in IgA nephropathy. Kidney Int 1985; 28:69.

81. Fogazzi GB, Imbasciati E, Moroni G, et al. Reversible acute renal failure from gross haematuria due toglomerulonephritis: not only in IgA nephropathy and not associated with intratubular obstruction. Nephrol DialTransplant 1995; 10:624.

82. Kriz W, Hähnel B, Hosser H, et al. Pathways to recovery and loss of nephrons in anti-Thy-1 nephritis. J AmSoc Nephrol 2003; 14:1904.

83. 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 8.0

GRAPHICS

Light micrograph showing crescentic

glomerulonephritis

High-power light micrograph in crescentic glomerulonephritis. The

hypercellular circumferential crescent (arrows) is compressing the

glomerular tuft in the center of the glomerulus and closing the

capillary lumens.

Courtesy of Helmut Rennke, MD.

Graphic 68861 Version 4.0

Normal glomerulus

Light micrograph of a normal glomerulus. There are only 1 or 2 cells

per capillary tuft, the capillary lumens are open, the thickness of

the glomerular capillary wall (long arrow) is similar to that of the

tubular basement membranes (short arrow), and the mesangial

cells and mesangial matrix are located in the central or stalk

regions of the tuft (arrows).

Courtesy of Helmut G Rennke, MD.

Graphic 75094 Version 4.0

Light micrograph showing crescentic

glomerulonephritis II

High-power light micrograph showing an active hypercellular crescent

containing fibrin, which has a bright red appearance (long arrow).

Note that the severe inflammatory injury has led to fragmentation of

the glomerular tuft (short arrow) and to creation of a rent in the

capsule (double arrow).

Courtesy of Helmut Rennke, MD.

Graphic 76472 Version 4.0

Normal glomerulus

Light micrograph of a normal glomerulus. There are only 1 or 2 cells

per capillary tuft, the capillary lumens are open, the thickness of

the glomerular capillary wall (long arrow) is similar to that of the

tubular basement membranes (short arrow), and the mesangial

cells and mesangial matrix are located in the central or stalk

regions of the tuft (arrows).

Courtesy of Helmut G Rennke, MD.

Graphic 75094 Version 4.0

Electron micrograph in crescentic glomerulonephritis

Electron micrograph in rapidly progressive glomerulonephritis (RPGN)

showing characteristic breaks in the glomerular basement membrane

(GBM) (arrows). These rents allow fibrin and cellular elements to enter

Bowman's space and initiate crescent formation.

Courtesy of Helmut Rennke, MD.

Graphic 78020 Version 4.0

Electron micrograph of a normal glomerulus

Electron micrograph of a normal glomerular capillary loop showing

the fenestrated endothelial cell (Endo), the glomerular basement

membrane (GBM), and the epithelial cells with its interdigitating

foot processes (arrow). The GBM is thin, and no electron-dense

deposits are present. Two normal platelets are seen in the capillary

lumen.

Courtesy of Helmut Rennke, MD.

Graphic 50018 Version 6.0

Immunofluorescence microscopy showing fibrin

deposition

Immunofluorescence microscopy showing intense deposition (bright

areas in the upper right portion of the glomerulus) of fibrin within a

circumferential crescent surrounding the glomerular tuft in any form of

crescentic or rapidly progressive glomerulonephritis, including that due

to anti-GBM antibody disease.

GBM: glomerular basement membrane.

Courtesy of Helmut Rennke, MD.

Graphic 57096 Version 3.0

The glomerular filtration barrier

Blood enters the glomerular capillaries and is filtered across the endothelium and the

glomerular basement membrane and through the filtration slits between podocyte foot

processes to produce the primary urine filtrate. In healthy glomeruli, this barrier restricts the

passage of macromolecules. CatL, the expression of which is increased in human proteinuric

diseases and in an LPS-induced mouse model of proteinuria, causes proteinuria and foot

process effacement through cleavage of the GTPase dynamin, an actin-binding protein. The

same effects are induced by gene delivery into mice of dynK44A—a mutant form of dynamin

that does not bind GTP—or of the CatL-cleaved product of dynamin (p40). Conversely, gene

delivery into proteinuric mice of dynL356Q and dynR725A, two CatL-resistant dynamin

mutants, reverses proteinuria and foot process effacement.

Reproduced with permission from: Ronco P. Proteinuria: is it all in the foot?. J Clin Invest 2007;

117:2079. Copyright ©2007 American Society for Clinical Investigation.

Graphic 70765 Version 3.0

Disclosures: Pierre Ronco, MD, PhD Nothing to disclose. Richard J Glassock, MD, MACPConsultant/Advisory Boards: Bristol-Myers-Squibb [lupus nephritis (Abatacept)]; Abbvie [lupus nephritis(no product)]; Sanofi-Genzyme [FSGS (Fresolimumab)]; Chemocentryx [diabetes (CCR2 antagonist)];QuestCor [nephrotic syndrome (ACTH Gel)]; Eli Lily [kidney disease (no product)]; Astellas [kidney disease(Tacrolimus)]. Speaker's Bureau: Genentech [vasculitis (Rituximab)]. Other Financial Interest: Karger[editor]; AAKP [patients w ith kidney disease]; American Renal Associates [dialysis]. EquityOw nership/Stock Options: Reata Stock [diabetes]. Fernando C Fervenza, MD, PhDGrant/Research/Clinical Trial Support: Genentech [Membranous nephropathy, f ibrillary glomerulonephritis(Rituximab)]; Questcor Pharmaceutic [Membranous nephropathy, IgA nephropathy (ACHTar gel)]; BiogenIdec [Lupus nephritis (BIIB023)]; Sanofi [FSGS (Fresolimumab)]. John P Forman, MD, MSc Nothing todisclose.

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