Overview of the Classification and Treatment of Rapidly Progressive (Crescentic) Glomerulonephritis

Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Aug 2013. | This topic last updated: oct 31, 2012.

INTRODUCTION Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome manifested

by features of glomerular disease in the urine and by progressive loss of renal function over a

comparatively short period of time (days, weeks or months). It is characterized morphologically by

extensive crescent formation [1]. This histologic finding is a common finding in the elderly presenting

with acute nephritis [2].

The severity of the disease is in part related to the degree of crescent formation: patients with

circumferential crescents in more than 80 percent of the glomeruli tend to present with advanced renal

failure that may not respond well to therapy (picture 1A-E). By comparison, patients with crescents in

less than 50 percent of the glomeruli, particularly if the crescents are noncircumferential, typically follow

a more indolent course or in rare cases even undergo a remission [3].

PATHOGENESIS OF CRESCENT FORMATION Crescent formation appears to represent a

nonspecific response to severe injury to the glomerular capillary wall [4]. Rents are induced in the

glomerular capillary wall, resulting in the movement of plasma products, including fibrinogen, into

Bowman's space with subsequent fibrin formation, the influx of macrophages and T cells, and the

release of proinflammatory cytokines, such as interleukin-1 and tumor necrosis factor-alpha [5,6]. Thus,

crescents may be seen with any form of severe glomerular disease, including lupus nephritis and

postinfectious glomerulonephritis, disorders that can usually be diagnosed from the history and typical

immunofluorescence and electron microscopic findings. (See "Mechanisms of glomerular crescent

formation".)

The stage of active inflammation is often followed by the development of fibrocellular and fibrous

crescents [5]. Collagen deposition is due to fibroblast proliferation that is driven by fibroblast growth

factors. Transforming growth factor-beta is also thought to play an important role. This transition is

important clinically because fibrous crescents represent a stage of the disease that is not likely to

respond to immunosuppressive therapy.

TYPES OF CRESCENTIC GN The term RPGN refers to crescentic glomerulonephritis that is usually

due to one of four disorders, which reflect different mechanisms of glomerular injury [1]:

Type 1: Anti-GBM antibody disease Type 1 refers to anti-glomerular basement membrane (GBM)

antibody disease. The pathogenesis, diagnosis, and treatment of this disorder are discussed

separately. (See "Treatment of anti-GBM antibody (Goodpasture's) disease".)

Type 2: Immune complex Type 2 refers to immune complex RPGN, in which the nature of the

immune deposits is not diagnostic of a specific disorder (which is rare). In most cases, however, the

serologic and histologic findings will point to an underlying systemic disease, such as mesangial IgA

deposits in IgA nephropathy, antistreptococcal antibodies and subepithelial humps in postinfectious

Official reprint from UpToDate

www.uptodate.com 2013 UpToDate

AuthorsGerald B Appel, MDAndre A Kaplan, MD

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

Deputy EditorJohn P Forman, MD, MSc

Pgina 1 de 6Overview of the classification and treatment of rapidly progressive (crescentic) glo...

16/09/2013http://www.uptodate.com/contents/overview-of-the-classification-and-treatment-of-ra...

glomerulonephritis, antinuclear antibodies and subendothelial deposits in lupus nephritis, and circulating

cryoglobulins and intraluminal "thrombi" in mixed cryoglobulinemia.

Crescent formation can also rarely be superimposed upon underlying membranous nephropathy. The

mechanism of crescent formation remains unclear, but some patients are antineutrophil cytoplasmic

antibody (ANCA)-positive. (See "Causes and diagnosis of membranous nephropathy", section

on 'Crescentic glomerulonephritis'.)

Type 3: Pauci-immune Type 3 refers to pauci-immune RPGN, in which there is a necrotizing

glomerulonephritis but few or no immune deposits by immunofluorescence or electron microscopy. The

majority of patients with renal-limited vasculitis are ANCA-positive, with 75 to 80 percent having

myeloperoxidase (MPO)-ANCA, and many have or will develop the systemic symptoms of

granulomatosis with polyangiitis (Wegener's)or microscopic polyangiitis [7,8]. Patients with ANCA-

negative, pauci-immune RPGN are considered part of this spectrum, and may have similar clinical

features, renal biopsy findings, and prognosis. (See "Clinical manifestations and diagnosis of

granulomatosis with polyangiitis (Wegener's) and microscopic polyangiitis", section on 'Renal disease'.)

A subtype of ANCA, antibodies directed against lysosome associated membrane protein 2 (LAMP-2),

are present in over 90 percent of ANCA-positive patients with pauci-immune necrotizing RPGN [9].

Initial studies in animal models suggest that anti-LAMP-2 antibodies may play a role in the

pathogenesis of the glomerulonephritis. (See "Pathogenesis of granulomatosis with polyangiitis

(Wegeners) and related vasculitides", section on 'Anti-LAMP-2 antibodies'.)

Some patients with pauci-immune RPGN have scattered small immune deposits in the mesangium and

glomerular capillary wall. In the proper clinical setting with a positive ANCA, this finding does not

preclude the diagnosis of type 3 RPGN.

The pathogenesis, diagnosis, and treatment of this condition is also discussed separately. Some cases

of MPO-ANCA positive disease are induced by drugs (eg, propylthiouracil, hydralazine, allopurinol,

penicillamine, minocycline). (See "Initial immunosuppressive therapy in granulomatosis with polyangiitis

(Wegener's) and microscopic polyangiitis" and "Clinical spectrum of antineutrophil cytoplasmic

antibodies".)

Type 4: Double-antibody positive disease Type 4 has features of both types 1 and 3. This is also

called "double-antibody" positive disease.

Idiopathic The term idiopathic RPGN is applied to two settings: an immune complex (type 2)

disease that does not fit into any of the identifiable categories; and a pauci-immune (type 3) disease

that is ANCA-negative. The former is rare [10], while the latter accounts for less than 5 percent of cases

of crescentic GN.

CLINICAL PRESENTATION The presenting complaints in RPGN may be similar to those in severe

postinfectious glomerulonephritis: the acute onset of macroscopic hematuria, decreased urine output,

and edema. More commonly, however, RPGN has an insidious onset with the initial symptoms being

fatigue or edema [1].

Renal insufficiency is present at diagnosis in almost all cases, with the plasma creatinine concentration

often exceeding 3 mg/dL (264 micromol/L). The urinalysis typically reveals dysmorphic hematuria, red

cell and other casts, and a variable degree of proteinuria. The marked reduction in glomerular filtration

rate usually limits the rate of protein filtration; the nephrotic syndrome is unusual and is most likely to

occur in patients with less severe renal insufficiency [3]. Occasional patients (3 of 23 in the largest

series) have no hematuria [11]. Why this occurs is not well understood but the absence of hematuria

has also been described in other types of glomerulonephritis. (See "Diagnosis and classification of renal

disease in systemic lupus erythematosus", section on 'Silent lupus nephritis' and "Differential diagnosis

and evaluation of glomerular disease", section on 'Limitations of this classification'.)

Systemic complaints, including extrarenal organ involvement, are common in patients with pauci-



immune RPGN. Although not observed in all studies [12], most reports have found a similar incidence

of systemic complaints in those with or without ANCA. One retrospective study, for example, evaluated

the presentation and outcome in 141 patients with pauci-immune RPGN, of whom 27 percent were

ANCA negative [13]. Other than a higher incidence of upper airway disease in ANCA positive patients

(60 versus 19 percent), a similar percentage of ANCA negative and positive patients with RPGN

presented with involvement of the lower airway, musculoskeletal system, skin, and/or nervous system.

These findings, as well as the observation that some patients with apparent nonantibody RPGN later

develop the characteristic pulmonary manifestations of ANCA positive disease (eg, upper airway

involvement) [7], strongly suggest that nonantibody RPGN is pathogenetically part of the ANCA positive

disorders [14].

The relative severity of disease at presentation tends to vary with the underlying cause. At the

University of North Carolina, for example, the average plasma creatinine concentration and the

proportion with >50 percent glomerular crescents at the time of diagnosis were [4]:

9.7 mg/dL (857 micromol/L) and 85 percent for anti-GBM antibody disease, respectively

6.5 mg/dL (575 micromol/L) and 50 percent for ANCA positive disease, respectively

4.9 mg/dL (433 micromol/L) and

plasmapheresis, especially if the patient has hemoptysis. This regimen will not alter the histologic

abnormalities observed with a renal biopsy that is performed soon after initiating empiric therapy.

More specific therapy can be given once the diagnosis is established:

Anti-GBM disease. (See "Treatment of anti-GBM antibody (Goodpasture's) disease".)

ANCA-positive pauci-immune RPGN disease. In addition, pauci-immune RPGN that is ANCA

negative is considered to be part of the granulomatosis with polyangiitis (Wegener's)/microscopic

polyangiitis spectrum and patients are treated with the same regimen used for ANCA-positive

disease. (See "Initial immunosuppressive therapy in granulomatosis with polyangiitis

(Wegener's) and microscopic polyangiitis".)

ANCA plus anti-GBM disease. (See "Initial immunosuppressive therapy in granulomatosis with

polyangiitis (Wegener's) and microscopic polyangiitis" and "Treatment of anti-GBM antibody

(Goodpasture's) disease".)

Type 2 RPGN due to IgA nephropathy, lupus, membranous nephropathy, cryoglobulinemia, and

others. (See "Treatment and prognosis of IgA nephropathy" and "Management of Henoch-

Schnlein purpura (IgA vasculitis)" and "Therapy of diffuse or focal proliferative lupus nephritis"

and "Treatment of the mixed cryoglobulinemia syndrome".)

Patients with poststreptococcal glomerulonephritis typically recover spontaneously, although

recovery may not be complete, particularly in adults. There is no evidence that aggressive

immunosuppressive therapy is beneficial [15,16]. (See "Poststreptococcal glomerulonephritis".)

For apparently idiopathic type 2 RPGN, which is now a rare disease [10], there are no clearly

useful data [17]. Such patients should be carefully evaluated both prior to and during therapy for

possible underlying infection as the cause. We use a regimen similar to that in lupus nephritis.

(See "Therapy of diffuse or focal proliferative lupus nephritis".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The

Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at

the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have

about a given condition. These articles are best for patients who want a general overview and who

prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more

sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and

are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-

mail these topics to your patients. (You can also locate patient education articles on a variety of

subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient information: Glomerular disease (The Basics)")

SUMMARY AND RECOMMENDATIONS Rapidly progressive glomerulonephritis (RPGN) is

characterized morphologically by extensive crescent formation and clinically by progression to end-

stage renal disease in most untreated patients within a period of weeks to months.

Types RPGN is usually due to one of three disorders, which reflect different mechanisms of

glomerular injury:

Type 1: Anti-GBM antibody disease Type 1 refers to anti-glomerular basement membrane

(GBM) antibody disease.

Type 2: Immune complex Type 2 refers to immune complex RPGN. In most cases, the



serologic and histologic findings point to an underlying disease, such as mesangial IgA deposits

in IgA nephropathy, antistreptococcal antibodies and subepithelial humps in postinfectious

glomerulonephritis, antinuclear antibodies and subendothelial deposits in lupus nephritis, and

circulating cryoglobulins and intraluminal "thrombi" in mixed cryoglobulinemia.

Type 3: Pauci-immune Type 3 refers to pauci-immune RPGN, in which there is a necrotizing

glomerulonephritis but few or no immune deposits by immunofluorescence or electron

microscopy. The majority of patients with renal-limited vasculitis are ANCA-positive, with 75 to 80

percent having myeloperoxidase (MPO)-ANCA, and many have or will develop the systemic

symptoms of a vasculitis. Patients with ANCA-negative, pauci-immune RPGN are also

considered part of this spectrum.

Clinical presentation The presenting complaints in RPGN may be similar to those in severe

postinfectious glomerulonephritis: the acute onset of macroscopic hematuria, decreased urine output,

and edema. More commonly, however, RPGN has an insidious onset with the initial symptoms being

fatigue or edema.

Renal insufficiency is present at diagnosis in almost all cases. The urinalysis typically reveals

hematuria, red cell and other casts, and a variable degree of proteinuria.

Patients with anti-GBM antibody disease may also have pulmonary hemorrhage and hemoptysis due to

antibodies directed against the alveolar basement membranes. Similar findings can be seen in other

causes of RPGN including granulomatosis with polyangiitis (Wegener's), in which there is also direct

lung involvement, and any glomerular disease complicated by marked fluid overload and pulmonary

edema. Systemic complaints, including extrarenal organ involvement, are common in patients with

pauci-immune RPGN, with or without ANCA positivity.

Evaluation and diagnosis An accurate and urgent diagnosis is essential in the patient presenting

with clinical findings suggestive of RPGN. Patients should undergo renal biopsy and appropriate

serologic assays. These include ANCA, anti-GBM antibodies, antinuclear antibodies, and others as

indicated from the biopsy results.

Therapy Early diagnosis with renal biopsy and serologic testing and early initiation of appropriate

therapy is essential to minimize the degree of irreversible renal injury. Empiric therapy may be begun in

patients with severe disease, particularly if either renal biopsy or interpretation of the biopsy will be

delayed.

Empiric initial therapy consists of intravenous pulse methylprednisolone (500 to 1000 mg/day for three

days), oral or intravenous cyclophosphamide, and consideration of plasmapheresis, especially if the

patient has hemoptysis or anti-GBM antibody disease. (See "Treatment of anti-GBM antibody

(Goodpasture's) disease" and "Initial immunosuppressive therapy in granulomatosis with polyangiitis

(Wegener's) and microscopic polyangiitis".)

More specific therapy can be given once a diagnosis of one of the following disorders is established:

Anti-GBM disease

ANCA-positive pauci-immune RPGN disease

ANCA-negative pauci-immune RPGN disease

ANCA plus anti-GBM disease

Type 2 RPGN due to an identified disorder

Apparently idiopathic type 2 RPGN, which is rarely observed

(See 'Treatment' above.)

Use of UpToDate is subject to the Subscription and License Agreement.



REFERENCES

1. Couser WG. Rapidly progressive glomerulonephritis: classification, pathogenetic mechanisms, and therapy. Am J Kidney Dis 1988; 11:449.

2. Nair R, Bell JM, Walker PD. Renal biopsy in patients aged 80 years and older. Am J Kidney Dis 2004; 44:618.

3. Baldwin DS, Neugarten J, Feiner HD, et al. The existence of a protracted course in crescentic glomerulonephritis. Kidney Int 1987; 31:790.

4. Jennette JC. Rapidly progressive crescentic glomerulonephritis. Kidney Int 2003; 63:1164.

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

6. Bonsib SM. Glomerular basement membrane necrosis and crescent organization. Kidney Int 1988; 33:966.

7. Woodworth, TG, Abuelo, JG, Austin, HA III, Esparza, A. Severe glomerulonephritis with late emergence of classic Wegener's granulomatosis. Report of 4 cases and review of the literature. Medicine (Baltimore) 1987; 66:181.

8. Seo P, Stone JH. The antineutrophil cytoplasmic antibody-associated vasculitides. Am J Med

2004; 117:39.

9. Kain R, Exner M, Brandes R, et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat Med 2008; 14:1088.

10. Angangco R, Thiru S, Esnault VL, et al. Does truly 'idiopathic' crescentic glomerulonephritis exist? Nephrol Dial Transplant 1994; 9:630.

11. Bruns FJ, Adler S, Fraley DS, Segel DP. Long-term follow-up of aggressively treated idiopathic rapidly progressive glomerulonephritis. Am J Med 1989; 86:400.

12. Chen M, Yu F, Wang SX, et al. Antineutrophil cytoplasmic autoantibody-negative Pauci-immune crescentic glomerulonephritis. J Am Soc Nephrol 2007; 18:599.

13. Hedger N, Stevens J, Drey N, et al. Incidence and outcome of pauci-immune rapidly progressive glomerulonephritis in Wessex, UK: a 10-year retrospective study. Nephrol Dial Transplant 2000; 15:1593.

14. Falk RJ, Hogan S, Carey TS, Jennette JC. Clinical course of anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and systemic vasculitis. The Glomerular Disease Collaborative Network. Ann Intern Med 1990; 113:656.

15. Roy S 3rd, Murphy WM, Arant BS Jr. Poststreptococcal crescenteric glomerulonephritis in children: comparison of quintuple therapy versus supportive care. J Pediatr 1981; 98:403.

16. Raff A, Hebert T, Pullman J, Coco M. Crescentic post-streptococcal glomerulonephritis with nephrotic syndrome in the adult: is aggressive therapy warranted? Clin Nephrol 2005; 63:375.

17. Zuner I, Bach D, Braun N, et al. Predictive value of initial histology and effect of plasmapheresis on long-term prognosis of rapidly progressive glomerulonephritis. Am J Kidney Dis 2002; 39:28.

Topic 3113 Version 18.0

2013 UpToDate, Inc. All rights reserved. | Subscription and License Agreement | Release: 21.8 - C21.121Licensed to: Consorci Sanitati del Maresme | Support Tag: [1105-85.52.244.57-FF9A9B30A9-I3867.14]



Overview of the Classification and Treatment of Rapidly Progressive (Crescentic) Glomerulonephritis

Documents

Transcript of Overview of the Classification and Treatment of Rapidly Progressive (Crescentic) Glomerulonephritis