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

glomerulonephritis
Literature review current through: Feb 2016. | This topic last updated: May 13, 2014.
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 most commonly characterized morphologically by
extensive crescent formation [1]. This histologic finding is a common finding in the elderly presenting with
acute nephritis [2,3].
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 and may even undergo a remission [4].
PATHOGENESIS OF CRESCENT FORMATION Crescent formation appears to represent a
nonspecific response to severe injury to the glomerular capillary wall [5]. 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 [6,7]. 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 [6]. 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 three broad mechanisms of glomerular injury [1]:
Anti-GBM antibody disease The pathogenesis, diagnosis, and treatment of this disorder are
discussed separately. (See "Treatment of anti-GBM antibody (Goodpasture's) disease".)
Immune complex Immune complex RPGN refers to the presence of immune deposits in the glomeruli.
In most cases, the serologic and histologic findings will point to the underlying disease, such as
mesangial IgA deposits in IgA nephropathy, antistreptococcal antibodies and subepithelial humps in
postinfectious glomerulonephritis, antinuclear antibodies, a "full house" immunofluorescence staining for
IgG, IgA, IgM, C3 and C1q, mesangial plus 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'.)

Pauci-immune Pauci-immune RPGN refers to a necrotizing glomerulonephritis in which there are 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 (GPA) or
microscopic polyangiitis (MPA) [8,9]. 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 and microscopic
polyangiitis", section on 'Renal manifestations'.)
Some studies suggest that autoantibodies directed against lysosome-associated membrane protein 2
(LAMP-2) may be present in over 90 percent of ANCA-positive patients with pauci-immune necrotizing
RPGN, as well as in patients with ANCA-negative pauci-immune glomerulonephritis. Others have been
unable to confirm this result. (See "Pathogenesis of granulomatosis with polyangiitis 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 are 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 and microscopic polyangiitis" and "Clinical spectrum of
antineutrophil cytoplasmic antibodies".)
Some patients have features of both ANCA-positive RPGN and anti-GBM disease. This has also been
called "double-antibody" positive disease.
Idiopathic The term idiopathic RPGN is applied to two settings: an immune complex disease that does
not fit into any of the identifiable categories, and a pauci-immune 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 [4]. Occasional patients 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 [12]. 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 antibody-negative RPGN later develop the
characteristic pulmonary manifestations of ANCA-positive disease (eg, upper airway involvement) [8],
strongly suggest that antibody-negative RPGN is pathogenetically part of the ANCA-positive disorders
[13].
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 [5]:
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 <13 percent for immune complex crescentic disease, respectively
Patients with anti-GBM antibody disease may also have pulmonary hemorrhage and hemoptysis due to
antibodies directed against the alveolar basement membranes. The bleeding may occur over a prolonged
period, leading to anemia and iron deficiency. Although the combination of glomerulonephritis and
hemoptysis should suggest this disorder, similar findings can be seen in other causes of RPGN including
granulomatosis with polyangiitis (GPA), which is more common and in which there is also direct lung
involvement, crescentic lupus nephritis, and any glomerular disease complicated by marked fluid overload
and pulmonary edema. (See "Differential diagnosis and evaluation of glomerular disease", section on
'Acute glomerulonephritis and pulmonary hemorrhage'.)
EVALUATION AND DIAGNOSIS An accurate and urgent diagnosis is essential in the patient
presenting with clinical findings suggestive of RPGN. Patients should undergo appropriate serologic tests
(ordered on a stat or rush basis) and, when indicated, a renal biopsy. Serologic tests include ANCA, antiGBM antibodies, complement component assays antinuclear antibodies, and others as indicated from the
clinical history, examination, and biopsy results. (See "Clinical spectrum of antineutrophil cytoplasmic
antibodies" and "Pathogenesis and diagnosis of anti-GBM antibody (Goodpasture's) disease".)
TREATMENT Untreated RPGN typically progresses to end-stage renal disease over a period of weeks
to a few months. However, patients with fewer crescents may have a more protracted, not so rapidly
progressive course [4].
Many of the older studies examining treatment in RPGN with pulse corticosteroids, cyclophosphamide,
and plasmapheresis are difficult to interpret because they were performed at a time before it was possible
to distinguish among the different types of RPGN. Nevertheless, these studies demonstrated that
conventional doses of oralprednisone, given alone or in combination with azathioprine, usually had little
beneficial effect [1].
As a result, the therapy of most patients with RPGN involves pulse methylprednisolone followed by daily
oral prednisone, oral or intravenous cyclophosphamide orrituximab, and, in some settings,
plasmapheresis. 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 with the above modalities 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) and consideration of
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 withpolyangiitis/microscopic polyangiitis
spectrum and patients are treated with the same regimens used for ANCA-positive disease.
(See "Initial immunosuppressive therapy in granulomatosis with polyangiitis and microscopic
polyangiitis".)
ANCA plus anti-GBM disease. (See "Initial immunosuppressive therapy in granulomatosis with
polyangiitis and microscopic polyangiitis" and "Treatment of anti-GBM antibody (Goodpasture's)
disease".)
Immune complex RPGN due to IgA nephropathy, lupus, membranous nephropathy with crescentic
transformation, cryoglobulinemia, and others. (See "Treatment and prognosis of IgA
nephropathy" and "Henoch-Schnlein purpura (immunoglobulin A vasculitis):
Management" 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 are no randomized controlled trials to
suggest that aggressive immunosuppressive therapy is beneficial in this condition, but some experts
recommend glucocorticoids in those patients with severe crescentic RPGN [14-16].
(See "Poststreptococcal glomerulonephritis".)
For apparently idiopathic immune complex RPGN, which is 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 and
ANCA-positive RPGN. (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 10 th 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:
Anti-glomerular basement membrane (GBM) antibody disease refers to glomerular disease caused
by anti-GBM antibodies.
Immune complex RPGN refers to glomerulonephritis associated with deposition of immune
complexes in the glomeruli. In most cases, the serologic and histologic findings point to an
underlying disease, such as dominant 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.
Pauci-immune RPGN refers to RPGN, in association with small vessel vasculitis, a necrotizing
glomerulonephritis with few or no immune deposits by immunofluorescence and electron
microscopy. The vast majority of patients with renal-limited vasculitis are ANCA positive, and many
have or will develop the systemic symptoms of a vasculitis. Patients with ANCA-negative, pauciimmune RPGN are also considered part of this spectrum. Some patients are positive for both ANCA
and anti-GBM antibodies.
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 (GPA), microscopic polyangiitis (MPA), and
lupus nephritis 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 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.)