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

Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis
Literature review current through: Jan 2024.
This topic last updated: Sep 26, 2022.

INTRODUCTION — Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome manifested by features of glomerular disease in the urinalysis and by progressive loss of kidney function over a comparatively short period of time (days, weeks, or a few months). It is most commonly characterized morphologically by extensive crescent formation (extracapillary proliferation in Bowman's space) [1]. This histologic finding is a common finding in the older adult presenting with acute nephritis [2,3]. However, RPGN can present in any age group, including children [4].

The severity of the disease is related to the nature and type of immunologic process causing the disease and in part to the degree of crescent formation. Patients with circumferential crescents in more than 80 percent of the glomeruli tend to present with advanced kidney failure that may not respond well to therapy (picture 1). 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 [5]. Some pathologists restrict the term crescentic glomerulonephritis (GN) to those biopsies with over 50 percent crescents, while others use the term for biopsies with 10 to 50 percent crescents as well. In general, biopsies with less than 10 percent crescents are not called crescentic and do not have an RPGN course or prognosis.

PATHOGENESIS OF CRESCENT FORMATION — Crescent formation appears to represent a nonspecific response to severe injury to the glomerular capillary wall [6]. Rents (focal gaps or discontinuities of the capillary wall) 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 (Th1 and Th17 CD4+ T cells), and the release of proinflammatory cytokines, such as interleukin-1 and tumor necrosis factor-alpha [7,8] and procoagulant and fibrinolytic inhibitory factors [9-11]. Thus, crescents may be seen with any form of inflammatory glomerular disease with severe damage to the glomerular capillary walls. These include immune complex diseases (such as lupus nephritis, IgA nephropathy and IgA vasculitis, and postinfectious glomerulonephritis [GN]) as well as anti-glomerular basement membrane (GBM) disease and glomerulonephritis associated with antineutrophil cytoplasmic antibody (ANCA) vasculitis. Many of these diseases can often be diagnosed from the history, clinical findings, and laboratory testing. Others require histologic findings in select involved organs. A number of them have typical immunofluorescence and electron microscopic findings. (See "Mechanisms of glomerular crescent formation".)

The early stage of active inflammation is often followed by the development of fibrocellular and fibrous crescents in Bowman's space [7,10]. 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 in the context of crescentic glomerulonephritis (GN) is usually due to one of three broad mechanisms of glomerular injury [1]: anti-GBM disease, immune complex-mediated injury, and pauci-immune necrotizing and crescentic GN.

The frequency of the various forms of crescentic GN in native biopsies depends upon the age of the patient. In one series of over 630 patients, 60 percent had pauci-immune crescentic GN, 24 percent had immune complex-mediated GN, and 15 percent had anti-GBM disease [6]. Among patients between 1 and 20 years old, 42 percent had pauci-immune crescentic GN, and 45 percent had immune complex-mediated GN. By contrast, among patients over 60 years old, 80 percent had pauci-immune crescentic GN, and only 6 percent had immune complex-mediated GN.

Anti-GBM disease — The pathogenesis, diagnosis, and treatment of this disorder are discussed separately. (See "Anti-GBM (Goodpasture) disease: Treatment and prognosis".)

Immune complex-mediated injury — Immune complex crescentic GN is defined by 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 and glomerular capillary wall immunoglobulin A (IgA) deposits in IgA nephropathy and IgA vasculitis; antistreptococcal antibodies and subepithelial humps in postinfectious GN; antinuclear antibodies, a "full house" immunofluorescence staining for immunoglobulin G (IgG), IgA, immunoglobulin M (IgM), C3 and C1q, with mesangial plus subendothelial deposits in lupus nephritis; and circulating cryoglobulins and intraluminal "thrombi" in mixed cryoglobulinemia.

Crescent formation can also rarely be superimposed upon or associated with underlying membranous nephropathy. The mechanism of crescent formation remains unclear, but some patients are antineutrophil cytoplasmic antibody (ANCA) positive and others have circulating anti-glomerular basement membrane (GBM) antibodies. Rapidly progressive crescentic GN is also rarely seen in a variety of other glomerular disorders such as fibrillary GN and C3 glomerulopathy [12,13]. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Crescentic glomerulonephritis'.)

Pauci-immune necrotizing and crescentic GN — This category refers to a necrotizing GN 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, and many have or will develop the systemic symptoms of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) [14,15]. Patients with ANCA-negative, pauci-immune crescentic GN limited to the kidney (renal-limited vasculitis) are considered part of this spectrum and may have similar clinical features, kidney biopsy findings, and prognosis. However, one study found that ANCA-negative pauci-immune crescentic GN may be due to abnormalities of the alternative pathway of complement [16]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis", section on 'Kidney involvement'.)

Some studies suggest that antibodies directed against lysosome-associated membrane protein 2 (LAMP-2) may be present in over 90 percent of ANCA-positive patients with pauci-immune necrotizing crescentic GN, as well as in patients with ANCA-negative pauci-immune crescentic GN. Others have been unable to confirm this result. (See "Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis".)

Some patients with pauci-immune crescentic GN 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 pauci-immune crescentic GN.

The pathogenesis, diagnosis, and treatment of ANCA-positive crescentic GN are also discussed separately. Some cases of ANCA-positive disease are induced by drugs (eg, propylthiouracil, hydralazine, allopurinol, penicillamine, minocycline, rifampicin, levamisole). Most such patients have circulating anti-myeloperoxidase (MPO) ANCA antibodies, but some have both high-titer MPO and PR3 ANCA antibodies.

(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy".)

(See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)

Some patients have features of both ANCA-positive RPGN and anti-GBM disease. This has also been called "double-antibody" positive disease [17]. Other ANCA-positive crescentic GN patients will have positive antinuclear antibody or other positive lupus serology. Some of these patients with systemic lupus erythematosus (SLE) will have a necrotizing and crescentic GN with only limited immunofluorescence and electron microscopic evidence of immune complex deposition [18].

Idiopathic — The term idiopathic RPGN with crescentic GN is often 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 [19], while the latter accounts for less than 5 percent of cases of crescentic GN.

CLINICAL PRESENTATION — The presenting complaints in RPGN with crescentic GN may be a severe nephritic syndrome similar to that seen in severe postinfectious glomerulonephritis (GN): the acute onset of macroscopic hematuria, decreased urine output, hypertension, and edema. More commonly, however, RPGN has an insidious onset with the initial symptoms being fatigue or edema [1].

Kidney function impairment 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 kidney function impairment [5]. Rare patients have no hematuria [20]. Why this occurs is not well understood but the absence of hematuria has also been described in other types of GN. Hypertension is not unusual but may be absent or mild. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

Systemic complaints, including extrarenal organ involvement, are common in patients with pauci-immune crescentic GN. Although not observed in all studies [21], 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 crescentic GN, of whom 27 percent were ANCA negative [21]. 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) [14], strongly suggest that antibody-negative RPGN is pathogenetically part of the ANCA-positive disorders [22].

The relative severity of disease at presentation tends to vary with the underlying cause. In a series from 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 [6]:

9.7 mg/dL (857 micromol/L) and 85 percent for anti-GBM 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 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 GN and hemoptysis should suggest this disorder, similar findings can be seen in other causes of crescentic GN including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), which are far more common and in which there is also direct lung involvement; crescentic lupus nephritis; and any glomerular disease complicated by pulmonary inflammation, such as pulmonary abscess with immune complex GN. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

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, unless contraindicated, a kidney biopsy. Serologic tests include ANCA, anti-GBM antibodies, complement component assays, antinuclear antibodies, cryoglobulins, and others as indicated from the clinical history, examination, and biopsy results.

(See "Glomerular disease: Evaluation and differential diagnosis in adults".)

(See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)

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

TREATMENT — Untreated RPGN typically progresses to end-stage kidney disease over a period of days to weeks to a few months. However, patients with fewer crescents (<50 percent of glomeruli affected by crescents on initial biopsy) may have a more protracted, not so rapidly progressive course [5].

Many of the older studies examining treatment in RPGN with pulse glucocorticoids, 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 oral prednisone, given alone or in combination with azathioprine, usually had only a marginal beneficial effect [1].

As a result, the initial therapy of most patients with RPGN involves pulse methylprednisolone followed by daily oral prednisone, oral or intravenous cyclophosphamide or rituximab, and, in some settings, plasmapheresis. Early diagnosis with kidney biopsy and serologic testing and early initiation of appropriate therapy is essential to minimize the degree of irreversible kidney injury.

Empiric therapy should be initiated in patients with severe disease, particularly if either kidney 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 kidney biopsy that is performed soon after initiating empiric therapy.

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

Anti-GBM disease. (See "Anti-GBM (Goodpasture) disease: Treatment and prognosis".)

ANCA-positive pauci-immune crescentic disease. In addition, pauci-immune crescentic disease that is ANCA negative is considered to be part of the granulomatosis with polyangiitis/microscopic polyangiitis spectrum and patients are treated with the same regimens used for ANCA-positive disease. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy".)

ANCA plus anti-GBM disease. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Double-positive ANCA and anti-GBM disease'.)

Immune complex crescentic disease due to IgA nephropathy, lupus, membranous nephropathy with crescentic transformation, cryoglobulinemia, and others.

(See "IgA nephropathy: Treatment and prognosis".)

(See "IgA vasculitis (Henoch-Schönlein purpura): Management".)

(See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis".)

(See "Mixed cryoglobulinemia syndrome: Treatment and prognosis".)

Patients with poststreptococcal glomerulonephritis (GN) and some other postinfectious glomerulonephritides 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 [23-25]. (See "Poststreptococcal glomerulonephritis".)

For apparently idiopathic immune complex RPGN, which is a rare disease [19], there are no clearly useful data [26]. 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 or ANCA-positive RPGN. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)

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 education: Glomerular disease (The Basics)")

SUMMARY AND RECOMMENDATIONS

Overview – Rapidly progressive glomerulonephritis (RPGN) is characterized morphologically by extensive crescent formation and clinically by progression to end-stage kidney disease in most untreated patients within a period of weeks to months. (See 'Introduction' above.)

Types of crescentic glomerulonephritis – RPGN is usually due to one of three disorders, which reflect different mechanisms of glomerular injury:

Anti-glomerular basement membrane (GBM) disease refers to glomerular disease caused by anti-GBM antibodies. Many such patients will have pulmonary involvement due to cross-reaction of the antibodies with membrane components of the pulmonary capillaries.

Immune complex RPGN refers to glomerulonephritis (GN) 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 IgA deposits in IgA nephropathy, antistreptococcal antibodies and subepithelial humps in postinfectious GN, 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 GN with few or no immune deposits by immunofluorescence and electron microscopy. The vast majority of patients with renal-limited vasculitis are antineutrophil cytoplasmic antibody (ANCA) positive, and many have or will develop the systemic symptoms of a vasculitis. Patients with ANCA-negative, pauci-immune RPGN have been considered part of this spectrum, but in some patients data suggest they may be due to abnormalities of the alternative pathway of complement.

Some patients are positive for both ANCA and anti-GBM antibodies and some for both ANCA and antinuclear/anti-DNA antibodies. (See 'Types of crescentic GN' above.)

Clinical presentation – The presenting complaints in RPGN may be of a severe nephritic syndrome similar to those in severe postinfectious GN: the acute onset of macroscopic hematuria, decreased urine output, hypertension, and edema. In other patients, RPGN has a more insidious onset with the initial symptoms being fatigue or edema. Kidney function impairment is present at diagnosis in almost all cases. The urinalysis typically reveals hematuria, red cell and other casts, and a variable degree of proteinuria. (See 'Clinical presentation' above.)

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.

Diagnosis – An accurate and urgent diagnosis is essential in the patient presenting with clinical findings suggestive of RPGN. Patients should undergo appropriate serologic assays and, unless contraindicated, a kidney biopsy. These serologic tests include ANCA, anti-GBM antibodies, antinuclear antibodies, and others as indicated from the biopsy results. (See 'Evaluation and diagnosis' above.)

Treatment – Early diagnosis with kidney biopsy and serologic testing and early initiation of appropriate therapy is essential to minimize the degree of irreversible kidney injury. Empiric therapy may be begun in patients with severe disease, particularly if either kidney biopsy or interpretation of the biopsy will be delayed. More specific therapy can be given once the diagnosis is established. (See 'Treatment' above.)

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