Year : 2000 | Volume
: 11 | Issue : 3 | Page : 353--361
Diagnosis and Management of Crescentic Glomerulonephritis: State of the Art
Nephrological Center, Medical Policlinic, Ludwig-Maximilians-University Munich, Germany
Medizinische Poliklinik LMU, Pettenkoferstr 8a, 80336 Munich
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Anders HJ. Diagnosis and Management of Crescentic Glomerulonephritis: State of the Art.Saudi J Kidney Dis Transpl 2000;11:353-361
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Anders HJ. Diagnosis and Management of Crescentic Glomerulonephritis: State of the Art. Saudi J Kidney Dis Transpl [serial online] 2000 [cited 2022 Jan 26 ];11:353-361
Available from: https://www.sjkdt.org/text.asp?2000/11/3/353/36657
Crescent formation is a result of severe glomerular injury. The percentage of glomeruli that exhibit crescents usually correlates with the severity of disease.  Crescentic glome-rulonephritis is most commonly found in patients with rapid decline of renal function due to various forms of glomerulonephritis, called rapidly progressive glomerulonephritis (RPGN). Severe antibody or immune-complex mediated glomerular injury may cause disruption of the glomerular basement membrane (GBM) allowing circulating leukocytes, inflammatory mediators, and coagulation factors to enter Bowman`s space. Subsequently, fibrin activation, and proliferation of parietal epithelial cells, activated macrophages, and interstitial fibroblasts result in crescent formation by obliteration of Bowman's space. 
Peri-glomerular macrophage accumulation can also result in disruption of Bowman`s capsule and subsequent macrophage and fibroblast immigration. Crescents with a predominant cellular composition which represent acute glomerulonephritis are able to resolve. On the other hand, signs of chronicity such as fibrous crescents, interstitial fibrosis and tubular atrophy indicate an unfavorable renal outcome. , Depending on the cause of crescentic glomerulonephritis adequate therapy can dramatically improve renal function. A rapid evaluation of the patient with RPGN including renal biopsy and testing of serum for various auto-antibodies is therefore required.
Diagnosis of crescentic glomerulonephritis
A rapid decline in renal function (reduction of more than 50% of glomerular filtration rate within 3 months) can be caused by various mechanisms but a nephritic urinary sediment and a normal or enlarged kidney size strongly argue for RPGN [Table 1]. RPGN is usually caused by one of the three following mechanisms: anti-GBM antibody disease with or without pulmonary hemorrhage, pauci-immune glomerulonephritis, and severe immunecomplex glomerulonephritis [Table 2].  Since untreated patients with RPGN may rapidly progress to end-stage renal disease, immediate renal biopsy and serological testing for C3, C4, anti-neutrophil cytoplasmic antibodies (c-ANCA, pANCA), ANA, dsDNA-, cryoglobulins, and anti-GBM antibodies is required to confirm the correct diagnosis.
This is the cause of RPGN in 10 to 20% of cases. When associated with pulmonary hemorrhage it is called Goodpasture`s syndrome. After an unknown triggering event, genetically susceptible individuals develop anti-GBM antibodies directed against specific epitopes located on the NC1 domain of the alpha-3 chain of collagen IV.  The limitation of organ injury reflects the tissue distribution of the alpha-3 chain which is predominant in glomerular and alveolar basement membranes.  The pathological effect of anti-GBM auto-antibodies relies on the contact of circulating antibodies with the GBM antigen. The fenestrated endothelium of glomerular capillaries allows auto-antibody binding and development of glomerulonephritis. However, anti-GBM disease without major renal dysfunction is present in up to 30% of patients with anti-GBM auto-antibodies.  The classic clinical presentation of Goodpasture`s syndrome includes symptoms of RPGN such as edema, hypertension, and uremia; and symptoms of pulmonary disease such as hemoptysis and dyspnea due to pulmonary hemorrhage. Goodpasture`s syndrome with pulmonary involvement seems to be restricted to individuals with an underlying pulmonary injury such as smoking or infection.  However, pulmonary hemorrhage may also be a sign of other diseases such as pulmonary edema, systemic vasculitis, or lupus erythematosus. Anti-GBM antibody testing should therefore immediately be performed in every patient with RPGN or acute glomerulo-nephritis without nephrotic syndrome. The presence of anti-GBM antibodies is diagnostic, but the sensitivity is low. Thus, a negative auto-antibody test does not exclude anti-GBM antibody disease. On renal biopsy, light microscopy usually reveals crescentic glomerulonephritis. Consistent with serum anti-GBM antibodies, immuno-fluorescence microscopy shows linear IgG deposition along the glomerular capillaries. Similar staining of tubular basement membrane correlates with anti-tubular basement membrane antibodies and tubulo-interstitial disease.  Linear IgG deposition can also be found in diabetic nephropathy and fibrillary glomerulonephritis, disorders that are easily distinguished from anti-GBM disease by light and electron microscopy.
In patients with anti-GBM autoantibodies, testing for ANCA should always be performed. Up to 38% of patients develop concomitant ANCA autoantibodies.  Patients with clinical signs of systemic vasculitis as a potential cause of anti-GBM disease should be treated accordingly.
Pauci-immune glomerulonephritis is another common cause of crescentic glomerulonephritis. It stands for the paucity of glomerular immunoglobulin deposits in renal biopsies of patients with RPGN. Apart from rare cases of idiopathic pauci-immune crescentic glomerulonephritis most patients develop pauci-immune RPGN as a manifestation of either c- or p-ANCA-associated vasculitis. The pathogenic role of c- and pANCA in systemic vasculitis is still unknown, but ANCA are of substantial diagnostic value. Patients with RPGN and ANCA have a 98% specificity for pauciimmune glomerulonephritis and almost all patients with active systemic Wegener`s granulomatosis have a positive ANCA directed against cytoplasmatic proteinase-3.  ANCA-associated systemic vasculitis typically affects the small arteries, arterioles, and venules. Clinical signs of cANCA-associated systemic small-vessel vasculitis include skin ulcers, neuropathy, and granulomatous lesions of eyes, sinuses, nose, throat, and lungs, known as Wegener`s granulomatosis.  P-ANCA, usually directed against cytoplas-matic myeloperoxidase of neutrophils, is associated with a variety of diseases such as microscopic polyangiitis, Churg-Strausssyndrome, and non-vasculitic rheumatic or gastrointestinal disorders.  When ANCA auto-antibody testing is positive, careful investigation for other manifestations of small vessel vasculitis including ENT examination, neural conduction studies, opthalmoscopy, and computed tomography of the lungs is required.
In c- or p-ANCA positive patients with RPGN, a renal biopsy is still required to exclude other forms of crescentic GN with concomitant ANCA auto-antibodies. This is particularly important for patients with underlying immune-complex disease, who require a different therapeutic approach.
This does not always induce crescentic lesions. However, severe post-infectious glomerulonephritis, renal manifestations of some immune-complex-related connective tissue diseases, and primary glomerulonephritides can induce crescent formation and RPGN.  Underlying connective tissue diseases such as systemic lupus erythematosus or mixed cryoglobulinemia can be diagnosed by the history of arthritis, rashes, ulcers or serological findings such as hypocomplementemia, cryoglobulinemia or specific auto-antibodies [Table 2]. A history of angina or cellulitis and RPGN indicates crescentic post-infectious glomerulonephritis. Bacterial endocarditis must be excluded in patients with concomitant fever and abnormal heart sounds. Primary glomerulopathies can also cause RPGN. About 10 percent of patients with IgA nephropathy present with acute glomerulonephritis and a decline of renal funtion.  Crescent formation is common during periods of gross hematuria, but crescentic lesions may resolve without scarring thereafter.  However, the amount of glomerular crescents and tubulointerstitial changes serve as prognostic factors for progression to end-stage renal disease in IgA nephropathy.  The rare diagnosis of crescentic membranoproliferative glomerulonephritis is also important because the disease does not respond to the immunosuppressive therapy regimen used in other forms of crescentic glomerulonephritis. 
Management of crescentic glomerulonephritis
All patients should receive supportive therapy to control the complications of glomerular disease such as uremia, hypervolemia, hypertension, hyperkalemia, and metabolic acidosis. If required, dialysis and ultrafiltration must be prescribed. Biocompatible dialysis membranes should be preferred, since cuprophane membranes activate circulating leukocytes, which may aggravate vasculitis.  Because untreated RPGN can rapidly progress to end-stage renal disease within weeks or months, immediate initiation of specific therapy is necessary.
Management of pauci-immune crescentic glomerulonephritis
Therapy options for patients with RPGN rely on the histopathological results of renal biopsy and serum testing. In an ANCA positive patient with RPGN, treatment should be started even while awaiting biopsy results, since pauci-immune crescentic glomerulonephritis is very likely. Since RPGN is a rare disease, randomized controlled trials are lacking. However, from the present data three treatment options have been evaluated to date: pulse methylprednisolone, cyclophos-phamide, and plasmapheresis.
Although, conventional doses of oral corticosteroids have no effect on RPGN, the intravenous administration of 1000 mg methylprednisolone daily for 3 to 5 days has demonstrated a beneficial effect on RPGN. ,, In these studies, a reduction of serum creatinine levels of more than 60% was observed in more than 50 % of all treated patients. Patients with fibrous crescents were less likely to respond.  Pulse therapy is followed by oral prednisone at a dose of 1 mg/kg daily for one month. After remission has been induced the dose is gradually tapered over the next 6 to 12 months. 
The evidence for the efficacy of cyclophosphamide in RPGN is not as good as for other manifestations of ANCA-associated vasculitis. Nevertheless, data from retrospective or uncontrolled studies indicates that addition of cyclophosphamide to prednisolone improves mortality and renal outcome of crescentic glomerulonephritis with a patient and renal survival of 75% at 24 months. ,,, Further evidence for the efficacy of cyclophosphamide in systemic vasculitis comes from a prospective, randomized trial comparing steroids plus daily oral cyclophosphamide or plus pulse cyclophophamide in patients with generalized Wegener`s granulomatosus.  Induction of initial remission was comparable in both groups, but patients with pulse cyclophosphamide had fewer side effects (40 % vs. 69%). Since the lower cumulative dose of the pulse cyclophosphamide regimen reduces the rate of infectious complications, leukopenia, and gonadal toxicity, oral prednisolone plus pulse cyclophosphamide is the preferred regimen by many centers. ,
Whether pulse cyclophosphamide is as effective as the oral regimen in maintaining remission is under debate. Despite data from retrospective or cohort studies indicating a comparable efficacy of pulse therapy, a recent prospective, randomized trial of patients with generalized Wegener`s granulomatosis indicates a higher relapse rate in patients on intermittent cyclophos phamide therapy (59% vs. 13%). ,, Therefore, it has been suggested that patients with severe and rapidly progressing forms of systemic vasculitis (more than four organs affected) should be treated with daily oral cyclophosphamide.  Oral cyclophosphamide should be given at a dose of 2 mg/kg/day adjusted to a leukocyte count between 3000 and 5000/cu mm for at least 6 to 12 months.  Pulse cyclophosphamide is given intravenously at a dose of 0.5 g/m 2 /month. In order to maintain the leukocyte nadir two weeks post-treatment between 3000 and 5000/μl the dose could be increased monthly by 0.25g to a maximum of 1 g/m 2 /month. 
Despite its theoretical effect of removing circulating immune-complexes, antibodies, complement, and cytokines, two controlled studies of plasma exchange have not shown any additional effect on idiopathic RPGN compared to the conventional prednisolone cyclophosphamide regimen. , However, guided by results from uncontrolled studies some centers consider plasma exchange in patients with lung hemorrhage or patients with severe vasculitis who do not respond to conventional therapy. 
Monitoring for disease activity is possible with clinical and laboratory parameters. ANCA titers have been shown to correlate with disease activity, and may indicate disease flairs before onset of clinical symptoms in individual patients.  However, rising ANCA titers in asymptomatic patients should rather result in closer follow-up visits than in immediate increase of immunosuppressive therapy.  Data from uncontrolled observations suggest that trimethoprim-sulfamethoxazole can prevent recurrent disease activity in patients with Wegener`s granulomatosis and ENT involvement.  This was not confirmed by a recent controlled study.  Low-dose methotrexate, given on a weekly base, seems to be more effective for maintenance therapy. 
Management of anti-GBM antibody-induced crescentic glomerulonephritis
Treatment strategies target anti-GBM antibody production by immunosuppressive drugs and removal of the antibody from the circulation by plasma exchange. Recommendations for treatment with prednisolone and cyclophosphamide are the same for anti-GBM antibody-induced and pauciimmune crescentic glomerulonephritis.  Immunosuppressive therapy is continued for 4 to 12 months until auto-antibody formation disappears. Additionally, several studies have demonstrated a beneficial effect of early therapeutic plasma exchange for anti-GBM antibody-induced disease. A favourable effect of plasma exchange can be expected on appro-ximately 90% of patients with pulmonary hemorrhage and 40% with RPGN. , Generally, daily 4-liter exchanges with albumin replacement are prescribed for a period of 14 days. Plasma exchange may be continued, if anti-GBM antibody titers have not declined.  However, renal function does not usually recover in patients with oligoanuria and marked elevation of serum creatinine levels.  Extensive immunosuppression and plasma exchange in these patients has therefore been questioned.  In oligoanuric patients, plasma exchange should only be considered, if one of the following conditions is present: pulmonary hemorrhage, crescent formation in less than 85% of glomeruli, positive serum testing for ANCA and clinical signs of systemic vasculitis, or very acute disease.  In all other oligoanuric patients the risk of therapy exceeds the small likelyhood of a beneficial effect, due to the self-limited nature of anti-GBM antibody disease.
Management of crescentic glomerulonephritis caused by immune-complex disease
Patients with RPGN secondary to an immune-complex disease should be treated according to their underlying etiology such as lupus nephritis, Schonlein-Henoch purpura, or primary glomerulonephritis [Table 2].
To discuss the broad spectrum of issues involved in the treatment of severe lupus nephritis is beyond the scope of this article. The subject has been extensively reviewed recently.  In brief, initial pulse prednisolone and cyclophosphamide is preferred for the treatment of severe or crescentic lupus nephritis.  The therapeutic regimens are largely comparable to those of ANCA-associated RPGN. Oral prednisolone and monthly pulse cyclophosphamide are given for 6 to 12 months until the patient has attained complete remission.  Superiority of oral or pulse cyclophosphamide over oral azathioprine for maintenance therapy has not been demonstrated.
Treatment studies of Schonlein-Henoch purpura nephritis largely rely on data derived from children. Since spontaneous recovery is often observed even in patients with rapidly progressive forms, uncontrolled studies are difficult to interpret. Some data suggest a role for pulse methylprednisolone therapy for three days followed by oral prednisolone.  Cyclophosphamide and azathioprine have not demonstrated a beneficial effect.
For the rare crescentic forms of primary glomerulonephritis such as IgA nephropathy only anecdotal data about efficacy of immuno-suppressive therapy or plasma exchange are available. , Based on these data, no firm recommendations can be given to date. 
In adults with RPGN without crescent formation, and glomerular changes limited to endocapillary proliferation, such as poststreptococcal glomerulonephritis in its classic form, the renal prognosis is good. In these patients treatment with immunosuppressive agents offers no benefit compared to supportive therapy only. ,
Crescentic glomerulonephritis is a severe form of glomerulonephritis. To make an early diagnosis, a complete history and physical examination are required. Immediate testing of serum for anti-GBM-antibodies, C3, C4, ANA, dsDNA, c-ANCA, p-ANCA, cryoglobulins and a renal biopsy are required. In patients with likely systemic vasculitis, anti-GBM disease or lupus nephritis, therapy should not await biopsy results. The classification of RPGN is based on the histopathology findings such as anti-GBM disease with linear IgG deposition, pauciimmune glomerulonephritis or immune complex disease with a granular mesangial or capillary staining of immune-complex deposits. Therapy for vasculitis, anti-GBM disease or connective tissue disease-related RPGN such as lupus nephritis include highdose methylprednisolone and cyclophos phamide for several months. Patients with Goodpasture`s syndrome require additional plasma exchanges. Overall patient and renal survival depends on the severity of nephritis before therapy is initiated. Once started, therapy should be continued for months. However, aggressive immunosuppressive therapy does also impair overall survival.
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