AUTHOR AND EDITOR INFORMATION

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• Follow-up
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INTRODUCTION

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Background

Rapidly progressive glomerulonephritis (RPGN) is defined as any glomerular disease characterized by extensive crescents (usually >50%) as the principal histologic finding and by a rapid loss of renal function (usually a 50% decline in the glomerular filtration rate [GFR] within 3 mo) as the clinical correlate. Transient azotemia with oliguria is common in patients with acute glomerulonephritis (GN).

Some patients have acute GN and present with rapidly progressive renal failure that develops within weeks to months and displays little tendency for spontaneous or complete recovery. Glomerular crescents can complicate any glomerulopathy, even noninflammatory glomerulopathy. In patients with noninflammatory glomerulopathies, the crescents tend to be fibrotic rather than cellular. Cellular crescents are a manifestation of a severe inflammatory process.

Classification: Idiopathic or primary crescentic GN is classified into the following types:

• Type I with linear deposits of immunoglobulin G (IgG) (anti–glomerular basement membrane [GBM] disease)
• Type II with granular deposits of immunoglobulin (immune-complex mediated)
• Type III with few or no immune deposits (pauci-immune) - Antineutrophil cytoplasmic antibody (ANCA)–associated (Renal-limited forms of ANCA-associated crescentic GN are thought to be related to small vessel vasculitis [SVV] with exclusive involvement of the glomerular capillaries.)
• Type IV combinations of types I and III
• Type V ANCA-negative renal vasculitis (5-10%)

Pathophysiology

RPGN can develop in any of the following clinical settings:

• Complication of acute or subacute infectious process
• Renal complication of multisystem disease: Secondary forms comprise more than 40% of cases.
• In association with use of certain drugs: A review of published data on an association between hydrocarbon exposure and anti-GBM antibody-mediated disease suggests the possibility of a casual relationship.
• Primary glomerular disease in which the kidney is the sole organ involved and in which extrarenal manifestations are caused by renal function disturbances

Acute RPGN is mediated by antibody or cellular immunity or by interaction of the two arms of the immune system. Deposition of antibody along the basement membrane and/or glomerular deposition of preformed soluble immune complexes can result in GN. Lymphocytes and macrophages, along with deposited antibody, are important in the production of proliferation and proteinuria. The involved lymphocytes are identified as T cells; most are helper T cells with some suppressor T cells. Antibody- and cell-mediated immunity are together responsible for many lesions observed in patients with acute RPGN, and cell-mediated immunity without antibody may produce crescentic GN.

Crescents are defined as the presence of 2 or more layers of cells in the Bowman space. The presence of crescents in glomeruli is a marker of severe injury.

The initiating event is the development of a physical disruption in the GBM. The lesions are mediated by processes involving macrophages and cell-mediated immunity. Following disruption of the glomerular capillary, circulating cells, inflammatory mediators, and plasma proteins pass through the capillary wall into the Bowman space. Cells and mediators from the interstitium enter the Bowman space with disruption of the Bowman capsule, which leads to development of crescents.

The major participants in crescent formation are coagulation proteins, macrophages, T cells, fibroblasts, and parietal epithelial cells. Activated macrophages contribute to the crescents by proliferating and releasing procoagulant tissue factor, interleukin-1 (IL-1) and tumor necrosis factor (TNF). T cells are not prominent components, but they play an important role in glomerular injury by antigen recognition and macrophage recruitment.

The reversibility of crescents correlates with relative predominance of cellular components. Whether crescents progress or resolve may depend upon the integrity of the Bowman capsule and resulting cellular composition of the crescent. Progression to fibrous crescents is more common when capsular rupture occurs and fibroblasts along with macrophages are prominent in the Bowman space. The presence of fibrous crescents usually correlates with glomerular sclerosis or irreversibility.

Frequency

United States

Idiopathic crescentic GN accounts for fewer than 10% of all patients presenting with primary glomerulopathy. RPGN type III is more common than RPGN types I or II. More than 50% of patients with crescentic GN present with acute nephritic syndrome and rapidly deteriorating renal function; however, other modes do occur (eg, asymptomatic, 15%; nephrotic, 10%; chronic renal failure, 15%).

International

Peak incidence of anti-GBM disease occurs in spring and early summer. No seasonal predilection is observed in patients with non–anti-GBM disease.

Mortality/Morbidity

Death or dialysis occurs in 73% of patients who are treated with conventional therapy and in 88% of patients if they are oligoanuric at time of presentation.

Race

No racial predilection exists.

Sex

For RPGN types I and III, a predilection for males exists.

Age

RPGN has a broad age distribution, as follows:

• RPGN type I generally occurs in young adults.
• RPGN types II and III generally occur in older adults (peak incidence occurs in the fourth to sixth decades of life).

CLINICAL

Section 3 of 11  

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History

Clinical and laboratory presentations of all types of acute RPGN are quite similar.

• Some patients present with signs and symptoms of renal disease, eg, anemia, hematuria, fluid retention, oliguria, or even uremia.
• Symptoms of weakness, nausea, and vomiting (indicative of azotemia) usually dominate the clinical picture.
• Other patients present with signs and symptoms of their primary etiology (eg, Goodpasture syndrome, Wegener granulomatosis, systemic lupus erythematosus [SLE]).
• Still others give a history of a flulike or viral prodrome. Vague aches and pains or frank arthritis, sinusitis, otitis, episcleritis, skin rash, neuritis, or encephalopathy are uncommon and are more common with a multisystem disease (suggesting secondary form).
• Oliguria, abdominal or flank pain, and hemoptysis may occur (eg, Goodpasture syndrome).
• Peripheral swelling may be present.
• Fifteen percent of patients may be asymptomatic.

Physical

• Blood pressure may be normal or slightly elevated.
• Peripheral edema may be present in 10% of patients.
• Pallor is common.
• Skin rash: A lesion suggesting leukocytoclastic vasculitis may be present.

Causes

• Infectious diseases
• • Poststreptococcal glomerulonephritis (PSGN)
  • Infective endocarditis
  • Occult visceral sepsis
  • Hepatitis B infection (with vasculitis and/or cryoglobulinemia)
• Multisystem diseases
• • SLE
  • Henoch-Schönlein purpura
  • Systemic necrotizing vasculitis (including Wegener granulomatosis)
  • Microscopic polyarteritis
  • Goodpasture syndrome
  • Essential mixed (IgG and immunoglobulin M [IgM]) cryoglobulinemia
  • Malignancy
  • Relapsing polychondritis
  • Rheumatoid vasculitis
• Drugs
• • Penicillamine
  • Hydralazine (rare case reports)
  • Allopurinol (with vasculitis)
  • Rifampin (rare case reports)
  • Propylthiouracil, thiamazole, carbimazole, benzylthiouracil
  • Aminoguanidine
• Primary glomerular disease
• • Idiopathic or primary crescentic GN
  • Type I with linear deposits of IgG (anti-GBM disease)
  • Type II with granular deposits of immunoglobulin (immune-complex mediated)
  • Type III with few or no immune deposits (pauci-immune) - ANCA-associated (renal-limited microscopic polyarteritis)
  • Type IV combinations of types I and IIIa
  • Type V ANCA-negative renal vasculitis (5-10%)
• Superimposed on another primary glomerular disease
• • Membranoproliferative GN (MPGN) type II
  • Membranous GN
  • Immunoglobulin A (IgA) nephropathy

DIFFERENTIALS

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Other Problems to be Considered

Acute interstitial nephritis

WORKUP

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Lab Studies

• CBC count may show leukocytosis and anemia.
• Erythrocyte sedimentation rate (ESR) is usually elevated.
• Blood urea nitrogen (BUN) and serum creatinine levels are usually elevated.
• Electrolytes, especially the serum potassium level, are consistent with the degree of renal failure.
• Urinalysis shows modest proteinuria (1-4 g/d), microscopic hematuria, RBCs, and RBC and WBC casts.
• Proteinuria could be quantified by timed (24-h collection) or spot urine protein/creatinine ratio.
• • Rarely, urine findings may be minimal.
  • An absence of active urine sediment does not exclude a diagnosis of RPGN.
• Complement levels (C3 and C4) are within reference ranges in patients with RPGN types I and III and may be decreased in patients with RPGN type II.
• Circulating anti-GBM antibodies are detected in plasma of patients with RPGN type I, but this finding is neither 100% sensitive nor 100% specific for type I.
• ANCAs: Typically, perinuclear ANCA (p-ANCA) is observed in 80-90% of patients with RPGN type III pauci-immune, but neither p-ANCA nor ANCA is 100% specific for type III.
• Antinuclear antibody findings are usually negative (unless lupus related).
• Serum cryoglobulin levels may be elevated in cryoglobulinemias and may be falsely negative.

Imaging Studies

• Abdominal ultrasound is used to assess renal size and echogenicity and to exclude obstruction.
• Chest x-ray films are indicated for patients with suspected Goodpasture syndrome and vasculitides and to help manage pulmonary renal syndromes.
• Sinus x-ray films and/or CT scans may show evidence of sinusitis in patients with Wegener granulomatosis.
• Chest CT scans may show reticulonodular infiltrate, even when chest radiographic findings are normal.

Procedures

• Renal biopsy is usually required to diagnose RPGN types I, II, or III.

Histologic Findings

Idiopathic RPGN is classified as follows:

• Type I (anti-GBM disease with or without lung hemorrhage) - Linear deposits of IgG (5-20%)
• Type II (immune complex-mediated disease) - Granular deposits of immunoglobulins by immunofluorescence and electron-dense deposits by electron microscopy (15-30%)
• Type III (pauci-immune GN) - Little or no deposits observed by immunofluorescence or electron microscopy (55%)

The normal renal architecture is lost, and the glomerulus is solid, hypercellular, and surrounded by severe interstitial mononuclear cell infiltrate (see Media file 2) is observed in patients with severe types. The glomerular tuft is distorted by proliferation of epithelial cells crescents that occupy most of the Bowman space (see Media file 1 and Media files 3-4). Anti-GBM disease is characterized by linear IgG deposits (see Media file 5). Endocapillary proliferation, if prominent, suggests the presence of infection. Segmental or diffuse endocapillary necrosis suggests underlying vasculitis.

TREATMENT

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Medical Care

Early and aggressive treatment is warranted to preserve renal function. Principles of general therapy are listed in Medication.

For specific therapies, see the following related chapters:

• RPGN type I: See Goodpasture Syndrome.
• RPGN type II: See Lupus Nephritis.
• RPGN type III: See Glomerulonephritis, Rapidly Progressive.

Consultations

A nephrologist should be involved early in the disease course.

Diet

• Renal diet: Provide a low-salt and low-protein (0.8 g/kg/d) diet, if renal dysfunction is present. Restrict potassium if the patient has hyperkalemia. Avoid malnutrition.

Activity

No specific limitations are necessary other than limiting activity after renal biopsy.

MEDICATION

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Principles of therapy include supportive and specific therapies. Supportive therapy involves control of infection, control of volume status (providing dialysis if required), and smoking cessation. Specific therapy is directed toward providing immunosuppressive therapy (eg, glucocorticoids, cyclophosphamide, azathioprine, mycophenolate [MMF]), plasma exchange (in patients presenting with life-threatening pulmonary hemorrhage), and anticoagulant agents.

Recently, monoclonal antibodies (infliximab, rituximab), pentoxifylline (reduces TNF), mizoribine (a purine synthesis inhibitor), and antithymocyte globulin have been used with encouraging results in a small number of patients, but controlled trials are needed.

At present, the mainstay of therapy remains cyclophosphamide and steroids for induction of remission.

Drug Category: Glucocorticoids

Pulses of intravenous methylprednisolone (5-20 mg/kg) followed by high-dose oral prednisone (2 mg/kg) daily or on alternate days for 2-3 months has shown improved 1-year renal survival rates of 40-70%.

Drug Category: Immunosuppressive agents (cytotoxics)

Addition of cytotoxic agents to corticosteroids has yielded varying success in treating patients with crescentic GN. Although pulse cyclophosphamide is often preferred in lupus nephritis, oral cyclophosphamide appears to have an advantage in Wegener granulomatosis.

Oral versus intravenous: Recently completed, prospectively randomized Cyclophosphamide daily oral versus PulSed (CYCLOPS) trial has shown very little difference in time to remission and time to relapse between daily oral or intermittent intravenous cyclophosphamide for induction therapy.

Cyclophosphamide 3 mg/kg/d for 12 weeks is a common recommendation, but the duration of therapy may be longer (4-6 mo) in patients with pauci-immune GN. This therapy should be followed by the administration of azathioprine (1.5-2 mg/kg/d) or methotrexate (5-20 mg qwk as a single dose) until the patient is in remission for at least 6-12 months. The duration of azathioprine therapy to prevent further relapses is unknown, but it should be at least for 2 years.

Continuing cyclophosphamide for longer than 6 months is not necessary, as recently shown by Cyclophosphamide versus Azathioprine during Remission (CYCAZAREM) trial, where the time to relapse was identical whether the patient was given cyclophosphamide for less than 6 months or more than 6 months.

Recent evidence suggests that mycophenolate mofetil (CellCept) 0.75-1 g bid may also be effective in patients with pauci-immune vasculitis.

Drug Category: Antibiotics

Therapy must be comprehensive and should cover all likely pathogens in the context of this clinical setting.

FOLLOW-UP

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Further Inpatient Care

• Intensive plasma exchange: Plasmapheresis (2-4 L of plasma qd or 3 times/wk), combined with glucocorticoids and cytotoxic agents, is beneficial in anti–GBM-mediated disease provided therapy is initiated before renal failure has progressed to require dialysis support. Plasma exchange is also valuable as an adjunctive measure in patients with positive ANCA results who present with life-threatening pulmonary hemorrhage (MEthylprednisolone versus Plasma EXchange [MEPEX], Rasmussen, 1995).
• Despite aggressive therapy, many patients with oliguria do not respond well.
• In the absence of any response within 3-5 weeks, acceptance of a diagnosis of end-stage renal disease is preferable to death secondary to iatrogenic causes.
• High-dose intravenous immunoglobulin has been reported to be successful in suppressing the activity of pauci-immune ANCA-positive vasculitis. The mechanism is not clear, but pooled normal immunoglobulin contains antibodies that neutralize ANCA and suppress complement activation through a nonspecific effect of the immunoglobulin heavy chains.
• Intravenous immunoglobulin may have a role in the temporary management of severe pauci-immune vasculitis when severe infection is present in patients in whom it is desirable to withhold cytotoxic agents and high-dose corticosteroids until the infection is controlled.

Further Outpatient Care

• After induction of remission with oral cyclophosphamide and steroids, conversion to oral azathioprine (2 mg/kg/d) at 3 months appears to be safe and effective compared to continuation of cyclophosphamide for 1 year (if clinical signs of activity are minimal and preferably ANCA is negative) (CYCAZAREM). The duration of maintenance therapy with azathioprine to prevent further relapses is unknown but should be at least for 2 years. Studies of longer periods of azathioprine maintenance (2 y vs 4 y) are in progress (Randomized trial of prolonged REmission-MAINtenance therapy in systemic vasculitis [REMAIN]).
• Monitor BUN, electrolyte, and serum creatinine levels in all patients.
• Drug-responsive relapses may occur as late as 2-4 years after remission.
• RPGN may recur after renal transplantation. At present, after initiating dialysis, a waiting period of 3-6 months is recommended before considering renal transplantation.
• No convincing evidence suggests that a bilateral nephrectomy performed before a renal transplantation reduces the risk of recurrent disease in patients with renal allografts.
• For patients who have achieved remission, evaluation at 2-month intervals is usually sufficient. The following testing is recommended:
• • Urinalysis with special emphasis on the presence of cellular casts: BUN, electrolyte, and serum creatinine levels should be evaluated in all patients.
  • C-reactive protein or ESR (whichever correlates better with disease activity in a given patient)
  • ANCA (in ANCA-positive patients at 6- to 9-mo intervals): An increasing ANCA titer is often evidence of an impending relapse. A 4-fold or higher rise in ANCA titer may herald a relapse and require preemptive intervention.
  • Anti-GBM titers in anti-GBM patients

In/Out Patient Meds

• Administer oral cyclophosphamide for 4-6 months, followed by azathioprine or methotrexate until the patient is in remission for 6 months to 1 year.
• Administer prednisone as a low-dose alternative for 6-9 months.
• Administer trimethoprim-sulfamethoxazole 160/800 mg bid (for Wegener granulomatosis) if renal function normal. Decrease the dose as guided by renal function. A lower dosage as PCP prophylaxis may be considered.

Transfer

• Patients may need to be transferred to another center for the following:
• • Plasmapheresis
  • Dialysis
  • Ventilatory support

Deterrence/Prevention

• Because patients with pauci-immune vasculitis typically have a prodrome lasting for weeks to months—during which time they experience 1 or more vague symptoms (eg, intermittent fever, weight loss, anorexia, arthralgias, shortness of breath, hemoptysis, middle ear effusions, conjunctivitis, episcleritis, nasal septal perforation, saddle nose deformity)—a high index of clinical awareness, early diagnosis, and treatment may prevent significant morbidity and mortality associated with this condition.

Complications

• Renal failure
• Pulmonary edema
• Pulmonary hemorrhage
• Respiratory failure

Prognosis

• In general, prognosis is poor and aggressive therapy is warranted.
• Fifty percent of patients require maintenance dialysis within 6 months of disease onset.
• Spontaneous remission is uncommon, except among patients with infection as the basis for formation of antigen-antibody complexes, in whom removal of the antigen can take place.
• Poor prognostic factors are as follows:
• • Large crescents in more than 80% of glomeruli (especially if fibrocellular or acellular)
  • Initial serum creatinine level of more than 500 µmol/L or GFR of less than 5 mL/min at presentation
  • Oliguria
  • Presence of anti-GBM antibody
  • Age older than 60 years
  • Coexistence of HLA-DR2 and HLA-B7

Patient Education

• Patients receiving immunosuppressive therapy should be educated about early signs of infection and advised to see their physician or health care worker at the early signs of infection in order to monitor WBC count.
• Patients on a high dose of prednisone should be monitored for the development of diabetes and peptic ulcer disease and receive therapy to prevent steroid-induced osteoporosis.

MISCELLANEOUS

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Medical/Legal Pitfalls

• A high index of clinical awareness is important in order to make an early diagnosis in patients presenting with ill-defined fever, weight loss, anorexia, arthralgias, hemoptysis, middle ear effusions, deafness, nasal septal perforation, and saddle nose deformity.
• Consider eradication of S aureus in anterior nares of patients with Wegener granulomatosis for sustained remission.
• Be careful with immunosuppressive therapy (both cytotoxic agents and high-dose corticosteroids) in patients who may have active infection.
• Ensuring that the patient has no active infection is important before starting immunosuppressive therapy in order to prevent significant morbidity and mortality associated with treatment of this disease.
• Intravenous immunoglobulin may be useful to control disease activity when the patient has associated active infection and the need to hold immunosuppressive agents.
• The adverse effects and toxicities of long-term corticosteroid and immunosuppressive therapy must be discussed with the patient.
• With long-term steroid use, monitoring the patient for the development of diabetes, peptic ulcer disease, and osteoporosis is important, as is prescribing cytoprotective agents (to prevent peptic ulceration) and preventive therapy for steroid-induced osteoporosis.
• In patients who are in the reproductive age group, discuss and document the effect on fertility of cytotoxic therapy. Patients should be counseled for sperm or egg preservation, or consideration should be given to leuprolide therapy to inhibit gametogenesis during treatment with cyclophosphamide therapy.
• To prevent risk of hemorrhagic cystitis, patients on oral cyclophosphamide should be encouraged to drink plenty of fluids so that the metabolites of cyclophosphamide do not concentrate in the bladder.
• The possibility of late malignancy associated with cytotoxic therapy should be discussed and documented in the patient's chart.
• Failure to diagnose or empirically treat pending diagnosis, with a resulting rise of serum creatinine to unsalvageable levels (>6 mg/dL or 500 µmol/L), is a potential medicolegal pitfall.

MULTIMEDIA

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Media file 1:  Glomerulonephritis, crescentic. Light microscopy (25x hematoxylin and eosin stain): Compression of the glomerular tuft with a circumferential cellular crescent that occupies most of the Bowman space. Image courtesy of Madeleine Moussa, MD, FRCPC, Department of Pathology, London Health Sciences Centre, London, Ontario, Canada.
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Media type:  Photo

Media file 2:  Glomerulonephritis, crescentic. Light microscopy (200x hematoxylin and eosin stain): The normal renal architecture is lost. The glomerulus (*) is solid and hypercellular and surrounded by severe interstitial inflammatory infiltrate. Image courtesy of Suzanne Meleg-Smith, MD, Department of Pathology, Tulane University School of Medicine, New Orleans.
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Media type:  Photo

Media file 3:  Glomerulonephritis, crescentic. Light microscopy (200x periodic acid-Schiff stain): Bowman capsule (arrow) surrounds each glomerulus. The glomerular tuft (*) is distorted by a proliferation of epithelial cells (crescent), which replaces the urinary space. Image courtesy of Suzanne Meleg-Smith, MD, Department of Pathology, Tulane University School of Medicine, New Orleans.
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Media type:  Photo

Media file 4:  Glomerulonephritis, crescentic. Light microscopy (400x trichrome stain): The remnant of the glomerular tuft (*) is surrounded by the cellular crescent with abundant fibrin–red on trichrome stain. Interstitial edema separates the tubules, and scarce inflammatory cells are present. Image courtesy of Suzanne Meleg-Smith, MD, Department of Pathology, Tulane University School of Medicine, New Orleans.
	View Full Size Image
Media type:  Photo

Media file 5:  Glomerulonephritis, crescentic. Immunofluorescence (25x): Anti–glomerular basement membrane characterized by the presence of linear immunoglobulin G deposit along the glomerular basement membrane. Image courtesy of Madeleine Moussa, MD, FRCPC, Department of Pathology, London Health Sciences Centre, London, Ontario, Canada.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

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• Differentials
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• Follow-up
• Miscellaneous
• Multimedia
• References

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• Ogata H, Kubo M, Tamaki K. Crescentic glomerulonephritis due to rifampin treatment in a patient with pulmonary atypical mycobacteriosis. Nephron. 1998;78(3):319-22.
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Article Last Updated: Nov 10, 2006