Sandbox: RPGN
Synonyms and keywords:: Crescentic glomerulonephritis; RPGN

# Overview
Rapidly progressive glomerulonephritis (RPGN) is one of the few nephrological emergency. However, it fortunately only affects 1-4% of all cases of glomerulonephritis. It is a clinical syndrome that includes signs and symptoms of glomerulonephritis, including hematuria, proteinuria, and edema with signs of renal failure and diffuse crescent formation on histopathology. Without appropriate treatment, RPGN progresses into end-stage renal disease within several days to only a few months yielding a very poor prognosis and renal outcome. RPGN is classified based on the presence of absence of anti-neutrophil cytoplasmic antibody (ANCA) and anti-GBM antibodies. Due to its rarity, the pathogenesis of RPGN is poorly understood and most probably is related to the type of RPGN and the circulating antibodies associated with each type. Evidence on treatment options for RPGN is poor; but the use of glucocorticoids and cyclophosphamide is currently recommended. Basic research and clinical data are currently emerging to better understand the disease pathogenesis and optimal therapeutic options.

# Definition
Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome characterized by features of glomerulonephritis associated with renal impairment that rapidly worsens over a very short duration - from weeks to a few months  into end-stage renal disease (ESRD).
In RPGN, renal failure is the rapid loss of renal function beyond 50% over a short span ranging to a maximum of 3 months. RPGN is thus one of several causes of rapidly progressive renal failure (RPRF).

# Classification

## Old Classification
Following its initial description in 1914, crescenteric glomerulonephritis was first classified by Couser in 1988 based on features of immunofluorescence.

### Type I: Anti-GBM Glomerulonephritis
20% of patients 
Presence of linear staining of glomerular basement membrane (GBM)

### Type II: Pauci-Immune Glomerulonephritis
50% of patients 
Absent or minimal immune deposits

### Type III: Immune Complex-Mediated Glomerulonephritis
30% of patients 
Presence of granular patterns of immune deposits within the glomerulus. Immune deposition may be associated with any of the following conditions:
- Infections
- Systemic illnesses
- Other primary glomerular diseases

## New Classification
Upon the detection of new serological markers such as anti-GBM antibodies and anti-neutrophil cytoplasmic antibodies (ANCA), the classification of RPGN has changed to involve several types of primary glomerulonephritis that correspond to the quantity and quality of such findings in patients sera. ANCA and anti-GBM may co-exist in approximately 20% of the patients.

### Type I: Anti-GBM Disease
- Anti-GBM antibody-mediated without pulmonary involvement
- Goodpastures disease: Anti-GBM antibody-mediated with pulmonary hemorrhage

### Type II: Immune Complex-Mediated Disease

### Type III: Pauci-Immune Disease
ANCA positive
- Idiopathic renal-limited vasculitis / renal-limited necrotizing crescenteric glomerulonephritis (NCGN)
- Granulomatosis with polyangiitis (formerly Wegeners granulomatosis")
- Microscopic polyangiitis
- Churg-Strauss syndrome

### Type IV: Mixed Anti-GBM and ANCA Associated Disease

### Type V: Pauci-Immune
ANCA negative

# Pathophysiology
The pathogenesis of RPGN is unclear and is poorly understood. Nonetheless, circulating factors are thought to play a significant role in the disease and its progression. RPGN, as an outcome, seems to be actually related to the type of RPGN. As such, there does not seem to be a unifying pathophysiology, but rather a combination of pathways that lead to a similar renal outcome. Genetic susceptibility has been shown to be associated with elevated levels of circulating antibodies, such as anti-GBM and ANCA, but little has been elaborated.
In type I anti-GBM glomerulonephritis, antibodies against the non-collagenous domain of alpha-3 chain of type IV collagen of the glomerular basement membrane with a linear pattern on immunofluorescence are responsible for renal involvement. The granular distribution along the GBM exhibit IgG and C3 deposits. Crescent formation is predominantly due to the formation of fibrin/fibrinogen.
In Type II pauci-immune glomerulonephritis, such as in polyangiitis with granulomatosis (formerly Wegener granulomatosis) and polyarteritis nodosa, findings of p-ANCA and c-ANCA in patients are considered landmarks in understanding these diseases; but their true significance has not yet been delineated. Studies have shown that ANCA may in fact interact with neutrophils due to the presence of myeloperixoidases on the surface of neutrophils. The interaction drives neutrophils to undergo activation via oxidative burst that finally leads to their dose-dependent degranulation and release of toxic oxygen radicals. TNF priming also seems to play an important role in the ANCA-induced degranulation of neutrophils. As such, it is perhaps that TNF production during infections and inflammatory diseases in vivo may prime neutrophils in ANCA-positive patients to facilitate neutrophilic activation and subsequent pro-inflammatory cascade of RPGN disease.
While the majority of patients with pauci-immune RPGN indeed have elevated levels of ANCA, the remaining 20% of patients with the same disease do not. Interestingly, 30% of patients in remission continue to have elevated levels of ANCA. Both these problematic findings raise the question of the actual importance of ANCA in the pathogenesis of RPGN. A novel hypothesis currently suggests that RPGN is in fact a podocytopathy, defined as an intrinsic disease of the podocytes that normally maintains glomerular capillary membranes. As such, it is thought that the CXCR4 and VHL-HIF pathway target gene expression in renal biopsies, based on experimental studies on mice.

# Causes

## Primary RPGN
RPGN may be a primary condition. The diagnosis of primary glomerulonephritis is made when the clinical syndrome of the disease complies with the new classification of RPGN based on the 5 types of disease.
Nonetheless, ruling out other causes of RPGN is necessary before the diagnosis of primary RPGN is made.
The cause of ANCA levels in patients with ANCA-associated glomerulonephritis is not known. Environmental and genetic factors have been postulated. It is believed that infectious etiologies, such as arboviruses, may be contributory. These findings are based only on observations and small studies that patients with ANCA-associated glomerulonephritis are more commonly diagnosed during flu season, flu-like prodrome is usually the most common presenting symptoms of these patients, and presence of serological proof of previous arbovirus infection. Further disease progression in ANCA-associated diseases into clinical syndromes of polyarteritis nodosa and Wegener granulomatosis has been postulated to be caused by activation of autoantibody-induced leukocytes. However, no consistent validation of such claims has been made.

## Secondary RPGN

### Infections
- Infective endocarditis
- Sepsis
- HBV infection with vasculitis or cryoglobulinemia
- HCV infection with vasculitis or cryoglobulinemia

### Drugs
- Allopurinol
- D-penicillamine
- Hydralazine
- Rifampin

### Multi-Organ Disease
- Systemic lupus erythematosus
- Henoch-Schonlein purpura
- Systemic necrotizing vasculitis
- Relapsing polychondritis
- Cryoglobulinemia
- Other vasculitides

### Malignancies
- Colon cancer
- Pulmonary cancer
- Lymphoma

### Other Conditions
- Behcets disease
- Membranoproliferative glomerulonephritis
- IgA nephropathy
- Poststreptococcal glomerulonephritis
- Hereditary nephritis

# Differential Diagnosis
During the evaluation of RPGN, the differential diagnosis of RPGN must first include secondary causes of RPGN and other forms of primary glomerulonephritis before the diagnosis of primary RPGN is to be made and before considering other differential diagnoses.
Other diseases that need that to be considered as differential diagnoses include:
- Amyloidosis
- Antiphospholipid syndrome
- Malignant hypertension
- Multiple myeloma
- Polyarteritis nodosa

# Epidemiology and Demographics
RPGN accounts for a small minority of all cases of glomerulonephritis. Only 1-4% of kidney biopsies are RPGN. The prevalence and predominance of RPGN among different ethnicities and geographical locations are currently not known.

# Clinical Presentation
RPGN is a difficult diagnosis because of its presenting insidious non-specific symptoms, especially when uncomplicated by other diseases or associated with secondary etiologies. Perhaps the most common presenting symptom of RPGN is just fatigue. Other constitutive symptoms, such as nausea, vomiting, unintentional weight loss, loss of appetite, and diffuse nonspecific abdominal and musculoskeletal pain, are also common. This nonspecific flu-like prodrome has raised the suspicion of whether RPGN is a rare unfortunate complication of an infectious etiology.
Renal symptoms, such as azotemia, oliguria, and nephritic syndrome, with gross hematuria are frequently seen in patients with RPGN. Patients might present with several chief complaints, such as symptoms associated with hypertension, such as headache or blurry vision, symptoms of renal insufficiency, or even symptoms of associated diseases such as hemoptysis, sinusitis, cough, and dyspnea in those who that have pulmonary involvement. It has been noted that adult population is less likely to experience hypertension in RPGN as compared to the pediatric population. As such, the presenting symptoms might vary significantly depending on the type of RPGN.
Most findings on physical examination are related to diseases that are associated with RPGN, such as skin lesions in vasculitis, or those associated with renal failure.

# Prognosis
The prognosis of RPGN is poor due to the rapid deterioration of kidney function into end-stage renal disease (ESRD) within a few weeks or months. Early diagnosis and management are both important factors to improve prognosis and avoid progression into ESRD. Histopathologically, the extent of fibrous crescents is associated with poorer renal survival. The degree of renal impairment at diagnosis is also a significant prognostic factor. Serum creatinine > 6 mg/dL is associated with very poor renal outcomes in patients with anti-GBM disease.
The prognosis of RPGN also depends on the exact diagnosis within subtypes of RPGN. The amount of studies that studied the natural history and prognosis of RPGN and its subtypes are very rare, especially because the disease itself is uncommon. Appropriate therapy in patients with anti-GBM disease and Goodpastures disease was shown to significantly alter prognosis, with survival rates reaching as high as 70-90%; but only 40% of patients do not require dialysis after 1 year.
Another study that enrolled patients with microscopic polyangiitis and glomerulonephritis and positive ANCA. Following appropriate therapy, more than 70% of the patients were in remission; almost half of which continued to be disease-free after 4 years. Similarly, renal function at diagnosis is associated with renal outcome in patients with positive ANCA.
Patients with poststreptococcal RPGN generally have better outcomes compared to those with primary RPGN. But these findings were observed in the adult population, and may not be true for pediatric patients.

# Diagnosis

## Blood Work-Up
- Complete blood count (CBC) differential and platelet count
- Serum electrolytes
- Creatinine and blood urea nitrogen (BUN)
- Lactate dehydrogenase (LDH)
- Creatine phosphokinase (CPK)
- Liver function tests
- Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
- Antinuclear antibody (ANA)
- Anti-GBM antibodies
- ANCA
- Cryoglobulins
- HBV and HCV titers
- Complement C3 and C4 levels
- Serum protein electrophoresis
Anemia is common among patient with RPGN, mostly due to renally impaired production of erythropoietin or GI bleeding. Eosinophilia may be seen in a subset of patients with Churg-Strauss disease.
Patients with RPGN may show formation of immune complexes and cryoglobulins. Complement C3 levels is usually low in immune-complex mediated RPGN. The presence of ANCA and anti-GBM is variable; their presence is important for classification of disease and further management planning. Anti-GBM levels is However, anti-GBM antibody level is not prognostic and is not associated with disease activity. On the contrary, literature regarding ANCA-associated glomerulonephritis suggests that levels of ANCA is associated with disease activity and may be used as an index for such purposes.
ESR and CRP may be elevated and are correlated with the level of inflammation and thus activity of the disease.

## Urine Work-Up
- Urinalysis
- Urinary protein electrophoresis
Patients with RPGN do not usually have a full-blown picture of nephrotic syndrome; Nephrotic syndrome only occurs in less than 30% of cases. Proteinuria, if present, is usually mild to moderate. Hematuria of glomerular type with dysmorphic red blood cells is usually present on urinalysis and associated with red cell casts. Mild to moderate leukocyturia may be seen and other casts, such as epithelial cell leukocyte, or fatty casts. Urinary findings in RPGN are important features that not only favor diagnostic work-up, but also follow-up and therapeutic effectiveness.

## Kidney Ultrasound
Kidney ultrasound is usually done during diagnostic biopsy. Due to its rapid progression, renal biopsy usually shows normal-sized kidneys. Although the test is not diagnostic, its non-invastive nature and the necessity to rule out other etiologies of renal impairment are both in favor of performing a renal ultrasound.

## Kidney Biopsy
An ultrasound or CT-guided kidney biopsy is the only gold standard to diagnose RPGN and determine prognosis of the disease. The pathological hallmark of RPGN is presence of epithelial crescents in the Bowmans capsule with or without endocapillary proliferation. The extent of fibrous crescents along the glomerulus are considered a poor prognostic element.

# Management
Treatment of RPGN must be very aggressive due to its generally poor prognosis if left unmanaged. Hence, treatment must not await the results of the kidney biopsy; but must be initiated as soon as possible because fibrosis may start very early during the course of the disease. Presence of fibrosis marks irreversible damage.
In some studies, patients already on dialysis were also responsive to therapy and treatment should not be delayed for these patients either. Nonetheless, the true response among this specific sub-population and their associated risks and outcomes are poorly understood.

## Pharmacologic Therapy
In 1990, the Glomerular Disease Collaborative Network published its findings after a 24-month follow-up of 70 patients with ANCA and pauci-immune necrotizing and crescentic glomerulonephritis. In the cohort trial, 14 patients were treated with corticosteroids, 30 patients received both corticosteroids and oral cyclophosphamide, 15 patients received both corticosteroids and intravenous cyclophosphamide, and 11 patients received no treatment. The authors concluded that oral corticosteroids with either oral or intravenous cyclophosphamide regimens are equally effective treatment options for patients with ANCA-associated glomerulonephritis for patients with renal-limited disease, glomerulonephritis, and alveolar hemorrhage.
In 1996, Nachman and colleagues outlined a protocol for therapeutic management of patients with microscopic polyangiitis and necrotizing and crescentic glomerulonephritis associated with ANCA. In the trial, 107 patients were enrolled. 25 patients received only corticosteroids, 72 received cyclophosphamide and corticosteroids, and 10 patients did not receive cyclophosphamide or corticosteroids. The authors concluded that 77.3% of those receiving therapy remitted, and 67% of those who were not in remission following the first regimen were in remission after a second course of the same regimen.

### Glucocorticoids
Follow step 1, then 2, then 3
1. Methylprednisone
- Route: Intravenous (IV)
- Dose: 7 mg/kg/d at a maximum dose of 1 g
- Duration: 3 days
2. Prednisone
- Route: Per Os (PO)
- First Dose: 1 mg/kg/d at a maximum dose of 80 mg for 3 weeks
- Second Dose: 2 mg/kg/d at a maximum dose of 120 mg for 3 months
3. Taper
- Taper patient off steroids by deceasing 25% of prednisone dose every 4 weeks until patient stops

### Immunosuppressive Therapy
Cyclophosphamide
- Route: IV or PO
- Dose:
IV: 0.5 g/m2, at a maximum dose of 1g/m2. Dose adjusted to a 2-week leukocyte nadir count goal 3000-4000/uL.
PO: 2 mg/kg. Dose adjusted to a 2-week leukocyte nadir count goal 3000-4000/uL
- IV: 0.5 g/m2, at a maximum dose of 1g/m2. Dose adjusted to a 2-week leukocyte nadir count goal 3000-4000/uL.
- PO: 2 mg/kg. Dose adjusted to a 2-week leukocyte nadir count goal 3000-4000/uL
Addition of cyclophosphamides for patients with RPGN is necessary to prevent relapse, which is commonly seen in patients receiving glucocorticoids alone and leads to remission in more than 80% of the cases.
The studies excluded patients with granulomatosis with polyangiitis (formerly Wegener granulomatosis). In cases of granulomatosis with polyangiitis (formerly Wegener granulomatosis), oral therapy has been preferred by some experts. IV cyclophosphamide generally have less total dose and thus less toxicity than its oral counterpart.
Azathioprine
PO azathioprine (AZA) has been recommended by some experts to replace cyclophosphamide after an initial 3-month induction period of cyclophosphamide.
- Route: PO
- Dose: 2 mg/kg
- Duration: 6-12 months
Methotrexate
Methotrexate (MTX) has been used in mild forms of granulomatosis with polyangiitis (formerly Wegener granulomatosis) as a replacement for cyclophosphamide. In more severe forms, it has been used following short-term induction therapy with cyclophosphamide. Villa-Forte and colleagues enrolled 82 patients in 2007; 70% of those had severe disease on admission and required cyclophosphamide for remission induction. Severity was based on clinical and histopathological findings: pulmonary hemorrhage, neurological abnormalities, need for dialysis, serum creatinine > 2 mg/dL, and RPGN. 72% of patients were in remission after 1 year, and 91% reached remission at any duration. Relapse rates were as high as 66% within 2 years, most of which responded to reinitiation of therapy.
Induction of Remission for Severe Cases:
- Cyclophosphamide
Route: PO
Dose: 2 mg/kg adjusted for renal function and WBC count
- Route: PO
- Dose: 2 mg/kg adjusted for renal function and WBC count
- Prednisone
Route: PO
Dose: 1 mg/kg
- Route: PO
- Dose: 1 mg/kg
Initial Treatment:
- Methotrexate (MTX)
Route: PO
Dose: 15 mg/wk increased over 4-8 weeks to 25 mg/wk if tolerated and if necessary
Duration: At least 2 years
- Route: PO
- Dose: 15 mg/wk increased over 4-8 weeks to 25 mg/wk if tolerated and if necessary
- Duration: At least 2 years
- Prednisone
Route: PO
Dose: 1 mg/kg/d to gradually decrease as long as no documented disease recurrence
- Route: PO
- Dose: 1 mg/kg/d to gradually decrease as long as no documented disease recurrence
Rituximab
The RITUXVAS (Randomized trial of Rituximab vs. Cyclophosphamide in ANCA-Associated Vasculitis) and RAVE (Rituximab in ANCA-Associated Vasculitis Trial) trials showed in 2012 that anti-B therapy by rituximab, a chimeric anti-human CD20 monoclonal antibody, may improve renal survival in patients with vasculitis and positive ANCA and had renal impairment, including patients with granulomatosis with polyangiitis (formerly Wegener granulomatosis). The findings were based on earlier reports of improved outcome using rituximab.
Regimen:
Rituximab:
- Route: IV
- Dose: 375 mg/m2
- Duration: Once weekly 4 consecutive weeks
Cyclophosphamide
- Route: IV
- Dose: 15 mg/kg
- Duration: Co-administed with 1st and 3rd rituximab doses
Methylprednisolone
- Route: IV and PO
- Dose: 1g IV then followed by daily low-dose oral corticosteroids for maintenance
Other
Some medications have never been studied. However, they have been shown to be effective based on findings in case reports. These medications include:
- IV immunoglobulins (Igs)
- Antithymocyte antibody
- Monoclonal antibodies to CD4
- Monoclonal antibodies to CD25

## Plasma Exchange
Indications of plasma exchange:
- Removal of circulating auto-antibodies in patients with anti-GBM antibody disease
- Patients with high risk of renal failure
- Patients with serum creatinine > 2.3 mg/dL
- Patients who do not respond to pharmacologic therapy
- Patients diagnosed with pauci-immune crescenteric glomerulonephriits with ESRD and need dialysis
The true value of plasma exchange has been demonstrated by a few small trials in secondary analysis. The real indications and benefit to risk ratio of plasma exchange are yet to be elucidated.