Continuing Education Activity

Rapidly progressive glomerulonephritis is the cause of rapid loss of renal function. It is a rare syndrome but has a high rate of renal failure and morbidity associated with it. Timely intervention is a key point in preserving renal function. This activity explains the epidemiology, etiology, and pathology, along with the treatment options. It highlights the role of the interprofessional team.

Objectives:

• Identify the etiology of rapidly progressive glomerulonephritis.
• Describe the histopathology of rapidly progressive glomerulonephritis.
• Review when to start immunosuppressive treatment for rapidly progressive glomerulonephritis.
• Summarize interprofessional team strategies for improving care coordination and communication to advance the care of patients with rapidly progressive glomerulonephritis and improve outcomes.

Introduction

Rapidly progressive glomerulonephritis (RPGN) is a clinical and pathological syndrome; a term used to describe the following:

1. Rapid loss of renal function over a very short period (days to weeks)
2. Nephritic urine analysis: proteinuria, micro or macroscopic hematuria, dysmorphic red blood cells (RBC), RBC casts
3. Histopathological characteristic on renal biopsy finding; cellular crescent formation in the glomeruli; which is proliferative cellular response seen outside the glomerular tuft within Bowman's capsule and because of its crescentic shape called crescentic glomerulonephritis.

Early diagnosis is very important for diagnosis and management, requiring preventing further renal function loss.

RPGN is broadly classified based on the histopathology and immune complex deposition as follow:

A. Linear antibody deposition.

B. Granular immune complex deposition disorders.

C. Pauci-immune (absence of deposition) disorders.

There are some mixed, as well as idiopathic variants are also reported.[1]

Etiology

Rapidly progressive glomerulonephritis is broadly classified based on the histopathology and immune complex deposition as follows:

A) Linear antibody deposition, anti-glomerular basement membrane (GBM) disease: it is circulating antibodies IgG directed against an antigen normally present in the GBM and/or alveolar basement membrane, specifically the non-collagenous domain of alpha-3 chain of type IV collagen. It is approximately 10% to 15% of all diffuse crescentic GN. It can be presented as one of the following features:

1. Crescentic glomerulonephritis alone (renal limited variant)

2. or with pulmonary hemorrhage; The combination of glomerulonephritis and pulmonary hemorrhage referred to as Goodpasture syndrome

3. or associated with the positive anti-neutrophil cytoplasmic antibody (ANCA), sometimes called “dual antibody disease” or “double positive; in which patient has crescentic GN and positive for both ANCA and anti-GBM antibody, some literature showed 10% to 50% of patients with the anti-GBM disease have detectable ANCA (usually recognizing myeloperoxidase [MPO]), and up to 10% of patients with ANCA also have circulating anti-GBM antibodies.

B) Granular immune complex disorder: it can be idiopathic or secondary to the following:

1. Postinfectious GN, especially after a Streptococcus infection

2. Collagen vascular disease

3. Lupus nephritis

4. Henoch-Schönlein purpura – there is immunoglobulin A deposits and associated systemic vasculitis

5. Immunoglobulin A nephropathy without vasculitis

6. Mixed cryoglobulinemia

7. Membranoproliferative glomerulonephritis

8. Fibrillary glomerulonephritis

9. Idiopathic

C) Pauci-immune disorder: almost 80 to 90% of cases are positive for ANCA.

1. Granulomatosis with polyangiitis [GPA], previously called Wegener granulomatosis

2. Microscopic polyangiitis -MPA

3. Eosinophilic granulomatosis with polyangiitis – EGPA, Churg-Strauss syndrome

4. There are various drugs associated with the GN (renal limited or systemic)

•  Hydralazine
•  Levamisole contaminated cocaine
•  Propylthiouracil and methimazole
•  Allopurinol
•  Sulfasalazine
•  Minocycline
•  Penicillamine
•  Rifampicin
•  Aminoguanidine
•  Sofosbuvir
•  Anti-TNF alfa therapy for rheumatoid arthritis and ankylosing spondylitis

 D) Idiopathic pauci-immune necrotizing and crescentic GN: with negative anti-GBM antibody and negative ANCA, and it is approximately 5 to 10% of the cases.[1][2]

Epidemiology

Rapidly progressive glomerulonephritis is very rare worldwide. The incidence in the United States of America is around 7 cases per 1 million person-years, while it is 2 cases per 1 million person-years reported in the United Kingdom. There are other reported clusters all over the world, suggesting a possible environmental influence on the pathogenesis.[3]

It is more common among the white population, and some reported incidences in the Asian population. It is relatively uncommon in African Americans. 

The male-to-female ratio in most of the studies is approximately 1:1. The disease represents a bimodal distribution related to the mean age for clinical manifestation. In most of the series, the mean age is around 30 years and the second peak in the late sixty to seventies. But the prevalence has been reported from the age group 2 years to 92 years, although it is very rare in the pediatric population.[4][5] 

For anti-glomerular basement membrane (GBM) disease: 10 to 15% of all diffuse crescentic glomerulonephritis, with an incidence of 0.5-0.9/million/year, mainly seen in white patients. It has a slight male predominance M: F 3:2 and has a bimodal distribution, and the mean age is around 30 years and the second peak in the late sixty to seventies.

Immune complex glomerulonephritis comprises 25 to 30% of all cases of rapid progressive glomerulonephritis.

Pauci-immune disorder: most common type of crescentic glomerulonephritis 65 to 70%, mainly white patients, with peak age 60 to 85 years, the majority of patients have anti neutrophilic antibody ANCA positive.

The cause of mortality in RPGN is usually pulmonary involvement in ANCA-associated disease. The younger population is more associated with this kind of presentation, but once immunosuppressive treatment started, the infection is the commonest cause for mortality.

RPGN is a very rare cause of end-stage kidney disease (ESKD) in various case studies.[1]

Pathophysiology

The primary feature of crescentic glomerulonephritis is the rupture of the basement membrane followed by extra capillary fibrin precipitate, and this, followed by the proliferation of parietal cells and formed capsular proliferate in a crescent shape. Hence, the name of crescentic GN. Each disease leads to this pathway in different ways:

In anti-GBM disorder, there are circulating antibodies; usually, IgG directed against an antigen present in the GBM and/or alveolar basement membrane, specifically the non-collagenous domain of alpha-3 chain of type IV collagen [6]. These antibodies will cause glomerular capillary wall injury by local complement activation and polymorphonuclear leukocytes. There is also the role of the T-cell-independent of this mechanism.[2] some precipitating factors are environmental triggers for the formation of these antibodies, like smoking, hydrocarbons. Also, there is a genetic association in which HLA-DR15 increases the risk of anti-GBM.

In another 10 to 15% of cases are associated with the immune complex deposition in the glomerular capillary tufts. The mechanism is either by the formation of the immune complex in the circulation and getting deposited at the glomerular capillary tuft or production of this immune complex in situ in the glomerular capillary wall. The antigen associated with the immune complex formation is heterogeneous, either exogenous (virus/bacteria) or autogenous (nuclear antigens/tumor antigens). Immune complex-mediated glomerulonephritis is often due to multisystem disease (lupus), or it can arise as a complication of another primary glomerulonephritis (membranous GN/C3 GN).[7]

Fifty to 80% of cases are involved with the anti-nuclear cytoplasmic antibody (ANCA). The ANCA is either directed against myeloperoxidase (MPO), proteinase 3 (PR3), or both. When MPO and PR3 are both involved, it usually suggests drug-induced pathogenesis. The precise mechanism by which ANCA arises is not clear, but it is evident that autoantibodies activate neutrophils to injure the glomerular capillary wall. There is the activation of local as well as systemic complement, mainly through an alternative pathway. Cytokines, including tumor necrosis factor alfa, also play a significant role in the pathogenesis. Also, there are the production of anti-plasminogen and plasminogen activator autoantibodies, which can inhibit fibrinolysis and predispose to fibrinoid necrosis and thrombophilia.[8] 

Ultimately, there is the proliferation of parietal and visceral epithelial cells, polymerization of fibrin, infiltration of monocyte/macrophages and t-cells, and myofibroblast cell invasion from the interstitium forming glomerular crescents. The interleukin-1 (IL-1), TNF- alfa, macrophage chemotactic protein-1 (MCP-1), macrophage inflammatory factor (MIF), Tumor growth factor-beta production play a role in the whole process.

Histopathology

The primary lesion of crescentic GN is the destruction of a glomerular capillary wall along with the accumulation of parietal and visceral epithelial cells in Bowmen’s space, forming a crescent. There is an accompanying accumulation of lymphocytes, macrophages, and myofibroblasts with the proliferation of podocytes. That leads to diffuse, proliferative, necrotizing glomerulonephritis with crescent formation. ANCA lesions can be found in various stages of crescents (cellular, fibrocellular, or fibrous) at the time of the biopsy, whereas all lesions in anti-GBM disease are in the same GN stage. Interstitial inflammation is also found mainly in the periglomerular region. In the later stage, fibrosis developed rapidly over a few days to weeks manifesting as glomerular sclerosis and obliteration. The immunofluorescence of the anti-GBM disease would show linear IgG deposition along the capillary wall and lesions on the same stage. While in immune complex deposition disease, there is the granular deposition of IgG, IgM, or IgA along the capillary wall, and lesions are in different stages. Pauci-immune disorder: There are no deposits, or very scant deposits of IgG or IgM or C3 is seen on immunofluorescent; the ANCA-associated GN lesions are also in various stages, and sometimes fibrinoid necrosis is found along with the other lesions.[9][10]

History and Physical

There is a rapid decline in renal function over weeks to months, with early clinical features usually non-specific. Sometimes hemoptysis and shortness of breath may be the first clinical feature.

• Anti-GMB disease may present with pulmonary involvement in the form of diffuse alveolar hemorrhage, and patients present with shortness of breath, cough, and hemoptysis, along with nephritis, hematuria, and edema.
• The extrarenal manifestations suggest the presence of the immune complex disorders or ANCA vasculitis include:
• General: fever, night sweat, weight loss, arthralgia
• Oral: mucosa ulceration.
• Eye: scleritis
• ENT: hearing impairment, otitis, epistaxis, nasal drainage, sinusitis, nasal cartilage necrosis.
• Respiratory: shortness of breath, cough, hoarseness of voice, tracheal or bronchial ulceration/stenosis, diffuse pulmonary hemorrhage, infiltrate.
• GI: abdominal pain secondary to ischemia, infarction, pancreatitis.
• CNS: mononeuritis multiplex, CNS vasculitis, so patient present with numbness, weakness, blurry vision, stroke.
• Skin: palpable purpura, ulcer, livedo reticularis

If not addressed promptly, there is a progressive and rapid loss of renal function and, eventually, renal failure. Once renal failure presents, the patient can have fatigue, loss of appetite, nausea, and vomiting, decreased urine output (oliguria).[10]

Evaluation

The clinical suspicion, as described in the section of the history and presentation, is backed with the laboratory test for the major causes of rapidly progressive glomerulonephritis:

1. Urinalysis, urine protein, and creatinine ratio: looking for microscopic hematuria and proteinuria. The microscopic examination can further detect the dysmorphic red blood cell characteristics of glomerular hematuria. Proteinuria can suggest sub nephrotic or nephrotic range proteinuria.
2. Elevated serum creatinine, abnormal electrolyte potassium, magnesium, and calcium
3. CBC with differential: eosinophilia with eosinophilic granulomatosis with polyangiitis (EGPA)
4. Serology for anti-GBM antibody through ELISA or western blot, approximately 10% of patients who have anti-GBM diagnosis through kidney biopsy do not have identifiable circulating antibodies with conventional assays. Serologic testing should not be the only method of diagnosis when kidney biopsy is available for that disease.[2]
5. ANCA test: the old test was through indirect immunofluorescence, and its qualitative assay resulted as P-ANCA or C-ANCA; the other newer method used now is through ELISA, which identifies specific antigen and provides titer (quantitative] for antiprotease 3 [PR-3] and anti-myeloperoxidase (MPO). It is essential to know that C-ANCA is 90% PR-3 reactive, 10% MPO reactive, while P-ANCA 90% MPO reactive, and 10% PR-3 is reactive.[11]
6. Serology to rule post infections: antistreptolysin titer for post Streptococcus infection, HIV, and Hepatitis B and C serology.
7. Complement C3, C4 level: may be low in some form of granular immune complex disorders causing RPGN like lupus, cryoglobulinemia, primary MPGN.
8. Serology for lupus: anti-nuclear antibody, ds DNA, anti-Smith
9. Rheumatoid factor and cryoglobulin level in suspected cases of cryoglobulinemia
10. Chest X-ray, chest of the chest CT if suspect diffuse alveolar hemorrhage, or looking for a cavitary lesion in case of vasculitis 
11. Bronchoscopy for diffuse alveolar hemorrhage if it is suspected.
12. Otolaryngologic evaluation and biopsy or skin biopsy for vasculitis
13. Histological diagnosis through renal biopsy is the mainstay for the definitive diagnosis
14. Other pathogenic antibodies in ANCA-associated disorder: two new antibodies have been identified and associated with ANCA disease:
    • LAMP-2 [lysosome-associated membrane protein-2] antibody: positive in more than 90% of ANCA positive patients and greater than 90% of ANCA negative pauci-immune crescentic GN patients, it activates neutrophil and also injure endothelium directly.[12][13][14] 
    • Anti-plasminogen antibodies: ranging between 22 and 43% for proteinase-3 (PR3)- ANCA-associated vasculitis (AAV) and 6% to 27% for myeloperoxidase (MPO) AAV, correlate with both venous thromboembolic event.[15] 
15. Other Tests: LDH, platelet, reticulocyte, blood film, anticardiolipin antibody to rule out other causes mimic RPGN like thrombotic thrombocytopenic purpura (TTP). 

Treatment / Management

The untreated rapidly progressive glomerulonephritis progress to rapid loss of renal function over weeks to months. It is very crucial to start treatment as soon as possible.

Empiric treatment is proposed to start before the definitive diagnosis is made, especially in the case where serology and kidney biopsy are delayed due to any reason.

This empiric therapy includes pulse IV dose of methylprednisolone, either 500 mg or 1 gm, for a minimum of 3 doses. Plasmapheresis may be considered specifically if the patient has hemoptysis raising concern for the severe form of Goodpasture disease until one has the definitive diagnosis.

Later more specific treatment is considered once the definitive diagnosis is made.

I Anti-GBM Disease

• An intravenous dose of methylprednisolone followed by oral prednisone
• PO cyclophosphamide
• Plasmapheresis

The choice of treatment is plasmapheresis in combination with the immunosuppressive agents.

The initiation of treatment as early as possible is the key to the prevention of progressive renal failure.

There is no evidence of the benefit of plasmapheresis so far, but still, it is considered the choice by the majority of nephrologists due to the fact that most of the data from the era from the plasmapheresis have shown improved morbidity and mortality than the earlier studies. The other possible reason is also that with plasmapheresis, there is a rapid removal of the harmful antibodies as compared to the immunosuppressive therapy alone.

The dose of plasmapheresis is 4 L of an exchange over 2 to 4 weeks. Usually, albumin is considered as a replacement fluid, but a portion of fresh frozen plasma should be considered in the case of a recent kidney biopsy and when there is pulmonary hemorrhage. After 2 to 4 weeks, the patient should be reevaluated whether further treatment is needed or not. Treatment may be considered for an extended period if there is still active pulmonary disease or the antibody level is not declined as expected.

Plasmapheresis is always followed by immunosuppressive therapy, glucocorticoid, and cyclophosphamide.

Usually, a methylprednisone pulse dose is given as described above, followed by oral prednisone. Very rarely, only oral prednisone is considered. The dose of cyclophosphamide is 2 mg/kg/day orally. It is recommended that the dose should not be more than 100 mg/day for patients with an age of more than 60 years to avoid toxicity.

Patients having side effects from cyclophosphamide or, due to any other reason, not able to tolerate cyclophosphamide, rituximab, or mycophenolate mofetil is recommended.

The optimal duration of treatment is not clear. Anti-GBM antibody levels should be measured for 1 to 2 weeks after initiation of the treatment until 2 consecutive negative levels a week apart. After this remission phase, an agent with lesser side effects like low-dose prednisone or azathioprine should be considered for the maintenance treatment.

There are recent studies showing the benefit of the use of immunoadsorption agents in the treatment of Anti- GBM disease.

II ANCA Positive Pauci-immune Crescentic Glomerulonephritis (GPA & MPA)

• An IV dose of methylprednisolone followed by oral prednisone
• IV or PO cyclophosphamide and/or rituximab
• Plasmapheresis
• Duration of therapy for 3 to 4 month
• Maintenance of therapy is mandatory

The recommended initial treatment is with glucocorticoids with either cyclophosphamide or rituximab with or without plasmapheresis. Plasmapheresis is indicated if there is a rapid deterioration of renal function or severe renal involvement at the time of presentation. Serum creatinine of more than 4 mg/ml or need for dialysis, or there is pulmonary hemorrhage, or if the disease is coexisting anti-GBM antibodies.

III Immune Complex Glomerulonephritis

The treatment depends on the etiology of the associated condition and should be treated accordingly (IgA GN, lupus nephritis, cryoglobulinemia, etc.)

The post-streptococcal GN is usually recovering spontaneously. Very rarely, glucocorticoids are indicated for severely crescentic RPGN.

IV Drug Associated GN

Usually recovers spontaneously after stopping the offending agent and sometimes need treatment as pauci-immune GN as above.

V Double Positive Antibody

This is the same as pauci immune GN, but plasmapheresis should be included.[16][17][18][19][20]

Differential Diagnosis

Various causes of rapidly progressive glomerulonephritis are described in the etiology section.

Before considering the diagnosis of RPGN, other etiology of reversible acute kidney injury (AKI), proteinuria, and hematuria other than RPGN are excluded.

1. Prerenal AKI
2. AKI due to acute tubular injury
3. Obstructive uropathy
4. Nephrotic syndrome – focal segmental GN, minimal change disease, membranous nephropathies, etc.
5. Hematuria- due to other urologic etiology
6. Antiphospholipid antibody 
7. Thrombotic microangiopathy (TMA)

Prognosis

1. Various histopathologic lesions are indicative of the prognosis. The extent of crescentic involvement on microscopic findings is indicative of the prognosis. Usually, a focal lesion with more than 50% normal glomeruli has a more favorable prognosis, almost 90% or more renal survival after 5 years follow up after treatment. Whereas more than 50% of glomeruli with cellular crescent has a less favorable prognosis of around 75% renal recovery at 5 years follow up. When more than 50% of glomeruli are globally sclerosed, the renal recovery is less than 25% up to 5 years follow-up period. Variants include cellular, fibrocellular, and fibrous crescent. The extent of chronic tubule-interstitial fibrosis lesions can also impact the prognosis inversely. The disruption of Bowmen’s capsule is associated with poor outcomes.[21]
2. The time of initiation of the treatment is very crucial for stopping the rapidly progressive irreversible damage. The early the treatment initiated, the better is the outcome.
3. Age and gender do not affect the overall prognosis greatly. Children usually tend to do well after the treatment as compared to the elderly.[21]
4. The magnitude of proteinuria has not been shown to affect short-term prognosis, but persistent proteinuria despite treatment is indicative of poor long-term outcomes.
5. Renal function at the presentation is reflecting the severity of the disease, and the higher serum creatinine, anuria, requirement of dialysis is associated with the poor outcome after the treatment and progression to renal failure.[21]
6. The pretreatment antibody level affects the prognosis. The higher the anti-GBM Ab level at the time of diagnosis is associated with the poor renal outcome. Whereas the ANCA level has a complex association with the renal outcome.[21]
7. DRB 1* 15 allele is a risk factor for Anti -PR3 ANCA vasculitis. HLA DR-2 and/or B-7 has a possible association with the severity of the disease and the outcome.[22]
8. RPGN associated with drugs and infection is associated with a better outcome.

Complications

The complications can be divided on the basis of related to the disease and related to the treatment.

Disease-related Complications

1. Pulmonary hemorrhage specifically is seen with anti-GBM disease.
2. Upper respiratory and lower respiratory involvement associated with ANCA GN
3. The various immune complex deposition GNs presents with extrarenal manifestations, e.g., lupus nephritis cases may have other organs involvement like serositis, cerebritis, skin lesions.

Treatment-related Complications

The primary complications related to immunosuppressive therapy are various opportunistic infections, sometimes life-threatening.

Cyclophosphamide has specific complications, including cystitis and hematuria.

Plasmapheresis is associated with the removal of clotting factors, putting the patient at a higher risk of bleeding-related complications.

Deterrence and Patient Education

The timely diagnosis and treatment are the key to the better outcome of most of the rapidly progressive glomerulonephritis. So the high-risk population should be educated about the presenting symptoms of the RPGN and instructed to ask for medical help in case of decreased urine output, blood in urine, along with other system involvement, specifically shortness of breath, hemoptysis, etc.

The treatment is associated with the immunosuppressive modalities and is usually long-term. All patients should be educated about the importance of compliance with the therapy and the complications related to the treatment and should be instructed to seek medical help before stopping any medication.

All patients should be educated about the major side effect of immunosuppressive drugs used in the treatment of GN, including various infections and the importance of antibiotic prophylaxis to decrease opportunistic infection.

Enhancing Healthcare Team Outcomes

Rapidly progressive glomerulonephritis is a complex set of diseases with the involvement of renal as well as other organs.

The timely diagnosis and treatment are the key. The primary care providers play a pivotal role by referring the patient to the nephrologist promptly. A patient needs to be admitted to a skilled facility where dialysis and other critical care facilities are within the premises. With the extrarenal manifestation, a comprehensive interprofessional team approach is crucial. Patients having pulmonary hemorrhage may require mechanical ventilator support in the ICU. Nephrology and intensive care nurses monitor patients and administer treatment. Pharmacists review medications and check for interactions. Both nurses and pharmacists are essential for patient education. [Level 5]

Even after the discharge, usually, patients are sent on immunosuppressive therapy. They need closed clinical follow up for possible recovery and opportunistic infections. Infection should be treated once diagnosed, and the decision should be made on either stopping or decreasing the doses of the therapy depending on individual cases.

Patients with poor outcomes usually end up on lifelong dialysis. They should be comprehensively managed as end-stage kidney disease patients requiring dialysis, and timely referrals for kidney transplants should be made as a modality of treatment.