Rapidly progressive glomerulonephritis (RPGN) is a clinical and pathological syndrome; a term used to describe the following:
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.
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
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)
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.
It is more common among the White population, and some reported incidences in the Asian population as well. 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 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.
For anti-glomerular basement membrane (GBM) disease: it is 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 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.
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. and each disease leads to this pathway in different ways as follow:
For 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 . 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. 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).
50% to 80% of cases are involved with the anti-nuclear cytoplasmic antibody (ANCA). The ANCA either directed against myeloperoxidase (MPO), proteinase 3 (PR3), or both. When MPO and PR3 both are 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 is the production of anti- plasminogen and plasminogen activator autoantibodies, which can inhibit fibrinolysis and predispose to fibrinoid necrosis and thrombophilia.
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.
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 myofibroblast 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. The 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.
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
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).
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:
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 (considering 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
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 harming 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 recent kidney biopsy and when there is pulmonary hemorrhage. After 2 to 4 weeks, the patient should be reevaluated whether further treatment id 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 recommended that the dose should not be more than 100 mg/day for patients with the age of more than 60 years to avoid the toxicity.
Patients having side effects form 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 1-2 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)
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 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
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 excluded.
The complications can be divided on the bases of related to the disease and related to the treatment.
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.
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 the 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 the opportunistic infection.
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 physician plays a pivotal role by referring the patient to the nephrologist promptly. A patient needs to be admitted with the skilled facility where dialysis and other critical care facilities are within the premises. With the extrarenal manifestation, a comprehensive team approach is crucial. Patients having pulmonary hemorrhage may require mechanical ventilator support in the ICU set up.
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 referral for kidney transplants should be made as a modality of treatment.
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