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]

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 has 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). Now it is essential to know C-ANCA is 90% PR-3 reactive, 10% MPO reactive while P-ANCA 90% MPO reactive, and 10% PR-3 are 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 pot infections, 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 >90% of ANCA + patient and greater than90% 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% to 43% for proteinase-3 (PR3)-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). 

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

• 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 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)

• 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 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]

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.

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)

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 outcome.[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 much affect the overall prognosis. Children usually tend to do well after the treatment as compared to the elderly.[21]
4. The magnitude of proteinuria has not 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.

The complications can be divided on the bases 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.

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.