Continuing Education Activity

Rapidly Progressing Glomerulonephritis (RPGN) is a challenging clinical condition that involves a rapid decline in kidney function and complex histopathological features. Distinctive clinical and pathological signs characterize the syndrome, such as a fast loss of renal function over a short period, unusual urine analysis, and a crescent formation in renal biopsies. An early diagnosis is crucial to prevent further renal function loss. RPGN is classified based on the histopathology of immune complex deposition, linear antibody deposition, granular immune complex deposition disorders, and pauci-immune disorders. The complex pathogenesis of RPGN involves basement membrane rupture, fibrin precipitate, and cellular proliferation. The multifaceted nature of RPGN requires a collaborative approach involving primary care clinicians, nephrologists, intensive care nurses, and pharmacists. Timely referrals for comprehensive management, including dialysis and potential kidney transplants, can improve patient outcomes. This comprehensive understanding of RPGN's clinical nuances will enable healthcare professionals to contribute effectively to the collaborative care needed for patients with this renal condition.

Objectives:

• Identify early signs and symptoms of rapidly progressive glomerulonephritis to enable timely intervention.

• Differentiate between rapidly progressive glomerulonephritis and other renal conditions through thorough diagnostic evaluation and histopathology results.

• Select appropriate immunosuppressive therapies tailored to the specific etiology of rapidly progressive glomerulonephritis and the appropriate timing of treatment initiation.

• Collaborate with nephrologists and other specialists in the interprofessional management of rapidly progressive glomerulonephritis cases to advance patient care and improve outcomes.

Introduction

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

• Rapid loss of renal function over a very short period (days to weeks)
• Nephritic urine analysis: proteinuria, micro or macroscopic hematuria, dysmorphic red blood cells (RBC), RBC casts
• Histopathological characteristic of renal biopsy findings: cellular crescent formation in the glomeruli, which is a proliferative cellular response seen outside the glomerular tuft within Bowman 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 follows:

• Linear antibody deposition.
• Granular immune complex deposition disorders.
• Pauci-immune (absence of deposition) disorders.

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

Etiology

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

Anti-Glomerular Basement Membrane Disease

Circulating antibodies IgG directed against an antigen normally present in the anti-glomerular basement membrane disease (GBM) and/or alveolar basement membrane, specifically the noncollagenous domain of α-3 chain of type IV collagen. The deposition is approximately 10% to 15% of all diffuse crescentic glomerulonephritis. 

The following are characteristic features:

• Crescentic glomerulonephritis (renal limited variant)
• Crescentic glomerulonephritis with pulmonary hemorrhage, the combination of glomerulonephritis and pulmonary hemorrhage referred to as Goodpasture syndrome
• Crescentic glomerulonephritis associated with the positive anti-neutrophil cytoplasmic antibody (ANCA), sometimes called “dual antibody disease” or “double positive," in which the patient has crescentic glomerulonephritis 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.

Granular Immune Complex Disorder

It can be idiopathic or secondary to the following:

• Postinfectious GN, especially after a Streptococcus infection
• Collagen vascular disease
• Lupus nephritis
• Henoch-Schönlein purpura – with immunoglobulin A deposits and associated systemic vasculitis
• Immunoglobulin A nephropathy without vasculitis
• Mixed cryoglobulinemia
• Membranoproliferative glomerulonephritis
• Fibrillary glomerulonephritis
• Idiopathic
• Pauci-immune disorder: almost 80% to 90% of cases are positive for ANCA.
• Granulomatosis with polyangiitis, previously called Wegener granulomatosis
• Microscopic polyangiitis (MPA)
• Eosinophilic granulomatosis with polyangiitis (EGPA), or Churg-Strauss syndrome

Drugs Associated with Limited or Systemic Glomerulonephritis

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

Idiopathic Pauci-Immune Necrotizing and Crescentic Glomerulonephritis

The hallmark features are negative anti-GBM antibodies and negative ANCA in approximately 5% to 10% of the cases.[1][2]

Epidemiology

RPGN is rare worldwide. The incidence in the United States is around 7 cases per 1 million person-years, while 2 cases per 1 million are reported in the United Kingdom. Reported clusters are recognized worldwide, suggesting a possible environmental influence on the pathogenesis.[3] The disease is more common among the white population, and some reported incidences in the Asian population. The prevalence is less common in African Americans. The male-to-female ratio in most studies is approximately 1:1. The disease represents a bimodal distribution related to the mean age for clinical manifestation. In most series, the mean age is around 30 years, and the second peak is in the late sixties to seventies. However, the prevalence has been reported from ages 2 to 92 years, although it is infrequent in the pediatric population.[4][5] 

For GBM disease, 10% to 15% of all diffuse crescentic glomerulonephritis, with an incidence of 0.5 to 0.9/million/year, is mainly seen in white patients. It has a slight male predominance, M: F 3:2, and a bimodal distribution. The mean age is around 30 years, and the second peak is in the late sixties to seventies. Immune complex glomerulonephritis comprises 25% to 30% of all cases of rapid progressive glomerulonephritis.

The pauci-immune disorder is the most common type of crescentic glomerulonephritis with 65% to 70% prevalence mainly in white patients, with peak age 60 to 85 years, and the majority of patients are 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 when immunosuppressive treatment starts, the infection is the most common cause of mortality. RPGN is an infrequent cause of end-stage kidney disease (ESKD) in various case studies.[1]

Pathophysiology

The primary feature of crescentic glomerulonephritis is the basement membrane rupture followed by extra capillary fibrin precipitation, the proliferation of parietal cells, and the formation of capsular proliferation in a crescent shape. Hence, the name of crescentic glomerulonephritis.

Each disease leads to this pathway in different ways. In anti-GBM disorder, circulating antibodies are usually IgG directed against an antigen present in the GBM and/or alveolar basement membrane, specifically the non-collagenous domain of the α-3 chain of type IV collagen.[6] These antibodies will cause glomerular capillary wall injury by local complement activation and polymorphonuclear leukocytes. The T-cell is independent of this mechanism.[2] Some precipitating factors are environmental triggers for forming these antibodies, like smoking and hydrocarbons. Also, a genetic association exists in which HLA-DR15 increases the risk of anti-GBM.

Another 10% to 15% of cases are associated with the immune complex deposition in the glomerular capillary tufts. The mechanism is either by forming the immune complex in the circulation and getting deposited at the glomerular capillary tuft or producing 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 become a complication of another primary glomerulonephritis (membranous/C3 glomerulonephritis).[7]

50% to 80% of cases involve the anti-nuclear cytoplasmic antibody (ANCA). The ANCA is 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. The activation of local and systemic complement occurs mainly through an alternative pathway. Cytokines, including TNF-α, also play a significant role in the pathogenesis. Also, producing anti-plasminogen and plasminogen activator autoantibodies can inhibit fibrinolysis and predispose to fibrinoid necrosis and thrombophilia.[8] 

Ultimately, the proliferation of parietal and visceral epithelial cells, fibrin polymerization, monocyte/macrophages and t-cells infiltration, and myofibroblast cell invasion from the interstitium forms glomerular crescents. Interleukin-1 (IL-1), TNF-α, macrophage chemotactic protein-1 (MCP-1), macrophage inflammatory factor (MIF), and TGF-β production play a role in the inflammatory process.

Histopathology

The primary lesion of crescentic glomerulonephritis is the destruction of a glomerular capillary wall and the accumulation of parietal and visceral epithelial cells in Bowmen’s space, forming a crescent. An accompanying accumulation of lymphocytes, macrophages, and myofibroblasts occurs with the proliferation of podocytes. That leads to diffuse, proliferative, necrotizing glomerulonephritis with crescent formation. During the biopsy, ANCA lesions can be found in various stages of crescents (cellular, fibrocellular, or fibrous). In contrast, all lesions in anti-GBM disease are in the same nephritic 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 at the same stage. In immune complex deposition disease, the granular deposition of IgG, IgM, or IgA along the capillary wall and lesions are in different stages. In Ppauci-immune disorder, no or scant IgG, IgM, or C3 deposits are seen on immunofluorescent. The ANCA-associated glomerulonephritic lesions are also in various stages; sometimes, fibrinoid necrosis is found along with other lesions.[9][10]

History and Physical

A rapid decline in renal function occurs over weeks to months, with early clinical features usually nonspecific. Sometimes, hemoptysis and shortness of breath may be the first clinical feature.

• Anti-GMB disease may present with pulmonary involvement in diffuse alveolar hemorrhage, and patients present with shortness of breath, cough, hemoptysis, nephritis, hematuria, and edema.
• The extrarenal manifestations suggest the presence of 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, numbness, weakness, blurry vision, stroke
  • Skin: palpable purpura, ulcer, livedo reticularis

If not addressed promptly, a progressive and rapid loss of renal function and, eventually, renal failure may occur. Once renal failure presents, the patient can have fatigue, loss of appetite, nausea, vomiting, and 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 RPGN:

• Urinalysis, urine protein, and creatinine ratio: The microscopic examination can further detect the dysmorphic red blood cell characteristics of glomerular hematuria. Proteinuria can suggest sub-nephrotic or nephrotic range proteinuria.
• Elevated serum creatinine, abnormal electrolyte potassium, magnesium, and calcium
• CBC with differential: Eosinophilia correlates eosinophilic granulomatosis with polyangiitis (EGPA).
• Serology for anti-GBM antibody through ELISA or western blot in approximately 10% of patients with 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 a kidney biopsy is available for that disease.[2]
• ANCA test: The old test was through indirect immunofluorescence, and its qualitative assay resulted in P-ANCA or C-ANCA; the other newer method used now is through ELISA, which identifies specific antigens and provides titer (quantitative] for antiprotease 3 [PR-3] and anti-myeloperoxidase (MPO). C-ANCA is 90% PR-3 reactive and 10% MPO reactive, while P-ANCA is 90% MPO reactive and 10% PR-3 reactive.[11]
• Serology to rule post infections: antistreptolysin titer for post-Streptococcus infection, HIV, and hepatitis B and C serology.
• Complement C3, C4 level: This may be low in some form of granular immune complex disorders causing RPGN, such as lupus, cryoglobulinemia, and primary membranoproliferative glomerulonephritis.
• Serology for lupus: anti-nuclear antibody, ds DNA, anti-Smith
• Rheumatoid factor and cryoglobulin level in suspected cases of cryoglobulinemia
• Chest x-ray, chest CT if suspecting diffuse alveolar hemorrhage, or looking for a cavitary lesion in case of vasculitis. 
• Bronchoscopy for diffuse alveolar hemorrhage if it is suspected.
• Otolaryngologic evaluation and biopsy or skin biopsy for vasculitis.
• Histological diagnosis through renal biopsy is the mainstay for the definitive diagnosis.
• 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 glomerulonephritis patients, it activates neutrophil and also injures 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] 
• Other Tests: LDH, platelet, reticulocyte, blood film, and anticardiolipin antibody to rule out other causes mimicking RPGN, like thrombotic thrombocytopenic purpura (TTP). 

Treatment / Management

The untreated RPGN progresses 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 begin before the definitive diagnosis is made, especially when serology and kidney biopsy are delayed. This empiric therapy includes a pulse IV dose of methylprednisolone, 500 mg or 1 g, for a minimum of 3 doses. Plasmapheresis may be explicitly considered 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 when the definitive diagnosis is made.

Anti-GBM Disease

The choice of treatment is plasmapheresis in combination with immunosuppressive agents. Initiating treatment as early as possible is the key to preventing progressive renal failure. No evidence of the benefit of plasmapheresis is apparent so far. However, it is still considered the choice by most nephrologists because most of the data from the era of plasmapheresis have shown improved morbidity and mortality compared to the earlier studies. Another possible reason is that with plasmapheresis, rapid removal of the harmful antibodies is compared to immunosuppressive therapy alone.

The dose of plasmapheresis is 4 L of an exchange over 2 to 4 weeks. Usually, albumin is considered a replacement fluid, but a portion of fresh frozen plasma should be considered in the case of a recent kidney biopsy and when pulmonary hemorrhage is also seen. After 2 to 4 weeks, the patient should be reevaluated whether further treatment is needed. Treatment may be considered for an extended period if active pulmonary disease is apparent or the antibody level does not decline 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 aged greater than 60 to avoid toxicity. Patients with adverse effects from cyclophosphamide or, for any other reason, cannot tolerate cyclophosphamide, rituximab, or mycophenolate mofetil is recommended.

The optimal duration of treatment is unclear. 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 fewer side effects, like low-dose Prednisone or Azathioprine, should be considered for maintenance treatment. Recent studies are showing the benefit of the use of immunoadsorption agents in the treatment of anti-GBM disease.

ANCA Positive Pauci-Immune Crescentic Glomerulonephritis

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

The recommended initial treatment is glucocorticoids with either cyclophosphamide or rituximab with or without plasmapheresis. Plasmapheresis is indicated if renal function rapidly deteriorates or severe renal involvement is seen during presentation. Serum creatinine level greater than 4 mg/mL, need for dialysis, presence of pulmonary hemorrhage, or coexisting anti-GBM antibodies are also indicative.

Immune Complex Glomerulonephritis

The treatment depends on the etiology of the associated condition and should be treated accordingly (IgA glomerulonephritis, lupus nephritis, cryoglobulinemia, etc). Post-streptococcal glomerulonephritis is usually recovering spontaneously. Very rarely, glucocorticoids are indicated for severely crescentic RPGN.

Drugs Associated with Glomerulonephritis

After stopping the medication, the condition usually resolves on its own, but sometimes treatment is necessary for pauci-immune glomerulonephritis, as mentioned above.

Double Positive Antibody

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

Differential Diagnosis

Various causes of RPGN 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.

• Prerenal AKI
• AKI due to acute tubular injury
• Obstructive uropathy
• Nephrotic syndrome – focal segmental glomerulonephritis, minimal change disease, membranous nephropathies, etc.
• Hematuria- due to other urologic etiology
• Antiphospholipid antibody 
• Thrombotic microangiopathy (TMA)

Prognosis

Various histopathologic lesions are indicative of the prognosis. The extent of crescentic involvement in 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. Meanwhile, more than 50% of glomeruli with cellular crescents have 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 a 5-year 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] 

The time of initiation of the treatment is very crucial for stopping the rapidly progressive irreversible damage. The earlier the treatment initiated, the better the outcome. Age and gender do not affect the overall prognosis significantly. Children usually do well after the treatment compared to older adults.[21] The magnitude of proteinuria has not been shown to affect short-term prognosis, but persistent proteinuria, despite treatment, indicates poor long-term outcomes. Renal function at the presentation reflects 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] The pretreatment antibody level affects the prognosis. The higher the anti-GBM Ab level at the time of diagnosis is associated with poor renal outcome. The ANCA level has a complex association with the renal outcome.[21] DRB 1* 15 allele is a risk factor for Anti-PR3 ANCA vasculitis. HLA DR-2 and/or B-7 are possibly associated with the disease's severity and outcome.[22] RPGN associated with drugs and infection is associated with a better outcome.

Complications

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

Disease-Related Complications

1. Pulmonary hemorrhage specifically is seen in anti-GBM disease.
2. Upper respiratory and lower respiratory involvement is associated with ANCA glomerulonephritis.
3. The various immune complex deposition glomerulonephritis present with extrarenal manifestations, eg, lupus nephritis cases, may have other organ involvement like serositis, cerebritis, and 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 removing clotting factors, putting the patient at a higher risk of bleeding-related complications.

Deterrence and Patient Education

Timely diagnosis and treatment improve outcomes of RPGN. 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, and other system involvement, specifically shortness of breath, hemoptysis, etc. The treatment is associated with 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 effects of immunosuppressive drugs used to treat glomerulonephritis, including various infections, and the importance of antibiotic prophylaxis to decrease opportunistic infections.

Enhancing Healthcare Team Outcomes

RPGN is a group of complex diseases that affect the kidneys and other organs. Early diagnosis and treatment are essential. Primary care clinicians should refer patients to nephrologists promptly. Dialysis and critical care facilities are necessary for treating RPGN patients. A comprehensive interprofessional team approach is crucial for managing extrarenal manifestations. Nurses, pharmacists, and clinicians are vital in patient care and education. After discharge, patients receive immunosuppressive therapy and require close follow-up to monitor recovery and opportunistic infections. Lifelong dialysis is necessary for patients with poor outcomes. Timely referrals for kidney transplants are indicated in cases of chronic kidney failure.