Anti-GBM disease

AGBM disease associated with circulating antibodies that are directed against an antigen normally present in the GBM and alveolar basement membrane. 

 

 

The target antigen is the alpha-3 chain of type IV collagen. 

 

The limited tissue involvement in anti-GBM disease results from the tissue-specific distribution of the alpha-3 chain of type IV collagen, the specificity of the anti-GBM antibodies, in the glomerular and alveolar capillaries. 

Pulmonary hemorrhage affect the integrity of lung capillaries and allow the anti-GBM antibodies to contact the alveolar basement membrane. 

The  disease usually progresses to renal failure or death if untreated.

 

Renal function ranges from normal to rapidly deteriorating over a few weeks to months, and electrolyte abnormalities, such as hyponatremia, hyperkalemia, hyperphosphatemia, and acidemia, may be seen with advanced disease.

Urinalysis may reveal gross or microscopic hematuria, nephritic urinary sediment with dysmorphic RBCs and RBC casts, and proteinuria.

Patients have a significant risk of morbidity and mortality from renal failure, pulmonary hemorrhage, or complications of treatment. 

 

Disease complications include: renal failure, hyperkalemia, pulmonary edema, hypertension, seizures, pulmonary hemorrhage include hemorrhagic shock and respiratory failure,  complications of immunosuppressive medications include infection, avascular bone necrosis, and bone marrow suppression, complications of plasmapheresis include infection, bleeding, hypocalcemia, and immunoglobulin deficiency, complications of renal transplantation include a recurrence rate of linear immunoglobulin G (IgG) staining in the graft as high as 50%. 

 

Factors play a permissive role in disease initiation of Anti-GBM disease: 

 

Respiratory infections or inhaled toxins may trigger pulmonary involvement.

Factors associated with renal manifestations are renal injury from ischemia or membranous glomerulonephritis.

 

It manifests as a spectrum of disease ranging from mild to no renal involvement to a rapidly progressive glomerulonephritis.

Typically associated with a rapidly progressive glomerulonephritis without prodromal symptoms.

Symptoms of systemic illness include: low-grade fever, malaise, headache, anorexia, nausea, vomiting, weight loss, and fatigue.

 

 

Renal  involvement findings include hematuria, oliguria, and edema.

 

ANCA positive patients may present with pruritic skin rashes and arthralgia.

Clinical  findings depend on the organ involvement, and severity disease. 

Renal symptoms include: 

volume overload may result in tachycardia, tachypnea, hypertension, pulmonary rales, pitting edema, and uremia.

Pulmonary involvement symptoms include.:

Respiratory distress, and pulmonary hemorrhage.

 

Lung involvement systems include shortness of breath, cough, and expectoration of blood-streaked sputum to include massive hemoptysis. 

Goodpasture syndrome patients are antineutrophilic cytoplasmic antibody (ANCA) positive  in about 30% of patients, at some point in their illness.

Has a bimodal distribution with younger adults 20 to 40 years of age, and more commonly involving men, with pulmonary-renal syndrome

Older patients tend to be 60 years of age or older and are frequently women, who often present with isolated renal involvement.

The autoantibody is expressed against the non-collagenous domain 1 of the alpha-3 chain of type IV collagen specific to specialize basement membranes of the glomeruli and alveoli.

Many develop pulmonary hemorrhage.

 

 

Most individuals have signs of a generalized systemic illness. 

 

 

Most patients present with features of systemic illness and either acute nephritis or pulmonary involvement.

 

More than 90% of patients survive the acute phase of the disease. 

The 2-year survival rate is less than 50%.

 

End-stage renal disease develops in 40-70% of patients who have nephritis mediated by anti-GBM antibodies and accounts for 10-15% of all cases of end-stage renal disease in the United States.

It is primarily a disease of white populations, with 83% of cases occurring in whites.

 

Goodpasture syndrome refers to the combination of glomerulonephritis and pulmonary hemorrhage.

 

 

A subset of patients may have all 3 findings. 

 

 CBC may reveal hypochromic microcytic anemia secondary to iron deficiency, and mild thrombocytopenia.

The C3 level is below the reference range in 30-80% of pediatric patients.

ANCA is detectable in as many as 30% of patients with anti-GBM disease. 

The titers  of ANCA and anti-GBM antibodies tend to be inversely related.

In anti-GBM disease the detection of ANCA is clinically relevant in because patients with this disease are more likely to respond to therapy.

 

The identification of anti-GBM antibodies in the patient’s serum or tissues is of paramount importance in the diagnosis of Goodpasture disease.

 

Detection of the anti-GBM antibodies is achieved by means of direct enzyme-linked immunoassay (ELISA), and the  specificity of the antibody can be confirmed with Western blotting.

Indirect immunofluorescent staining  is performed by incubating normal renal tissue with the patient’s serum and then treating it with fluorescein-labeled anti–IgG. 

Immunofluorescence indicates of immunoglobulin G (IgG) deposition and is diagnostic, but false-negative results are seen in 10-40% of patients. 

 

Immunofluorescent microscopy, demonstrated finding of linear deposition of IgG along the glomerular capillaries and, occasionally, along the tubules is nearly pathognomonic. 

Linear deposits of IgG along the alveolar basement membrane may also be seen in anti-GBM disease. 

Susceptibility to anti-GBM disease in humans is strongly linked to class II major histocompatibility complex (MHC II). 

Anti-GBM disease has a strong positive association with the human leukocyte antigen (HLA)–DR15 haplotype, particularly the DRB1*1501 allele, which is found in more that 80% of patients with anti-GBM disease. 

 

Strong protection from the disease is associated with the expression of DRB1*0701, such that the risk of disease is the same in individuals inheriting DRB1*1501 and DRB1*0701 and in the general population.

In addition, the DRB1*0101 allele offers relatively weak protection. 

 

Normally, these epitopes are destroyed by antigen-presenting cells before they are able to induce thymic deletion of potentially pathogenic T cells. 

The key epitope in the pathogenesis of anti-GBM antibody disease binds with high affinity to the disease associated HLA-DRB1*1501 MHC II molecule. 

The key stimulatory epitope has the ability to stimulate Goodpasture T-cells to proliferate and secrete interferon (IFN)-gamma.

T cells from patients with anti-GBM antibody disease recognize 2 epitopes located in regions that are highly susceptible to antigen processing by endosomal proteases.

 

CD4+ cells escape thymic deletion and participate in the anti-GBM antibody disease. 

Normal individuals have been shown to have low titers of antibodies to alpha-3(IV)NC1 and the alpha-3(IV)NC1 responsive naive T-cells. 

T cells may have an indirect role in facilitating the anti-GBM antibody production by B cells and that they may also cause direct injury to the glomerulus and alveoli. 

Regulatory CD25+T-cells may attenuate the glomerular injury. 

T-cell–mediated mechanisms may play a similar role in human anti-GBM antibody disease. 

The development of self-immunoregulation and the re-establishment of tolerance in the convalescent phase of the disease coincides with the emergence of the regulatory CD25+T-cells. 

Depletion of regulatory CD25+T-cells increases the number of Goodpasture antigen-specific IFN-gamma–producing cells.

Goodpasture disease and anti-GBM disease are used synonymously and refer to the presence of anti-GBM antibodies in kidney, lungs, or both, independent of clinical manifestations. 

Anti-GBM antibodies are almost exclusively of the immunoglobulin G (IgG) isotype. 

The principal targets for anti-GBM antibodies are type IV collagen. 

Some patients with Goodpasture syndrome do not develop pulmonary disease.

Pulmonary involvement as seen in 30-60% of patients at presentation.

Pulmonary involvement is more common among smokers, manifest with cough, hemoptysis, dyspnea, and hypoxemia.

Alveolar infiltrates on chest imaging may be noted.

Rapidly progressive glomerulonephritis with coexistent ANCAs and anti-GBM antibodies is referred to as a double antibody-positive disease.

Patient with double antibody-positive disease have clinical prognostic and pathological features of anti-GBM disease and ANCA associated vasculitis.

In patients with double antibody-positive disease they are more likely to have fulminant renal dysfunction.

Double positive-antibody disease requires treatment as for anti-GBM disease and involves high-dose glucocorticoids, cyclophosphamide, and plasmapheresis.

Management: Hospitalization is required for prompt diagnosis and treatment, and some patients may initially require intensive care.

 

Patients who are antineutrophilic cytoplasmic antibody (ANCA) positive with clinical vasculitis are likely to benefit from aggressive therapy independent of the severity of disease. 

With pulmonary hemorrhage there is a rapid response to methylprednisolone pulses, plasma exchange, or plasmapheresis.

With mild renal disease, without pulmonary hemorrhage may be treated with prednisone alone.

 

 

Patients with moderate glomerulonephritis with serum creatinine level < 5 mg/dL and crescents in < 50-75% of glomeruli and patients with acute disease are likely to respond to therapy. 

 

In individuals with advanced disease with serum creatinine level >5 mg/dL and crescents in >75% of glomeruli and histologic signs of chronicity are unlikely to improve with any therapy and should receive supportive care and eventual renal transplantation.

 

Early plasmapheresis removes circulating anti-GBM antibodies and other mediators of inflammation and has been advocated as the treatment of choice for AGBM disease.

Plasmapheresis along with immunosuppression is effective in the treatment of pulmonary hemorrhage.

Plasmapheresis along with immunosuppression substantially improves renal function in patients with serum creatinine levels of less than 7 mg/dL or with crescents in less than 50% of the glomeruli.

Plasmapheresis usually consists of 14 treatments during 2-3 weeks.

 

 

Treatment consists of repeated plasmapheresis combined with glucocorticosteroids and cyclophosphamide.

Concomitant administration of cyclophosphamide and steroids is essential to prevent rebound antibody formation.

 

 

Therapy is continued for 6-12 months, the time usually required to stop the formation of anti-GBM antibodies.

 

 

With irreversible renal failure, renal transplantation is usually deferred for at least 1 year to decrease the risk of recurrence.

 

Most remain asymptomatic after renal transplantation, probably because of inhibition of autoantibody production with routine posttransplantational immunosuppression: The risk of graft loss due to recurrent anti-GBM disease is low.

 

Differential Diagnoses: 

 

 

Acute Poststreptococcal Glomerulonephritis

 

 

Goodpasture Syndrome

 

 

Granulomatosis with Polyangiitis 

 

 

Juvenile Systemic Sclerosis

 

 

Legionella Infection

 

 

Pediatric Antiphospholipid Antibody 

 

Syndrome

 

 

Pediatric Bronchitis

 

 

Pediatric Nephritis

 

 

Pediatric Pneumonia

 

 

Pediatric Tuberculosis

 

 

Pulmonary Infarction

 

 

Systemic Lupus Erythematosus (SLE)

 

 

Vasculitis and Thrombophlebitis

 

Renal ultrasonography reveals kidneys of normal size, with no anatomic abnormalities.

With pulmonary hemorrhage present, chest radiography may reveal alveolar infiltrates spreading from the hilum.

Renal biopsy is not required for diagnosis if circulating anti-GBM antibodies are present. 

However, renal biopsy  findings are an important guide to therapy and prognosis, and it is recommended unless the procedure is contraindicated.

The prognosis is poor.

Without treatment, 90% of patients progress to dialysis or die, and only 10% improve. 

Improvement occurs in 50% of treated patients.

Patients who survive the first year with normal renal function have a good long-term prognosis, though late relapses can occur. 

Histologic findings: in the active phase of the disease, cellular crescents are usually seen in the glomeruli, in advanced cases, fibrous crescents and tubulointerstitial involvement with tubular atrophy, interstitial infiltrate, fibrosis may be present. 

Histologic findings of the lungs demonstrate intra-alveolar hemorrhages and iron.

 

Prognostic factors:

Chronic disease.

A need for dialysis.

A serum creatinine level of more than 5 mg/dL.

Crescent formation in 50-75% of the glomeruli at the time of diagnosis.

Fibrous crescents.

Widespread necrosis

Tubulointerstitial changes.

Patients who are antineutrophilic cytoplasmic antibody (ANCA) positive vasculitis  tend to respond well to treatment and recover renal function despite an increased frequency of vasculitic relapses.