Goodpasture Syndrome

DEFINITION A disease of the glomerular and alveolar basement membranes, characterized by pulmonary hemorrhage and crescentic glomerulonephritis. It’s associated with serum antibodies to glomerular basement membrane and linear deposits of antibodies along the glomerular and alveolar basement membrane and may result in rapidly progressive glomerulonephritis

Goodpasture disease vs Goodpasture syndrome Goodpasture disease is characterized by the presence of antibodies to glomerular basement membrane. Goodpasture syndrome is the rapidly progressive glomerulonephritis and pulmonary hemorrhage.

Background In 1919, Ernest Goodpasture described an 18 year- old man with a fever and cough, followed by hemoptysis and renal failure. The discovery of the role of anti GBM antibodies by Lerner et al in 1967 helped to provide both a better understanding of the pathogeneses for this specific form of pulmonary renal syndrome and a more rational approach to treatment.

Goodpasture syndrome is diagnosed in 1 in 1 million persons each year. Epidemiology Goodpasture syndrome is diagnosed in 1 in 1 million persons each year. Whites are affected more than in any other races. Incidence is slightly higher in men than in women. The syndrome affects 2 different age groups persons in their mid 30s and persons in their late 50s.

Genetic predispositions Causes Genetic predispositions Anti-GBM antibody has been described in identical twins, siblings and first cousins. HLA-DR2 is expressed in 88% of patients with anti-GBM disease compared to 25-32% of a control group of blood donors. Anti-GBM antibody is strongly associated with HLA DR15 and HLA-DR11 alleles. HLA-DR7 and HLA-DR5 have strong negative associations; both are highly protective.

2. Environmental insults: Cigarette smoking. Inhaled hydrocarbons. Gasoline fumes or industrial solvents are believed to induce chemical injury to the lung or kidney .

3. Viral infections: Influenza type A2. Upper respiratory tract infection or flu like illness occurred the onset of disease in 20-61% of adults with ant GBM disease

Pathophysiology Patients with Goodpasture syndrome is a type II hypersensitivity reaction In Good pasture syndrome the antibodies attack the NC1 domain of the α3 chain of type IV collagen factor in the basement membranes of the kidney and alevoli. In the kidney the basement membrane is the principal selective barrier of the glomerulus preventing plasma proteins, erythrocytes and platelets from passing through into the nephrone. Deposit of IgG, IgA and sometimes IgM antibodies in the basement membrane breakdown collagen and interrupt membrane integrity. This causes proteinuria, hematuria, oligouria and alveolar damage with sub-basement pulmonary hemorrhage.

Clinical Manifestation The clinical manifestations vary, in some patients pulmonary signs and symptoms occur weeks to months before renal manifestations are evident. The initial signs and symptoms consist of a flu like malaise followed by a rapid onsets of microscopic hematuria and proteinuria. More than half of patients have pulmonary signs and symptoms including (cough, mild shortness of breath and hemoptysis). The skin appears pale because of iron deficiency anemia. Renal manifestations can also include oedema and hypertension Rarely patients may have arthritis, peripheral neuropathy, uveities or leukocytoclastic vasculitis of the skin.

Histopathological Features of Kidneys Goodpasture’s Syndromes. Panel B (hematoxylin and eosin) shows focal, segmental necrosis of the glomerular tuft in a kidney from a patient with Goodpasture’s syndrome. Panel C (hematoxylin and eosin) shows the crescent formation of the glomerular tuft in such a kidney.

Differential diagnosis Systemic vasculitis Wagner granulomatosis Polyarteritis Nodosa Systemic lupus erytheromatosis Infection The occurrence of hemoptysis may be differentiated from other diseases, including: atrioventricular fistula, left ventricular failure, pulmonary embolism, pulmonary hypertension, thrombocytopenia bronchitis, cystic fibrosis, lung cancer, and multiple other causes.

Investigations Urine analysis, CBC current with differential BUN, creatnine and electrolyte levels. ESR is usually mildly elevated. Specific serologic tests include assessments of anti GBM titers and ANCA titers through indirect immunofluorescence testing, as well as enzyme linked immunosorbet assay (ELISA) or radioimminssay (RIA) to evaluate protease 3 and myeloperoxidase Circulating anti GBM titers may be elevated in more than 90% of patients. Results from serologic studies such as antistreptolysim O (ASO) titers and complement studies are usually negative. ANCA titers are elevated in 20-30% of patients with anti GBM disease. Tests of ANA and rheumatoid factor are usually negative

Imaging Chest radiography: Shows patchy or diffuse infiltrates with spacing of the upper lung fields N.B: Pulmonary infiltrates from hemorrhage may be resolve within few days Chest CT has a limited role but it may be helpful in identifying localized areas of hemoptysis. Other tests Pulmonary function tests: Progressive decline in vital capacity or total lung capacity suggests developing interstitial fibrosis. Renal biopsy: allows assessment of the severity of the glomerulo Nephritis and examination of the characteristic linear IgG deposition along the GBM. Lung biopsy is rarely indicated Renal biopsy is a superior diagnostic test compared to lung biopsy

Management Sodium restriction: Fluid restriction Die The daily total intake should not exceed 2gm Fluid restriction Depends on the patients renal function and whether the patient is taking cyclophosphamide or not. Plasma exchange Every day for 14 days or every third day for a month and its replacement with albumin and Fresh frozen plasma

Dose Immuno suppressive drugs Glucocorticoids e.g Methyl prednisolone These agents have anti inflammatory properties and caused profound and varied metabolic effects. It’s used to treat pulmonary hemorrhage and rapidly progressing glomerular Nephritis. Dose 1gm IV qd for 3d (adult dose) Or Pulse dose of 10-30 mg/kg IV qd for 3d not exceeding 1g/d (pediatric dose).

Prednisone It decreases anti GBM antibody production. Adult: 1-2 mg/kg/d for 8-12 w, alternatively, taper weekly to 20mg/d with slower taper over 1-2 y. Children: 2mg/kg/d orally in divided doses for 1 month Not to exceed 80mg/d, then often 1 month 60-80mg/d given every morning for 1 additional month.

Alkylating agent- (Cyclophosphamide) Interferes with inflammatory response by decreasing bone marrow response through the interference of DNA cross linking. Decrease anti GBM antibody production. Adult: 2-3mg/kg/d orally for 8-12 wk Children: 2mg/kg/d orally for 8-12wk Not to exceed 150mg/dose

Monoclonal antibodies (Rituximab) anti-CD20) Monoclonal antibody binds to pre B cells and Mature B cells. It results in lymphocytotoxic effects to B cells, which should results in reduced autoantibody production. Antibiotics These agents are used to prevent opportunistic infection with pneumocystis carinii. Trimethoprim and Sulfamethoxazole

Prognosis Has greatly improved in the past 15 years. Reports from the 1960s, before the advent of immunosuppressive therapy and plasma exchange indicate a 96% mortality rate in adults. In the era of plasma exchange, the mortality rate in adults is 0-41%.