Item 1 You are asked to consult on a 22-year-old woman who presents to the emergency department.

She complains of dyspnea that started 2 days previously and coughing up of some blood. She tells you that she has been in good health until about 2 weeks ago when she noticed some flu-like symptoms. She saw her general internist who prescribed her a 4-day course of azithromycin. Otherwise, she has no complaints. Past medical history is unremarkable. She has no allergies and is currently on no medications. Physical examination shows a pale woman who is moderately tachypneic. Her blood pressure is 120/82 mmHg in the right arm, with a heart rate of 104 bpm. Her respiratory rate is 28 per minute. She has an oxygen saturation of 94% on room air. The remainder of the examination is unremarkable. Urinalysis in the emergency department shows a specific gravity of 1.020, pH 5.0, 1+ albumin, large blood, and is otherwise negative. The sediment exam shows too numerous to count red blood cells, 1 red cell cast and a few coarse granular casts. Laboratory data reveals diffuse infiltrates in both lung fields. Her complete blood count shows a hematocrit of 32%, hemoglobin of 9.9 g/dL, WBC of 6.8. Electrolytes are normal. Her BUN is 28 mg/dL and creatinine 2.8 mg/dL. The most next most appropriate step for this patient should be: A.) Check an IgA level to confirm a diagnosis of Bergers disease. B.) Pulse this patient with solumedrol, initiate plasmapheresis and cyclophosphamide treatment. C.) Arrange for a percutaneous renal biopsy the next week. D.) Recommend a second course of antibiotics and arrange to see this patient in renal clinic next week. E.) Prescribe prednisone 60 mg per day and arrange for a percutaneous renal biopsy as an outpatient.

Item 1 Answer: B The patient has the pulmonary-renal syndrome. The differential diagnosis includes Goodpastures syndrome, ANCA-associated vasculitis, lupus nephritis, cryoglobulinemic vasculitis, and postinfectious nephritis with an underlying pneumonia. However, of these possibilities, the most likely and worrisome diagnosis is Goodpastures syndrome. Patients with anti-glomerular basement membrane disease (anti-GBM nephritis) may have a respiratory prodrome. Her clinical picture suggests a pulmonary hemorrhage. The most urgent issue is to prevent a life-threatening pulmonary hemorrhage. It is critical for this patient to be admitted to the hospital, receive treatment with a pulse dose of steroids, and start of plasmapheresis and cyclophosphamide therapy as quickly as possible. An anti-GBM antibody assay and a renal biopsy should be performed as soon as possible to confirm the diagnosis. ***** Goodpastures Syndrome Teaching Points Proliferative, usually crescentic, glomerulonephritis Pulmonary hemorrhage Presence of anti-GBM antibodies Demographic Factors Bimodal distribution with the first peak at age 30 years and second peak at 60 years. (Older patients usually present with primarily kidney disease presentation with an equal distribution in both sexes). Incidence 0.1/million. Gender: male-female ratio of 6:1. More common in whites than blacks. Genetic predisposition associated with HLA-DR2, DR4, and DRw15. Risk factors: association with hydrocarbon exposure, cigarette smoking, metallic dust, D-penicillamine, cocaine, and influenza A2 infections. Clinical Features Rapidly progressive renal failure and dyspnea with severe hemoptysis. Prodrome in approximately 20-60%, upper respiratory tract infection precedes the disease. Sub-nephrotic proteinuria, hematuria, nephritic urinary sediments and hypochromic miccrocytic, anemia of the iron deficiency type. Hypertension uncommon (20% of the patients). Rapid deterioration in renal function (days to weeks) with the need for dialysis.

Pathogenesis Anti-GBM autoantibodies react with the target antigen of the noncollagenous domain of the alpha chain of type IV collagen. The gene located in the q35-37 region of chromosome 2. Collagens (expressed predominantly in the glomerular and pulmonary alveolar capillary basement membrane) cross react with autoantibodies (predominately IgG1) after chronic insult of the GBM. This reaction induces activation of complement and leukocyte recruitment, resulting in necrotizing segmental proliferative glomerulonephritis, disruption of capillary walls, and eventually crescent formation. Pathology Light microscopy: most common picture is a diffuse crescentic glomerulonephritis with a tubulointerstitial nephritis (inflammatory cell infiltration and edema). Patients with milder disease will show focal segmental proliferative or a normal biopsy. Linear deposits of IgG1 and IgG4 along the GBM identified with immunofluorescence in about 60-80% of the cases. (Similar immunofluorescence pattern observed in biopsies of the alveolar basement membrane). Electron microscopy: widening of the subendothelial space with fibrin-like material inter-spaced in the gap between the GBM and Bowman capsule. (Electron-dense deposits are generally not seen in Goodpastures disease). Diagnosis Chest X-ray: abnormal bilateral hilar and basilar interstitial shadowing of the involved areas. Anti-GBM ELISA: A specific immunoassay can be used to detect serologic marker of circulating anti-GBM antibodies; the assay is specific for the NCI domain of the alpha 3 chain of collagen type IV collagen. This antibody is detected in more than 90% of the individuals with the presenting symptoms. Other antibody markers such as perinuclear ANCA will be positive in 10-38% of the cases with unknown association to the severity of the disease. ESR may be elevated -- seldom greater than 100 mm/hr. The level of plasma creatinine is usually a good indication of the dregree of progression. The gold standard for diagnosis is renal biopsy. Treatment and Prognosis Without treatment, patients with Goodpasture diseases have a very poor prognosis. Most patients die of either severe renal or pulmonary complications. End stage renal disease is not uncommon in patients who are oliguric, anuric, or with a plasma creatinine of greater than 5-7 mg/dL.

Goal of therapy is to suppress the formation of new antibodies and remove pre-existing antibodies. This strategy has decreased the death of these patients to less than 10% for one-year survival. Therapy is: Plasmapheresis with plasma exchange for 2 weeks on consecutive days, prednisone 1 mg/kg (after an initial methyl prednisone pulse of 1 gram/day for 3 consecutive days) and cyclophosphamide 2-3 mg/kg orally once each day. Patients with RPGN have a worse prognosis. The end point of treatment is until the anti-GBM antibodies are undetectable in the blood. With early treatment, patients may be able to preserve renal function. Relapse is common and can be monitored by a rise in anti-GBM antibodies.