IMAGES OF OSLER

Cases from the Osler Medical Service atJohns Hopkins University

Prepared by David Riedel, MD , and David Zaas, MD

PRESENTING FEATURES: A 47-year-old Taiwanese manwith no notable medical history was admitted with low-gradefevers and night sweats that had persisted for 5 to 6 weeks. Anextensive investigation at another hospital could not determinethe cause of the fevers, but documented acute renal failure witha blood urea nitrogen level of 60 mg/dL and a serum creatininelevel of 5.6 mg/dL. He was admitted to the Johns Hopkins Hos-pital for further evaluation.

The patient, who had been living in the United States forthe past 20 years, reported no recent travel and no behaviorsthat are associated with transmission of human immunode-ficiency virus. He was not taking any medications, and hedenied using herbal or nutritional supplements. He had norecent weight loss. There were no specific complaints on re-view of systems.

On physical examination, he was a thin, middle-aged man inno distress. Vital signs included a temperature of 37.5°C, ablood pressure of 166/86 mm Hg, a pulse of 70 beats per minute,a respiratory rate of 16 breaths per minute, and 99% oxygen

saturation on room air. Sclera were anicteric, and he had nopalpable adenopathy. His lungs were clear, and his heart ratewas regular without extra sounds. His abdomen was thin, non-tender, and without masses or organomegaly. There was noedema or signs of embolism in the extremities.

Laboratory studies revealed a white blood cell count of14,200/mL3, a hematocrit of 23.1%, and a platelet count of456,000/mL3. Blood chemistries were notable for a blood ureanitrogen level of 61 mg/dL and a serum creatinine level of 7.6mg/dL. Levels of aminotransferases, total bilirubin, and alkalinephosphatase were within normal limits. Urinalysis revealedlarge hemoglobin, 1� protein, numerous red blood cells, and 3to 5 white blood cells. Numerous red blood cell casts were seenon microscopic examination of the urine sediment. The pa-tient’s erythrocyte sedimentation rate was �130 mm/h, and hisC-reactive protein level was elevated at 12.6 mg/dL. Serologieswere negative for antinuclear antibodies and antineutrophil cy-toplasmic antibodies; serum complement levels were normal.

What is the diagnosis?

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DIAGNOSIS: Antiglomerular basement membrane disease

DISCUSSION: A renal biopsy specimen (Figures 1 and 2)showed severe crescentic and necrotizing glomerulone-phritis and moderate scarring with diffuse, linear glomer-ular capillary loop staining noted for immunoglobulin(Ig) G (3�), IgA (1�), � light chains (3�), � light chains(2 to 3�), and albumin (1�).

The serum antiglomerular basement membrane dis-ease antibody was 128 units per mL (normal �3 units permL). The chest radiograph was clear except for minimalright apical pleural thickening. The linear staining of thebasement membrane, the presence of antiglomerularbasement membrane disease antibodies, and the lack ofpulmonary involvement were diagnostic of antiglomeru-lar basement membrane disease.

Antiglomerular basement membrane disease is a raredisorder that predominantly affects people of Europeandescent. There is a bimodal incidence, with an initial peakin the third decade for men and in the sixth decade forboth men and women. When pulmonary hemorrhageand renal disease are found together, the syndrome iscommonly called Goodpasture syndrome, after ErnestGoodpasture, an acclaimed pathologist who first de-scribed the syndrome in 1919 (1).

Antiglomerular basement membrane disease, which isone of several causes of the syndrome (2), is caused byautoantibodies to the �3 chain of type IV collagen that isfound primarily in the glomerular and alveolar basementmembranes. There is a strong genetic association with thehuman leukocyte antigen haplotypes DR15 and DR4, but

environmental factors are also believed to be involved(3–5). The activity of the disease is closely correlated withantibody titers (3).

On biopsy, the characteristic lesion is a crescentic glo-merulonephritis in which the crescents are of similarstage. Immune staining reveals linear immunoglobulindeposition with IgG and, sometimes, C3, IgA, and IgM.Approximately 50% of patients also develop pulmonaryalveolitis, which is marked by alveolar hemorrhage (3).

Similar to systemic vasculitides, antiglomerular base-ment membrane disease often manifests initially withgeneral constitutional symptoms, such as malaise, weightloss, fever, or arthralgia. Hemoptysis is the presentingfeature in 70% of patients, and pulmonary disease oftenprecedes renal disease. Pulmonary hemorrhage, the pri-mary cause of early death in this disease (1), occurs al-most exclusively in patients who smoke and is often trig-gered by infections or fluid overload.

Urinalysis shows microscopic hematuria and modestproteinuria; the sediment reveals red cell cast formation. Re-nal disease has a fulminant course. It rarely resolves sponta-neously, and progressive renal failure is common. With-out swift initiation of therapy, renal failure is certain (1).

Treatment is directed primarily at removal and sup-pression of the autoantibodies. Plasmapheresis, whichcan remove the antibody, is usually used in 14 daily ses-sions or until titers are undetectable. Oral steroids andcyclophosphamide can also suppress antibody produc-tion. Higher creatinine levels and a higher percentage of

Figure 1. Fluorescent microscopy of renal biopsy specimen demonstrating linear deposition of immunoglobulin along basementmembrane (immunoglobulin G stain).

Images of Osler/Riedel and Zaas

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crescents on biopsy specimens predict less recovery ofrenal function after treatment. Patients with moderaterenal failure often recover renal function if treated earlyand appropriately; patients who present with renal failureand require dialysis are less likely to recover full renalfunction. Renal transplantation has been shown to be ef-fective if the antibodies to antiglomerular basementmembrane disease have been suppressed completely (6).

This patient received 14 days of plasmapheresis, pulse-dose corticosteroids, and oral cyclophosphamide. Hemo-dialysis was initiated and was continued for 6 weeks, atwhich time his renal function stabilized with a serum cre-atinine of 3.2 mg/dL.

REFERENCES1. Salama AD, Levy JB, Lightstone L, et al. Goodpasture’s disease. Lan-

cet. 2001;358:917–920.2. Kluth DC, Rees AJ. Anti-glomerular basement membrane disease.

J Am Soc Nephrol. 1999;10:2446 –2453.3. Salama AD, Pusey CD. Immunology of anti-glomerular basement

membrane disease. Curr Opin Nephrol Hypertens. 2002;11:279 –286.4. Gunnarsson A, Hellmark T, Wieslander J. Molecular properties of

the Goodpasture epitope. J Biol Chem. 2000;275:30844 –30848.5. Borza DB, Netzer KO, Leinonen A, et al. The Goodpasture autoan-

tigen. J Biol Chem. 2000;275:6030 –6037.6. Levy JB, Turner AN, Rees AJ, Pusey CD. Long-term outcome of

anti-glomerular basement membrane antibody disease treated withplasma exchange and immunosuppression. Ann Intern Med. 2001;134:1033–1042.

Figure 2. Fluorescent microscopy of renal biopsy demonstrating linear deposition of immunoglobulin along basement membraneand crescentic changes superiorly (immunoglobulin G stain).

Images of Osler/Riedel and Zaas

508 April 15, 2003 THE AMERICAN JOURNAL OF MEDICINE� Volume 114