Gerren Hobby, MD
Updated: Mar 18, 2022
A #ThrowbackThursday post about the discovery of anti-GBM Disease
by Gerren Hobby, MD (@ghobby)
The history of anti-glomerular basement membrane disease started in the midst of the 1918 influenza pandemic.
In late September 1918, Dr. Erenest Goodpasture admitted a patient to the hospital with what initially appeared to be a “typical attack of influenza.” He presented with a three day history of cough and fever to 103.0°F. Evaluation revealed no evidence of bacterial pneumonia. His fever resolved, and he was discharged three days later. After hospital discharge, he again fell ill, but returned to work. Unfortunately, his cough persisted and weight loss and fatigue ensued.
He was readmitted to the hospital on November 6, 1918 with fever, cough, pleuritic chest pain, bloody sputum, physical exam findings concerning for right lower lobe pneumonia, and anemia. He had a temperature of 100.4°F, a heart rate of 120 beats per minute, and a respiratory rate of 28 breaths per minute. His white blood count was 17.6 K/uL and his urinalysis showed trace protein. What was presumed to be pneumonia quickly spread to the left lung, followed by rapid clinical decline and death three days after admission. An autopsy was performed. Lung gross pathology and histology was consistent with diffuse pulmonary hemorrhage. Light microscopy of the kidney showed glomerulonephritis with crescents as well as tubular RBC casts. The case was described as “a more unusual one, being the only instance of its kind observed by us, and I have not seen a similar one described.” Ultimately, Dr. Goodpasture attributed the case to influenza though.
Although we now believe the described patient likely had ANCA vasculitis, its occurrence sparked interest in disease processes involving kidney and lung, now termed pulmonary-renal syndrome. Over the following years, similar cases were described and collected to form a case series of nine patients published by Stanton and Tange in 1958 and coining the term Goodpasture’s Syndrome.
Later, the pathogenicity of anti-GBM antibodies in humans was proven by Lerner, Glassock and Dixon in this paper published in 1967.
In the most notable experiment, researchers sought to examine the effect of anti-GBM disease IgG antibodies on the kidneys of monkeys. Glomerular basement membrane-specific IgG antibodies were eluted from the nephrectomized kidneys of two anti-GBM disease patients. Because these antibodies were bound to kidney tissue, it was postulated they had a higher probability of being pathogenic. In a Koch postulate-like line of thinking, it was believed that these antibodies would produce a similar phenotype when injected into monkeys.
The isolated IgG antibodies were injected into unilaterally nephrectomized monkeys. At 24 hours, the monkeys developed proteinuria and kidney biopsies showed cellular proliferation of the glomerulus and linear deposition of IgG along the basement membrane. By day four, one monkey was anuric and died two days later with a BUN of 100 mg/dL. Kidney biopsy showed severe proliferative glomerulonephritis. The other monkey was sacrificed on day 6 with a BUN of 80 mg/dL and the kidney biopsy showed similar biopsy findings of proliferative glomerulonephritis.
With time, we have learned a great deal more about the pathogenesis of anti-GBM glomerulonephritis. We now understand that the NC1 domain of the alpha-3 chain of type IV collagen serves as the principal target for anti-GBM antibodies. Furthermore, the inflammatory milieu resulting from activation of T cells, B cells, and complement create the classic presentation of diffuse crescentic disease and pulmonary injury with hemorrhage. Through understanding of the disease pathogenesis, we have abandoned the eponym of Goodpasture disease and have renamed it anti-GBM disease. Treatment for anti-GBM disease has remained remarkably unchanged over time with use of plasma exchange, glucocorticoids, and cyclophosphamide serving as staples of management.
Several variations of anti-GBM disease have been noted including atypical anti-GBM disease described in a case report by Nasr, et al. These patients don’t have diffuse crescentic disease and lack pulmonary involvement. Double-seropositive ANCA and anti-GBM disease has also been observed. These patients present in a similar manner to anti-GBM disease, but have the tendency for relapse as seen in ANCA vasculitis patients. Lastly, anti-GBM disease associated with membranous nephropathy has been described. Just as the initial, careful observations of pulmonary-renal syndrome led to the discovery of anti-GBM disease, these other descriptions of anti-GBM disease variations provide better differentiation of phenotypes for more focused treatments and the hope of better outcomes.