FINAL DIAGNOSIS: DIFFUSE ANTI-BASEMENT MEMBRANE ANTIBODY GLOMERULONEPHRITIS WITH CELLULAR CRESCENTS
The differential for crescentic glomerulonephritis includes anti-glomerular basement membrane antibody mediated glomerulonephritis, immune complex glomerulonephritis, and pauci-immune (ANCA-associated) glomerulonephritis. This patient was found to have markedly elevated levels of anti-basement membrane antibodies in the serum consistent with the classic histologic findings of anti-glomerular basement membrane (anti-GBM) antibody mediated glomerulonephritis seen on renal biopsy. The presence of increased interstitial eosinophils suggests the possibility of a co-existing acute interstitial nephritis but likely represents reactive inflammation due to the glomerular injury. Patients with anti-GBM antibody mediated glomerulonephritis typically present with rapidly progressive glomerulonephritis. However, the clinical presentation can be variable, and some patients may present with only hematuria and proteinuria in the absence of renal insufficiency. Patients may also have pulmonary hemorrhage due to cross-reactivity of the antibodies with the alveolar basement membranes. The term Goodpasture's syndrome is usually reserved for these patients with an anti-GBM antibody mediated pulmonary-renal syndrome. As in this case, up to 65% of patients with anti-GBM antibody mediated glomerulonephritis will not have pulmonary disease. A small proportion of patients have pulmonary disease without glomerulonephritis. The disease can occur at any age but is most commonly seen in those 20-40 years of age. Men are affected more than women. A flu-like illness may precede the onset of Goodpasture's syndrome.
On gross examination, the kidneys are of normal size or slightly enlarged and have small red dots scattered over the outer and cut cortical surfaces corresponding to blood within tubular lumens or within Bowman's capsule. With advancing disease, progressive shrinking and scarring of the cortical parenchyma is seen.
Serologic testing for anti-GBM has been reported to produce false positive results. The gold standard for diagnosis remains the renal biopsy. While there are some histologic features which help differentiate the causes of crescentic glomerulonephritis, the immunofluorescence findings are often the most useful diagnostic modality. The characteristic finding is diffuse, strong linear staining of the glomerular basement membranes for IgG. There are also usually lesser amounts of linear or granular staining for C3. Linear staining for IgM and IgA can less commonly be seen, but the staining is rarely as intense as IgG. Linear staining for IgG in the tubular basement membranes is also a frequent finding.
The acute ultrastructural appearance of anti-GBM antibody mediated glomerulonephritis is similar to that of pauci-immune crescentic glomerulonephritis and is therefore not helpful in distinguishing the two diseases. The acute phase ultrastructural findings include variable endothelial swelling, rupture of basement membranes or Bowman's capsule with associated fibrin, focal effacement of epithelial foot processes, and accumulation of epithelial cells and macrophages in Bowman's space. Fibrin may also be found within capillary lumens or between crescent cells in Bowman's space. The fibrin appears as very electron-dense, irregular, curvilinear masses measuring approximately 10 nm. Immune complexes should not be identified. If complexes are present, this would represent the presence of a co-existing immune complex glomerulonephritis. In the chronic phase, collagenous matrix replaces foci of necrosis and the cellular elements of crescents. Glomerular basement membranes become thickened and wrinkled, and the mesangial matrix expands.
The differential diagnosis of the pulmonary-renal syndrome is the same as that for crescentic glomerulonephritis and includes anti-GBM disease, immune complex disease, and pauci-immune disease. Approximately one third of patients with anti-GBM antibody mediated disease will also be ANCA positive. It has been shown that these patients have a better renal outcome than patients with anti-GBM antibodies alone.
Treatment of anti-GBM antibody mediated glomerulonephritis includes high-dose corticosteroids, immunosuppressive therapy, and plasmapheresis. Aggressive therapy does improve patient morbidity and mortality. Despite therapy, anti-GBM antibody mediated crescentic glomerulonephritis carries a worse prognosis than immune complex crescentic glomerulonephritis or ANCA-associated crescentic glomerulonephritis. After successful remission, recurrence is uncommon but may occur many years after the initial episode. Recurrence in an allograft kidney is extremely uncommon if the anti-GBM antibodies are undetectable at the time of transplantation. A six to twelve month period of dialysis is recommended before transplantation.
Contributed by James T. Edinger, M.D., Ibrahim Batal, M.D. and Lawrence Kiss, M.D.