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Clinical History
A 73-year-old white female presented with fever and nausea of several weeks duration. She ahd recently received a course of antibiotics (ciprofloxacin and amoxicillin) for ear infection. She had diet-controlled type II diabetes mellitus for 3 years, and mild well-controlled hypertension. Physical exam revealed BP 140/70, normal chest exam, no edema, and no retinopathy. Labs revealed serum creatinine 6.5 mg/dL (baseline 1.0 mg/dl 2 months previously). 1Urinalysis showed 2+ protein, microhematuria with RBC casts, and no WBCs. Chest Xray was unremarkable. Additional lab tests revealed positive anti-GBM antibody >8 (negative <1), negative ANCA, negative SPEP and UPEP, and negative hepatitis B surface antigen and HCV antibodies. Hematocrit was 27% and serum albumin 2.3 g/dL.
Biopsy findings
Figure 1
H&E (40x)
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Figure 2
PAS, 40x.
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Figure 3
H&E, 20X.
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Figure 4
Immunofluorescence stain for IgG.
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What is your diagnosis?
a. Membranous nephropathy (0)
c. Diabetic glomerulosclerosis (0)
b. Anti-GBM nephritis (12)
d. Collapsing glomerulopathy (1)
e. Thrombotic microangiopathy (0)
Total Votes (13)
Figure 1
Glomerulus shows a circumferential cellular crescent and segmental fibrinoid necrosis (H&E 40x).
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Figure 2
Segmental rupture of glomerular basement membranes is seen (PAS, 40x).
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Figure 3
Tubules display numerous RBC casts (H&E, 20x).
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Figure 4
There is smooth linear GBM staining for IgG.
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PATHOLOGIC DIAGNOSIS
Anti-GBM nephritis
DISCUSSION
]]>Anti-glomerular basement membrane (GBM) nephritis is a severe form of glomerulonephritis characterized by crescent formation and linear GBM staining for IgG, associated with circulating anti-GBM autoantibodies. Approximately 45% of affected patients have pulmonary and renal involvement (i.e. Goodpasture syndrome), 50% have renal-limited disease (Goodpasture nephritis), and a small minority (5%) has pulmonary involvement alone. The renal manifestations of anti-GBM nephritis include acute kidney failure, rapidly progressive glomerulonephritis, hematuria, and subnephrotic proteinuria. Renal insufficiency is nearly always present. The overall sex ratio is equal but men tend to present at a younger age with pulmonary-renal disease, whereas women usually present later with renal-limited disease. Caucasians are more commonly affected than blacks. Pulmonary manifestations include hemoptysis and alveolar hemorrhage, which may be life-threatening. ]]>The pathologic characteristics of acute anti-GBM nephritis include crescent formation in >50% of glomeruli in most cases, with varying degrees of fibrinoid necrosis. Variable neutrophil infiltrates may be seen, but the underlying glomerular tuft is usually normocellualr and GBMs are of normal thickness. Crescents vary in size from small and segmental or to large and circumferential. The crescents of anti-GBM nephritis contain frequent macrophages and may form multinucleated giant cells or granulomas, either within Bowman’s space in the periglomerular region. Fibrous crescents and segmental glomerulosclerosis are seen with more chronic disease. The presence of necrotizing arteritis is more common in patients with combined anti-GBM disease and ANCA. IF shows diffuse linear GBM staining for IgG, with weaker staining for C3. Rare cases of anti-GBM disease have IgA specificity. Focal staining of distal TBMs for IgG may be seen. By electron microscopy, no immune type electron dense deposits are seen. The pathogenesis of anti-GBM nephritis involves autoantibodies directed against epitopes in the non-collagenous (NC) domain of type IV collagen (1,2). Exogenous factors, such has tobacco smoking and hydrocarbon exposure, may predispose to formation of anti-GBM antibodies by causing conformational changes in the NC1 domain that expose these hidden epitopes. In addition, smokers with anti-GBM disease are more likely to develop pulmonary involvement. Genetic factors (e.g. HLA DR and DQ antigens) likely play a predisposing role (3). Approximately one-third of patients have circulating ANCA (usually with anti-myeloperoxidase specificity), which may also be playing a pathogenic role. Interestingly, the renal biopsy findings in patients with concurrent anti-GBM and ANCA are intermediate in severity between those with pure anti-GBM nephritis and pure ANCA-related crescentic disease (4), but the impact on prognosis is unclear (5). ]]>Anti-GBM nephritis requires aggressive immunosuppressive therapy, including steroids, cyclophosphamide, and plasmapheresis. The overall outcome is worse than for crescentic disease caused by ANCA or immune complex glomerulonephritis. Outcomes are worse in those with serum creatinine >5 mg/dL or who are on dialysis before treatment is started (6). Other factors that may negatively impact outcomes include absence of non-affected glomeruli and higher percentage of circumferential crescents on biopsy, and anti-GBM titer (7).
REFERENCES
]]>1. Kalluri R, Wilson CB, Weber M, et al. Identification of the alpha 3 chain of type IV collagen as the common autoantigen in antibasement membrane disease and Goodpasture syndrome. J Am Soc Nephrol. 1995;6(4):1178-85. 2. Pedchenko V, Bondar O, Fogo AB, et al. Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis. N Engl J Med;363(4):343-54. 3. Huey B, McCormick K, Capper J, et al. Associations of HLA-DR and HLA-DQ types with anti-GBM nephritis by sequence-specific oligonucleotide probe hybridization. Kidney Int. 1993;44(2):307-12. 4. Rutgers A, Slot M, van Paassen P, van Breda Vriesman P, Heeringa P, Tervaert JW. Coexistence of anti-glomerular basement membrane antibodies and myeloperoxidase-ANCAs in crescentic glomerulonephritis. Am J Kidney Dis. 2005;46(2):253-62. 5. Bosch X, Mirapeix E, Font J, et al. Prognostic implication of anti-neutrophil cytoplasmic autoantibodies with myeloperoxidase specificity in anti-glomerular basement membrane disease. Clin Nephrol. 1991;36(3):107-13. 6. Levy JB, Turner AN, Rees AJ, Pusey CD. Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med. 2001;134(11):1033-42. 7. Herody M, Bobrie G, Gouarin C, Grunfeld JP, Noel LH. Anti-GBM disease: predictive value of clinical, histological and serological data. Clin Nephrol. 1993;40(5):249-55. ...
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