By Donna J. Lager, M.D.
Former Director of Renal Pathology
Case History
A 79-year-old man with long-standing hypertension and diabetes mellitus, presented with fever, pulmonary infiltrates, and a rapid deterioration in renal function from a baseline serum creatinine of 1.3 mg/dl to 3.8 mg/dl. Urinalysis showed hematuria with dysmorphic RBCs, and erythrocyte sedimentation rate was 86 mm/hr.
Diagnosis: Microscopic polyangiitis with necrotizing and crescentic glomerulonephritis (pauci-immune), and necrotizing arteritis.
Vasculitis in general terms describes inflammation of vessel walls and is manifest in the kidney most commonly as necrotizing and crescentic glomerulonephritis. Necrotizing and crescentic glomerulonephritis can occur in the kidney as (Table 1): 1) Immune complex-mediated disease characterized by deposits of immunoglobulin and complement within the glomeruli resulting is damage to the glomerular capillaries (e.g. IgA Nephropathy, lupus nephritis); 2) Anti-glomerular basement membrane antibody-mediated disease characterized by linear capillary wall staining for IgG and the presence of a serum anti-GBM antibody (e.g. Goodpasture’s syndrome), and 3) Pauci-immune disease in which no immune deposits or antiglomerular basement membrane antibody is detected (1). Pauci-immune necrotizing and crescentic glomerulonephritis is often associated with anti-neutrophil cytoplasmic antibodies (ANCA).
A consensus conference in the mid-1990’s helped to clarify and standardize the nomenclature of systemic vasculitis (2). In general vasculitis is classified by the size of the vessel affected (Table 2). Large vessel vasculitis includes giant cell or temporal arteritis, and Takayasu’s arteritis. Medium-sized vessel vasculitis includes polyarteritis nodosa (PAN) and Kawasaki’s disease and small-vessel vasculitis includes Wegener’s granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis and cutaneous leukocytoclastic angiitis. Henoch-Schonlein purpura and cryoglobulinemic vasculitis are also included and are examples of immune complex-mediated vasculitis (2, 3).
Vasculitides most commonly encountered on renal biopsy are the small vessel vasculitides, particularly Wegener’s granulomatosis and microscopic polyangiitis. Most patients with vasculitis have anti-neutrophil cytoplasmic antibodies (ANCA). ANCA antibodies have two major antigen specificities in patients with vasculitis: anti-myeloperoxidase (MPO)-ANCA and anti-proteinase 3 (PR3)-ANCA. While there is overlap, most patients with Wegener’s granulomatosis have PR3-ANCA and most patients with microscopic polyangiitis have MPO-ANCA (4-7).
In general, patients with small-vessel vasculitis present with fever, myalgias, arthralgias, and malaise, and many describe a prior “flu-like” illness. Vessels in the skin, respiratory tract, kidneys, gut, peripheral nerves, and skeletal muscle are often involved causing leukocytoclastic vasculitis in the skin, pulmonary hemorrhage, renal failure and hematuria, abdominal pain, and gastrointestinal bleeding, peripheral neuropathy, and muscle pain with elevated muscle enzymes, respectively. Respiratory tract disease is common in ANCA-associated vasculitis and both microscopic polyangiitis and Wegener’s granulomatosis are associated with a “pulmonary-renal” syndrome. Many patients with Wegener’s granulomatosis have upper respiratory tract disease, characterized by sinus pain and/or purulent drainage, nasal mucosal ulceration, and otitis media. Tracheal inflammation and sclerosis may also occur. Lower respiratory tract disease is characterized by granulomatous necrotizing pulmonary inflammation that produces nodular densities radiographically. Inflammation of alveolar capillaries (alveolar capillaritis) can result in pulmonary hemorrhage (3).
While clinically somewhat distinctive, Wegener’s granulomatosis and microscopic polyangiitis are indistinguishable on renal biopsy and both are characterized by a necrotizing and crescentic glomerulonephritis without immune complex deposition (pauci-immune). The glomeruli show focal and segmental disruption of the capillary wall with fibrin, neutrophils and cellular crescents within Bowman’s space. The glomeruli are involved to variable degrees and stages such that normal glomeruli, active lesions and chronic sclerosing lesions occur in the same biopsy (Figure 2). Uninvolved glomeruli appear normal and no immune complex deposition is detected. Interstitial inflammation is common and the tubules often show evidence of epithelial cell injury with luminal red blood cell casts. Necrotizing arteritis may be present; however is less commonly seen on biopsy. In suboptimal biopsies with few glomeruli, a necrotizing and crescentic glomerular lesion may not be present; however tubular injury, red blood cell casts and inflammation of peritubular capillaries (capillaritis) should raise the suspicion of ANCA-associated disease. Rarely, Wegener’s granulomatosis can cause granulomatous inflammation in the renal parenchyma that mimics a neoplastic process (8).
Once a diagnosis of vasculitis is confirmed, patients are treated with corticosteroids and cyclophosphamide. Approximately 50% of patients will experience a relapse of disease within 4-5 years of initial treatment, with some studies suggesting a higher rate of relapse in PR3-ANCA positive patients (4, 5).
References:
1. Jennette JC, Thomas DB. Crescentic glomerulonephritis. Nephrol Dial Transplant 16[Suppl 6]:80-82, 2001.
2. Jennette JC, Falk RJ, Andrassy K etal. Nomenclature of Systemic Vasculitides. Proposal of an International Consensus Conference. Arthritis & Rheumatism 37(2):187-192, 1994.
3. Jennette JC, Falk RJ. Small-Vessel Vasculitis. NEJM 337(21):1512-1523, 1997.
4. Savige J, Davies D, Falk RJ, Jennette JC, Wiik A. Antineutrophil cytoplasmic antibodies and associated diseases: A review of the clinical and laboratory features. Kidney International 57:846-862, 2000.
5. Franssen CFM, Stegeman CA, Kallenberg CGM, Gans ROB, DeJong PE, Hoorntje SJ, Tervaert JWC. Anitproteinase3- and antimyeloperoxidase-associated vasculitis. Kidney International 57:2195-2206, 2000.
6. Hauer HA, Bajema IM, Van Houwelingen HC etal. Renal histology in ANCA-associated vasculitis: Differences between diagnostic and serologic subgroups. Kidney International 61:80-89, 2002.
7. Wiik A. Rational use of ANCA in the diagnosis of vasculitis (Editorial). Rheumatology 41:481-483, 2002.
8. Leung N, Ytterberg SR, Blute ML, Lager DJ, Specks U, Fervenza FC. Wegener’s granulomatosis presenting as multiple bilateral renal masses. Nephrol Dial Transplant 19:984-987, 2004.
Date of last revision: September 2009.