1. Which of the vasculitides are most often associated with glomerular disease?

The small-vessel vasculitides are most often associated with glomerular disease ( Fig. 33.1 ). Immunoglobulin (Ig)A vasculitis (Henoch-Schölein-purpura) and cryoglobulinemic vasculitis are associated with immune complex deposition. Pauci-immune glomerulonephritis demonstrates little to no immune deposits and is seen in the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides, including granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome), as well as kidney-limited pauci-immune necrotizing and crescentic glomerulonephritis (NCGN).

Distribution of vessel involvement by large-vessel vasculitis, medium-vessel vasculitis, and small-vessel vasculitis. There may be substantial overlap with respect to arterial involvement, and an important concept is that all three major categories of vasculitis can affect any size of artery. The diagram depicts (from left to right) aorta, large artery, medium artery, small artery/arteriole, capillary, venule, and vein. Anti-GBM, Anti-glomerular basement membrane; ANCA, antineutrophil cytoplasmic antibody; Anti-GBM, a nti-glomerular basement membrane. (Modified and reproduced with permission from Jennette, J. C., Falk, R. J., Bacon, P. A., et al. (2013). 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis & Rheumatology, 65, 1–11.)

Polyarteritis nodosa (PAN), a medium-vessel vasculitis typically affecting medium-sized or small arteries and sparing arterioles, capillaries, and venules, does not cause glomerulonephritis but may cause ischemic kidney injury via inflammation of the larger kidney vessels.

2. What features distinguish the small-vessel vasculitides?

The small-vessel vasculitides have significant overlap in their manifestations and affect small vessels including intraparenchymal arteries, arterioles, capillaries, and venules. Features that distinguish them have been used in proposed classification schemes:

GPA is associated with granulomatous inflammation that may affect the lower and upper respiratory tracts, often causing sinus symptoms, in addition to glomerulonephritis.

MPA also leads to necrotizing vasculitis of small vessels and often leads to glomerulonephritis as well as pulmonary capillaritis and pulmonary hemorrhage. Notably, granulomatous inflammation is absent .

EGPA also demonstrates granulomatous inflammation of small- and medium-sized vessels and involves the respiratory tract. The distinguishing histologic feature is that of eosinophil-rich inflammation with peripheral eosinophilia. Patients also have associated asthma. ANCA are found in about 40% of patients with EGPA compared with about 90% of patients with MPA, GPA, or pauci-immune NCGN.

IgA vasculitis (Henoch-Schölein purpura) demonstrates IgA1 immune deposits with vasculitis affecting small vessels. In addition to glomeruli, skin and gastrointestinal involvement are common. Patients often have arthralgias or arthritis.

Cryoglobulinemic vasculitis leads to skin and glomerular lesions with cryoglobulin immune deposits in affected small vessels. Neurologic involvement may also occur. Cryoglobulins may be present in serum.

3. What findings in the urinalysis suggest kidney involvement from vasculitis?

Microscopic hematuria, typically with dysmorphic red blood cells and red blood cell casts, suggests kidney vasculitis. Proteinuria is often present but is usually subnephrotic. Inflammation in the form of white blood cells in the urine may also be an accompanying feature.

4. What serologic markers may be helpful in the distinguishing the kidney vasculitides?

Complement levels may be depressed in patients with cryoglobulinemic vasculitis and other vasculitides, including systemic lupus erythematosus (SLE) and postinfectious glomerulonephritis. Complement levels are typically normal in the other small-vessel vasculitides. Although technically difficult to measure, cryoglobulins can be directly measured in serum. Antinuclear antibodies suggest connective-tissue-related disorders, such as SLE, and may be further distinguished by extractable nuclear antigen panel testing. Patients with the small-vessel vasculitides (GPA, MPA, and EGPA) often have positive anti-neutrophil cytoplasmic antibodies (ANCAs) directed to either myeloperoxidase (MPO, MPO-ANCA) or proteinase 3 (PR3, PR3-ANCA). Anti-glomerular basement membrane (anti-GBM) antibodies are detected in patients with anti-GBM disease whether limited to the kidney or associated with diffuse alveolar hemorrhage.

There is a broad overlap in the clinical presentation of the various small-vessel vasculitides. In addition, overlap syndromes can occur. For instance, one-third to one-half of patients with anti-GBM disease will also have circulating ANCA, which is more often directed against MPO. In addition to the clinical presentation and serologic studies, a kidney biopsy is usually indicated to provide a definitive diagnosis and valuable information on the extent of glomerular injury and glomerular and interstitial scarring.

5. What is the relevance of ANCAs?

ANCAs are present in 90% of patients with pauci-immune glomerulonephritis, seen in GPA, MPA, and kidney-limited disease. ANCAs are also present in about 40% of patients with EGPA. They are typically absent in patients with PAN. Immunofluorescence is most sensitive to the detection of ANCAs and demonstrates distinct patterns, either a cytoplasmic pattern (C-ANCA) or perinuclear pattern (P-ANCA).

The antigen specificity of C-ANCA is usually directed to a neutrophil and monocyte protease -proteinase-3 (PR3), while P-ANCAs are usually directed to myeloperoxidase (MPO). While both MPO and PR3 may be seen in any of the described manifestations, MPO-ANCA (P-ANCA) is more common in patients with MPA, and PR3-ANCA (C-ANCA) is more common in GPA. Approximately 40% of patients with EGPA will manifest ANCAs, and may be directed to either MPO or PR3. Again, 10% of patients with pauci-immune glomerulonephritis do not demonstrate ANCAs despite kidney biopsy findings consistent with this diagnosis. MPO-ANCA and PR3-ANCA rarely coexist in a patient with idiopathic ANCA vasculitis (<5%). The coexistence of high-titer MPO- and PR3-ANCA has been reported in patients with drug-associated vasculitis, such as that associated with levamisole-adulterated cocaine.

Both in vitro and in vivo studies support a pathogenic role of ANCAs in vasculitis and glomerulonephritis. Neutrophils and monocytes primed by inflammation express ANCA antigens near or on cell surfaces. Interaction between these antigens and ANCAs activate neutrophils and monocytes, leading to degranulation at the vessel wall and resulting in endothelial cell damage. In vivo , the transfer of mouse anti-MPO IgG to MPO-competent mice results in NCGN and pulmonary vasculitis, which is similar to the human disease, thus demonstrating the ability of these antibodies to confer disease. This same mouse model has demonstrated a role for complement activation via the alternative pathway in the pathogenesis of MPO-ANCA glomerulonephritis.

Other antigens besides MPO and PR3 that interact with ANCAs have also been reported. ANCAs directed to elastase have been reported in drug-induced ANCA vasculitis. Antibodies directed to lysosomal membrane protein-2 have also been reported, although their association with small-vessel vasculitis is controversial. In patients with inflammatory bowel diseases, ANCAs have also been described directed to catalase, α-enolase, lactotransferrin, and bactericidal permeability-increasing protein.

6. Which of the kidney vasculitides are associated with Pulmonary-renal syndrome?

Pulmonary-renal syndrome describes the presentation of acute glomerulonephritis with alveolar hemorrhage, as demonstrated by radiographic demonstration of pulmonary infiltrates and varying degrees of hypoxia, hemoptysis, and anemia. It is a life-threatening complication of small-vessel vasculitis.

The ANCA small-vessel vasculitides are the most common cause of pulmonary-renal syndrome. Anti-GBM disease, or Goodpasture’s disease, may also present with pulmonary hemorrhage and concomitant rapidly progressive glomerulonephritis. This syndrome may also be seen in patients with SLE and similar connective tissue diseases, IgA vasculitis (Henoch-Schölein purpura), and in cryoglobulinemic vasculitis.

Patients with this presentation should also be evaluated for other conditions accompanying kidney failure that may have similar presentations, including pneumonia and pulmonary embolus.

7. What primary rapidly progressive glomerulonephritis may occur in conjunction with ANCA glomerulonephritis?

Anti-GBM disease (Goodpasture’s disease) may occur concurrently with ANCA small-vessel vasculitis. About 45% of patients with anti-GBM disease also have positive ANCA testing, more commonly MPO-ANCA. In patients with a history of anti-GBM disease who develop recurrent signs of disease, ANCA testing should be obtained, even if originally negative, as relapsing anti-GBM disease is rare. The kidney survival of patients with both antibodies appears to be worse than those with ANCA disease alone, but it is better than those with anti-GBM disease alone.

8. What are the histologic findings of a kidney biopsy in patients with ANCA vasculitis?

Kidney biopsy usually demonstrates the presence of focal segmental to global fibrinoid necrosis and crescent formation affecting variable proportions of glomeruli. By both immunoflorescence and electron microscopy, glomeruli demonstrate few or no immune depositions, lending to the term pauci-immune glomerulonephritis, and distinguishing ANCA vasculitis from other diseases that may produce similar features by light microscopy, such as anti-GBM disease or immune complex-mediated glomerulonephritis (e.g., lupus nephritis). The glomerular lesions are usually associated with little or no endocapillary proliferation.

9. What drugs have been implicated in inducing ANCA vasculitis?

The development of vasculitis with ANCAs has been associated with many agents. The most commonly implicated drug is the anti-thyroid medication, propothiouracil (PTU), with other thyroid agents, including methimazole and carbimazole, also implicated. Other agents reported to be associated with ANCA vasculitis include hydralazine, minocycline, allopurinol, phenytoin, and penicillamine, among others. Both PTU and hydralazine are typically associated high-titer MPO antibodies, and the latter also with antibodies directed to elastase and lactoferrin. Withdrawal of the offending agent is, at times, sufficient to prompt resolution of the vasculitis, while, in some instances, immunosuppressive therapy is necessary, depending on the severity of the presentation.

Levamisole, originally utilized as an anti-helminthic, has been used as an adulterant to “cut” cocaine. Reports of vasculitis associated with the use of this agent have emerged over the last decade with a severe presentation of vasculitis that may also present with necrotizing skin lesions, glomerulonephritis, or pulmonary hemorrhage. Patients with levamisole-associated ANCA vasculitis may often be “dual positive” for both MPO- and PR3-ANCA.