ANCA Glomerulonephritis and Vasculitis

Abstract

ANCA vasculitis has an associated autoimmune response that produces ANCAs that induce distinct pathologic lesions. Pauci-immune necrotizing and crescentic GN is a frequent component of ANCA vasculitis. ANCA vasculitis is associated with ANCA specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA). A diagnosis of ANCA vasculitis should always specify the serotype as MPO-ANCA positive, PR3-ANCA positive, or ANCA-negative. To fully characterize a patient, the serotype also should be accompanied by the clinicopathologic variant if this can be determined: microscopic polyangiitis, granulomatosis with polyangiitis (Wegener), eosinophilic granulomatosis with polyangiitis (Churg-Strauss), or renal-limited vasculitis. ANCA vasculitis is most prevalent in individuals >50 years old. There are racial/ethnic and geographic influences on the prevalence, serotype frequencies, and clinicopathologic phenotypes. There is clinical, in vitro, and animal model evidence that ANCAs cause disease by activating neutrophils to attack small vessels. Immunomodulatory and immunosuppressive therapies are used to induce remission, maintain remission, and treat relapses. Over recent years, there have been major advances in optimizing treatment by minimizing toxic therapy and utilizing more targeted therapy.

Keywords: ANCA; Animal; Antibodies; Antineutrophil Cytoplasmic; Autoantibodies; Autoimmunity; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Microscopic Polyangiitis; Models; Myeloblastin; Neutrophil Activation; Neutrophils; Peroxidase; Prevalence; Recurrence; Serogroup; glomerulonephritis; vasculitis.

Figure 1.

Photomicrographs of a kidney biopsy specimen from a patient with ANCA vasculitis showing segmental fibrinoid necrosis. In a glomerulus (A) and an interlobular artery (B) (short arrows). The glomerulus has a small cellular crescent (long arrow), and a break in Bowman’s capsule in the upper left corner. (Masson trichrome stain.)

Figure 2.

Frequency of PR3-ANCA and MPO-ANCA positivity in ANCA-positive patients with a particular organ system involvement in an inception cohort of 502 ANCA vasculitis patients with MPA, GPA, or RLV evaluated at the University of North Carolina Kidney Center (excluding patients with EGPA) (Modified from Lionaki et al. [5]). Organ groupings are not mutually exclusive. ‘No lung and no ENT’ has vasculitis in some other organs. Plus means there is vasculitis in an additional organ. EGPA, eosinophilic granulomatosis with polyangiitis; ENT, ear, nose and throat; GI, gastrointestinal tract; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; MPO-ANCA, ANCA specific for myeloperoxidase; PR3-ANCA, PR3-ANCA, ANCA specific for proteinase 3; RLV, renal-limited vasculitis.

Figure 3.

These data are derived from 21,374 patients with any form of glomerular disease identified in renal biopsy specimens evaluated by the University of North Carolina Nephropathology Laboratory from 1986 to 2015. Only a subset of the most common glomerular disease categories that cause GN are shown on these graphs (modified from reference , with permission). Anti-GBM GN, anti–glomerular basement membrane GN.

Figure 4.

Diagram depicting the pathogenesis of vascular lesions in ANCA vasculitis and GN. The events from left to right occur sequentially at each site of injury, and are repeatedly initiated at multiple sites until induction of remission. Neutrophil priming, for example by cytokines generated by a synergistic infection, primes neutrophils and presents ANCA antigens at the surface and in the microenvironment of neutrophils. ANCA-activated neutrophils adhere to and penetrate vessel walls, and release destructive inflammatory mediators and undergo NETosis. ANCA-activated neutrophils release factors that activate the alternative complement pathway, which generates C5a and amplifies the inflammation by attracting and priming more neutrophils. At sites of vessel wall disruption, plasma spills into the necrotic zone and coagulation factors are activated to produce fibrin, resulting in a fibrinoid necrosis in vessels in tissue and crescents in glomeruli. Leukocytes undergo apoptosis and necrosis producing leukocytoclasia. Within a few days, the acute inflammation and necrosis is replaced by infiltrating macrophages and lymphocytes, and scarring begins as activated fibroblasts and myofibroblasts lay down collagen. (Shown only at the right side of the acute lesion is monocyte activation by ANCA, which is occurring in parallel with neutrophil activation at all sites of acute injury.) NET, neutrophil extracellular trap.

Figure 5.

ANCA vasculitis treatments algorithm in accord with current practice at the University of North Carolina Kidney Center. IV, intravenous.