Renal involvement in eosinophilic granulomatosis with polyangiitis

Abstract

Eosinophilic granulomatosis with polyangiitis (EGPA) is a necrotizing vasculitis, which typically affects small-to medium-sized blood vessels. It is characterized by the presence of tissue infiltrates rich in eosinophils, along with the formation of granulomatous lesions. About 40% of cases have positive anti-neutrophil cytoplasm antibodies (ANCA), with predominant perinuclear staining, and anti-myeloperoxidase (anti-MPO) specificity in about 65% of cases. Typical manifestations of EGPA include the late onset of asthma, nasal and sinus-related symptoms, peripheral neuropathy, and significant eosinophilia observed in the peripheral blood. In contrast to granulomatosis with polyangiitis and microscopic polyangiitis, renal involvement in EGPA is less frequent (about 25%) and poorly studied. Necrotizing pauci-immune crescentic glomerulonephritis is the most common renal presentation in patients with ANCA-positive EGPA. Although rarely, other forms of renal involvement may also be observed, such as eosinophilic interstitial nephritis, mesangial glomerulonephritis, membranous nephropathy, or focal sclerosis. A standardized treatment for EGPA with renal involvement has not been defined, however the survival and the renal outcomes are usually better than in the other ANCA-associated vasculitides. Nonetheless, kidney disease is an adverse prognostic factor for EGPA patients. Larger studies are required to better describe the renal involvement, in particular for patterns different from crescentic glomerulonephritis, and to favor the development of a consensual therapeutic approach. In this article, in addition to personal data, we will review recent findings on patient clinical phenotypes based on ANCA, genetics and the impact of biological drugs on disease management.

Keywords: ANCA antibodies; EGPA; glucocorticoids; immunosuppressive therapies; interstitial infiltration; necrotizing vasculitis; rapidly progressive glomerulonephritis.

Figure 1

Proposed Pathogenesis of Renal Involvement in EGPA. EGPA pathogenesis is driven by environmental and genetic factors. GPA33 and IL5 are linked to ANCA-negative EGPA, HLA-DQ to ANCA-positive phenotype. CD4+ T cells polarized toward a T helper 2 (Th2) phenotype orchestrate the adaptive immune response and enhance eosinophilic reactions through IL-5 secretion. This mechanism may determine the eosinophilic feature, in which eosinophils are essential to mediate tissue damage. B cells may be involved through IgG4 production, with possible overlap with IgG4 related disease. T helper 1 (Th1), T helper 17 (Th17), and B cells potentially play a role in the development of vasculitis and the formation of granulomas. ANCA, anti-neutrophil cytoplasmic antibodies; MPO, Myeloperoxidase; ROS, reactive oxygen species; TNFα, tumor necrosis factor-α.

Figure 2

Renal histological modifications during EGPA. In (A) the most frequent renal manifestation of EGPA, paucimmune crescentic glomerulonephritis, with the formation of a cellular crescent, associated with fibrinoid necrosis (white asterisk) and Bowman capsule rupture (white arrowheads, Jones methenamine silver stain, x40). (B) Rarely, EGPA can show necrotizing, transmural arteritis involving small or medium sized arteries, as shown in Masson trichrome stain (x40). (C) Occasional interstitial giant cell reaction or non-necrotizing granulomas can be identified (white arrowheads), especially associated with Bowman capsule ruptures (Jones, x40). (D) Rarely, especially in ANCA-negative cases, the histology can be exclusively characterized by tubule-interstitial nephritis with a predominant eosinophilic infiltrate, reaching >50 elements/HPF (Hematoxylin and Eosin, x40). HPF, high power field.

Figure 3

Histological overlap between EGPA and IgG4-related disease. Some cases can show “classic” aspects of ANCA-associated glomerulonephritis (A) with formation of crescents (white arrowheads) and fibrinoid necrosis (white asterisk, Jones, x40), associated with diffuse tubule-interstitial nephritis [(B), x20] enriched with plasma cells (bottom right red inset). These cases generally show polytypic expression of lambda [(C), top half of the picture] and kappa (bottom half) light chains, but with increased density of IgG4-restricted plasma cells (D).

Figure 4

Schematic representation of severe EGPA treatment according to the three main guidelines (12, 48, 49). IV pulses = IV methylprednisolone 500–1,000 mg/day for 3–5 days (total cumulative dose 3 g). High dose oral GCs = prednisone 0.75–1 mg/kg/day (up to 80 mg/day). ACR/VF, American College of Rheumatology/Vasculitis Foundation; AZA, azathioprine; CYC, cyclophosphamide; DMARDs, disease-modifying antirheumatic drugs; EULAR, indications from the three main references for the treatment of EGPA are summarized; GCs, glucocorticoids; IV, intravenous; MEPO, mepolizumab; MTX, methotrexate; RTX, rituximab.