Renal Involvement in IgG4-Related Disease: From Sunlight to Twilight

Abstract

IgG4-Related Disease (IgG4-RD) is a fibroinflammatory condition characterized by a typical histopathological pattern (dense lymphoplasmacytic infiltrate with prevalent IgG4+ plasma cells and storiform fibrosis), which may involve the kidney both directly (IgG4-related kidney disease, IgG4-RKD) or indirectly, as a consequence of post-renal ureteral obstruction due to retroperitoneal fibrosis (IgG4-RD RF). The most frequent presentation of IgG4-RKD is IgG4-related tubulointerstitial nephritis (TIN), but a glomerular disease can be present, in most of the cases a membranous nephropathy. Albeit steroid-responsive, in some cases renal manifestations may lead to progressive and permanent organ damage. In this review we describe four clinical cases representative of typical and less typical renal manifestations of IgG4-RD, emphasizing a potential, subclinical, early involvement of the kidney in the disease.

Keywords: ANCA - associated vasculitis; IgG4-related disease; membranous nephropathy; retroperitoneal fibrosis; tubulointerstitial nephritis (TIN).

Figure 1

Histopathology of renal biopsy (case 1), showing IgG4-RD TIN. (A): Diffuse tubulo-interstitial infiltrate associated with various degrees of tubular damage: initial thinning of tubular cells with cytoplasmic material in the tubular lumen (green circle); marked de-epithelialization of the tubular epithelium with inflammatory cells and tubulitis (yellow circle); tubular thyroidization due to disappearance of epithelial cells (blue circle); interstitial fibrosis is also evident (red arrow) (20x). (B): CD138 staining, showing plasma cells in the inflammatory infiltrate (20x). (C): immunohistochemistry for IgG4, showing positivity in the interstitium (20x).

Figure 2

Histopathology of renal biopsy in case 2, indicative of membranous glomerulonephritis. Membrane (yellow arrow) and capillary loops (black arrow) thickening demonstrated by hematoxylin and eosin stain (A, 40x) and by Masson's trichrome stain (B, 10x). Some inflammatory cells (granulocytes) are present in the capillary lumens (green arrow), confirming the hypothesis of a secondary membranous glomerulonephritis. The interstitium, lacking infiltrates or fibrosis, and the tubules, arranged in a palisade, are not affected by the disease (C, 40x). IgG4 immunohistochemistry demonstrates positivity in the glomerular basal membrane (blue arrow) (D, 20x).

Figure 3

Histological findings in AAV-IgG4-RD overlap (case 3). Acute diffuse tubulointerstitial infiltrate (green circle) associated with fibrotic involvement (yellow circle) and with destruction of renal structures, highlighted by the Masson trichrome stain (A, 10x). Necrotizing arteritis (blue circle) (B, 20x). CD138 staining, highlighting plasma cells in the infiltrate (C, 10x). Lesions in (A) are suggestive of IgG4-RD, lesions in (B) are typical of AAV.