IgG4-related TIN is characterized by a dense lymphoplasmacytic infiltrate associated with abundant IgG4-positive plasma cells and fibrosis, and the presence of >10 IgG4-positive plasma cells per high-power field or >40 % IgG4/IgG-positive plasma cells is required for diagnosis of renal specimens obtained by needle biopsy [8, 9]. In type 1 AIP, storiform-type fibrosis, in which bands of fibrosis radiate to various directions from the center, sometimes showing a swirling pattern, has been described as a characteristic feature [19, 20]. Also in IgG4-related TIN, such storiform fibrosis is often evident in hematoxylin and eosin (HE)-stained preparations (Fig. 18.2a) [21]. With periodic acid-methenamine silver or periodic acid-Schiff staining, which are routine in renal pathological studies, a unique so-called “bird’s eye” pattern comprising nests of inflammatory cells surrounding irregular fibers is characteristic (Fig. 18.2b) [22]. The lesion distribution in IgG4-related TIN is also characteristic; affected and unaffected areas are clearly demarcated (Fig. 18.2c) [21, 22], and this correlates with the radiologic findings of well-demarcated multiple low-density lesions on enhanced CT. In addition, eosinophil infiltration or extension of lesions into the renal capsule is also positively suggestive of IgG4-related TIN [21, 22]. Conversely, necrotizing angiitis, granulomatous lesions, neutrophil infiltration, and advanced tubulitis are very rare in IgG4-related TIN [21]. Such histological characteristics are basically common to those in type 1 AIP [20], although obliterative phlebitis, which is also a critical pathologic feature of type 1 AIP [19, 20], is rarely seen in specimens of IgG4-related TIN obtained by kidney needle biopsy [22].

In addition to light microscopy, immunofluorescence and electron microscopy studies of the kidney are conducted routinely, and these often reveal deposition of immunoglobulin and/or complement or electron-dense deposits in the renal tubular basement membrane (TBM) in IgG4-related TIN [8, 22]. Raissian et al. reported immune complex deposition in the TBM in ≥80 % of patients with IgG4-related TIN [8]. Immunofluorescence microscopy demonstrates granular deposits of IgG4 (usually concurrent with other subtypes of IgG such as IgG1 and IgG3) and C3, with occasional C1q. These TBM deposits are mainly demonstrated in areas affected by fibro-inflammatory changes, and not in adjacent areas that are unaffected [8, 22].

Although TIN is the major lesion in IgG4-RKD, some glomerular lesions have been reported in type 1 AIP. Membranous nephropathy (MN) is the most common glomerular lesion and has been reported in 7–10 % of patients with IgG4-related TIN [8, 23]. Recently, several cases of MN without TIN in the setting of IgG4-RD, including type 1 AIP, have been reported [24], and this is attracting attention as a pathophysiological aspect other than ordinary fibro-inflammatory lesions in IgG4-RD [25]. MN is an antibody-mediated autoimmune glomerular disease and one of the most common causes of nephrotic syndrome in adults. MN occurs as an idiopathic disease or secondary to conditions such as autoimmune disease (e.g., systemic lupus erythematosus), infection (e.g., hepatitis B, hepatitis C), drug reactions, and malignancies [26]. Pathologically, MN is characterized by subepithelial deposition of immune complexes containing IgG and usually C3, and IgG4 predominance in such glomerular immune complexes has been documented in idiopathic MN [26]. Recently, the M-type phospholipase A2 receptor (PLA2R) has been identified as a target antigen common to about 70 % of patients with idiopathic MN, and the anti-PLA2R antibodies are predominantly of the IgG4 subclasses [27]. Also in MN in IgG4-RD, either with or without TIN, IgG4 is usually (but not always) predominant in glomerular immune complexes, although usually concurrent with other types of IgG subclasses [24, 28]. However, anti-PLA2R antibodies have been negative in all cases of MN in IgG4-RD [24] (and also all cases of IgG4-RD [29]) evaluated, suggesting that the condition differs from idiopathic MN and may be secondary to IgG4-RD. However, MN can be associated with malignancies, and patients with AIP are reported to be at high risk of having cancers [30]. Although IgG4 is not usually dominant in glomerular immune complexes in MN associated with malignancy, IgG4 is not always dominant in cases of MN associated with IgG4-RD. Therefore, an extensive survey for malignancy is necessary in any case of MN in type 1 AIP, especially in the absence of TIN. In addition to MN, various types of glomerular lesions have been reported to be concurrent with IgG4-related TIN, including Henoch-Schönlein purpura nephritis, IgA nephropathy, endocapillary proliferative glomerulonephritis, membranoproliferative glomerulonephritis, and mesangial proliferative glomerulonephritis [7, 9].

Although the number of case reports of IgG4-related pyelitis is limited, dense lymphoplasma cell infiltration with numerous IgG4-positive plasma cells and fibrosis has been described in the renal pelvis in IgG4-RD, similar to those in other affected organs [31, 32]. Lymphocytes and plasma cells markedly infiltrate beneath the urothelial epithelium of the renal pelvis, and multiple lymphoid follicles may be evident [32]. In spite of severe inflammation, the urothelial epithelium is relatively well preserved (Fig. 18.3). Storiform fibrosis, obliterative phlebitis, and eosinophil infiltration are also evident is some lesions [32].