(a) Contrast-enhanced renal CT finding in a patient with IgG4-related TIN. Multiple low-density lesions are evident. (b) Pelvic lesion in IgG4-RD. Bilateral renal pelvis wall thickening is found. The luminal surface is smooth
In addition to these renal lesions directly associated with IgG4-RD, hydronephrosis due to ureteral obstruction in patients with IgG4-related ureteral or periaortic/retroperitoneal lesions is sometimes evident in patients with type 1 AIP. In such cases of hydronephrosis concurrent with type 1 AIP, physicians should bear in mind that overlapping of IgG4-TIN is possible, and renal histological examination should be considered when recovery of renal function is insufficient after resolution of the hydronephrosis following the placement of ureteral stents . For cases in which contrast CT cannot be performed, MRI is also recommended to evaluate the presence, absence, or distribution of renal parenchymal lesions . Gallium citrate scintigraphy and FDG-PET studies are also useful for detection of IgG4-related TIN even in patients showing no renal abnormalities by CT examination [7, 18].
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) . 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) . 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 . Such histological characteristics are basically common to those in type 1 AIP , 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 .
Characteristic light microscopic findings of IgG4-related TIN. (a) A swirling pattern consisting inflammatory cells and collagen fibers, corresponding to storiform fibrosis in type 1 AIP, is evident (hematoxylin and eosin stain, ×100). (b) The “bird’s eye” appearance of irregular fibers surrounding nests of inflammatory cells (periodic acid-methenamine silver stain, ×400). (c) A regional lesion distribution. Affected and unaffected areas are clearly demarcated (hematoxylin and eosin stain, ×60)
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 . 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 , and this is attracting attention as a pathophysiological aspect other than ordinary fibro-inflammatory lesions in IgG4-RD . 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 . 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 . 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 . 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  (and also all cases of IgG4-RD ) 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 . 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 . 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 .
Histological findings of IgG4-related pyelitis. (a) Lymphocytes and plasma cells markedly infiltrate beneath the urothelial epithelium of the renal pelvis. The urothelial epithelium is relatively well preserved (hematoxylin and eosin stain, ×100). (b) Lymphoid follicles are evident (hematoxylin and eosin stain, ×40)
A diagnostic algorithm using a set of diagnostic criteria for IgG4-RKD has been proposed by the Japanese Society of Nephrology  and is useful for finding renal lesions in patients with type 1 AIP (Fig. 18.4). In this algorithm, the presence of some kidney damage, as manifested by abnormal urinalysis data or urine marker(s), abnormal radiologic findings, or decreased kidney function, with either an elevated total IgG level, hypocomplementemia, or an elevated serum IgE level, is the first step at which IgG4-RKD should be suspected. After exclusion of other renal diseases, the serum IgG4 level is confirmed, and then radiological and histological examinations are evaluated.
The diagnostic algorithm for IgG4-RKD proposed by the Japanese Society of Nephrology  (*Characteristic radiological findings in the kidney include (a) multiple low-density lesions on enhanced computed tomography, (b) diffuse kidney enlargement, (c) hypovascular solitary mass in the kidney, (d) hypertrophic lesion of renal pelvic wall without irregularity of the renal pelvic surface. **Characteristic tubulointerstitial findings include (a) dense lymphoplasmacytic infiltration with infiltrating IgG4-positive plasma cells >10/high-power field (HPF) and/or IgG4/IgG-positive plasma cells >40 %, (b) characteristic fibrosis surrounding nests of lymphocytes and/or plasma cells)
Treatment and Clinical Course
Similar to type 1 AIP, corticosteroid is quite effective in most cases of IgG4-RKD. Corticosteroid therapy leads to a rapid improvement in terms of renal function, radiology, and serology at 1 month after the start of therapy in most patients with IgG4-RKD, although the response in terms of urinalysis parameters after therapy varies . However, renal function does not recover completely in patients with advanced renal damage. In patients whose estimated glomerular filtration rate (eGFR) before treatment was <60 ml/min, eGFR before treatment (34.1 ± 15.8 ml/min) was significantly improved at 1 month after the start of treatment (45.0 ± 13.8 ml/min, p < 0.01), but recovery of renal function reached a plateau during the initial one month of corticosteroid treatment in most cases. Thereafter, renal atrophy developed in a considerable proportion of treated patients, especially those in whom advanced renal damage had already been evident before therapy, although, fortunately, recovery of renal function persisted for a relatively long period under low-dose corticosteroid maintenance therapy . These results suggest that irreversible lesions remain in patients at the advanced stage of IgG4-related TIN, despite corticosteroid therapy, and therefore early diagnosis and therapy are important. Although indications for corticosteroid therapy in IgG4-RKD have not been established, patients with renal dysfunction should receive it immediately and careful attention should be paid to patients who do not receive therapy. For induction therapy, prednisolone 0.6 mg/kg daily is recommended in Japan for type 1 AIP , and our data (unpublished) indicate that this therapy also seems to be appropriate for IgG4-RKD. Withdrawal of maintenance therapy for IgG4-related TIN should be considered very carefully, in view of possible progression of irreversible renal damage. The efficacy of immunosuppressant for treatment of IgG4-RKD has not been clarified, and the related data are rather sparse.