A biopsy of a mass lesion in a 62-year-old man shows an expansile “storiform” interstitial fibrosis with marked interstitial inflammation. A silver stain (upper left panel) highlights tubular basement membranes (arrows) of tubules that have been pushed apart by the interstitial fibrosis. On higher magnification (upper right panel), the inflammatory infiltrate is seen to be composed of numerous eosinophils and plasma cells, as well as mononuclear cells. An immunoperoxidase stain for IgG4 (lower left panel) shows markedly increased IgG4+ plasma cells. As this biopsy was performed for a mass, no tissue was submitted for immunofluorescence staining, but deparaffinized tissue processed for electron microscopy reveals tubular basement membrane immune complex deposits (arrow; lower right panel)
Glomeruli generally appear normal or show mild mesangial matrix expansion or hypercellularity. If there is a concurrent membranous glomerulonephritis (MGN), then glomeruli may show thickened glomerular capillary loops, glomerular basement membrane “spikes” on silver or PAS stains, or subepithelial immune deposits on a trichrome stain. Arteries show no specific features in IgG4-TIN.
By immunofluorescence, >80 % of cases show TBM immune complex deposits, which stain for IgG and kappa and lambda light chains and usually stain for C3, and occasionally for C1q [14, 24]. Biopsies can show focal or diffuse TBM granular staining. Several cases stained by immunofluorescence for IgG subclasses show IgG4-dominant staining of TBMs, although other IgG subclasses are also variably present (LD Cornell, unpublished data). TBM deposits are found more frequently in cases with fibrosis than in cases with a pattern of acute interstitial nephritis [14, 24] and are found only in areas of the fibroinflammatory process and not in adjacent unaffected areas. Glomeruli are usually negative by immunofluorescence unless there is a concurrent membranous glomerulonephritis, in which case glomeruli show granular subepithelial glomerular basement membrane staining for IgG, C3, and kappa and lambda light chains. Some cases have been described to show mesangial immune deposits without a more specific glomerular disease assigned [12, 16].
Biopsies with deposits seen by immunofluorescence show corresponding electron-dense deposits by electron microscopy. TBM deposits are present in areas with inflammation or fibrosis and are not present in the unaffected areas of the kidney. The deposits appear finely granular and do not show substructure. Occasional interstitial deposits may also be seen within areas of fibrosis. Glomeruli typically are free of deposits, unless there is a concurrent membranous glomerulonephritis, in which case there are numerous subepithelial electron-dense deposits. Formalin-fixed, paraffin-embedded tissue from biopsy or nephrectomy samples done for a mass lesion may be deparaffinized for electron microscopy in order to visualize immune complex deposits.
Value of IgG4 Staining
Zhang et al. and others have found that IgG4 staining in pancreas for increased IgG4+ plasma cells is useful to distinguish AIP from other forms of pancreatic inflammation, including chronic alcoholic pancreatitis and inflammatory infiltrates surrounding pancreatic cancers . In the kidney, more types and causes of inflammatory infiltrates are recognized that give a pattern of TIN. Raissian et al. examined the concentration of IgG4+ plasma cells in IgG4-TIN and in a variety of other forms of TIN that could mimic IgG4-TIN clinically and histologically [14, 24]. The authors found a sensitivity of 100 % [95 % confidence interval (CI), 0.9–1] and specificity of 92 % (CI 0.86–0.95) using a cutoff of focal moderate (11–30 IgG4+ cells/40× field) to marked (>30 IgG4+ cells/40× field) increase in IgG4+ plasma cells for distinguishing IgG4-TIN from other forms of TIN, with the exception of inflammatory infiltrates in pauci-immune necrotizing and crescentic glomerulonephritis. In pauci-immune necrotizing and crescentic glomerulonephritis, >30 % of cases showed a moderate to marked increase in IgG4+ plasma cells. Similar findings have been noted in granulomatosis with polyangiitis (Wegener’s) affecting other organs . The absence of a serum ANCA (or anti-myeloperoxidase or -proteinase 3 antibodies) and a necrotizing or crescentic glomerulonephritis on the tissue specimen helps to exclude pauci-immune glomerulonephritis as a cause of the interstitial inflammation in these cases. A few other causes of interstitial inflammation could also give focally increased IgG4+ plasma cells, including chronic pyelonephritis; these other causes usually can be distinguished by other clinical and histopathologic features. Notably, nearly all cases of Sjögren syndrome-related TIN did not show increased IgG4+ plasma cells. Clinicians and pathologists should keep in mind that IgG4 staining alone is not diagnostic of IgG4-related disease.
Diagnosis of IgG4-TIN
Two papers, from Japan and from North America, have proposed similar diagnostic criteria for IgG4-TIN that include clinical, histopathologic, serologic, and radiographic features [14, 27] (Table 17.1).
Proposed diagnostic criteria for IgG4-TIN 
Plasma cell-rich tubulointerstitial nephritis with >10 IgG4+ plasma cells/hpf field in the most concentrated fielda
Tubular basement membrane immune complex deposits by immunofluorescence, immuno-histochemistry, and/or electron microscopyb
Small peripheral low-attenuation cortical nodules, round or wedge-shaped lesions, or diffuse patchy involvement
Diffuse marked enlargement of kidneys
Elevated serum IgG4 or total IgG level
Other organ involvement
Includes autoimmune pancreatitis, sclerosing cholangitis, inflammatory masses in any organ, sialadenitis, inflammatory aortic aneurysm, lung involvement, retroperitoneal fibrosis
Diagnosis of IgG4-TIN requires the histologic feature of plasma cell-rich TIN with increased IgG4+ plasma cells and at least one other feature from the Imaging, Serology, or Other organ involvement categories.
Response to Therapy
Similar to AIP, IgG4-TIN also usually shows a rapid response to steroid therapy. In both the Saeki and Raissian series, 90 % of patients with elevated serum creatinine at presentation who were treated with steroids showed decreased creatinine at follow-up, from 1 to 36 months, including 90 % at 1 month follow-up in the Saeki series. While TIN of different causes may respond to steroid therapy, IgG4-TIN tends to show a more brisk response, even in cases with severe interstitial fibrosis on the biopsy sample.
On imaging, renal lesions improve or resolve after steroid treatment. Focal cortical parenchymal loss (scars) may be present after treatment. Similar to involvement of other organs by IgG4-RD, relapse of renal lesions may occur after cessation of steroid treatment. Without steroid treatment, renal lesions may progress.
Other Renal Involvement
Glomerular diseases have also been seen in patients with IgG4-RD. Membranous glomerulonephritis (MGN) is most commonly observed, present in approximately 7 % of IgG4-RD patients in two biopsy series of renal parenchymal involvement by TIN, and has been noted in case reports [14, 16, 24, 28, 29]. This glomerular disease may also occur in patients without TIN but with other features of IgG4-RD: one series of MGN in IgG4-RD patients showed that 50 % lacked concurrent TIN on the biopsy .
Other glomerular diseases have been variably reported in IgG4-RD, including IgA nephropathy and membranoproliferative glomerulonephritis [16, 31] and minimal change disease (Takako Saeki, personal communication). Although common in patients without AIP, diabetes mellitus may be a manifestation of AIP due to pancreatic endocrine insufficiency, and this may also affect the glomeruli in the form of diabetic glomerulosclerosis.
Obstruction Related to Retroperitoneal Fibrosis
The extrarenal manifestation of retroperitoneal fibrosis or ureteral inflammatory mass(es) may give rise to hydronephrosis, with or without accompanying renal parenchymal involvement. Histologic sections reveal storiform fibrosis with scattered areas of plasma cell-rich inflammation, similar to what is described in other organs involved by IgG4-RD.