Diagnosis of IgG4-related tubulointerstitial nephritis

Abstract

IgG4-related systemic disease is an autoimmune disease that was first recognized in the pancreas but also affects other organs. This disease may manifest as tubulointerstitial nephritis (IgG4-TIN), but its clinicopathologic features in the kidney are not well described. Of the 35 patients with IgG4-TIN whose renal tissue specimens we examined, 27 (77%) had acute or progressive chronic renal failure, 29 (83%) had involvement of other organ systems, and 18 of 23 (78%) had radiographic abnormalities. Elevated total IgG or IgG4 serum levels were present in 79%. All pathologic specimens featured plasma cell-rich TIN, with most showing diffuse, expansile interstitial fibrosis. Immune complexes along the tubular basement membranes were present in 25 of 30 (83%). All specimens had a moderate to marked increase in IgG4+ plasma cells by immunohistochemistry. We used a control group of 175 pathologic specimens with plasma cell-rich interstitial infiltrates that can mimic IgG4-TIN to examine the diagnostic utility of IgG4 immunostaining. Excluding pauci-immune necrotizing and crescentic glomerulonephritis, IgG4 immunohistochemistry had a sensitivity of 100% (95% CI 90-100%) and a specificity of 92% (95% CI 86-95%) for IgG4-TIN. Of the 19 patients with renal failure for whom treatment and follow-up data were available, 17 (89%) responded to prednisone. In summary, because no single test definitively diagnoses IgG4-related systemic disease, we rely on a combination of histologic, immunophenotypic, clinical, radiographic, and laboratory features. When the disease manifests in the kidney, our data support diagnostic criteria that can distinguish IgG4-TIN from other types of TIN.

Figure 1.

Typical pathologic features of IgG4-related TIN. Representative light, immunofluorescence, and electron microscopy images from patient #8. Top, left: An expansile, destructive fibroinflammatory process with residual tubular basement, membranes seen on a silver stain. Glomeruli are unaffected except for periglomerular fibrosis and global glomerulosclerosis (Jones-methenamine silver, ×200). Top right: The interstitial infiltrate is composed of mononuclear cells, plasma cells, and several eosinophils. Mononuclear cell tubulitis is seen focally (hematoxylin and eosin, ×400). Middle left: Immunofluorescence for IgG shows diffuse granular tubular basement membrane staining, as well as Bowman's capsule staining. The glomerular tuft is negative (immunofluorescence IgG-FITC, ×200). Middle right: Immunohistochemical staining for IgG4 shows a marked increase in IgG4-positive plasma cells in the infiltrate (×200). Bottom left: Electron microscopy reveals thickened tubular basement membranes with scattered electron dense immune complex deposits in an atrophic tubule (×5800). Bottom right: Amorphous tubular basement membrane deposits (×9700).