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  • Review Article
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IgG4-related disease and the kidney

Nature Reviews Nephrology volume 11, pages 599–609 (2015)Cite this article

Subjects

Key Points

  • IgG4-related disease (IgG4-RD) is a systemic disease that can affect almost every organ system, including the kidney

  • Diagnosis of IgG4-RD is based on characteristic pathology: a lymphoplasmacytic infiltrate enriched with IgG4+ plasma cells, and storiform fibrosis

  • Serum IgG4 levels are elevated in most patients with IgG4-RD, but are neither sufficiently sensitive nor sufficiently specific to enable diagnosis of the disease

  • IgG4-related tubulointerstitial nephritis is the most common form of IgG4-related kidney disease; the condition is characterized by unique findings on contrast-enhanced CT and the hallmark pathology of IgG4-RD

  • Membranous glomerulonephropathy secondary to IgG4-RD is a rare manifestation of IgG4-RD that is not associated with antibodies against the secretory phospholipase A2 receptor

  • Glucocorticoids are the standard therapy for IgG4-RD, but frequent relapses and adverse effects limit their use; B-cell depletion is an alternative approach

Abstract

IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition that involves almost every organ system. In this Review, we summarize current knowledge of IgG4-RD and its most frequent manifestations in the kidney—IgG4-related tubulointerstitial nephritis (TIN) and membranous glomerulonephropathy (MGN). Diagnosis of IgG4-RD relies on histopathology: the typical features are a dense lymphoplasmacytic infiltrate and storiform fibrosis. A high percentage of plasma cells observed within lesions stain positively for IgG4. IgG4-related TIN bears the hallmark pathological findings of IgG4-RD; distinctive radiographic characteristics are also frequently observed with use of contrast-enhanced CT. MGN secondary to IgG4-RD seems to be distinct from idiopathic MGN. Humoral and cell-mediated immunity seem to have roles in the pathophysiology of IgG4-RD, but the details of these roles remain unclear. The IgG4 molecule itself is unlikely to be the primary driver of inflammation; rather, it probably downregulates the immune response. Fibrosis might be caused by activation of innate immune cells by polarized CD4+ T cells. Glucocorticoids are the standard initial treatment for IgG4-RD, but their long-term adverse effects and the high frequency of relapse and renal damage associated with use of this treatment has prompted a search for more effective options. B-cell depletion and the targeting of plasmablasts are both promising approaches.

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Figure 1: Typical pathological features of IgG4-related disease in the lung, retroperitoneum and mediastinum.
Figure 2: Fab arm exchange among IgG4 antibodies.
Figure 3: The possible pathophysiology of IgG4-related disease.
Figure 4: CT scan of the kidneys in a patient with IgG4-related tubulointerstitial nephritis.
Figure 5: Renal pathology in IgG4-related tubulointerstital nephritis.
Figure 6: Renal pathology in MGN secondary to IgG4-RD.

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Acknowledgements

The authors thank Vikram Deshpande from the Massachusetts General Hospital, Boston, USA, for providing Figures 1 and 5, and Helmut Rennke from the Brigham & Women's Hospital, Boston, USA, for providing Figure 6.

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Authors and Affiliations

  1. Nephrology Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, 02114, MA, USA

    Frank B. Cortazar

  2. Rheumatology Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, 02114, MA, USA

    John H. Stone

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Both authors researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to John H. Stone.

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Cortazar, F., Stone, J. IgG4-related disease and the kidney. Nat Rev Nephrol 11, 599–609 (2015). https://doi.org/10.1038/nrneph.2015.95

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