Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

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.

References

  1. Stone, J. H., Zen, Y. & Deshpande, V. IgG4-related disease. N. Engl. J. Med. 366, 539–551 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Hamano, H. et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N. Engl. J. Med. 344, 732–738 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Deshpande, V. et al. Subclassification of autoimmune pancreatitis: a histologic classification with clinical significance. Am. J. Surg. Pathol. 35, 26–35 (2011).

    Article  PubMed  Google Scholar 

  4. Kamisawa, T. et al. A new clinicopathological entity of IgG4-related autoimmune disease. J. Gastroenterol. 38, 982–984 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Saeki, T. et al. Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis. Kidney Int. 78, 1016–1023 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Zen, Y. & Nakanuma, Y. IgG4-related disease: a cross-sectional study of 114 cases. Am. J. Surg. Pathol. 34, 1812–1819 (2010).

    Article  PubMed  Google Scholar 

  7. Cheuk, W. & Chan, J. K. IgG4-related sclerosing disease: a critical appraisal of an evolving clinicopathologic entity. Adv. Anat. Pathol. 17, 303–332 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Deshpande, V. et al. Consensus statement on the pathology of IgG4-related disease. Mod. Pathol. 25, 1181–1192 (2012).

    Article  PubMed  Google Scholar 

  9. Raissian, Y. et al. Diagnosis of IgG4-related tubulointerstitial nephritis. J. Am. Soc. Nephrol. 22, 1343–1352 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Khosroshahi, A. et al. Brief report: spuriously low serum IgG4 concentrations caused by the prozone phenomenon in patients with IgG4-related disease. Arthritis Rheumatol. 66, 213–217 (2014).

    Article  PubMed  Google Scholar 

  11. Ryu, J. H., Horie, R., Sekiguchi, H., Peikert, T. & Yi, E. S. Spectrum of disorders associated with elevated serum IgG4 levels encountered in clinical practice. Int. J. Rheumatol. 2012, 232960 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Carruthers, M. N., Khosroshahi, A., Augustin, T., Deshpande, V. & Stone, J. H. The diagnostic utility of serum IgG4 concentrations in IgG4-related disease. Ann. Rheum. Dis. 74, 14–18 (2015).

    Article  CAS  PubMed  Google Scholar 

  13. Wallace, Z. et al. IgG4-related disease: baseline clinical and laboratory features in 125 patients with biopsy-proven disease. Arthritis Rheumatol. http://dx.doi.org/10.1002/art.39205

  14. Kamisawa, T. et al. Standard steroid treatment for autoimmune pancreatitis. Gut 58, 1504–1507 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Sah, R. P. & Chari, S. T. Serologic issues in IgG4-related systemic disease and autoimmune pancreatitis. Curr. Opin. Rheumatol. 23, 108–113 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Nirula, A., Glaser, S. M., Kalled, S. L. & Taylor, F. R. What is IgG4? A review of the biology of a unique immunoglobulin subtype. Curr. Opin. Rheumatol. 23, 119–124 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Aalberse, R. C., Stapel, S. O., Schuurman, J. & Rispens, T. Immunoglobulin G4: an odd antibody. Clin. Exp. Allergy 39, 469–477 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Mattoo, H. et al. De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease. J. Allergy Clin. Immunol. 134, 679–687 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zen, Y. et al. Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis. Hepatology 45, 1538–1546 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Okazaki, K. et al. Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2-type cellular immune response. Gastroenterology 118, 573–581 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Zen, Y. & Nakanuma, Y. Pathogenesis of IgG4-related disease. Curr. Opin. Rheumatol. 23, 114–118 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Khosroshahi, A., Bloch, D. B., Deshpande, V. & Stone, J. H. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease. Arthritis Rheum. 62, 1755–1762 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Khosroshahi, A. et al. Rituximab for the treatment of IgG4-related disease: lessons from 10 consecutive patients. Medicine (Baltimore) 91, 57–66 (2012).

    Article  CAS  Google Scholar 

  24. Vaseemuddin, M., Schwartz, M. M., Dunea, G. & Kraus, M. A. Idiopathic hypocomplementemic immune-complex-mediated tubulointerstitial nephritis. Nat. Clin. Pract. Nephrol. 3, 50–58 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Baker, R. J. & Pusey, C. D. The changing profile of acute tubulointerstitial nephritis. Nephrol. Dial. Transplant. 19, 8–11 (2004).

    Article  PubMed  Google Scholar 

  26. Takahashi, N., Kawashima, A., Fletcher, J. G. & Chari, S. T. Renal involvement in patients with autoimmune pancreatitis: CT and MR imaging findings. Radiology 242, 791–801 (2007).

    Article  PubMed  Google Scholar 

  27. Cornell, L. D. et al. Pseudotumors due to IgG4 immune-complex tubulointerstitial nephritis associated with autoimmune pancreatocentric disease. Am. J. Surg. Pathol. 31, 1586–1597 (2007).

    Article  PubMed  Google Scholar 

  28. Alkhasawneh, A. & Allan, R. W. IgG4 inflammatory pseudotumor of the kidney. Case Rep. Urol. 2012, 919087 (2012).

    PubMed  PubMed Central  Google Scholar 

  29. Yoshita, K. et al. Light-microscopic characteristics of IgG4-related tubulointerstitial nephritis: distinction from non-IgG4-related tubulointerstitial nephritis. Nephrol. Dial. Transplant. 27, 2755–2761 (2012).

    Article  PubMed  Google Scholar 

  30. Kawano, M. et al. Immunohistochemical characteristics of IgG4-related tubulointerstitial nephritis: detailed analysis of 20 Japanese cases. Int. J. Rheumatol. 2012, 609795 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Yamaguchi, Y. et al. Characteristic tubulointerstitial nephritis in IgG4-related disease. Hum. Pathol. 43, 536–549 (2012).

    Article  PubMed  Google Scholar 

  32. Kawano, M. et al. Proposal for diagnostic criteria for IgG4-related kidney disease. Clin. Exp. Nephrol. 15, 615–626 (2011).

    Article  PubMed  Google Scholar 

  33. Beck, L. H. Jr et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N. Engl. J. Med. 361, 11–21 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Alexander, M. P. et al. Membranous glomerulonephritis is a manifestation of IgG4-related disease. Kidney Int. 83, 455–462 (2013).

    Article  CAS  PubMed  Google Scholar 

  35. Ong, A. C. & Fine, L. G. Loss of glomerular function and tubulointerstitial fibrosis: cause or effect? Kidney Int. 45, 345–351 (1994).

    Article  CAS  PubMed  Google Scholar 

  36. Debiec, H. & Ronco, P. PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy. N. Engl. J. Med. 364, 689–690 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Jennette, J. C., Iskandar, S. S. & Dalldorf, F. G. Pathologic differentiation between lupus and nonlupus membranous glomerulopathy. Kidney Int. 24, 377–385 (1983).

    Article  CAS  PubMed  Google Scholar 

  38. Davenport, A., Maciver, A. G., Hall, C. L. & MacKenzie, J. C. Do mesangial immune complex deposits affect the renal prognosis in membranous glomerulonephritis? Clin. Nephrol. 41, 271–276 (1994).

    CAS  PubMed  Google Scholar 

  39. Vaglio, A., Salvarani, C. & Buzio, C. Retroperitoneal fibrosis. Lancet 367, 241–251 (2006).

    Article  PubMed  Google Scholar 

  40. van Bommel, E. F., Jansen, I., Hendriksz, T. R. & Aarnoudse, A. L. Idiopathic retroperitoneal fibrosis: prospective evaluation of incidence and clinicoradiologic presentation. Medicine (Baltimore) 88, 193–201 (2009).

    Article  CAS  Google Scholar 

  41. Kermani, T. A., Crowson, C. S., Achenbach, S. J. & Luthra, H. S. Idiopathic retroperitoneal fibrosis: a retrospective review of clinical presentation, treatment, and outcomes. Mayo Clin. Proc. 86, 297–303 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Stone, J. R. Aortitis, periaortitis, and retroperitoneal fibrosis, as manifestations of IgG4-related systemic disease. Curr. Opin. Rheumatol. 23, 88–94 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Khosroshahi, A. et al. Rethinking Ormond's disease: “idiopathic” retroperitoneal fibrosis in the era of IgG4-related disease. Medicine (Baltimore) 92, 82–91 (2013).

    Article  CAS  Google Scholar 

  44. Saeki, T. et al. The clinical course of patients with IgG4-related kidney disease. Kidney Int. 84, 826–833 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. Khosroshahi, A. & Stone, J. H. Treatment approaches to IgG4-related systemic disease. Curr. Opin. Rheumatol. 23, 67–71 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Ghazale, A. et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology 134, 706–715 (2008).

    Article  PubMed  Google Scholar 

  47. Wallace, Z. S. et al. Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations. Ann. Rheum. Dis. 74, 190–195 (2015).

    Article  CAS  PubMed  Google Scholar 

  48. González, E. et al. Early steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis. Kidney Int. 73, 940–946 (2008).

    Article  PubMed  Google Scholar 

  49. Mizushima, I. et al. Clinical and histological changes associated with corticosteroid therapy in IgG4-related tubulointerstitial nephritis. Mod. Rheumatol. 22, 859–870 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Austin, H. A. 3rd, Illei, G. G., Braun, M. J. & Balow, J. E. Randomized, controlled trial of prednisone, cyclophosphamide, and cyclosporine in lupus membranous nephropathy. J. Am. Soc. Nephrol. 20, 901–911 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sarafidis, P. A., Khosla, N. & Bakris, G. L. Antihypertensive therapy in the presence of proteinuria. Am. J. Kidney Dis. 49, 12–26 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Wheeler, D. C. & Bernard, D. B. Lipid abnormalities in the nephrotic syndrome: causes, consequences, and treatment. Am. J. Kidney Dis. 23, 331–346 (1994).

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

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

Authors
  1. Frank B. Cortazar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John H. Stone
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to John H. Stone.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2015.95

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing