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Year : 2017  |  Volume : 60  |  Issue : 4  |  Page : 577-580
Immunoglobulin G4-related tubulointerstitial nephritis: A not to be missed diagnosis

Department of Nephrology and Pathology, Central Electron Microscopy Unit, Wellcome Trust Research Laboratory, Division of GI Sciences, Christian Medical College, Vellore, Tamil Nadu, India

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Date of Web Publication12-Jan-2018


Immunoglobulin G4-related tubulointerstitial nephritis (IgG4-TIN) is a newly recognized clinicopathological entity characterized by a dense interstitial infiltrate of IgG4-positive plasma cells accompanied by fibrosis and obliterative phlebitis causing acute or chronic renal dysfunction amenable to corticosteroid therapy. IgG4-TIN is the dominant manifestation of renal involvement in IgG4-related disease (IgG4-RD) which is a novel, immune-mediated, fibroinflammatory and multiorgan disorder. We describe a case of IgG4-TIN with isolated renal involvement in an elderly male patient with poor response to corticosteroid therapy. The distinctive serological, histopathological, and ultrastructural features of this condition which can facilitate differential diagnosis of TIN are highlighted to emphasize the need for early diagnosis and preservation of kidney function.

Keywords: Corticosteroid therapy, immunoglobulin G4-related disease, tubulointerstitial nephritis

How to cite this article:
Matthai SM, Mohapatra A, Palak R, Basu G. Immunoglobulin G4-related tubulointerstitial nephritis: A not to be missed diagnosis. Indian J Pathol Microbiol 2017;60:577-80

How to cite this URL:
Matthai SM, Mohapatra A, Palak R, Basu G. Immunoglobulin G4-related tubulointerstitial nephritis: A not to be missed diagnosis. Indian J Pathol Microbiol [serial online] 2017 [cited 2022 Sep 26];60:577-80. Available from:

   Introduction Top

Immunoglobulin G4-related disease (IgG4-RD) is a systemic, immune-mediated disorder associated with high serum IgG4 levels (in approximately 70–80%), that was first identified in Japan and is now emerging worldwide.[1] The hallmark of IgG4-RD is dense lymphoplasmacytic infiltration, rich in IgG4-secreting plasma cells with ensuing fibrosclerosis and tumefactive lesions of the involved organs. Depending on the organ involved, IgG4RD encompasses varied clinical manifestations, the prototype being autoimmune pancreatitis (AIP).[1],[2],[3] A dramatic response to corticosteroid therapy is the reported clinical course, irrespective of the organ of involvement in IgG4-RD. IgG4-related kidney disease (IgG4-RKD) is a comprehensive term for renal lesions associated with IgG4-RD, the dominant manifestation of which is tubulointerstitial nephritis (TIN), which may occur synchronously or metachronously with lesions in other organs.[4] We report a rare case of IgG4-TIN with isolated renal involvement which showed poor response to steroid therapy, contrary to established norms.

   Case Report Top

A 66-year-old male was referred with rising serum creatinine following an episode of acute kidney injury (AKI) 3 years back requiring 3 sessions of hemodialysis at the time of initial presentation. His medical history before the first episode of AKI was uneventful. He underwent a renal biopsy which showed TIN and was treated with steroids for a period of 2 years. His creatinine gradually improved but did not touch baseline. After the initial response to treatment, he developed rapid worsening of creatinine over the last 6 months and was referred to us for further management. He was detected to have diabetes 3 years back and was on treatment for the same.

Investigations revealed serum creatinine 5.5 mg%, active urine sediments (8 white blood cells, 6 red blood cells), subnephrotic proteinuria (796 mg) and low serum C3 25.9 mg/dL and serum C4 <5.87 mg/dL. Serum electrophoresis was normal.

Renal biopsy showed diffuse global glomerulosclerosis and severe chronic TIN with dense lymphoplasmacytic interstitial infiltrates, tubular destruction, and extensive fibrosis with focal storiform pattern on light microscopy [Figure 1]a and [Figure 1]b. Immunofluorescence showed nonspecific trapping of C3 in sclerosed tufts. The IgG4 immunostain showed more than 25 IgG4-positive plasma cells per high-power field [Figure 1]c. Electron microscopy confirmed the above findings and demonstrated tubular basement membrane electron dense deposits in addition to characteristic bird's eye fibrosis [Figure 2]a,[Figure 2]b,[Figure 2]c. The final diagnosis was IgG4-TIN. Serum IgG4 levels were also elevated (3337 mg/L).
Figure 1: (a) Low power view of tubulointerstitial nephritis with dense lymphoplasmacytic infiltrate (H and E, ×100). (b) Plasma cell-rich interstitial infiltrate associated with extensive fibrosis (H and E, ×400). (c) Immunostaining for immunoglobulin G4 shows >25 immunoglobulin G4-positive plasma cells in single high-power field (IHC, ×400)

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Figure 2: (a) Bands of fibrosis encircling dense interstitial infiltrate of plasma cells and lymphocytes (transmission electron microscopy, ×1050). (b) Swollen plasma cells surrounded by thick fibrotic bands giving appearance of bird's eye fibrosis (transmission electron microscopy, ×4200). (c) Tubular basement membrane deposits (transmission electron microscopy, ×1250)

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The patient was restarted on steroid therapy, but his renal function showed only minimal improvement. On follow-up after 1 year, serum creatinine remains elevated at 3.68 mg/dL.

   Discussion Top

IgG4-RD is a newly characterized systemic disease, the hallmark of which is infiltration of affected organs by IgG4-secreting plasma cells with resultant fibrosclerosis and tumefactive masses, elevated serum IgG4 levels, and favorable response to corticosteroid therapy.[1],[2],[3],[4] The first description of this entity was in 2001 by Hamano et al. with relation to AIP.[5] Subsequently, similar lesions were identified in multiple other organs such as salivary glands (sialadenitis), eye/orbit (dacryoadenitis and pseudotumor), aorta/retroperitoneum (periaortitis and retroperitoneal fibrosis), biliary system (sclerosing cholangitis and cholecystitis), lymph nodes (lymphadenopathy), liver (pseudotumor and hepatopathy), lung (inflammatory pseudotumor and alveolar interstitial disease), endocrine system (hypophysitis and thyroiditis), and kidney (IgG4-RKD).[4] Numerous conditions previously considered to be unrelated single organ diseases have been integrated under the unified disorder IgG4-RD.

The clinical manifestations vary depending on the organ of involvement. However, common features include predominant occurrence in middle aged to elderly male patients [6] and diagnostic histology of involved organs comprising of dense lymphoplasmacytic infiltrate rich in IgG4-secreting plasma cells and fibrosis accompanied in most cases by elevated serum IgG4 levels.[7] Renal involvement, i.e., IgG4-RKD, manifests predominantly as TIN although membranous nephropathy, endocapillary proliferative glomerulonephritis, HSP nephritis/IgA nephropathy, and hydronephrosis secondary to retroperitoneal fibrosis may also occur concurrently.[8],[9] Most patients with IgG4-RKD have associated IgG4-related extrarenal lesions, frequently involving salivary glands, pancreas, lymph nodes and lacrimal glands.[10] Our case presented with isolated renal involvement which is unusual in this multisystemic disorder although subtle involvement of other organs was not excluded by contrast-enhanced CT scan.

The diagnostic criteria for IgG4-TIN proposed by Raissian et al. are summarized in [Table 1].[10] Renal histology is fundamental in the diagnosis of TIN in IgG4-RD. Three features are characteristic: (1) interstitial lymphoplasmacytic infiltrates with dominant IgG4-positive plasma cells; (2) the ratio of IgG4-positive/IgG-positive plasma cells over 40%; and (3) obliterative phlebitis. Our case showed all the mandatory diagnostic histological, immunohistochemical, and ultrastructural findings as well as serological criteria which enabled us to diagnose IgG4-TIN even in the absence of other organ IgG4-RD. Exclusion of other etiologies of TIN such as autoimmune, inflammatory, or malignancies was also done based on elevated IgG4 serology and IgG4 immunostaining. Quantification of IgG4-positive cells is important to rule out conditions with increased interstitial infiltrates of plasma cells such as multicentric Castleman's disease, some cases of antineutrophil cytoplasmic antibody -associated vasculitis, lupus nephritis, and idiopathic TIN.
Table 1: Diagnostic criteria for immunoglobulin G4-tubulointerstitial nephritis proposed by Raissian et al.[10]

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IgG4 is the rarest of all the subclasses of IgG, accounting for only 3%–6% of serum IgG levels. Due to its weaker interchain disulfide bridges, IgG4 can dissociate into half-molecules composed of one heavy and one light chain which reassociate with half-molecules of different specificity. This “half exchange antibody reaction” renders IgG4 incapable of forming immune complexes or fixing complement.[2] The role of IgG4 in the pathogenesis of IgG4-RD remains poorly understood.[11] Several mechanisms including autoimmunity, allergy, and innate immunity have been proposed based on features such as predominance of a Th2-cell response, activation of regulatory T-cells, increased production of interleukin (IL)-4, IL-10, and transforming growth factor beta, association with a specific Class II histocompatibility antigen genotype, elevated serum IgE levels, and presence of peripheral eosinophilia in 40% of patients.[12]

The first line of therapy in IgG4-RD is corticosteroids which elicit dramatic amelioration of symptoms in most cases. However, a 20% relapse rate while on maintenance steroid therapy has been documented.[13] Our case also showed only a partial response to steroid therapy which may be due to late stage of presentation to us. The extent of renal fibrosis at time of initial diagnosis may be a determinant of steroid responsiveness. Azathioprine, methotrexate, and mycophenolate mofetil can be used as steroid-sparing drugs;[14] rituximab therapy has been used in recurrent/refractory disease.[15]

   Conclusion Top

IgG4-TIN remains a largely unrecognized entity which should be compulsively entertained in the differential diagnosis of TIN in the elderly, given its rewarding responsiveness to steroid therapy. As the clinical, laboratory, and renal imaging features of IgG4-RD are atypical in some patients, renal biopsy is required to make a definitive diagnosis of IgG4-TIN. Histopathology, electron microscopy, and immunohistochemical or immunofluorescence staining for IgG4 are the most valuable diagnostic tools in IgG4-TIN. The diagnosis of isolated IgG4-TIN is difficult to make and delay in diagnosis as seen in our case may yield unsatisfactory results. Increased awareness and appropriate application of diagnostic criteria can facilitate early diagnosis and institution of therapy to impede disease progression.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Stone JH. IgG4-related disease: Nomenclature, clinical features, and treatment. Semin Diagn Pathol 2012;29:177-90.  Back to cited text no. 1
Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012;366:539-51.  Back to cited text no. 2
Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012;25:1181-92.  Back to cited text no. 3
Saeki T, Kawano M. IgG4-related kidney disease. Kidney Int 2014;85:251-7.  Back to cited text no. 4
Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 2001;344:732-8.  Back to cited text no. 5
Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. Anovel clinical entity, IgG4-related disease (IgG4RD): General concept and details. Mod Rheumatol 2012;22:1-14.  Back to cited text no. 6
Stone JH, Khosroshahi A, Deshpande V, Chan JK, Heathcote JG, Aalberse R, et al. Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations. Arthritis Rheum 2012;64:3061-7.  Back to cited text no. 7
Saeki T, Nishi S, Imai N, Ito T, Yamazaki H, Kawano M, et al. Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis. Kidney Int 2010;78:1016-23.  Back to cited text no. 8
Tsubata Y, Akiyama F, Oya T, Ajiro J, Saeki T, Nishi S, et al. IgG4-related chronic tubulointerstitial nephritis without autoimmune pancreatitis and the time course of renal function. Intern Med 2010;49:1593-8.  Back to cited text no. 9
Raissian Y, Nasr SH, Larsen CP, Colvin RB, Smyrk TC, Takahashi N, et al. Diagnosis of IgG4-related tubulointerstitial nephritis. J Am Soc Nephrol 2011;22:1343-52.  Back to cited text no. 10
Cornell LD. IgG4-related kidney disease. Curr Opin Nephrol Hypertens 2012;21:279-88.  Back to cited text no. 11
Nakashima H, Miyake K, Moriyama M, Tanaka A, Watanabe M, Abe Y, et al. An amplification of IL-10 and TGF-beta in patients with IgG4-related tubulointerstitial nephritis. Clin Nephrol 2010;73:385-91.  Back to cited text no. 12
Saeki T, Kawano M, Mizushima I, Yamamoto M, Wada Y, Nakashima H, et al. The clinical course of patients with IgG4-related kidney disease. Kidney Int 2013;84:826-33.  Back to cited text no. 13
Kamisawa T, Okazaki K, Kawa S, Shimosegawa T, Tanaka M; Research Committee for Intractable Pancreatic Disease and Japan Pancreas Society. Japanese consensus guidelines for management of autoimmune pancreatitis: III. Treatment and prognosis of AIP. J Gastroenterol 2010;45:471-7.  Back to cited text no. 14
Khosroshahi A, Carruthers MN, Deshpande V, Unizony S, Bloch DB, Stone JH. Rituximab for the treatment of IgG4-related disease: Lessons from 10 consecutive patients. Medicine (Baltimore) 2012;91:57-66.  Back to cited text no. 15

Correspondence Address:
Dr. Smita Mary Matthai
Central Electron Microscopy Unit, Wellcome Trust Research Laboratory, Division of GI Sciences, Christian Medical College, Vellore - 632 004, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_37_17

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