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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2015  |  Volume : 26  |  Issue : 6  |  Page : 1282-1288
Immunoglobin G4-related disease: Two case reports and review of the recent literature

1 Department of Nephrology, Kokilaben Dhirubhai Ambani Hospital, Andheri (West), Mumbai, India
2 Department of Pathology, Kokilaben Dhirubhai Ambani Hospital, Andheri (West), Mumbai, India

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Date of Web Publication30-Oct-2015


IgG4-related disease (IgG4-RD) is a new, multiorgan and constantly evolving disease characterized by IgG4-positive plasma cells in the affected organ. This disease often affects the elderly. The pancreas is the main target organ affected, with almost all organs in the body being affected. A large amount of studies have been conducted to understand the pathogenesis of the disease and its spectrum. For accurate diagnosis of the condition, an adequate knowledge of imaging findings, clinical presentations and laboratory reports is essential. We report two cases of the IgG4-RD and review the recent literature about this increasingly recognized entity.

How to cite this article:
Anandh U, Virarkar M, Shah A, Hastak M. Immunoglobin G4-related disease: Two case reports and review of the recent literature. Saudi J Kidney Dis Transpl 2015;26:1282-8

How to cite this URL:
Anandh U, Virarkar M, Shah A, Hastak M. Immunoglobin G4-related disease: Two case reports and review of the recent literature. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2023 Feb 4];26:1282-8. Available from: https://www.sjkdt.org/text.asp?2015/26/6/1282/168674

   Introduction Top

The immunoglobulin G4-related disease (IgG4RD) is a recent entity characterized by dense infiltrations of the affected organs with plasma cells and fibrosis. The presence of IgG4-positive plasma cells and characteristic storiform fibrosis are the histological hallmarks of the disease. Lesions with characteristic clinicopathological features have been reported in virtually all organs of the body. The term "inflammatory pseudo-tumor (IPT)" was often used in the literature to describe this disease before the introduction of IgG4-RD. [1]

We report two cases of IgG4-RD and review the recent literature about this increasingly recognized entity.

   Case Reports Top

Case 1

A 41-year-old man presented to our outpatient clinic for the evaluation of renal failure and proteinuria. He had a past history of asthmatic bronchitis and his renal failure was detected six months earlier on routine evaluation. His clinical examination revealed hypertension and pedal edema beside occasional rhonchi in his chest.

His routine laboratory investigations are shown in [Table 1]. His 24-h protein excretion was 2.33 g. As he had hypergammaglobulinemia, he was extensively investigated for the presence of monoclonal disorders. His serum and urine electrophoresis/immunoelectrophoresis did not reveal any monoclonal gammopathy. His light chain assay was normal. His serological markers for autoimmune diseases were non-contributory. A magnetic resonance imaging (MRI) coronal scan of the abdomen showed massive increase in size of the kidneys (right kidney 17.05 cm, left kidney 16.13 cm) as shown in [Figure 1].
Figure 1: MRI of the abdomen showing a massive increase in the size of the kidneys.

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Table 1: Hematochemical parameters of the patients.

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He then underwent a renal biopsy. The histopathology revealed dense inflammatory infiltrates composed of lymphocytes and storiform fibrosis [Figure 2]. Immunological staining showed heavy plasma cell infiltrate. His IgG4 immuno-staining showed extensive infiltration with IgG4-positive cells, which were more than 50% of the IgG-stained plasma cells [Figure 3]. A diagnosis of IgG4-related interstitial nephritis was established.
Figure 2: Histopathology showing dense inflammatory infiltrate.

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Figure 3: Immunohistochemistry showing IgG4-stained plasma cells.

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Then, the patient was managed with steroids (Prednisolone 1 mg/kg once a day). On continuation of steroids, he experienced excessive weight gain and developed steroid-induced acne. He was then started on Mycophenolate mofetil 500 mg tablets once a day to facilitate a rapid taper of steroids. After six months, he was on low-dose steroids (Prednisolone 5 mg once a day) and Mycophenolate mofetil 1 g/day. On follow-up, there was improvement in his renal functions (creatinine 1.3 mg/dL) and hypergamamaglobulinemia (total protein 7.8 g/dL, albumin 3.2 g/dL and globulin 4.6 g/dL), and an ultrasonography of his abdomen showed reduction in the size of the kidneys (right kidney 13.7 cm, left kidney 14.5 cm).

Case 2

A 35-year-old man presented to us with intermittent fever, back pain and reduced urine output of two weeks' duration. His clinical examination was remarkable for only the presence of bilateral pedal edema. He was investigated for the cause of his symptoms and his routine investigations are shown in [Table 1] (Case 2), which showed increased levels of IgG4. He underwent an abdominal computerized tomography (CT) scan, which revealed the presence of retroperitoneal fibrosis [Figure 4] and [Figure 5]. A rheumatology consultation also suggested the presence of retroperitoneal fibrosis with no evidence of connective tissue disease or malignancy.
Figure 4: CT scan of the abdomen showing retroperitoneal fibrosis.

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Figure 5: CT reconstruction of the retroperitoneal fibrosis involving both ureters.

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A CT-guided kidney biopsy was performed. The histopathology showed extensive fibrosis and scant inflammatory infiltrate. Immunological staining did not reveal any IgG4 staining as there was paucity of cells. A urological consultation suggested ureteric stenting, which was subsequently performed. A possible diagnosis of IgG4-related retroperitoneal fibrosis was made as a definite diagnosis could not be made in the absence of IgG4 staining.

The patient was started on prednisolone 1 mg/kg/day (which was tapered later) and Mycophenolate sodium 720 mg/day was added as a steroid-sparing drug. On follow-up, the stents were removed after 3 months and there was no recurrence of hydronephrosis or renal failure. On his last follow-up, he had normal renal function (creatinine 0.7 mg/dL and normal urinary sediment) and he was clinically asymptomatic.

   Discussion Top

A case of pancreatitis with hypergammaglobulinemia, which now appears to be the first reported case of IgG4-related disease (- IgG4-RD), was first described by Sarles in 1961. [2] Over the years, a study on Japanese patients by Hammano et al reported an increase in serum IgG4 in autoimmune pancreatitis. [3] The association of IgG4 with this disease entity was shown by Kamisawa in 2003. [4] Many names were designated to IgG4RD, depending on the organ involved. An international symposium in Boston in 2011 coined the term "IgG4-Related Disease." [5] However, when a single organ is involved, the term disease can be replaced by the term "itis" to the name of the organ involved, as in the kidney where the disease can be called as IgG4-related interstitial nephritis. [6] The Japanese comprehensive diagnostic criteria for IgG4-RD aids in accurate diagnosis. [7]

The underlying pathogenesis of the disease is unknown. However, many hypotheses [8] have been put forward to explain the involved pathophysiological mechanisms. The following factors are considered to play a contributory role in the overall pathogenesis:

  • Genetics a study reported association of autoimmune pancreatitis (AIP) with human leukocyte antigen (HLA) molecule with DRB1*0405 and DQB*0401 in the Japnese population. [9] A study in the Korean population shows the association of the non-aspartic acid DQB1-57 with the disease. [10] Also, others have associated AIP encoding proteins with cytotoxic T lymphocyte-associated antigen 4, [11] tumor necrosis factor alfa [12] and Fc receptor-like 3 molecule. [13]
  • Autoimmunity several reports demonstrated the presence of autoantibodies against different epithelial targets such as lactoferrin, carbonic anhydrase II and IV, [14] trypsinogens [15] and pancreatic secretory trypsin inhibitor [16] ; however, the significance of these proteins remain unclear.
  • Infectious agents in 2009, autoantibody against plasminogen-binding protein of Helicobacter pylori was present in a significant number of the AIP patients. [17] A significant similarity was reported between human carbonic anhydrase 2 and alfa carbonic anhydrase of H. pylori. [18] It is speculated that H. pylori antigen-related antibody production may cross-react with human carbonic anhydrase thus contributing to the disease symptomatology.
  • Cytokine imbalance an immune reaction, predominantly type 2 helper cell response, was seen in the AIP patients in many experimental studies. [19] The peripheral blood mononuclear cells and the frozen section of the affected organs in IgG4-RD showed an increase in Th2 type cytokine, such as IL-4, IL-5, IL-10 and IL-13. [20] The Th2 response in these individuals is suppressed by CD4+ CD25+ T regulatory cells (Tregs) and IL-10 producing Tregs. The suppression by these Tregs is reduced in these patients. IL-10 Tregs can also switch antibody production from IgE to IgG4.

In summary, in individuals with genetic predisposition, infections or allergic reactions coupled with immune dysregulation lead to an increased Th2 response. There is a subsequent switch of antibody production that results predominantly in the IgG4 formation in these patients.

IgG4-RD has a male predominance, occurring at an elderly age. Both our patients were men. However, they were relatively young when they presented to us. This early occurrence of the disease could not be explained. The incidence and prevalence is unknown. The disease affects most organs systems, and clinical symptoms and signs depend on the organs affected.

A sub-acute presentation is related to the swelling of the affected organs. Our first case had a massive increase in the size of the kidneys, which led us to suspect infiltrative disorders of the kidneys. This case also had a history of allergy, which has been reported in 40% of the patients.

A review of the literature showed that many conditions thought to be a unique disease are now recognized to fall in the spectrum of IgG4-RD. A diagnostic guideline has been established for IgG4-RD, considering histopathological investigations as the gold standard for the diagnosis of the disease. The findings include dense lymphoplasmacytic infiltrate, fibrosis arranged in storiform pattern and obliterative phlebitis. On the other hand, IgG4 immuno-staining is also an essential step in the diagnosis of IgG4-RD. The presence of heavy infiltrate with IgG4-positive plasma cells is highly specific. An IgG4:IgG plasma cell ratio >40% is important for histological diagnosis combined with other features. Elevated serum IgG4 concentration (>135 mg/dL) is seen in most of the patients of IgG4-RD; however, a normal level does not exclude disease. A higher elevation in the serum IgG4 is seen with multiple organ involvement. Both our patients had high levels of IgG4. The radiological findings can aid in the diagnosis of diseases of the pancreas and aorta, as in our second case of retroperitoneal fibrosis, but it is less useful when other organs are involved.

Renal involvement in association with the AIP is seen in about 30% of the patients. [21],[22] The most common manifestation is tubulo-interstitial nephritis, followed by membranous glomerulonephritis. [23]

There are published proposed diagnostic criteria for IgG4-related kidney diseases (IgG4- RRD), [24] and criteria for tubulo-interstitial nephritis are shown in [Table 2]. [25] Interstitial nephritis is manifested by proteinuria and renal dysfunction. Three patterns of renal lesions have been described in IgG4-RRD: (i) diffuse tubulo-interstitial nephritis with characteristic fibrosis and IgG4-positive plasma cells, (ii) focal lymphoplasmacytic infiltration with an appearance of a tumor-like mass mimicking renal cell carcinoma and (iii) hydronephrosis secondary to retroperitoneal fibrosis. [26] In a study on patients with renal involvement, the majority had renal parenchymal involvement, followed by peri-renal, renal sinus and renal pelvis wall involvement. The renal lesions were described into categories of round or wedge-shaped renal cortical nodules, small peripheral cortical lesions, mass lesions and renal pelvis involvement. [27]
Table 2: Proposed diagnostic criteria for IgG4-related TIN.

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Unilateral and bilateral kidney pseudotumors are characteristic. CT abnormalities consist of diffuse kidney enlargement, scattered nodules and decreased attenuation compared with normal renal parenchyma on contrast examination. [28] On contrast-enhanced CT scan, the renal lesions typically are hypodense on earlyphase images and show mild enhancement on delayed images. On MRI, the renal lesions are isoto hypointense on T1-weighted images and hypointense on T2-weighted images and show enhancement on contrast-enhanced MRI. [29] Our first case with tubulointerstitial nephritis had similar findings. Differential diagnosis of kidney lesions includes renal cell carcinoma. For wedge-shaped lesions, the diagnosis of renal infarction should be excluded. Multiple kidney lesions may mimic pyelonephritis, metastasis and lymphoma.

Although no randomized controlled trials have been conducted on IgG4-RRD, most treatment approaches come from retrospective and observational studies. The tubulo-interstitial nephritis in IgG4-RD is responsive to steroid treatment, but the response to membranous nephropathy to steroid is variable. The treatment with glucocorticoids is considered as the first line of therapy. [30],[31],[32] A rapid response to glucocorticoids is considered a useful prognostic marker. The initiation of treatment depends on degree of fibrosis and personalized approach. Immunosupressive therapy such as azothioprine, Mycophenolate mofetil and methotrexate have shown good clinical and serological response in the patients. These drugs are used as glucocorticoid-sparing therapy or for remission maintenance, as was performed in both our patients. [33] We used Mycophenolate mofetil as a steroid-sparing drug. B cell depletion with rituximab therapy is an alternative approach for glucocorticoid resistance, dependence or relapses. [34]

   References Top

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Correspondence Address:
Urmila Anandh
Department of Nephrology, Kokilaben Dhirubhai Ambani Hospital, Andheri (West), Mumbai 400 053
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.168674

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1], [Table 2]


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