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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2017  |  Volume : 28  |  Issue : 1  |  Page : 149-153
Membranous glomerulopathy and massive cervical lymphadenopathy due to immunoglobulin G4-disease

1 Department of Medicine, Faculty of Medicine, Kuwait University, Kuwait
2 Department of Medicine, Al-Amiri Hospital, Kuwait City, Kuwait
3 Department of Pathology, Al-Amiri Hospital, Kuwait City, Kuwait

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Date of Web Publication12-Jan-2017


A 32-year-old male presented with acute and severe nephrotic syndrome as well as massive right cervical lymphadenopathy for <2 years. Computed tomography scan of the chest, abdomen, and pelvis did not reveal any lymphadenopathy. Histopathology and immunohistochemical testing of his lymph node biopsy showed infiltrate enriched with immunoglobulin G4 (IgG4)-positive plasma cells. His kidney biopsy showed granular membranous deposits of IgG4 in the basement membrane without interstitial infiltrate. Antiphospholipid 2 receptor antibodies were absent excluding its "idiopathic" nature. Since he was allergic to rituximab, he was treated with corticosteroids for two months and a combination of tacrolimus and mycophenolate. His lymphadenopathy disappeared, and his proteinuria abated. The dose of the latter two medications was reduced to half after four months and will be maintained for a minimum of two years to prevent relapse of his disease.

How to cite this article:
El-Reshaid K, Al-Bader S, Madda J. Membranous glomerulopathy and massive cervical lymphadenopathy due to immunoglobulin G4-disease. Saudi J Kidney Dis Transpl 2017;28:149-53

How to cite this URL:
El-Reshaid K, Al-Bader S, Madda J. Membranous glomerulopathy and massive cervical lymphadenopathy due to immunoglobulin G4-disease. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2022 Dec 8];28:149-53. Available from: https://www.sjkdt.org/text.asp?2017/28/1/149/198167

   Introduction Top

Immunoglobulin G4 (IgG4)-related disease is a systemic syndrome of unknown etiology characterized by tumor-like swelling of the involved organs and/or a lymphoplasmacytic infiltrate enriched with IgG4-positive plasma cells. If untreated, fibrosis of the involved organs with a characteristic "storiform" pattern may result in end-organ failure.[1] The prototype is IgG4-related sclerosing pancreatitis (also known as autoimmune pancreatitis), most commonly presenting as painless obstructive jaundice with or without a pancreatic mass. Other sites of involvement are the hepatobiliary tract, salivary gland, orbit, and lymph nodes. In a large study, 41% of the 114 patients, with varied organ involvement, had lymphadenopathy.[2] Multiple groups of lymph nodes were involved, especially the mediastinal, hilar, intra-abdominal, and axillary ones. Individual nodes are typically no more than 2 cm in diameter.[3] Massive isolated cervical lymphadenopathy for <2 years associated with membranous glomerulopathy without tubulointerstitial infiltrate is rarely reported with this disease.[4]

   Case Report Top

A 32-year-old male presented with progressive lower limbs edema for two weeks. He denied fever, skin rash, joint disease, weight loss, shortness of breath, or localized body ache. Past history included a persistent right cervical lymphadenopathy for the past two years. Their previous biopsy was labeled as reactive hyperplasia. He did not have past history of other significant medical illness, surgery, allergy, or chronic intake of medications. On his initial examination, he was conscious, oriented X3, and without distress of shortness of breath or pain. Blood pressure was 120/80 mm Hg. He was afebrile with a body weight of 77 kg. He had multiple 8 cm cervical lymph nodes on the right side. They were firm in consistency, freely mobile, and with normal overlying skin ([Figure 1]a). Systemic examination did not show abnormality except for massive lower limbs and sacral edema as well as ascites. Laboratory investigations showed normal peripheral leukocytic and platelets counts. Hemoglobin was normal. Serum glucose, urea, creatinine, electrolytes, amylase, and liver functions were normal except for albumin at 9 g/L. Serum cholesterol was 8 mmol/L. Thyroid-stimulating hormone was normal. Urine routine and microscopy showed 4+ proteinuria without hematuria or pyuria. Serum complements (C3 and C4) were normal. Serum protein electrophoresis showed polyclonal hypergammaglobulinemia and hypoalbuminemia. antinuclear antibody, antineutrophil cytoplasmic antibody, and hepatitis B and C serology were negative. Chest X-ray and plain X-ray of abdomen and pelvis were normal. Abdominal and pelvic ultrasound was normal except for ascites. Computed tomography scan of the chest, abdomen, and pelvis did not show abnormal lymphadenopathy or organomegaly. Biopsy of the lymph node showed follicular hyperplasia with diffuse lymphoplasmacytic infiltrate enriched with IgG4-positive plasma cells. The interfollicular areas were slightly expanded and contained lymphocytes, few macrophages, eosinophils, and plasma cells. Plasma cells were dense and stained positive with anti-IgG ([Figure 2]). Their counts averaged 120 plasma cells/HPF. Those areas were also stained by anti-IgG4, and the counts averaged 90 plasma cells/HPF, and hence the ratio IgG4/IgG was ¾. Serum IgG4 was elevated at 750 mg/dL (normal 9-89). On the other hand, his kidney biopsy showed diffuse thickening of glomerular basement membrane without interstitial, tubular, or vascular disease. Immunofluorescent stains showed deposition of IgG on glomerular basement membrane. There were no "spikes" on Jones' (silver) stain. Immunoperoxidase stains showed diffuse staining of the glomerular basement membrane with IgG4 without interstitial involvement ([Figure 3]). Antiphospholipase 2 receptor antibodies were absent. The patient was treated with 1 g of Solumedrol intravenous for three consecutive days, followed by prednisone 1 mg/kg/day for one month which was tapered down gradually till discontinuation after two months. His lymphadenopathy disappeared, and his proteinuria abated ([Figure 1]b). Since he was allergic to rituximab, he received tacrolimus (2 mg twice daily) and mycophenolate (1 g twice daily). The dose of the latter two medications was reduced to half four months later and he remains well. The later dose of medications will be maintained for two years to prevent future relapse of his disease.
Figure 1. Photograph of the patient neck showing: (a) the massively enlarged right cervical lymph nodes at presentation and (b) 2 months after treatment.

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Figure 2. Photomicrograph of the lymph node biopsy showing (a) follicular hyperplasia with a rim of small lymphocytes (H and E, ×100), (b) Expanded interfollicular area with lymphocytes, macrophages, and plasma cells without malignant cells (H and E, ×200), (c) predominant staining of lymphocytes with anti-IgG4stain (Immunoperoxidase IgG4, ×200).

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Figure 3. Photomicrograph of kidney biopsy showing: (a) Diffuse thickening of glomerular basement membrane on (H and E, ×100), (b) Diffuse granular membranous staining with IgG4 (Immunoperoxidase IgG4, ×100).

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   Discussion Top

The hallmark of IgG4-related disease is lymphoplasmacytic tissue infiltration with a predominance of IgG4-positive plasma cells and T-lymphocytes. The etiology of this disease remains elusive, yet its rapid response to corticosteroids indicates an autoimmune or allergic disorder.[1] High serum IgG4 was detected in 70% of the reported cases, yet it is not pathognomonic nor the pathogenic of the disease since it was also found in disorders such as multicentric Castleman disease, allergic disorders, Churg-Strauss syndrome, sarcoidosis, and a large number of other conditions.[5] The disease affects middle-aged and older men. Manifestations of the disease include autoimmune pancreatitis and IgG4-related sclerosing cholangitis, Mikulicz's disease and sclerosing sialadenitis (Küttner's tumor), inflammatory orbital pseudotumor, and chronic sclerosing dacryoadenitis, idiopathic retroperitoneal fibrosis, chronic sclerosing aortitis and periaortitis, Riedel's thyroiditis, and a subset of Hashimoto's thyroiditis, interstitial pneumonitis, and pulmonary inflammatory pseudotumors. The natural history is characterized by the development of multiple sites of involvement with time, sometimes after many years. If untreated, the initial lymphoplasmacytic infiltrate can progress to obliterative phlebitis and fibrosis. The fibrosis associated with IgG4-related disease has a characteristic "storiform" pattern, typified by a cartwheel appearance of the arranged fibroblasts and inflammatory cells, termed the "nuclear streaming artifact."[1] Progressive fibrosis can lead to end-organ damage which is poorly responsive to corticosteroids. Moreover, the disease may herald the development of malignant lymphoma and possibly carcinoma.[1] Asymptomatic IgG4-related lymphadenopathy has been reported.[2] ,[3] However, isolated, massive, and persistent IgG4-cervical lymphadenopathy for <2 years, as described in our patient, has not been reported to the best of our knowledge. Large and localized lymphadenopathy can be seen with tuberculosis, lymphoma, Castleman disease, or malignancy. However, histopathological examination and immunohistochemical testing are diagnostic for each disorder. The presence of 11-30 IgG4 cells/40 IgG cells/HPF is essential to distinguish IgG4-disease, as in our patient, from other forms of inflammations.[6] On the other hand, IgG4-renal disease is rare. Most of the reported cases describe tubulointerstitial nephritis with IgG4-positive plasma cells and Tlymphocytes. However, in a large study, five of their nine patients had isolated membranous glomerulonephritis (MG).[4] Those patients as our patient did not have antiphospholipid 2 receptor antibodies akin to "idiopathic" MG.[7] However, their patients had visceral evidence of IgG4-relared disease elsewhere rather than isolated MG and massive lymphadenopathy as in our case. Moreover, the lack of "typical spikes on glomerular basement membrane" on Jones' (silver) stain indicates the absence of the immune deposits usually seen in idiopathic MG and should be a clue to suspect the nonidiopathic one.[8] The optimal treatment for IgG4-related disease has not been established, and there are no randomized trials that have evaluated the different approaches including its corticosteroid therapy. Most patients respond to glucocorticoids within several weeks, and the duration of treatment is uncertain. Those who respond less well may have included patients with more advanced fibrotic changes. Moreover, even in those who exhibited an initial response, relapses were common following discontinuation of therapy. Corticosteroid-sparing drugs, for example, azathioprine and mycophenolate have been used as a maintenance therapy to avoid relapses, and rituximab has been used to treat the refractory ones.[9] ,[10] The latter drug would have been an ideal one with its ease of administration as once yearly and its lack of significant side effects. Unfortunately, he was allergic to it. Hence, after his initial response to corticosteroids, mycophenolate, and tacrolimus, we elected to keep him on 1/2 of the initial dose of the latter two drugs for a minimum period of two years to prevent future relapse.

Conflict of interest: None declared.

   References Top

Cheuk W, Chan JK. IgG4-related sclerosing disease: A critical appraisal of an evolving clinicopathologic entity. Adv Anat Pathol 2010;17:303-32.  Back to cited text no. 1
Zen Y, Nakanuma Y. IgG4-related disease: a cross-sectional study of 114 cases. Am J Surg Pathol 2010;34:1812-9.  Back to cited text no. 2
Cheuk W, Yuen HK, Chu SY, Chiu EK, Lam LK, Chan JK. Lymphadenopathy of IgG4- related sclerosing disease. Am J Surg Pathol 2008;32:671-81.  Back to cited text no. 3
Alexander MP, Larsen CP, Gibson IW, et al. Membranous glomerulonephritis is a manifestation of IgG4-related disease. Kidney Int 2013;83:455-62.  Back to cited text no. 4
Aalberse RC, Stapel SO, Schuurman J, Rispens T. Immunoglobulin G4: an odd antibody. Clin Exp Allergy 2009;39:469-77.  Back to cited text no. 5
Raissian Y, Nasr SH, Larsen CP, et al. Diagnosis of IgG4-related tubulointerstitial nephritis. J Am Soc Nephrol 2011;22:1343-52.  Back to cited text no. 6
Beck LH Jr., Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009;361:11-21.  Back to cited text no. 7
Kuroki A, Shibata T, Honda H, Totsuka D, Kobayashi K, Sugisaki T. Glomerular and serum IgG subclasses in diffuse proliferative lupus nephritis, membranous lupus nephritis, and idiopathic membranous nephropathy. Intern Med 2002;41:936-42.  Back to cited text no. 8
Khosroshahi A, Stone JH. Treatment approaches to IgG4-related systemic disease. Curr Opin Rheumatol 2011;23:67-71.  Back to cited text no. 9
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. 10

Correspondence Address:
Kamel El-Reshaid
Department of Medicine, Faculty of Medicine, Kuwait University, P. O. Box 24923, 13110 Safat
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.198167

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