Saudi Journal of Kidney Diseases and Transplantation

: 2021  |  Volume : 32  |  Issue : 1  |  Page : 249--254

Isolated Renal Involvement by IG4-Related Disorder Mimicking Multiple Myeloma, a Diagnosis Not to Miss

Muhammad Abdul Mabood Khalil1, Ahmed Suleman Rajput1, Ruzita Ghani1, SM Rahmat Ullah1, May Kyaw Thet1, Rajendra Govindrao Daiwajna1, Pemasiri Upali Telisinghe2, Vui Heng Chong1, Jackson Tan1,  
1 Department of Renal Medicine, RIPAS Hospital Bandar Seri Begawan, Brunei, Darussalam, Brunei
2 Department of Histopathology, RIPAS Hospital Bandar Seri Begawan, Brunei, Darussalam, Brunei

Correspondence Address:
Muhammad Abdul Mabood Khalil
Department of Renal Medicine, RIPAS Hospital Bandar Seri Begawan BA 1710


IG4-related disorder (IgG4-RD) with isolated kidney involvement is rare. IG4-RD is a fibroinflammatory disorder leading to polyclonal activation of plasma cell and can affect kidney, orbital tissues, salivary glands, pancreas, bile duct, lymph nodes, and can cause inflammatory mass in any organ. Isolated kidney involvement is rare in this order. We share a case of isolated kidney involvement by this order presenting as enlarged kidneys with renal impairment. Kidney biopsy showed CD138 plasma cell interstitial nephritis. The biopsy also showed kappa light chain along IgG on immunofluorescence and was reported as light chain deposition disease initially. In view of hyperproteinemia and initial renal biopsy finding, workup was done for myeloma. Bone marrow biopsy showed around 20% of plasma cell infiltration. Skeletal survey did not show any lytic lesions and immunofixation did not reveal any paraprotein. Flowcytometry of the bone marrow showed nonclonal plasma cell. In view of negative workup for myeloma and nonclonal cells, re-evaluation of the kidney biopsy was done. Biopsy was reanalyzed for both IgG and IgG4. It showed 30 IgG4 cells per high-power field with a ratio of IgG4 / IgG of 40%. The staining for IgM, IgA C3, and C1q was negative. The patient was labeled as having plasma cell interstitial nephritis due toIgG4-RD. The patient responded well to oral prednisolone. It is important not to miss this potentially treatable and reversible condition by staining the biopsy sample for both IgG and IgG4 in clinically suspected cases.

How to cite this article:
Mabood Khalil MA, Rajput AS, Ghani R, Rahmat Ullah S M, Thet MK, Daiwajna RG, Telisinghe PU, Chong VH, Tan J. Isolated Renal Involvement by IG4-Related Disorder Mimicking Multiple Myeloma, a Diagnosis Not to Miss.Saudi J Kidney Dis Transpl 2021;32:249-254

How to cite this URL:
Mabood Khalil MA, Rajput AS, Ghani R, Rahmat Ullah S M, Thet MK, Daiwajna RG, Telisinghe PU, Chong VH, Tan J. Isolated Renal Involvement by IG4-Related Disorder Mimicking Multiple Myeloma, a Diagnosis Not to Miss. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 Jan 18 ];32:249-254
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Full Text


Plasma cell interstitial nephritis is a rare finding.[1],[2] Interstitial infiltrates consist mainly of T-cells, followed by monocytes and B-cells in majority of the cases.[1],[2],[3] Plasma cell interstitial nephritis can be monoclonal or polyclonal.[4],[5] Monoclonal interstitial nephritis occurs in myeloma and other hematological disorders,[4] while polyclonal can occur in lupus nephritis, vasculitis, Sjögren’s syndrome, autoimmune hepatitis, rheumatoid arthritis, infections, and IgG4-related disorder.[6] IgG4-related disorder is a fibroinflammatory disorder that can involve many organs including kidney, orbital tissues, pancreas, and salivary glands. The finding of >10 IgG4 plasma cell in a biopsy and greater than >40 IgG4 plasma cells in a nephrectomy specimen is required for the diagnosis. The finding of IgG4/IgG of more than 40% is also a criterion for histological diagnosis of IgG4-related interstitial nephritis.[7] The prevalence of the disease has been approximately 0.28 to 1.08 per 100,000 of the population.[8] Fifteen percent of IG4-related disorder has tubulointerstitial nephritis and 96% of tubulointerstitial nephritis exhibit other organs’ involvement.[9] Our case is unique as it has only isolated kidney involvement. Our case is about a young man who was found to have renal dysfunction, hyperproteinemia, enlarged kidney, polyclonal plasma cell infiltration in the bone marrow, and having CD138 plasma cell infiltration in the interstitium of the renal tissues due to IgG4-related interstitial nephritis.

 Case Report

Informed consent was obtained from the patient for the publication of this case report.

A 35-year-old man was referred for renal dysfunctions from the general practitioner clinic. He was found to have creatinine (Cr) of 224 umol/L (eGFR 31 mL/min). There was no history of nausea, anorexia, pedal swelling, breathing difficulties, confusion, dry mouth, dry eyes, or any other symptoms on systemic enquiry. There was no past history of diabetes, herbal or traditional medicines, skin rashes, and arthralgia. The patient denied any intake of nonsteroidal anti-inflammatory medications. Only significant past history was that of hypertension, which was present for 1½ years. He was using amlodipine 2.5 mg once a day. He had a normal renal function in past and his Cr in November 2016 was 98.3 umol/L (normal range: 3.6–110 umol/L). He had evidence of microalbuminuria in the past and his albumin-to-creatinine ratio was 5.1 (normal range: <2.5 mg/mmol). There was no past history of joint problem, tuberculosis, chronic infection, liver problem, connective tissue disorder, or hematological diseases.

On examination, his blood pressure was 128/76. There was no edema. Jugular venous pressure was not raised. There was no lymphadenopathy. Abdominal examination did not reveal hepatosplenomegaly or ascites. No stigmata of chronic liver disease were found. Chest showed normal vesicular breathing with no added sounds.

On workup, the urine routine examination was bland showing no hematuria or proteinuria. Investigation showed Cr of 224 umol/L (normal range: 63.6–110.5 umol/L). Sodium was 135 mmol/L, potassium: 5.1 mmol/L, and bicarbonate was 18 mmol/L. The patient was found to be having a high protein of 110 g/L (normal range: 60–80 g/L). However, his serum albumin was low 30 g/L (normal range: 35–50 g/L).Serum protein electrophoresis showed raised alpha 1 globulin 3.1 g /L (normal range: 1–3 g/L) and raised gamma globulin 46.1 g/L (normal range: 10–19 g/L). Immunoglobulin showed raised IgG 59.46 g/L (normal range: 5.40–18.22 g/L). Serum IgA and IgM levels were all normal. C3 levels were low and reported as 0.43 g/L (normal range: 0.82–1.85 g/L). C4 levels were normal. His full blood count showed normal hemoglobin (11 g/dL), normal white cell count (7.4 × 109), and platelet (210 × 109). ESR was 137 mm/h and C-reactive protein was 2.06 mg/dL (normal range: 0.0–0.490 mg/dL). His serum calcium was 2.20 mmol/L and phosphate was 1.8 mmol/L. Chest X-ray did not show any abnormality. Ultrasound of the abdomen showed bilateral enlarged kidneys. Right kidney was 17.7 cm and left kidney was 18.5 cm. Cortical echogenicity was mildly increased. There was no lymphadenopathy or organomegaly. Ultrasound-guided kidney biopsy showed three glomeruli which were normal. There was infiltration of plasma cells in the interstitium. These cells were CD138 positive. There was storiform fibrosis in the interstitium on trichrome staining. The biopsy also showed kappa light chain along with IgG and was initially reported as a light chain deposition disease [Figure 1]. The staining for IgM, IgA C3, and C1q was negative. Extensive workup was done to rule out myeloma. Bone marrow aspiration was done and it showed normocellular marrow with normal active trilineage hematopoiesis. Increased plasma cell infiltration was found which accounted for 20% of total nucleated cells. Skeletal survey revealed no lytic lesions. Immunophenotyping of the bone marrow showed polyclonal plasma cells. Furthermore, immunofixation did not show any paraprotein with anti-IgG, anti-IgA, anti-IgM, anti-kappa, and anti-lambda. Due to negative workup for the myeloma, renal biopsy specimen was retrospectively stained for both IgG and IG4 to rule out IgG4-related disorder. The specimen showed 30 IgG4 cells per high-power field. The ratio of IgG4/IgG was 40% [Figure 1]. In view of renal dysfunction, hyperproteinemia, enlarged kidney, negative workup for myeloma, and biopsy finding of IgG4 cells with a ratio IgG4/IgG of 40%, the patient was labeled as having interstitial nephritis due to IgG4-related disorder. Our patient did not have any nonrenal manifestation of this disorder.{Figure 1}

We did extensive workup to rule out other close differentials. His liver function tests were normal. Screening for viral and autoimmune hepatitis was negative. His screening for HIV was negative. Screening for connective tissues and vasculitic disorder with antinuclear antibody, anti-double-stranded DNA, cytoplasmic antineutrophil cytoplasmic antibodies (C-ANCA), perinuclearantineutrophil cytoplasmic antibodies (P-ANCA), extractable nuclear antigen (ENA-Jo-1), anti-LA, anti-ribonucleoprotein (anti-RN), anti-topoisomerase (anti-SCL70), and antimitchondrial antibodies were all negative. Ultrasound of the abdomen showed enlarged kidneys but did not reveal any other pathology. Chest X-ray was also normal. Screening for tuberculosis was also negative. Thus, extensive clinical evaluation and laboratory workup did not show any liver disease, connective tissue disorder, infection, or hematological dyscrasia.

The patient was started on prednisolone 60 mg once a day. Over period of time, his creatinine came down to 128 umol/L. His total protein normalized to 74 g/L. His albumin level went up to 47 g/L. At present, the patient is still under regular follow-up and prednisolone has been tapered down to 5 mg once a day.


IG4-RD with isolated kidney involvement is very rare. Renal involvement in IG4-RD has been reported with lymphadenopathy,[10],[11],[12] lesion in pancreas and retroperitoneum,[12],[13] bile duct stenosis,[13] and parotid enlargement.[12] Our case has CD138 plasma cell interstitial nephritis with positive kappa light chain and weakly positive IgG, and initial suspicion of light chain deposition disease was made. Our patient has hyperproteinemia and polyclonal protein on serum protein electrophoresis. Bone marrow examination showed 20% of plasma cells. However, immunophenotyping on the bone marrow revealed that plasma cells were polyclonal. A skeletal survey did not show any lytic lesions and immunofixation did not reveal any paraprotein.

A multidisciplinary discussion between nephrologist, hematologist, and histopathologist in such clinical scenarios is very important. In our case, re-evaluation of the biopsy with staining for both IgG and IgG4 led to the diagnosis of IgG4-RD. Therefore, it is extremely important to do routine staining for both IgG and IgG4 in cases of unexplained polyclonal plasma cell activation with renal dysfunction or lymphocytic plasma cell interstitial nephritis. Picking up the diagnosis in time can preserve renal function and can prevent further deterioration in renal function.

IgG4-RD can affect kidney in a variety of ways. It causes tubulointerstitial nephritis, membranous nephropathy, or obstructive nephropathy due to retroperitoneal fibrosis.[7] IgG4-related disorders can also present as autoimmune pancreatitis, orbital disease, and can affect major salivary glands.[14] IgG4 is the rarest of all IgG subclasses accounting for 3%–6% of total immunoglobulin G and it does not bind complement to form immune complexes.[15] The pathogenesis of IgG4-related disorder is less understood. There is increased Th2-cell response, activation of regulatory T-cells, increased production of interleukin (IL)-4, IL-10, and transforming growth factor-beta, elevated serum IgE levels, and presence of peripheral eosinophilia in 40% of patients.[16] Based on these findings, the presumed probable mechanisms include autoimmunity, allergy, and innate immunity.

A variety of other diseases can present as IgG4-related disorder. It is important to look for these differentials. Lupus can cause polyclonal gammopathy and tubular interstitial nephritis. Our patient has no clinical or laboratory evidence of lupus. In lupus, interstitial inflammatory infiltrate is mostly composed of mixture of CD4+ and CD8+ T-cells, B-cells, macrophages, and plasma cells rather than pure plasma cells which was not the case in our patient.[7],[17],[18] Sjögren’s syndrome can also lead to inflammation which can cause polyclonal activations of lymphocytes and interstitial nephritis. Lack of clinical symptoms and laboratory findings along with predominant T-cell dominance and macrophage infiltrate in the interstitium on kidney biopsy makes it less likely.[19],[20] ANCA-associated vasculitis is another close differential but lack of skin rashes, ear–nose–throat symptoms, negative C-ANCA, and P-ANCA along with biopsy finding ruled out this close differrential.[21] Similarly, we rule out auto-immune hepatitis, HIV, hepatitis C virus, and tuberculosis which can cause plasma cell activation. Lack of lymphadenopathy and hepatosplenomegaly along with normal abdominal ultrasound and lack of hematological malignancies on bone marrow examination ruled out hematological disorders.

Steroids are the first-line therapy for IgG4-related disease. The response rate to steroids therapy is 93% and a complete response rate of 66% in a phase 2 trial has been reported Japan.[22] Rituximab has also been studied in IgG4-related disorders and has been found highly effective with a response rate of 97%.[23] We, in our case, started prednisolone 60 mg once a day and was gradually tapered down over four months to 5 mg once a day. His creatinine came down to 126.9 mmol/L. His hyperproteinemia also normalized [Table 1].{Table 1}

It is important not to miss this diagnosis. In any case of plasma cell interstitial nephritis with polyclonal activation of plasma cell and no apparent etiology, it is important to rule out IgG4-related interstitial nephritis by doing staining for both IgG and IgG4. An early diagnosis and appropriate therapy can induce remission and preserve renal function.

Conflict of interest: None declared.


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