American Journal of Kidney Diseases
Volume 54, Issue 2 , Pages 375-380, August 2009

Acute Kidney Injury and Proteinuria in a Patient With Diabetes and a Submandibular Mass

  • Prue Hill, MD, PhD

      Affiliations

    • Department of Anatomical Pathology, St Vincent's Hospital, Fitzroy, Victoria, Australia
    • Corresponding Author InformationAddress correspondence to Prue Hill, MD, PhD, Department of Anatomical Pathology, St Vincent's Hospital, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia
    • ,
  • Prue Russell, MD

      Affiliations

    • Department of Anatomical Pathology, St Vincent's Hospital, Fitzroy, Victoria, Australia
    • ,
  • Christine Sammartino, MD

      Affiliations

    • Department of Nephrology, St Vincent's Hospital, Fitzroy, Victoria, Australia
    • ,
  • Katherine Wiggins, MD

      Affiliations

    • Department of Nephrology, St Vincent's Hospital, Fitzroy, Victoria, Australia
    • ,
  • Karen Dwyer, MD, PhD

      Affiliations

    • Department of Nephrology, St Vincent's Hospital, Fitzroy, Victoria, Australia

Received 2 July 2008; accepted 9 September 2008. published online 03 November 2008.

Article Outline

Index Words: Interstitial nephritis, immunoglobulin G4 (IgG4)-related disease, autoimmune diabetes mellitus

 

Various etiologic factors have been identified in patients with tubulointerstitial nephritis (TIN), including allergic drug reaction, infection, and immune-mediated disease. Immune-mediated TIN has been reported to occur in patients with Sjögren syndrome, systemic lupus erythematosus, anti–tubular basement membrane antibody-related disease, and the recently recognized entity immunoglobulin G4 (IgG4)-related systemic disease. We present a case of the latter entity presenting as acute kidney failure and proteinuria in a man with known autoimmune diabetes mellitus.

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Case Report 

Clinical History 

A 64-year-old white man was transferred from a rural center with rapidly deteriorating kidney function and a left submandibular mass on a background of autoimmune diabetes mellitus of adulthood, diagnosed 10 years previously. Serum creatinine level had increased from a baseline of 1.5 mg/dL (131 μmol/L) to 4.8 mg/dL (423 μmol/L) during 2 months. Urine sediment was inactive, and total protein excretion was mildly increased at 0.35 g/L (normal, <0.1 g/L). Microalbumin concentration was 73 mg/L. The submandibular mass had been present for 2 months and was not associated with sicca symptoms or swallowing difficulties. No constitutional symptoms were present.

On examination, he was normotensive and euvolemic. The left submandibular mass was 2 cm in diameter, firm to palpation, and not tethered to the underlying muscle. There was no associated lymphadenopathy or hepatosplenomegaly. He had a sensory peripheral neuropathy in a stocking distribution consistent with his long-standing diabetes mellitus.

Blood tests on admission showed serum creatinine level of 4.8 mg/dL (423 μmol/L). Serum urea level was 60 mg/dL (21.3 μmol/L), and serum albumin level was 3.2 g/dL (32 g/L). He was anemic (hemoglobin, 10.6 g/dL [106 g/L]) with an increased ferritin level (159 ng/mL [159 μg/L]; range, 7 to 134 ng/mL [7 to 134 μg/L]) and had secondary hyperparathyroidism (parathyroid, 246 pg/mL [246 ng/L]; range, 12 to 65 pg/mL [12 to 65 ng/L). Serological testing showed increased antinuclear antibody (1:160, homogenous pattern), rheumatoid factor level of 663 IU/mL (normal, <14 IU/mL), double-stranded DNA level of 25 IU/mL (normal, <7 IU/mL), and low C3 (50 mg/mL [0.5 g/L]; range, 90 to 180 mg/mL [0.90 to 1.80 g/L]) and C4 levels (<2 mg/mL [<0.02 g/L]; range, 16 to 47 mg/mL [0.16 to 0.47 g/L]). Antineutrophil cytoplasmic antibody, anti–glomerular basement membrane antibody, cryoglobulins, hepatitis, and human immunodeficiency virus (HIV) serological test results were negative. Extractable nuclear antigens, in particular Ro/SS-A and La/SS-B, were negative. A polyclonal increase in serum IgG was noted (3,060 mg/dL [30.6 g/L]; range, 700 to 1,600 mg/dL [7 to 16 g/L]) with no monoclonal bands on protein electrophoresis. An increase in IgG4 fraction was most pronounced at 617 mg/dL (6.17 g/L; range, 4 to 86 mg/dL [0.04 to 0.86 g/L]), with significant increases also noted in IgG1 (1,860 mg/dL [18.6 g/L]; range, 380 to 930 mg/dL [3.8 to 9.3 g/L]) and IgG3 (326 mg/dL [3.26 g/L]; range, 22 to 176 mg/dL [0.22 to 1.76 g/L]). IgG2 level was within normal limits (460 mg/dL [4.6 g/L]; range, 240 to 700 mg/dL [2.4 to 7 g/L]). Urine electrophoresis showed no monoclonal protein or free light chains.

Kidney ultrasound and duplex showed normal-sized kidneys (13 and 14.2 cm) without evidence of hydronephrosis or renal artery stenosis. No kidney mass lesions were seen. Computed tomography of neck to pelvis showed mediastinal and para-aortic lymphadenopathy (largest, 12 mm) without hepatosplenomegaly. A kidney biopsy was performed, and the left submandibular mass was excised.

First Kidney Biopsy 

Light Microscopy 

There were 2 cores with only 5 glomeruli present, which appeared normocellular and showed thickening of peripheral capillary walls. On silver trichrome stain, small subepithelial proteinaceous deposits were evident with early basement membrane spike formation. The interstitium contained a dense mixed inflammatory infiltrate that appeared expansile and destructive, causing marked separation of tubules (Fig 1A). The infiltrate included numerous plasma cells and moderate numbers of eosinophils. There was associated interstitial edema and moderate tubulitis (Fig 1B). No granulomas or multinucleated giant cells were seen. No viral inclusions were identified. CD138 immunoperoxidase stain highlighted the numerous plasma cells, approximately half of which were IgG4 positive (Fig 1C and D).

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  • Figure 1. 

    (A) Dense interstitial inflammatory infiltrate and edema expand the interstitium. The glomerulus shows thickened peripheral capillary walls (periodic acid–Schiff stain; original magnification ×200). (B) The majority of cells within the inflammatory infiltrate are plasma cells (periodic acid–Schiff stain). (C) CD138 immunoperoxidase stain highlights the large number of plasma cells within the interstitial infiltrate. (D) Approximately half the plasma cells are positive on immunoglobulin G4 immunoperoxidase stain (original magnification ×400).

Immunofluorescence Microscopy 

Two glomeruli showed strong granular staining for IgG and C3 along glomerular capillary walls (Fig 2A and B). There was also moderately strong granular staining of Bowman capsule and tubular basement membranes for IgG and C3 (Fig 2A and B). IgA, IgM, C1q, and fibrin were negative.

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  • Figure 2. 

    Direct immunofluorescence shows strong granular glomerular peripheral capillary wall staining for (A) immunoglobulin G (IgG) and (B) C3. There is also strong granular staining of Bowman capsule and tubular basement membranes for both (A) IgG and (B) C3 (original magnification: [A] ×400, [B] ×250). (C) Electron microscopy shows subepithelial electron-dense deposits (arrows) with basement membrane spike formation (original magnification ×30,000). (D) Electron-dense deposits are present within thickened tubular basement membrane (arrows) (original magnification ×40,000). Abbreviation: T, tubular epithelial cell.

Electron Microscopy 

Within glomeruli, there were numerous small subepithelial electron-dense deposits with early basement membrane spike formation (Fig 2C). No deposits were seen in subendothelial or mesangial regions. There was diffuse effacement of visceral epithelial cell foot processes. Electron-dense deposits were also present within thickened tubular basement membrane (Fig 2D).

Submandibular Salivary Gland 

There was patchy chronic sialadenitis with numerous plasma cells in the inflammatory infiltrate. As in the kidney, moderate numbers of IgG4-positive plasma cells were seen (not illustrated).

Diagnosis 

The kidney biopsy diagnosis was IgG4-immune complex–mediated TIN and membranous nephropathy stage 2. This patient also had involvement of the pancreas and salivary gland by IgG4-related systemic autoimmune disease.

Clinical Follow-up 

The patient was managed with oral prednisolone, 40 mg/d, with an immediate decrease in serum creatinine level. The dose was weaned by 5 mg/mo, and after 3 months of therapy, serum IgG level had normalized and serum creatinine level had decreased to 2 mg/dL (180μ mol/L). However, 2 months later, serum creatinine level remained increased at 2 mg/dL (180 μmol/L), and estimated glomerular filtration rate was 40 mL/min/1.73 m2 (0.67 mL/s/1.73 m2). A second kidney biopsy was performed (5 months after the initial biopsy) to determine whether there was ongoing active disease.

Second Kidney Biopsy 

There was a decrease in intensity of the interstitial infiltrate, with only sparse numbers of IgG4-positive plasma cells present (Fig 3A and B). There were broad areas/stripes of interstitial fibrosis and tubular atrophy with relatively well-preserved cortex in between (Fig 3A). The membranous nephropathy was still present, with more prominent basement membrane spike formation than in the earlier biopsy specimen. Immunofluorescence showed persistence of strong granular staining for IgG and C3 in glomerular capillary walls, Bowman capsule, and tubular basement membranes (Fig 3C).

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  • Figure 3. 

    Second kidney biopsy specimen. (A) Note the broad stripe of interstitial fibrosis and tubular atrophy in the bottom half of the core, contrasting with well-preserved cortex at the top (periodic acid–Schiff stain; original magnification ×100). (B) Note very sparse positive cells within the interstitial infiltrate on immunoglobulin G4 immunoperoxidase stain (arrows) (original magnification ×400). (C) Direct immunofluorescence shows persistence of strong granular staining for C3 in glomerular peripheral capillary walls (g), Bowman capsule, and tubular basement membranes (original magnification ×200).

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Discussion 

Autoimmune-related pancreatitis (AIP), also known as sclerosing pancreatitis, is a relatively rare type of pancreatitis with characteristic histopathologic and clinical features.1, 2 AIP is a chronic fibroinflammatory process that may present as a mass lesion mimicking malignancy. Hence, a number of patients have undergone Whipple pancreaticoduodenectomy.3 The recognition of a link between AIP and high serum IgG4 levels has provided both a useful diagnostic test for suspected cases and an appreciation that this is a systemic disorder of immune regulation.4 Other manifestations of AIP have now been recognized, including sclerosing cholangitis, Mikulicz disease, pneumonitis, retroperitoneal fibrosis, and periarteritis.5, 6, 7, 8, 9 The disease has been variably referred to as IgG4-related systemic5 or autoimmune6 disease and more recently as IgG4-associated immune complex multiorgan autoimmune disease.10 The disease is predominantly seen in middle age, with an average patient age of 64 years. The man-woman ratio is 4:1. As seen in the present patient, increased antinuclear antibody and rheumatoid factor and low serum complement levels are often present.5, 10 The disease characteristically shows an excellent clinical response to steroids.7, 8

TIN6, 10, 11, 12, 13, 14, 15 is now a well-recognized manifestation of IgG4-related disease. The interstitial infiltrate is classically expansile and destructive and may present as a mass lesion, raising clinical concerns of malignancy. The infiltrate is mixed and includes numerous IgG4-positive plasma cells and eosinophils. The presence of immune deposits on immunofluorescence and electron microscopy supports an immune complex–mediated cause.

The present patient showed membranous nephropathy in addition to TIN. There have been only 2 previously reported cases of membranous nephropathy in association with TIN in patients with IgG4-related disease.11, 12 It is of interest that IgG4 has been recognized as the predominant form of IgG in idiopathic membranous nephropathy.16 Oliveira16 argued that the properties of IgG4 (inability to fix complement and therefore impaired clearance of IgG4-containing complexes and low affinity for target antigens) make it easier for IgG4-containing complexes to dissociate and traverse the glomerular basement membrane and reform immune complexes on the epithelial side.

IgG4 is the rarest IgG subclass in the circulation of healthy individuals; increased levels are found in patients with conditions of long-term antigen exposure.17 IgG4 is functionally monovalent because of random exchange between IgG4 half molecules and hence on contact with antigen forms “small and harmless immune complexes.”7 IgG4 is considered to be a noninflammatory isotype predominant in interleukin 4/T-helper cell subtype 2–biased immune responses.18 However the T-helper cell subtype 2 cytokine-rich environment (interleukin 4, interleukin 10, and transforming growth factor β) that might be expected in the setting of local IgG4 production may foster a fibrogenic phenotype in macrophages and other resident connective tissue-remodeling cells.19

In the present patient, the combination of sialadenitis and TIN raised the possibility of Sjögren syndrome. However, sicca symptoms were absent and extractable nuclear antigens Ro/SS-A and La/SS-b were negative, making a diagnosis of Sjögren syndrome unlikely. Subsequently, as discussed, the other clinical and pathological features in this man led to a diagnosis of IgG4-related autoimmune disease.

The present patient showed a good clinical response to steroids, with a rapid decrease in serum creatinine, although not to baseline levels. This prompted a repeated kidney biopsy to assess ongoing activity. This showed a marked decrease in the interstitial inflammatory infiltrate with only very sparse IgG4-positive cells present. However, there was significant long-term tubulointerstitial damage. There have been only 2 previous reports of follow-up biopsies in patients with steroid-treated IgG4-related TIN.11, 13 Both these patients also showed a decrease in interstitial infiltrate with some residual chronic tubulointerstitial damage. However, in contrast to our patient, one of these patients had reported disappearance of the accompanying membranous change in the repeated biopsy specimen.11 In our patient, the membranous change persisted and appeared slightly more advanced in the second biopsy specimen. There was also persistence of immunofluorescence staining for IgG and C3 in Bowman capsule and tubular basement membranes.

In conclusion, this man had multiorgan involvement by IgG4-related autoimmune disease. Kidney failure and proteinuria prompted a kidney biopsy that showed TIN and membranous nephropathy. Although he showed a good clinical response to steroids, repeated kidney biopsy showed significant residual chronic interstitial fibrosis and tubular atrophy. This highlights the importance of early diagnosis in this disease because prompt treatment may help minimize irreversible end-organ damage.

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Acknowledgements 

Support: None.

Financial Disclosure: None.

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References 

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 Originally published online as doi:10.1053/j.ajkd.2008.09.012 on November 3, 2008.

PII: S0272-6386(08)01366-8

doi:10.1053/j.ajkd.2008.09.012

American Journal of Kidney Diseases
Volume 54, Issue 2 , Pages 375-380, August 2009

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