Quiz Page July 2010:

Article Outline

• Clinical Presentation
• Discussion
  • What is the differential diagnosis for this presentation?
  • What additional evaluation would be appropriate?
  • How might this patient be managed?
• Final Diagnosis
• Acknowledgements
• References
• Copyright

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Clinical Presentation 

A 69-year-old man was referred to the nephrology unit of our hospital with a 20-month history of worsening kidney function. Originally, this patient had been admitted to the respiratory unit of the hospital for evaluation of multiple lung consolidation using computed tomographic (CT) scan performed as part of a 2-year follow-up for pyothorax managed with antibiotic therapy.

Physical examination showed blood pressure of 96/64 mm Hg and mild pretibial edema. Laboratory tests showed chronic kidney failure associated with hypergammaglobulinemia and hypocomplementemia (Table 1). Antinuclear and anti-DNA antibodies were detectable, although at low titers of 1:80 and 12 IU/mL (reference ranges, <1:40 and <6 IU/mL), respectively. CT examination of the chest showed multiple lesions of ill-defined consolidation with spiculation in the bilateral lungs (Fig 1A) and enlargement of the mediastinal lymph nodes. Gallium scintigraphy showed abnormal uptake in the bilateral lungs, hilar lymph nodes, and kidneys (Fig 1B). A transbronchial lung biopsy and kidney biopsy were performed (Fig 2).

Table 1. Laboratory Data

	20 Months Prior	At Presentation	Reference Range
Proteinuria (g/g creatinine)	NA	1.7	<0.2
Serum urea nitrogen (mg/dL)	21.9	55.6	8-20
Serum creatinine (mg/dL)	1	3.5	0.4-1
eGFR (mL/min/1.73 m2)	58.0	14.0	≥90.0
Total protein (g/dL)	8.2	9.4	6.5-8
Immunoglobulin G (mg/dL)	3,940	7,408	870-1,700
Immunoglobulin G4 (mg/dL)		2,579	4.8-105
C3 (mg/dL)	NA	46	86-160
C4 (mg/dL)	NA	<1	17-45
CH50 (U/mL)	NA	<12	25.0-48.0

Note: Conversion factors for units: serum urea nitrogen in mg/dL to mmol/L, ×0.357; serum creatinine in mg/dL to μmol/L, ×88.4; eGFR in mL/min/1.73 m² to mL/s/1.73 m², ×0.01667; total protein in g/dL to g/L, ×10; immunoglobulin G and G4 in mg/dL to g/L, ×0.01. No conversion necessary for serum complements in mg/dL and g/L.

Abbreviations: eGFR, estimated glomerular filtration rate; NA, not available.

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• Figure 1. 

  Chest computed tomographic (CT) scans and gallium scintigraphic images of the patient. (A) Chest CT scan shows multiple ill-defined consolidations with spiculation in bilateral lungs. (B) Gallium scintigraphy shows abnormal gallium accumulation in the hilar lymph nodes, lungs, and kidneys (arrows).

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• Figure 2. 

  Microscopic analysis of biopsy specimens from the lung and kidney of the patient. Light microscopy of (A, B) transbronchial lung and (C-F) kidney biopsy specimens (A-D, hematoxylin and eosin stain; E, methenamine-silver stain; F, immunofluoresent immunoglobulin G staining). (G, H) Electron micrographs of the kidney biopsy specimen.

■ What is the differential diagnosis for this presentation?

■ What additional evaluation would be appropriate?

■ How might this patient be managed?

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Discussion 

What is the differential diagnosis for this presentation? 

This case highlights decreased kidney function associated with pulmonary consolidation, and pulmonary-renal syndrome, such as antineutrophil cytoplasmic antibody–associated vasculitis, could be implicated in the pathogenesis of this patient. Castleman disease, particularly the multicentric type, can present with systemic symptoms similar to those in our patient. Because of the slightly increased level of anti-DNA antibodies with hypocomplementemia, systemic lupus erythematosus also should be considered.

What additional evaluation would be appropriate? 

Transbronchial lung biopsy samples showed fibrosis along the bronchovascular bundles with marked plasma cell infiltration (Fig 2A and B). These infiltrates were observed even in the intima of the pulmonary artery (Fig 2B), but neither active vasculitis nor fibrinoid necrosis was observed. Immunohistochemistry showed that ∼50% of the infiltrating immunoglobulin G (IgG)-bearing plasma cells were positive for IgG4 (data not shown).

A kidney biopsy showed extensive interstitial fibrosis with severe lymphoplasmacytic infiltration and prominent atrophic tubules (Fig 2C and D). Eosinophils also were observed. The glomerular basement membrane (GBM) was thickened with signs of bubbling indicative of membranous nephropathy (Fig 2E). No crescent formation or vasculitis was noted, and Congo Red staining was negative. Immunofluorescence showed granular IgG deposition along the GBM and tubular basement membrane (Fig 2F). Mild deposition of C3 and C1q and weak deposition of IgM and IgA also were noted along the capillary walls of glomeruli, but C4 staining was negative (data not shown). Of IgG subclasses, IgG1 and IgG4 staining was positive along the GBM (data not shown). Using electron microscopy, we observed numerous subepithelial and intramembranous deposits along the GBM (Fig 2G) and a few dense deposits in the tubular basement membrane (arrowheads in Fig 2H).

To determine the IgG4-positive plasma cell population, immunohistochemical staining against IgG and IgG4 was performed and showed that ∼60%-70% of IgG-bearing plasma cells were positive for IgG4 (Fig 3A and B). Collectively, our findings are clinicopathologically compatible with previously reported cases of IgG4-related disease.¹, ², ³, ⁴

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• Figure 3. 

  (A) Immunostaining showed that most immunoglobulin G (IgG)-bearing cells are (B) positive for IgG4.

To confirm the diagnosis, additional serologic analyses were performed; antineutrophil cytoplasmic antibodies, hepatitis B, hepatitis C, and HIV (human immunodeficiency virus) were negative. Neither cryoglogulin, serum M-protein, nor Bence-Jones protein was detected. Serum interleukin 6 level was 8.9 pg/mL (reference range, <4.0 pg/mL), and copy number of human herpesvirus 8 DNA per 1,000,000 leukocytes was <2 × 10, making Castleman disease less likely.⁵ Although the possibility of class V lupus nephritis remained, the patient showed no additional lupus-like signs or symptoms, such as rash or arthritis. Therefore, we conclude that membranous nephropathy in this patient was closely related to hyper-IgG4 secretion. Characteristic findings of IgG4-related nephropathy are listed in Box 1.

How might this patient be managed? 

One of the major features of IgG4-related diseases is their strong response to steroid therapies.² Oral prednisone was administered at 30 mg/d for the first month, then gradually tapered by 5 mg every month thereafter. After the first month of prednisone therapy, serum creatinine level decreased to 2 mg/dL (176.8 μmol/L; estimated glomerular filtration rate, 27 mL/min/1.73 m² [0.45 mL/s/1.73 m²]), and IgG level, to 1,519 mg/dL (15.19 g/L). Hypocomplementemia resolved during the same period. A follow-up CT scan performed after 3 months of prednisone therapy showed that most pulmonary foci of consolidation were diminished (Fig 4).

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• Figure 4. 

  Consolidation lesions are diminished and inconspicuous in a follow-up chest computed tomographic scan for the patient after 3 months of prednisone therapy.

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Final Diagnosis 

IgG4-related nephropathy and interstitial pneumonia.

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Acknowledgements 

We thank Junji Kato, Yasuko Watanabe, and Hajime Sakamoto (Hiratsuka Kyosai Hospital) for excellent technical assistance, and Drs Yasushi Ryujin (Tokyo Medical and Dental University, Tokyo, Japan), Ayumi Murakami, Yoji Nagashima, and Ichiro Aoki (Yokohama City University School of Medicine) for helpful advice.

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References 

1. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344(10):732–738
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2. Yoneda K, Murata K, Katayama K, et al. Tubulointerstitial nephritis associated with IgG4-related autoimmune disease. Am J Kidney Dis. 2007;50(3):455–462
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   • Abstract
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3. Cornell LD, Chicano SL, Deshpande V, et al. Pseudotumors due to IgG4 immune-complex tubulointerstitial nephritis associated with autoimmune pancreatocentric disease. Am J Surg Pathol. 2007;31(10):1586–1597
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4. Cheuk W, Yuen HK, Chu SY, Chiu EK, Lam LK, Chan JK. Lymphadenopathy of IgG4-related sclerosing disease. Am J Surg Pathol. 2008;32(5):671–681
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5. Sato Y, Kojima M, Takata K, et al. Systemic IgG4-related lymphadenopathy: a clinical and pathologic comparison to multicentric Castleman's disease. Mod Pathol. 2009;22(4):589–599
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