Renal Pathology Case Conference. Case 2
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1 Renal Pathology Case Conference Case 2 Lynn D. Cornell, M.D. Mayo Clinic, Rochester, MN cornell.lynn@mayo.edu March 2, 2008
2 Clinical presentation 68 year old woman, initially with normal renal function Creatinine 0.9 mg/dl No proteinuria or hematuria Renal biopsy for a mass lesion detected on abdominal CT scan
3 Clinical presentation: Medical history Hypertension Type II diabetes mellitus Crohn s disease Sclerosing cholangitis Bilateral orbital inflammatory lesions Pancreatic insufficiency (intermittent)
4 99 lbs Clinical presentation: Physical examination Blood pressure 160/60 Lungs clear, normal cardiac sounds No palpable masses on abdominal exam No edema
5 Clinical presentation: Laboratory findings Creatinine 0.9 mg/dl No hematuria or proteinuria Positive ANA (1:80) Normal serum C3 level; decreased serum C4 level
6 Renal biopsy
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13 Electron dense tubular basement membrane deposits
14 Differential diagnosis Interstitial nephritis Infection Drugs Hereditary/metabolic Immunologically-mediated Idiopathic Other
15 Differential diagnosis Interstitial nephritis Infection Drugs Hereditary/metabolic Immunologically-mediated mediated Idiopathic Other With immune complex deposition
16 Interstitial nephritis with immune complex deposition Primary disease in kidney Immune complex deposition in TBM and GBM (e.g., membranous GN) Idiopathic hypocomplementemic interstitial nephritis with extensive tubulointerstitial deposits Giant cell tubulitis with TBM immune deposits (?drug reaction) Polyomavirus interstitial nephritis Idiopathic
17 Interstitial nephritis with immune complex deposition Associated with (other) autoimmune diseases Systemic lupus erythematosus (SLE) Sjögren s syndrome Autoimmune pancreatitis/ IgG4-related systemic disease
18 Distinguishing features in the present case No clinical evidence of SLE or Sjögren s syndrome No glomerular immune complex deposits Mass-forming lesions in kidney and other organs Autoimmune pancreatitis?
19 Autoimmune Pancreatitis Chronic fibroinflammatory disease Mimics carcinoma clinically and radiographically Elevated IgG4 in serum and IgG4+ plasma cells in lesions Multiorgan involvement more recently recognized
20 Autoimmune Pancreatitis Associated with Inflammatory pseudotumors: lung, breast, liver, orbit, salivary gland, pituitary Sclerosing cholangitis Inflammatory bowel disease Retroperitoneal fibrosis Prostatitis Interstitial nephritis (IgG4-immune complex tubulointerstitial nephritis)
21 IgG4-immune complex tubulointerstitial nephritis Typically older males (mean age 64 yrs) Clinical impression Renal mass(es) or vasculitis Occasional renal insufficiency at presentation May have other manifestations of autoimmune pancreatitis
22 Light microscopy Lymphoplasmacytic tubulointerstitial nephritis (TIN); eosinophils often numerous Tubulitis and tubular injury/destruction Range of histologic patterns: Cellular inflammatory pattern Expansile interstitial fibrosis Glomeruli relatively normal
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25 Immunofluorescence Granular TBM staining for IgG, IgM, C3, and kappa and lambda light chains IgG
26 IgG4 staining
27 Numerous IgG4- positive plasma cells
28 IgG4-positive tubulointerstitial deposits
29 IgG4 (present case)
30 IgG4 Least common IgG subclass in the serum IgG1 serum conc: ~9 mg/ml IgG4: ~0.5 mg/ml Usually expressed in setting of antigen desensitization/ chronic antigen exposure Some unusual characteristics
31 IgG4 structure Versus IgG1, IgG4 shows a shift in equilibrium between inter- and intrachain S-S bridges 25-75% absence of a covalent interaction between the Ig heavy chains Functionally monovalent Aalberse et al, Immunology 105 (1), 9-19.
32 IgG4: structural implications Cannot form large immune complexes Forms small and harmless immune complexes upon contact with Ag? Interferes with complement-fixing Abs? Anti-inflammatory antibody? Relation to autoimmune pancreatitis Aalberse et al, Immunology 105 (1), 9-19.
33 Diagnosis: Tubulointerstitial nephritis associated with autoimmune pancreatitis (IgG4-associated Immune complex Multiorgan Autoimmune Disease/ IMAD)
34 Summary: Tubulointerstitial nephritis associated with autoimmune pancreatitis/ IMAD Renal involvement by a multiorgan autoimmune IgG4 immune complex disease Mass-forming lesion or patchy inflammatory involvement on renal biopsy Plasma cell-rich infiltrate, many IgG4+ Eosinophils may be present IgG4+ TBM deposits by IF, IHC, and EM
35 References 1. Cornell LD, Chicano SL, Deshpande V, Collins AB, Selig MK, Lauwers GY, Barisoni L, Colvin RB: Pseudotumors due to IgG4 immune-complex tubulointerstitial nephritis associated with autoimmune pancreatocentric disease. Am J Surg Pathol 31: , Deshpande V, Chicano S, Finkelberg D, Selig MK, Mino-Kenudson M, Brugge WR, Colvin RB, Lauwers GY: Autoimmune pancreatitis: a systemic immune complex mediated disease. Am J Surg Pathol 30: , Kambham N, Markowitz GS, Tanji N, Mansukhani MM, Orazi A, D'Agati VD: Idiopathic hypocomplementemic interstitial nephritis with extensive tubulointerstitial deposits. Am J Kidney Dis 37: , Uchiyama-Tanaka Y, Mori Y, Kimura T, Sonomura K, Umemura S, Kishimoto N, Nose A, Tokoro T, Kijima Y, Yamahara H, Nagata T, Masaki H, Umeda Y, Okazaki K, Iwasaka T: Acute tubulointerstitial nephritis associated with autoimmune-related pancreatitis. Am J Kidney Dis 43:e18-25, Takeda S, Haratake J, Kasai T, Takaeda C, Takazakura E: IgG4-associated idiopathic tubulointerstitial nephritis complicating autoimmune pancreatitis. Nephrol Dial Transplant 19: , Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, Fukushima M, Nikaido T, Nakayama K, Usuda N, Kiyosawa K: High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 344: , Aoki S, Nakazawa T, Ohara H, Sano H, Nakao H, Joh T, Murase T, Eimoto T, Itoh M: Immunohistochemical study of autoimmune pancreatitis using anti-igg4 antibody and patients' sera. Histopathology 47: , Aalberse RC, Schuurman J: IgG4 breaking the rules. Immunology 105:9-19, 2002
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