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USCAP 2008 Renal Evening Specialty
Conference
Case #1
Vivette D’Agati, MDColumbia University
New York, NY
Case #1• 74 y.o. white female referred to
nephrologist for edema and proteinuria• PMH: longstanding hypothyroidism and
depression, HTN x 3 y, resection of cerebellar hemangioblastoma 2003
• HPI: 2/06: asymptomatic hematuria 7/06: U/A 3+ prot, 0-3 rbc, 6-10 rbc
12/06: onset LE edema• Meds: Avalide, Zoloft, Singulair, Allegra,
Toprol, Synthroid
Nephrologic Workup 1/07
• BP 138/80, 2+ LE edema• No fever, rash, arthralgias, gross hematuria• S creat 1.3 mg/dL, BUN 43 mg/dL• U pr 5.2 g/day, s albumin 3.3 g/dL,
Hct 31% WBC 7.2, platelets 340K, nl serum electrolytes (Na, K, Cl, CO2, Ca)
• U/A: 3+ prot, microhematuria, no RBC casts• Kidney size 10.4 cm by US
Nephrologic Workup 1/07• Serologies:
negative ANA, ANCA, HBsAg, HCV, HIV, RFnormal C3, C4, CH50
• SPEP: reduced albumin 3.0 (nl 3.6-4.7 g/dL)reduced gamma globulins 0.4 g/dL
(nl 0.6-1.6 g/dL)• Renal biopsy: 1/07
IgG
IgG
C3
C3
lambdakappa
IgG3
IgG1 IgG2
IgG4
Differential Dx of Renal Disease with Monoclonal IgGκ Glomerular Deposits
• Monoclonal immunoglobulin deposition disease (LHCDD)
• Type 1 cryoglobulinemic GN• Immunotactoid GN• Fibrillary GN (rare)• Proliferative GN with monoclonal IgGk
deposits (Nasr disease)
Differential Dx of Renal Disease with Monoclonal IgGκ Glomerular Deposits
• Exclude: Monoclonal immunoglobulin deposition disease (LHCDD) (no punctate BM deposits by EM, no TBM involvement)
• Exclude: Type 1 cryoglobulinemic GN (cryos neg x3; no systemic features of cryoglobulinemia)
• Exclude: Immunotactoid GN and Fibrillary GN (no microtubular or fibrillar substructure)
• Diagnosis of exclusion: Proliferative GN with monoclonal IgGk deposits (Nasr disease)
Diagnosis
Proliferative GN with Monoclonal IgG3κ Deposits
Clinical Followup 12/07• Mycophenolate x 6 monthsLabs 12/07:• Creat 1.3 mg/dL• U prot 2.0 grams• Negative cryoglobulins x3• UPEP and SPEP negative for M proteinNo signs or symptoms of myeloma or
lymphoproliferative disorder
Proliferative Glomerulonephritis with Monoclonal IgG Deposits: A Distinct
Entity Mimicking Immune Complex GN(Nasr et al. Kidney Int 65: 85, 2004)
• Retrospective biopsy study 2000-2003• 10 cases of GN with monoclonal IgG
deposition that could not be assigned to any previously recognized diagnostic category
• Biopsy incidence 0.21%(vs AL amyloid 1.66%, MIDD 0.52%)
Proliferative Glomerulonephritis with Monoclonal IgG Deposits: A Distinct
Entity Mimicking Immune Complex GN(Nasr et al. Kidney Int 65: 85, 2004)
• 10 pts (5M, 5F), all Caucasian• Mean age 58 y (44-78)• Presenting features:
RI 80%: mean Cr 2.8 (0.9-8.0 mg/dL) proteinuria 100%: mean U pr 5.8 (1.9-13.0 g) Nephrotic Syndrome 44% Microhematuria 60%
Proliferative Glomerulonephritis with Monoclonal IgG Deposits: A Distinct
Entity Mimicking Immune Complex GN(Nasr et al. Kidney Int 65: 85, 2004)
• 5/10 M spike on SPEP and/or UPEP(with same heavy and light chain isotype as glomerular deposits)
3 IgGκ, 2 IgGλ• 40% hypocomplementemia (C3 and/or C4)• All cryoglobulin neg x2; other serologies neg• No overt myeloma or lymphoma at
presentation or over 12 mo follow
Proliferative Glomerulonephritis with Monoclonal IgG Deposits: A Distinct Entity Mimicking Immune Complex
GN (Nasr et al. Kidney Int 65: 85, 2004)
LM 5 DPGN, 4 with seg MP features4 MPGN, 1 with membranous features1 MGN with seg MP features
IF Granular GCW and Mes deposits, no TBMIgG subtypes: 5 IgG3, 3 IgG1, 1IgG2Light chain isotypes: 6 IgGκ, 4 IgGλCo-deposits C3 (9), C1q (3)
EM Granular subendo, mes +/- subepi deposits
IgG structureIgG structure
→→Deletion:Deletion:HCDDHCDDHCDHCDLHCDDLHCDD
Gamma Constant Domains in Proliferative Gamma Constant Domains in Proliferative GN with Monoclonal IgG DepositsGN with Monoclonal IgG Deposits
CH1CH1 CH2CH2 CH3CH3
Hypothetical PathomechanismHypothetical PathomechanismLight chain restriction argues against antigenLight chain restriction argues against antigen--driven driven
immune response (immune response (κκ::λλ of circulating IgG is 2:1)of circulating IgG is 2:1)
Clinical and immunopathologic findings favor that Clinical and immunopathologic findings favor that monoclonal IgG is deposited as a free, noncomplexed monoclonal IgG is deposited as a free, noncomplexed Ig that has ability to aggregate to form definable Ig that has ability to aggregate to form definable electron dense deposits electron dense deposits
The presence of a CH2 domain permits complement The presence of a CH2 domain permits complement fixation in the absence of circulating ICs (as can occur fixation in the absence of circulating ICs (as can occur in LHCDD, HCDD, Immunotactoid and Type 1 Cryo GN)in LHCDD, HCDD, Immunotactoid and Type 1 Cryo GN)
17 ADDITIONAL CASES OF PGNMD AT CPMC: PATHOLOGIC FINDINGS
• LM pattern: 59% DPGN; 39% MPGN, 17% additional membranous features
• IF: Monoclonal IgGLight chain isotype: k (14); λ (3) IgG subtype: IgG3 (12/12;100%)
• EM: Non-organized electron dense deposits (3 with variegated texture)
When is IgG subtype staining useful?When LC restriction by IF suggests monoclonality• Type 1 cryo (usually IgG3κ)• Immunotactoid GN (usually IgG1 or IgG3)• HCDD and LHCDD To define isotype predominance in polyclonal IgG
deposits• Fibrillary GN (usually oligotypic IgG1 and IgG4)• IgG4 autoimmune interstitial nephritisAs research tool to provide pathogenetic insights• Idiopathic MGN (IgG4 predominates)• Lupus nephritis ( IgG3>IgG2>IgG1>IgG4)
Major physicochemical properties of 4 IgG heavy chain isotypes
(from Stanworth and Turner 1978, Capra and Kunkel 1970)
<6.0-21146 K0.5IgG4
8.2-9.0+++7170 K1IgG3
6.8-8.3+20146 K3IgG2
6.8-9.5++21146 K9IgG1
pICompl Fixation
T1/2 (days)
MWserum mg/ml
Properties of IgG3 that could make it “nephritogenic”
• Most positively charged IgG (can interact with negatively charged GBM)
• Highest MW; more size-restricted by Glom filter• Greatest complement fixing ability• Ability to self-associate spontaneously through
Fc-Fc interactions• Reduced solubility in cold• Selectively enriched in human mixed cryos• Major IgG in glomerular deposits of murine and
human lupus nephritis, murine cryoglobulinemia
Conclusions1. Glomerular deposition of monoclonal IgG
(single IgG subclass, single LC isotype) can produce proliferative GN that mimics IC-GN
2. Proper recognition requires staining for gamma heavy chain subtypes
3. This novel form of “non-Randall” type MIDD enlarges the spectrum of renal disease related to monoclonal gammopathy
4. Longer follow-up needed to determine implications for possible development of myeloma/LPD
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