USCAP 2008 Renal Evening Specialty...

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

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%)



• 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%



• 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

USCAP 2008 Renal Evening Specialty...

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