Renal Lesions in Plasma cell Dyscrasias

Surya V. Seshan, M.D.

New York-Presbyterian Hospital

Weill Cornell Medical College

New York, NY

WHO Diagnostic Criteria for Plasma Cell Myeloma

• 10% of all hematologic malignancies

• Major criteria – Marrow plasmacytosis (>30%)

– Plasmacytoma

– M-component (abnormal Ig or Ig fragment)

Serum: IgG >3.5 g/dl, IgA >2 g/dl

Urine: >1g/24hr of BJ protein

• Minor criteria – Minor plasmacytosis (10-30%)

– M component present but < above

– Lytic bone lesions

– Reduced normal immunoglobulins (<50% of normal)

IgG <600 mg/dl, IgA <100 mg/dl, IgM <50 mg/dl

• Minimum of 1 major and 1 minor or 3 minor criteria (must include A & B)

Various Renal Lesions Secondary to Multiple

Myeloma

• Bence Jones cast nephropathy – “Myeloma kidney”

• Light chain (AL) amyloidosis

• Monoclonal immunoglobulin deposition disease

• Cryoglobulinemic glomerulonephritis

• Other forms of proliferative glomerulonephritis

• Acute tubulo-toxicity to abnormal light chains

• Acute interstitial nephritis to abnormal light chains

• Crystal storing disease

• Fanconi syndrome (renal tubular dysfunction)

• Hypercalcemia

• Hyperuricemia

• Nodular or diffuse plasma cell infiltration

Parry HM et al, Adv Chronic Kidney Dis 2012

Dysproteinemias

Noncryoglobulin

Granular Organized

Fibrillar Other

crystalline

Composition: IgG, IGA, IgM,

kappa/lambda (HC, LC, L&HC)

Cryoglobulins

Granular Organized

Tubular Other

IgM, IgG, IgA,

kappa/lambda

Monoclonal

Mixed (mono, poly)

Polyclonal

Amyloid

Kappa Lambda

It is defined as excessive production of abnormal immunoglobulin molecules or its subunits due to

various molecular modifications and /or defects under strict genetic control, by a single clone of B

lymphocytes or plasma cells, characterized by a single light chain restriction with or without a single

heavy chain.

What is the cause of the wide range of

clinical and pathologic heterogeneity?

Size

pI

Glycosylation

Concentration/titer

Resistance to proteolysis

Binding to Tamm-Horsfall protein

Abnormal host response or properties of abnormal protein?

Properties of abnormal light /(heavy) chains rather than

host response determines the nature of the tissue damage. Solomon A et al NEJM, 1991

Tendency to bind tissues

Tendency to precipitate as:

Granular

Fibrillar

Tubular

Crystalline

Physicochemical properties of abnormal LC/HC

Immunoglobulin Molecule

Renal Lesions at Autopsy in Plasma Cell

Myeloma

77pts 57pts

Light chain deposition

disease 2 (2.5%) 3 (5%)

Amyloidosis 25

(32.4%)

6 (11%)

Bence Jones cast

nephropathy

22

(28.5%) 18 (32%)

Plasma cell tumor nodules 3 (3.8%)

Herrera et al, Arch Pathol 128: 875, 2004

Ivanyi B, Arch Pathol 114: 986, 1990

Occurrence of Dysproteinemia Associated

Lesions in Renal Biopsies

Cornell Experience (2000-2006)

0

5

10

15

20

25

30

35

40

AL Amyloid (36)

My cast Nephr(34)

Proliferative GN (23)MIDD (10)

Tubular injury (6)

Total renal cases studied – 5000

Dysproteinemia ass. Diseases - 109

Bence Jones (Myeloma) Cast

Nephropathy

• Abnormal (monoclonal) LC-containing tubular cast with characteristic staining, morphologic features and tubulo-interstital inflammation with foreign body reaction.

Clinical features

• Acute renal failure – First manifestation

– Precipitated by dehydration, infections, medications

• Chronic renal failure

• Underlying multiple myeloma (MM)

• Glomerular findings (proteinuria) if co-existent LC/HCDD or amyloidosis are present.

Myeloma Cast Nephropathy Morphologic characteristics:

Irregular, fragmented

Fracture lines

Angulated borders

Variegated staining

Multinucleated giant cells

Tubular cell damage

Interstitial inflammation

PAS H&E TRI THP

Myeloma Cast Nephropathy

Tamm-Horsfall protein - Uromodulin

Lambda LC Kappa LC

Characteristics of Tamm Horsfall Protein

• Mucoprotein secreted by cells of TAL

• Precipitates in tubular lumina

• Strongly PAS positive

• Constituent of casts

• Binds and neutralizes cytokines/other

substances in tubular fluid from glomerular

ultrafiltrate

Renal Amyloidosis

Amyloidosis

Evaluation for amyloidosis in patients with a monoclonal protein in serum or urine plus:

Nephrotic syndrome or renal insufficiency (37-46%)

Congestive heart failure (23-30%)

Peripheral neuropathy (10-20%)

Carpal tunnel syndrome (21%)

Hepatomegaly (9%)

Idiopathic malabsorption (7%)

Soft tissue (3%)

• Usually in older age groups

• Varied presentations leads

to delays in diagnosis

Features of AL Amyloidosis

• 89% have M protein, 70% lambda

72% serum

73% urine

• 7% >3gm/dL M protein

• 20% - hypogammaglobulinemia

• Median BM plasma cells – 7%

• 20% of patients have myeloma

Renal Disease in AL Amyloidosis

With myeloma Without myeloma

Nephrotic syndrome 32% 13%

Significant

proteinuria 52% 54%

S Cr > 2mg/dl 23% 22%

Urine – kappa LC 50% 18%

Urine – lambda LC 43% 48%

Urine - negative 7% 34%

No hematuria, less hypercholesterolemia

Spectrum of Glomerular AL Amyloidosis

AL Renal Amyloidosis - Pathologic Variants

Congo red Lambda LC

PASM

Glomerular AL Amyloid Deposits

Making The Diagnosis

Biopsy Site Sensitivity

Serum+Urine

Immunofixation

>90%

Bone marrow 30-50%

Fat Pad Aspirate 60-80%

Target Organ >90%

Rectal 50-80%

Gingival /Dermal 50%

Amyloidosis

• High clinical suspicion

• High awareness on the part of the pathologist

• Unequivocal diagnosis of amyloid deposits

– Early diagnosis of minimal amyloid

Abdominal fat biopsy

Target organ biopsy

– Typing of specific amyloid proteins

AL (lambda/kappa LC), Amyloid A, Transthyretin, Apoprotein B, beta 2 microglobulin, Amyloid P component, fibrinogen.

Genetic studies

– Quantitative assessment and extent of tissue involvement Glomeruli, tubules, interstitium, blood vessels

– Therapy and prognosis

– Efficacy of therapeutic protocols

– Comparison of published data

Advanced techniques for diagnosis and typing of

small/undetectable amyloid deposits

Immunohistochemical studies to type the amyloid deposits

Enzyme linked Immunosorbent Assay (ELISA)

Western blot study

Immunoelectron microscopy

Molecular analysis of isolated and purified amyloid fibrils

Mass Spectrometry/proteomics

Ig VL Germline Gene Use and Organ Tropism

in AL Amyloidosis

Germline done # of cases Organ

1C, 2a2 & 3v 21 Dominant cardiac (10)

Multisystemic disease (12)

6a 18 Dominant renal (16)

(9 < 0.01, x2)

Vk 12 Dominant hepatic (5)

83 patients – 60 (72%) Ig VL sequences identified

Comenzo et al, 2001

AL Amyloidosis - Pathogenesis

• Monoclonal light chains

• Not all LC are amyloidogenic

• Aberrant primary protein sequence

Destabilize the protein

Proteolysis/glycosylation – low pI

Aggregation with Congo red reactive fibrils Amyloid-P component prevents proteolysis,

Laminin, collagen IV, GAG anchor to ECM

unfolding

C lambda 3 constant region

V lambda 6 subgroup

renotropic

Gertz, et al. Arch Int Med, 1992

AL amyloid:

Predictors of Survival

Monoclonal Immunoglobulin

Deposition Disease: Light chain, light & heavy chain and Heavy

chains

Light Chain and Light and Heavy Chain

Deposition Disease

• Amorphous deposits

• Lack Congo red staining

• Lack amyloid P-component

• Stain with antibodies for the class of light or

heavy chain

• ~70% kappa – abnormal, i.e. partial or

excessively large light chain

Light Chain and Light and Heavy Chain

Deposition Disease

• Amorphous deposits

• Lack Congo red staining

• Lack amyloid P-component

• Stain with antibodies for the class of light or

heavy chain

• ~70% kappa – abnormal, i.e. partial or

excessively large light chain

Light Chain Deposit Disease

Light Microscopy

• Glomerular morphology variable

– Typically nodular-similar to diabetic

glomerulosclerosis

• Tubular basement membranes

– Thickened

• Vessels

– Thickened smooth muscle basement membranes

Morphologic Variants of Light Chain Deposition Disease – (our cohort)

Glomerular lesions Minimal glomerular changes (3)

Mild GBM & mesangial thickening

(2)

Focal or diffuse proliferative GN (2)

Nodular glomerulosclerosis (4)

Pure Tubulo-Interstitial disease (3)

Tubular Lesions Thickened TBM with TBM deposits

(100%)

Interstitium Inflammation

Fibrosis

Vascular lesions Varied thickening

4-MM, 1 BM 10%, 3 BM -,

2 SCC Lymphoma,

K:L 11:3

Monoclonal Immunoglobulin Deposition Disease

Nodular glomerular sclerosis variant

Differential Diagnosis of Nodular

Glomerulopathies

Diabetic glomerulosclerosis

Monoclonal immunoglobulin deposition disease

Renal Amyloidosis

Advanced membranoproliferative glomerulonephritis

Idiopathic (lobular) nodular glomerulosclerosis

Fibrillary/Immunotactoid Glomerulonephritis

Fibronectin glomerulopathy

Collagenofibrotic (type III collagen) glomerulopathy

Monoclonal (Light Chain) Deposit Disease (MIDD)

Immunohistology

• Diffuse linear binding of abnormal light chain

to all basement membranes

• κ>λ

• Renal basement membranes

– Glomerular capillary

– Tubular

– Peritubular capillary

– Vascular smooth muscular

MIDD- Immunofluorescence

Monoclonal Immunoglobulin

Deposition Disease

Glomerular basement membrane deposits

Mesangial deposits

GBM

GBM

TBM

Herrera et al. Lab Invest, 2001;

Ultrastruc Pathol 1999

Light Chain Interactions with Mesangial Cells

• Amyloidogenic light chains may be

endocytosed through clathrin coated

pits

• Result in cytoskeletal changes

• Nuclear translocation of NF-kB

• Decreased TGF-beta and increased

MMP allows deposition of fibrils and

impaired matrix repair

Abnormal property of light chains

Concept of glomeruolopathic and

tubulopathic light chains

G. Herrera, Am Anat Pathol 2000

Mesangial cells cultured with light chains

from patients with:

- MIDD → myofibroblasts

- AL amyloid → macrophages

Keeling et al, Lab Invest 2005

Heavy Chain Deposit Disease

• Heavy chain deposition in all renal basement

membranes

• Nodular glomerulopathy

• IgG most common

– IgG3 typical

– CH1 deletion of constant domain of γ heavy chain

• Hypocomplementemia

Waldenstrom’s Macroglobulinemia

Monoclonal IgM and Renal Disease (Waldenstrom’s Macroglobulinemia)

Malignancy

Chronic lymphocytic

leukemia

B cell lymphoma

Plasma cell myeloma

Benign monoclonal

gammopathy

Clinical

Nephrotic syndrome

Acute renal failure

Hyperviscosity

syndrome

IgM k/l

HCV positive (12/46)

Pathological

Intracapillary deposits

Proliferative GN

Amyloidosis

Granular/organized

deposits

Waldenstrom’s Macroglobulinemia – Glomerular Lesions

Proliferative glomerular lesions

resembling immune-complex

glomerulonephritis

Proliferative Glomerulonephritis with monoclonal IgG

deposits: A distinct entity mimicking immune complex GN

(10 cases) Nasr et al Kidney Int 65:85,2004

Clinical Data

Proteinuria 100%

1.9-13.0gms/d

Nephrotic syndrome 44%

Microhematuria 60%

Renal insufficiency 80%

Cr 0.9-8.0mg/dl

Serum M protein 50%

3 IgGk, 2IgGl

Urine M protein 40%

3 IgGk, 1 IgGl

Low complement 40%

No MM, lymphoma or

cryoglobulinemia

Pathology

Diffuse endocapillary

proliferative GN 5

Membranoproliferative GN 4

Membranous GN 1

IF

IgGk 6, IgGl 4

IgG isoforms

IgG1-3, IgG2-2,

IgG3-5

Diffuse (Global) Endocapillary Proliferative Glomerulonephritis

IgG + Kappa Lambda C3

Immunopathology of Monoclonal Deposits

Crystal Storage disease

Dysproteinemia – Intracellular Crystal

Storage Diseases

Monoclonal LCs

Plasma cells

Glomerular epithelial cells

Tubular cells

Histiocytes

(kidney/other locations)

Multinucleated giant cells

Bence Jones protein casts

Diseases

Tubular injury

Fanconi syndrome

Interstitial nephritis

Glomerular proteinuria

Source

Benign monoclonal gammopathy

Low monoclonal plasma cells

smoldering multiple myeloma

Multiple myeloma

Lymphoproliferative disorders

B cell type

Clinical

Varying tubular dysfunction

Proteinuria

Renal failure (rare)

Indolent disease

Pathology – LC Crystal Storage Diseases

LM – proximal tubular injury

– Intracytoplasmic

– Needle/geometric shapes

– Non-polarizable

– Staining characteristics of monoclonal LC

IF – Intralobular

LC +ve

HC –ve

May coexist with M cast nephropathy or amyloidosis

Kappa LC (90%) > Lambda LC

H&E PAS TRI

IF-KLC KLC

Monoclonal LC

Crystal Storing Disease – IgA Kappa

Glomerular

Tubular

Tubular injury and / or Interstitial

inflammation

Acute Tubular Injury/Interstitial Inflammation (nonspecific by LM)

Courtesy of

Dr. G. Herrera

Courtesy of Dr. G. Herrera

Courtesy of

Dr. G. Herrera

Renal Disease in Dysproteinemias

To all Nephrologists and pathologists,

The varied/inconsistent clinical, hematological,

laboratory and renal pathological findings, particularly in

older individuals, warrants a high degree of suspicion,

adequate lab workup and detailed tissue examination,

using all modalities (LM, IF, EM & other) to make a

accurate and timely diagnosis.

Thank you!