Plasma Cell Disorders Kristi McIntyre M.D. Texas Oncology 2004 Monoclonal Gammopathies.
Renal diseases in monoclonal gammopathies and cryoglobulinemia
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Transcript of Renal diseases in monoclonal gammopathies and cryoglobulinemia
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Renal Diseases in Monoclonal Gammopathies & Cryoglobulinemia
Dr. Pallavi PrasadPDCC Renal PathologySGPGIMS, Lucknow
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Nephrotic syndromeCardiomegalyNeuropathy
hepatomegaly
Inflammatory syndromes
Familial historyM-component (serum/urine)
Biopsy of superficial
organ/ kidney
Congo-red
amyloid
LCDDHCDD
Others:IC like
glomerulonephritisImmunotactoid
cryoglobulinemia
+
-
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Introduction• Multiple myeloma
• Plasma cell dyscrasias
• MGUS
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Immunoglobulins
• Light chains: kappa and lambda( κ and λ)
• Heavy chains: Alpha, Gamma, Mu, Delta and Epsilon (α,
γ,μ,δ,ε)
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MetabolismLight chains filtered by
glomerulus
90% reabsorbed by proximal tubule
Catabolized by endolysosomes
Small amount of FLC in urine normally..
Plasma cell dyscrasias
LC overproduction
Precipitate in tubular filtrate
Bence Jones proteins
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• Does not meet the criteria for overt myeloma/ B-cell
proliferation
• Overall survival significantly better than that of MM
▫MGUS: treatment is not recommended
▫MGRS: treatment is fundamental
• Transplant: high rates of recurrence in MGRS
Monoclonal gammopathy of renal significance [MGRS]
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Monoclonal gammopathy of renal significance• Defined as a causal relationship between a small B-cell clone and
renal damage
• Organized deposits
▫ Fibrillar deposits: Amyloidosis (AL, AH, ALH)
▫ Micro tubular: Type I and type II cryoglobulinemias and
immunotactoid glomerulopathy
• Non-organized deposits
▫ monoclonal immunoglobulin deposits
• Light-chain proximal tubulopathy (with or without Fanconi
syndrome)
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Lab features s/o monoclonal gammopathy
• High serum globulin fraction
• Abnormally low anion gap
• Unexplained hyponatremia
• Hypercalcemia
• Hypophosphatemia or hyperphosphatemia
• Fanconi syndrome, distal renal tubular acidosis
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Urine analysis
• Light chain proteinuria
• Amyloid : nephrotic range proteinuria + bland urinary
sediments
• MIDD: microscopic hematuria
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Lab detection of monoclonal Ig
Immunoelectrophoresis
Immunofixation
Western blotting
Nephelometry : both monomers and dimers of kappa and
lambda (< 2 to 4 mg/L)
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Renal Involvement in Plasma Cell Dyscrasias
•Heterogeneous
•~85% of all light chains : nephrotoxic
•~70%) :“tubulopathies”
•~30% :“glomerulopathies”
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Renal Involvement in Plasma Cell Dyscrasias
Light chain (myeloma) cast nephropathy
Acute tubulopathy (acute tubular damage or necrosis)
Inflammatory tubulointerstitial nephritis
Amyloidosis (light chain- [AL] or heavy chain- [AH] related amyloidosis)
Deposition diseases (LCDD/HCDD)
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I) Acute tubular damage (acute tubulopathy)• Pathogenesis :
• Inability of lysosomal system to degrade nephrotoxic
light chain
• Lysosomal release of proteolytic enzymes into cytosol
• Leading to cytoplasmic vacuolization, simplification, and
necrosis
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Light Microscopy
• Proximal tubular damage
• ATN: vacuolization of tubular cells, apical blebbing, loss
of surface microvilli, desquamation, fragmentation
tubular regeneration- mitotic figures
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fragmentation and desquamation
Severe tubulopathy-cell necrosis
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• Tubulopathy with crystalline inclusion (clinical Fanconi
syndrome)
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Immunofluorescence
• Monotypic staining for a type of LC
• In cytoplasm of tubular cells
•Electron microscopy• Large, atypical lysosomes
• Fanconi syndrome = crystalline
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Differential Diagnosis
ATN from other causes
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II) Inflammatory tubulointerstitial Nephritis
• ~10% of cases
• Acute renal failure
• Non-nephrotic range proteinuria
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PathogenesisAlter intrinsic tissue antigens
Release of cytokines
Chemoattraction
Activation of inflammatory cells- TIN
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Light Microscopy
• Glomeruli, vessels : unremarkable
• No tubular cast formation
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Intense inflammation
Lymphocytes, plasma cells
Tubulitis
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Immunofluorescence
• Linear monoclonal light
chain staining along TBM
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Immunohistochemistry
for к and λ light chains
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Electron Microscopy
• punctate to powdery, electron-dense material along
outer aspect of tubular basement membranes
• Prominent lysosomes
D/D:
• Allergic TIN
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Case-1
• 45y/M
• C/O generalised weakness x 6 months
• Off and on fever
• Multiple bone pains
• Advanced rapid renal failure
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Cr 6.8 mg/dl
Ca 12 mg/dl
ALP 258U/l
24 hr urinary protein 4.99 gm
Serum electrophoresis M-band in gamma region
Serum Immunofixation IgG lambda monoclonal light chains
Bone marrow biopsy Fibrotic with increased plasma cells (6-8%)
Investigations
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Irregular, refractile, angular or geometric shapes with fracture
planes
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Weak PAS positivity
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Interstitial inflammation
Interstitial fibrosis
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III) Light Chain (Myeloma) Cast Nephropathy
• 1st renal lesion to be recognised in myeloma
• Nephrotic range proteinuria [light chains]
• Urine analysis: dipstick test fails to pick up light chain
proteinuria
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Pathogenesis
Excess of light chains
distal nephron
Tamm horsfall protein
Co-aggregationcasts
Resistant to metalloproteinas
es
Cytokine release and interstitial
nephritis
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• Crystals in some
• Some are congophillic with apple green birefringence
• Thioflavin T, S
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Immunofluorescence
• Restricted light chain staining : casts formed acutely
• Trapping of other LC : long duration
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Electron microscopy
• Fibrillary material,
granular electron
dense material
• Variably-shaped
crystalline material
(specific)
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Differential diagnosis
Nephropathies with cast formation
Rifampin associated light chain proteinuria
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Case-2
• 56y/M
• K/C/O hypothroidism
• C/O swelling of lower limbs x 2 yrs
• Joint pains b/l knee joints off and on
• Bleeding per-rectum. On colonoscopy- tuberculous colonic
ulcer
• Nephrotic range proteinuria and normal S. Creatinine
• Clinical diagnosis ? amyloidosis
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Cr 1.1 mg/dl
C3, C4 normal
ANA negative
24 hr urinary protein 3.5 gm
Serum electrophoresis M-band in gamma region
Abdominal fat pad negative
Investigations
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eosinophilic, amorphous, hyaline material
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Weak PAS positivity
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Blood vessel
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ATNFoam cells
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Tubular atrophy
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Congo-red
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Apple-green birefringence
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lambda
Lambda>kappa
Immunofluorescence
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IV) Amyloidosis
• Protein folding disorder
• AL amyloidosis (74%)
• AA amyloidosis: 2nd most common (4%)
• Localised amyloidosis (20%)
• Familial amyloidosis (2%)
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• Nephrotic range proteinuria with or without renal failure
Gross Pathology:
• Enlarged kidneys with pale, waxy-
appearing cut surfaces
• Normal/small size
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Light Microscopy
• Same regardless of type of amyloid
• In any renal compartments
• Glomeruli : mesangium extending into peripheral
capillary walls and vessels
• Spikes segmental
Diffuse mesangia
l
nodular Pure GBM
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Light Microscopy
• Interstitium : deposits, foam cells, lymphoplasmacytic
infiltrate
• Tubules : atrophy (advanced cases)
• Blood vessels : m/c in arterioles. Resembles hyalinosis
or fibrinoid necrosis
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Fluorescence with thioflavin T
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Immunohistochemistry
Human amyloid P component
К- and λ immunoglobulin light chains
Amyloid A protein
Transthyretin
Fibrinogen
ᵝ2-microglobulin
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?AL vs AA amyloid
• Specific antibody
• Potassium permanganate pretreatment
• Eliminate Congo red positivity for AA amyloid but not for
AL amyloid
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Electron Microscopy:• Randomly arranged, rigid, nonbranching 8- to 10-nm
diameter fibrils
• Extracellular
• In mesangium peripheral
capillary walls, subendothelial/
subepithelial
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Differential diagnosis of amyloid
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Pathogenesis of AL amyloid
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Pathogenesis of AA amyloid
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Case-3
• 20y/m
• C/O swelling over body x 2 months
• Hypertension x 1 month
• Low-grade fever x 1 week
Advanced renal failure
Subnephrotic proteinuria ? MPGN
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Cr 6.3 mg/dl
Ca 8.2 mg/dl
Albumin 2.9 g/dl
24 hr urinary protein 4.99 gm
Serum elecrophoresis Bands in albumin, α1, α2,ᵦ . No M band
Kappa/ lambda ratio 3.6
Lambda free LC assay 139 mg/l [5.7-26.3]
Bone marrow biopsy 6-8% plasma cells
Investigations
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nodular glomerulopathy
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hypercellular nodules
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vessels
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IHC for к light chain
Thickened tubular basement membranes
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ATN
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Kappa>lambda
kappa
lambda
Immunofluorescence
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V) Monoclonal Immunoglobulin Deposition Disease
• Deposition of monoclonal Ig in many organs
• LCDD
• HCDD
• Combined LHCDD (~10%)
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Pathogenesis of LCDD
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Light microscopy of LCDD• Other patterns:
▫Mesangial hypercellularity
▫Membranoproliferative
▫Crescent formation
• D/D : early LCDD with minimal change disease
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Mesangial LCD
Continuous, punctate, subendothelial & along peri glomerular capillary wall
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Along vessel wall
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Heavy Chain Deposition Disease (HCDD)
• α-HCD
• Ƴ-HCD (renal disease)
• µ-HCD
• Combined LCDD and HCDD = LHCDD (Ƴ)
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Etiology and pathogenesis:Deletions in heavy chain portions (CH1, CH2) of
immunoglobulin molecule
Premature secretion of HC into circulation
structurally abnormal HC
deposit in organs
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Light Microscopy• Nodular glomerulosclerosis similar to LCDD• Crescents (11-75%)• TBM deposits• Congo red - negative
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Immunofluorescence
• Heavy chains+
• Distribution similar to LCDD
• linear > granular
E/M :Similar to LCDD
• deposition of fibrils 13-18nmDirect immunofluorescence (µ heavy chain)
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Differential Diagnosis
Minimal change disease
Mesangial proliferative glomerulonephritis
MPGN
Crescentic glomerulonephritis
Diabetic nephropathy
Idiopathic nodular glomerulosclerosis
Amyloid
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Cryoglobulinemic Nephropathy
• Cryoglobulins are serum proteins (immunoglobulins) that
are soluble at 37°C (i.e., monoclonal cryoglobulins)
• Precipitate in the cold and redissolve when heated.
• Precipitate in the vasculature
• Precipitation of cryoglobulins depends on temperature, pH,
cryoglobulin concentration and weak noncovalent factors
• Vasculitis
thrombi
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Test for cryoglobulins
• Blood specimen is drawn and maintained at 37°C until
clotting is completed.
• Serum is separated and incubated at 4°C. for 72 hrs.
• Agglutination or gelation = cryoglobulins.
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• Type of cryoglobulins :-
• IgM; a/w monoclonal gammopathies, B-cell neoplasms, plasma cell dyscrasias
Type I
• IgM - exhibits activity against the Fc portion of polyclonal IgGType II
• polyclonal immunoglobulinsType III
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Light Microscopy
• m/c= Membranoproliferative glomerulonephritis (MPGN)
type I
• Infiltration of capillary spaces by monocytes and
polymorphonuclear cells may also be seen.
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Glomerular capillaries completely filled with
thrombi containing cryoglobulins (PAS stain)
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Immunofluorescence
a) Strong staining of intraluminal thrombi+granular to
pseudolinear staining along peripheral capillary walls
(most characteristic pattern)
b) Granular to pseudolinear subendothelial staining
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• IgG > IgM> C3
Because of the cyclical nature of this disorder, deposits
can be abundant / scanty in a given patient during the
course of the disease.
Immunofluorescence
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Electron Microscopy
• Paired, randomly arranged or in groups [paracrystalline
arrays]
• Fingerprints/ fibrillary/ crystalloid substructure
•Classic curved microtubular
Aggregates..
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Differential Diagnosis
1) Lupus nephritis
2) Thrombotic microangiopathy (hyaline thrombi)
• The fact that cryoglobulins can be seen in otherwise
typical lupus nephritis further complicates the differential
diagnosis.
• IF, EM, clinical and serologic findings