renal diseases in monoclonal gammopathies and cryoglobulinemia
TRANSCRIPT
Renal Diseases in Monoclonal Gammopathies & Cryoglobulinemia
Dr. Pallavi PrasadPDCC Renal PathologySGPGIMS, Lucknow
Nephrotic syndromeCardiomegalyNeuropathy
hepatomegaly
Inflammatory syndromes
Familial historyM-component (serum/urine)
Biopsy of superficial
organ/ kidney
Congo-red
amyloid
LCDDHCDD
Others:IC like
glomerulonephritisImmunotactoid
cryoglobulinemia
+
-
Introduction• Multiple myeloma
• Plasma cell dyscrasias
• MGUS
Immunoglobulins
• Light chains: kappa and lambda( κ and λ)
• Heavy chains: Alpha, Gamma, Mu, Delta and Epsilon (α,
γ,μ,δ,ε)
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
• 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]
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)
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
Urine analysis
• Light chain proteinuria
• Amyloid : nephrotic range proteinuria + bland urinary
sediments
• MIDD: microscopic hematuria
Lab detection of monoclonal Ig
Immunoelectrophoresis
Immunofixation
Western blotting
Nephelometry : both monomers and dimers of kappa and
lambda (< 2 to 4 mg/L)
Renal Involvement in Plasma Cell Dyscrasias
•Heterogeneous
•~85% of all light chains : nephrotoxic
•~70%) :“tubulopathies”
•~30% :“glomerulopathies”
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)
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
Light Microscopy
• Proximal tubular damage
• ATN: vacuolization of tubular cells, apical blebbing, loss
of surface microvilli, desquamation, fragmentation
tubular regeneration- mitotic figures
fragmentation and desquamation
Severe tubulopathy-cell necrosis
• Tubulopathy with crystalline inclusion (clinical Fanconi
syndrome)
Immunofluorescence
• Monotypic staining for a type of LC
• In cytoplasm of tubular cells
•Electron microscopy• Large, atypical lysosomes
• Fanconi syndrome = crystalline
Differential Diagnosis
ATN from other causes
II) Inflammatory tubulointerstitial Nephritis
• ~10% of cases
• Acute renal failure
• Non-nephrotic range proteinuria
PathogenesisAlter intrinsic tissue antigens
Release of cytokines
Chemoattraction
Activation of inflammatory cells- TIN
Light Microscopy
• Glomeruli, vessels : unremarkable
• No tubular cast formation
Intense inflammation
Lymphocytes, plasma cells
Tubulitis
Immunofluorescence
• Linear monoclonal light
chain staining along TBM
Immunohistochemistry
for к and λ light chains
Electron Microscopy
• punctate to powdery, electron-dense material along
outer aspect of tubular basement membranes
• Prominent lysosomes
D/D:
• Allergic TIN
Case-1
• 45y/M
• C/O generalised weakness x 6 months
• Off and on fever
• Multiple bone pains
• Advanced rapid renal failure
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
Irregular, refractile, angular or geometric shapes with fracture
planes
Weak PAS positivity
Interstitial inflammation
Interstitial fibrosis
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
Pathogenesis
Excess of light chains
distal nephron
Tamm horsfall protein
Co-aggregationcasts
Resistant to metalloproteinas
es
Cytokine release and interstitial
nephritis
• Crystals in some
• Some are congophillic with apple green birefringence
• Thioflavin T, S
Immunofluorescence
• Restricted light chain staining : casts formed acutely
• Trapping of other LC : long duration
Electron microscopy
• Fibrillary material,
granular electron
dense material
• Variably-shaped
crystalline material
(specific)
Differential diagnosis
Nephropathies with cast formation
Rifampin associated light chain proteinuria
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
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
eosinophilic, amorphous, hyaline material
Weak PAS positivity
Blood vessel
ATNFoam cells
Tubular atrophy
Congo-red
Apple-green birefringence
lambda
Lambda>kappa
Immunofluorescence
IV) Amyloidosis
• Protein folding disorder
• AL amyloidosis (74%)
• AA amyloidosis: 2nd most common (4%)
• Localised amyloidosis (20%)
• Familial amyloidosis (2%)
• Nephrotic range proteinuria with or without renal failure
Gross Pathology:
• Enlarged kidneys with pale, waxy-
appearing cut surfaces
• Normal/small size
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
Light Microscopy
• Interstitium : deposits, foam cells, lymphoplasmacytic
infiltrate
• Tubules : atrophy (advanced cases)
• Blood vessels : m/c in arterioles. Resembles hyalinosis
or fibrinoid necrosis
Fluorescence with thioflavin T
Immunohistochemistry
Human amyloid P component
К- and λ immunoglobulin light chains
Amyloid A protein
Transthyretin
Fibrinogen
ᵝ2-microglobulin
?AL vs AA amyloid
• Specific antibody
• Potassium permanganate pretreatment
• Eliminate Congo red positivity for AA amyloid but not for
AL amyloid
Electron Microscopy:• Randomly arranged, rigid, nonbranching 8- to 10-nm
diameter fibrils
• Extracellular
• In mesangium peripheral
capillary walls, subendothelial/
subepithelial
Differential diagnosis of amyloid
Pathogenesis of AL amyloid
Pathogenesis of AA amyloid
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
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
nodular glomerulopathy
hypercellular nodules
vessels
IHC for к light chain
Thickened tubular basement membranes
ATN
Kappa>lambda
kappa
lambda
Immunofluorescence
V) Monoclonal Immunoglobulin Deposition Disease
• Deposition of monoclonal Ig in many organs
• LCDD
• HCDD
• Combined LHCDD (~10%)
Pathogenesis of LCDD
Light microscopy of LCDD• Other patterns:
▫Mesangial hypercellularity
▫Membranoproliferative
▫Crescent formation
• D/D : early LCDD with minimal change disease
Mesangial LCD
Continuous, punctate, subendothelial & along peri glomerular capillary wall
Along vessel wall
Heavy Chain Deposition Disease (HCDD)
• α-HCD
• Ƴ-HCD (renal disease)
• µ-HCD
• Combined LCDD and HCDD = LHCDD (Ƴ)
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
Light Microscopy• Nodular glomerulosclerosis similar to LCDD• Crescents (11-75%)• TBM deposits• Congo red - negative
Immunofluorescence
• Heavy chains+
• Distribution similar to LCDD
• linear > granular
E/M :Similar to LCDD
• deposition of fibrils 13-18nmDirect immunofluorescence (µ heavy chain)
Differential Diagnosis
Minimal change disease
Mesangial proliferative glomerulonephritis
MPGN
Crescentic glomerulonephritis
Diabetic nephropathy
Idiopathic nodular glomerulosclerosis
Amyloid
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
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.
• 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
Light Microscopy
• m/c= Membranoproliferative glomerulonephritis (MPGN)
type I
• Infiltration of capillary spaces by monocytes and
polymorphonuclear cells may also be seen.
Glomerular capillaries completely filled with
thrombi containing cryoglobulins (PAS stain)
Immunofluorescence
a) Strong staining of intraluminal thrombi+granular to
pseudolinear staining along peripheral capillary walls
(most characteristic pattern)
b) Granular to pseudolinear subendothelial staining
• 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
Electron Microscopy
• Paired, randomly arranged or in groups [paracrystalline
arrays]
• Fingerprints/ fibrillary/ crystalloid substructure
•Classic curved microtubular
Aggregates..
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