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Monoclonal Gammopathy and Renal Disease
1. Monoclonal Gammopathies and Kidney
Disease
Mostafa Gaafar O. Aly
MD (Heidelberg University), MD (Assiut University)
Lecturer of Nephrology, Assiut University
German Board of Internal Medicine and Nephrology
Hypertensiologist at the German Hypertension League (DHL)
3. Immunoglobulin Structure
Each immunoglobulin consists of 2 identical heavy chains and 2 identical
light chains (kappa and lambda)
A particular plasma cell produces only one type of immunoglobulin.
Normally, there is slight excess of free light chains produced>> detected in
blood
4. Monoclonal Gammopathy
Plasma cells divide more than it should >>produce a large amount of
copies (clones) of itself.
These plasma cell clones crowd out other cells in bone marrow >> eg.
anemia
Since the clones come from a single plasma cell, they produce a large
amount of the same type of abnormal monoclonal Ig (M-protein)
M-protein can be an intact Ig, only a light chain, or rarely a heavy chain.
6. Monoclonal Gammopathy
Proliferation of a single (or 2 or 3 ) clone/clones of plasma cells, which
produce/s an immunologically homogeneous protein (M protein)
M protein can be an intact Ig (containing both heavy and light chains), only
light chains (as in light chain myeloma, light chain deposition disease, o AL-
Amyloidosis), or rarely heavy chains only (heavy chain disease, heavy chain
deposition disease).
7. Significance of M protein
• Indicates the presence of underlying clonal plasma cell or
lymphoproliferative disorder.
• This clonal proliferation is either malignant, non- or premalignant
• Even premalignant clonal proliferation can have many adverse
effects-
8. Consequences of M proteins (either
malignant or premalignant)
• Agglutinate RBCs (Cold
agglutinin disease)
• Insoluble at low Temp.
(Cryoglobulinemia)
• Increases viscosity
(Waldenström
macroglobulinemia)
• Deposition in tissues
(Amyloidosis)
• Neuropathy (Waldenström,
amyloidosis, POEMS)
9. MGUS Smouldering
myeloma
MM (symptomatic)
M-protein <30 g/l
AND
>30 g/l in serum or
>500 mg/24 h urine
AND/OR
>30 g/l in serum or
>500 mg/24h urine
AND/OR
% plasma cell in
BM
<10% >10-60%
AND
>10% or
extramedullary
MM
AND
Organ damage No No and no
amyloidosis
Yes (CRAB)
Or
Biomarkers % plasma cells in
BM >60%
Invloved/uninvolve
d free light chains
ratio >100
2 or more lesions in
MRI
Diagnostic Criteria according to IMWG
10. Monoclonal gammopathie of renal
significance (MGRS)
• A group of disorders in which a monoclonal Ig secreted by a
nonmalignant or premalignant B cell or plasma cell clone leads to
renal damage. These disorders do not meet the criteria of
symptomatic MM or a lymphoproliferative disorder.
• The term was used to differentiate MGUS (no organ damage) from
MGRS (at risk of progressive renal damage).
• MGRS can be associated with other hematologic disorders such as
smoldering myeloma, smoldering Waldenström, monoclonal B cell
lymphocytosis (MGUS of the CLL)
11. Types of kidney affection through Paraproteinemia
AKI CKD, proteinuria Tubular dysfunction (Fanconi
Synd., RTA type II)
Cast nephropathy Immunoglobulin amyloidosis
(AL, AH, AHL)
Immunoglobulin Amyloidosis
Hypercalcemia Cast nephropathy Light chain-associated proximal
tubulopathy
Hyperuricemia Monoclonal Ig deposition
disease (MIDD, LCDD, HCDD,
L/HCDD)
Crystal-storing histiocytosis
Kidney infiltration with plasma
cells
Proliferative GN with
monoclonal immunoglobulin
deposits (PGNMID)
Acute free light chain-mediated
interstitial nephritis
Immunotactoid GN, fibrillary GN
Cryoglobulinemic GN type I or II
Crystalloglobulin-induced
nephropathy
C3GN
12. Most common forms of kidney affection by
paraproteinemia
• AL-AMYLOIDOSIS
• Cast nephropathy
• LCDD
• More than one lesion can exist:
• Example. LCDD+ cast nephropathy
• The best survival was noticed with LCDD and the worst with cast
nephropathy
13. Cast nephropathy
Overflow proteinuria > in distal tubuls free LC complex with Tamm-Horsfall
protein> precipitate> tubular obstruction
Histologically:
- casts appear fractured, eosinophilic, taking many geometric shapes,
surrounded by inflammatory cells.
- Congo red negative
- No fibrils
14. Precipitation of light chains is increased by NSAIDs, contrast agents,
dehydration,etc.
Urine Stix: negative (detects only albumin!!!)
Cast nephropathy
Light chain cast nephropathy is highly probable if sFLC >1500mg/l, and
light chains predominate in 24h UPEP + Urine Immunofix
18. MGRS
• The character of the monoclonal protein not its amount determines
the form of kidney affection (fibrils, microtubules, amorphous).
• Serum electrophoresis and serum immunofixation might be negative.
• The diagnosis can usually be confirmed by serum kappa/lambda free
light chain ratio.
• Deposition of monoclonal proteins can be systemic (amyloidosis,
MIDD,crystal-storing histiocytosis, cryoglobulinemia) or restricted to
the kidney.
19. MGRS
No monoclonal
IG deposition
MONOCLONAL
IG deposition
Non-organised
deposits
Fibrillary Microtubular
Inclusion or
crystalline
deposits
IG-associated
amyloidosis
Monoclonal
fibrillary GN
Immunotactoid GN
Cryoglobulinemic
GN I and II
LC assoc. proximal
tubulopathy
Crystal-storing
histiocytosis
Cryocrystalloglobulin
-GN
Monoclonal IG
deposition disease
(MIDD)
Proliferative GN with
monoclonal IG deposits
(PGNMID)
C3GN with monoclonal
gammopathy
TMA
Organised deposits
20. 1) MGRS with organized monoclonal Ig deposits
2) MGRS with non-organized monoclonal Ig deposits
3) MGRS without Ig deposits
21. 1) MGRS with organized monoclonal Ig deposits
2) MGRS with non-organized monoclonal Ig deposits
3) MGRS without Ig deposits
24. MGRS
No monoclonal
IG deposition
MONOCLONAL
IG deposition
Non-organised
deposits
Fibrillary Microtubular
Inclusion or
crystalline
deposits
IG-associated
amyloidosis
Monoclonal
fibrillary GN
Immunotactoid GN
Cryoglobulinemic
GN I and II
LC assoc. proximal
tubulopathy
Crystal-storing
histiocytosis
Cryocrystalloglobulin
-GN
Monoclonal IG
deposition disease
(MIDD)
Proliferative GN with
monoclonal IG deposits
(PGNMID)
C3GN with monoclonal
gammopathy
TMA
Organised deposits
25. IG-associated amyloidosis (AL/AH/AHL amyloidosis)
Pathological picture
- Light microscopy:
Monoclonal Ig deposit either in glomeruli, tubules or vessels
Congo-red positive and causes a characteristic apple green
birefringence under polarized light.
- EM: Amyloid fibrils about 7-12 nm
26. AL/AH/AHL Amyloidosis
AL/AH/AHLAmyloidosis is a systemic disease (Heart, liver)
In only in 10-20% of amyloidosis cases, a MM is found
In AL-Amyloidosis, in 75% of cases the deposits are of Lambda chains
27. MGRS
No monoclonal
IG deposition
MONOCLONAL
IG deposition
Non-organised
deposits
Fibrillary Microtubular
Inclusion or
crystalline
deposits
IG-associated
amyloidosis
Monoclonal
fibrillary GN
Immunotactoid GN
Cryoglobulinemic
GN I and II
LC assoc. proximal
tubulopathy
Crystal-storing
histiocytosis
Cryocrystalloglobulin
-GN
Monoclonal IG
deposition disease
(MIDD)
Proliferative GN with
monoclonal IG deposits
(PGNMID)
C3GN with monoclonal
gammopathy
TMA
Organised deposits
28. Monoclonal fibrillary GN
Fibrillary deposits are about 2 times thicker than those of amyloidosis (10-
30nm)
Congo-red negative
If fibrillary GN is diagnosed, search for monoclonal gammopathy (7-17% of
fibrillary GN have a monoclonal gammopathy) (Controversial !!! In the
majority of cases, IF on frozen sections not paraffin tissue !!)
DnaJB9 staining of glomeruli is a reliable marker for fibrillary GN
30. Immunofluorescence on paraffin tissue after pronase digestion is
important to unmask polytypic IgG deposits
Polytypic fibrillary GN frequently exhibits IgG subclass restriction (most
commonly IgG4)
31. MGRS with Organized Microtubular Deposits
Microtubules are different from fibrils in that they are hollow fibers with a
larger diameter 17-52 nm.
32. MGRS
No monoclonal
IG deposition
MONOCLONAL
IG deposition
Non-organised
deposits
Fibrillary Microtubular
Inclusion or
crystalline
deposits
IG-associated
amyloidosis
Monoclonal
fibrillary GN
Immunotactoid GN
Cryoglobulinemic
GN I and II
LC assoc. proximal
tubulopathy
Crystal-storing
histiocytosis
Cryocrystalloglobulin
-GN
Monoclonal IG
deposition disease
(MIDD)
Proliferative GN with
monoclonal IG deposits
(PGNMID)
C3GN with monoclonal
gammopathy
TMA
Organised deposits
34. Immunotactoid GN
LM: MPGN (common), MN, endocapillary proliferative GN (rare)
Immunohistology: IgG (rarely IgM or IgA) and C3 deposits, Light chain
restriction in 70-90%
EM:mesangial, subendothelial, and subepithelial hollow microtubules.
Parallelly organized, around 30 nm in diameter.
36. MGRS
No monoclonal
IG deposition
MONOCLONAL
IG deposition
Non-organised
deposits
Fibrillary Microtubular
Inclusion or
crystalline
deposits
IG-associated
amyloidosis
Monoclonal
fibrillary GN
Immunotactoid GN
Cryoglobulinemic
GN I and II
LC assoc. proximal
tubulopathy
Crystal-storing
histiocytosis
Cryocrystalloglobulin
-GN
Monoclonal IG
deposition disease
(MIDD)
Proliferative GN with
monoclonal IG deposits
(PGNMID)
C3GN with monoclonal
gammopathy
TMA
Organised deposits
37. Cryoglobulinemic GN
Cryoglobulins are Igs that precipitae when temp <37°C and redissolve upon
rewarming.
Only type I and II cryoglobulinemia contain monoclonal immunoglobulins
Cryoglobulinemia is a systemic disease (Meltzer’s triad, skin, neuropathy).
All type I and some type II cryoglobulinemia are due to plasma cell
dyscrasia or lymphoproliferative disease.
Type I Cryo mostly cause vascular symptoms (hyperviscosity, thrombosis)
Type II and III: non specific sympt, Meltzer’s, neuropathy,etc.
40. Cryoglobulinemic GN
LM: MPGN (most common), microthrombi in capillary lumens
Immunohistology: Ig deposition is dependent on cryoglobulin type:
Type I: light chain restriction is found
Type II:both IgG and IgM are deposited. Light chain restriction is usually
not found
EM: microtubular straight or curved deposits.
44. MGRS
No monoclonal
IG deposition
MONOCLONAL
IG deposition
Non-organised
deposits
Fibrillary Microtubular
Inclusion or
crystalline
deposits
IG-associated
amyloidosis
Monoclonal
fibrillary GN
Immunotactoid GN
Cryoglobulinemic
GN I and II
Crystal-storing
histiocytosis
Cryocrystalloglobulin
-GN
Monoclonal IG
deposition disease
(MIDD)
Proliferative GN with
monoclonal IG deposits
(PGNMID)
C3GN with monoclonal
gammopathy
TMA
Organised deposits
LC assoc. proximal
tubulopathy
45. Light chain-associated proximal tubulopathy
Deposition of light chain crystalls in different forms in lysosomes or
cytoplasm of proximal tubule cells
Most commonly kappa >>> Fanconi Syndrome
Rarely Lambda deposits >>> ATN or acute interstitial nephritis
46. MGRS
No monoclonal
IG deposition
MONOCLONAL
IG deposition
Non-organised
deposits
Fibrillary Microtubular
Inclusion or
crystalline
deposits
IG-associated
amyloidosis
Monoclonal
fibrillary GN
Immunotactoid GN
Cryoglobulinemic
GN I and II
Crystal-storing
histiocytosis
Cryocrystalloglobulin
-GN
Monoclonal IG
deposition disease
(MIDD)
Proliferative GN with
monoclonal IG deposits
(PGNMID)
C3GN with monoclonal
gammopathy
TMA
Organised deposits
LC assoc. proximal
tubulopathy
49. MGRS
No monoclonal
IG deposition
MONOCLONAL
IG deposition
Non-organised
deposits
Fibrillary Microtubular
Inclusion or
crystalline
deposits
IG-associated
amyloidosis
Monoclonal
fibrillary GN
Immunotactoid GN
Cryoglobulinemic
GN I and II
Crystal-storing
histiocytosis
Cryocrystalloglobulin
-GN
Monoclonal IG
deposition disease
(MIDD)
Proliferative GN with
monoclonal IG deposits
(PGNMID)
C3GN with monoclonal
gammopathy
TMA
Organised deposits
LC assoc. proximal
tubulopathy
50. Crystalloglobulin GN
Crystalline Ig thrombosis in arterioles and glomerular capillaries
Triggered by cold exposure in some pts (Cryocrystalglobulin-GN)
Causes systemic vasculopathy
53. What Do You Know About Crystalline Nephropathy?
54. 1) MGRS with organized monoclonal Ig deposits
2) MGRS with non-organized monoclonal Ig deposits
3) MGRS without Ig deposits
55. 1) MGRS with organized monoclonal Ig deposits
2) MGRS with non-organized monoclonal Ig deposits
3) MGRS without Ig deposits
56. MGRS
No monoclonal
IG deposition
MONOCLONAL
IG deposition
Non-organised
deposits
Fibrillary Microtubular
Inclusion or
crystalline
deposits
IG-associated
amyloidosis
Monoclonal
fibrillary GN
Immunotactoid GN
Cryoglobulinemic
GN I and II
LC assoc. proximal
tubulopathy
Crystal-storing
histiocytosis
Cryocrystalloglobulin
-GN
Monoclonal IG
deposition disease
(MIDD)
Proliferative GN with
monoclonal IG deposits
(PGNMID)
C3GN with monoclonal
gammopathy
TMA
Organised deposits
57. Monoclonal Ig Deposition Disease (MIDD)
In 70% of cases, light chains will be deposited (mainly kappa, rarely
Lambda, heavy chains, or light and heavy chains)
In LM, the deposits are hardly differentiated from those of amyloidosis
Congo red negative (opposite to amyloidosis)
40% of pts have MM
58. Monoclonal Ig Deposition Disease (MIDD)
In 15-30% of cases, no paraproteins are detected in serum and urine using
standard methods (electrophoresis and immunofixation)
Assessment of free light chains and kappa/lambda ratio is essential
59. Monoclonal Ig Deposition Disease (MIDD)
C/P: renal insufficiency, nephrotic syndrome in 40%, systemic disease
(liver, heart)
Renal biopsy: LM: nodular glomerulosclerosis (DD: DN)
EM: granular amorphous deposits in mesangium, TBM,
endothelial side of GBM, and in vessel walls
Coincidental cast nephropathy (30%) >>> poor prognosis
63. MGRS
No monoclonal
IG deposition
MONOCLONAL
IG deposition
Non-organised
deposits
Fibrillary Microtubular
Inclusion or
crystalline
deposits
IG-associated
amyloidosis
Monoclonal
fibrillary GN
Immunotactoid GN
Cryoglobulinemic
GN I and II
LC assoc. proximal
tubulopathy
Crystal-storing
histiocytosis
Cryocrystalloglobulin
-GN
Monoclonal IG
deposition disease
(MIDD)
Proliferative GN with
monoclonal IG deposits
(PGNMID)
C3GN with monoclonal
gammopathy
TMA
Organised deposits
64. Proliferative GN with Monoclonal IG-Deposits
(PGNMID)
LM: MPGN (common), mesangioproliferative GN, endocapillary
proliferative, necrotizing GN
Immunohistology: C3+ C1q+ Ig deposits mainly IgG3 and kappa DD: C3
glomerulopathy (only C3 deposits)
EM: lesions restricted to glomeruli (opposite to MIDD). Non-organized
deposits of monoclonal Ab. in mesangium and subendothelial.
65. Proliferative GN with Monoclonal IG-Deposits
(PGNMID)
C/P: HTN, proteinuria, renal insufficiency
C3 and C4 ↓ in 40% of cases (monoclonal Ab activates complement)
A few amount of paraprotein is sufficient to maintain the renal disease >>
serum electrophoresis and immunofix might be negative >> serum free
light chains should be assessed (only in 30% of cases detectable!!!)
In cases with negative paraproteins with serum electrophoresis, immunfix,
and free light chains >> diagnosis with free light chain restriction in renal
biopsy (NB IF on paraffin tissue with pronase)
66. 1) MGRS with organized monoclonal Ig deposits
2) MGRS with non-organized monoclonal Ig deposits
3) MGRS without Ig deposits
67. 1) MGRS with organized monoclonal Ig deposits
2) MGRS with non-organized monoclonal Ig deposits
3) MGRS without Ig deposits
68. MGRS without Ig deposits
No IG, light chains, or heavy chains are deposited in the kidney
Paraproteins cause a renal injury indirectly through activating complement
components
69. MGRS
No monoclonal
IG deposition
MONOCLONAL
IG deposition
Non-organised
deposits
Fibrillary Microtubular
Inclusion or
crystalline
deposits
IG-associated
amyloidosis
Monoclonal
fibrillary GN
Immunotactoid GN
Cryoglobulinemic
GN I and II
LC assoc. proximal
tubulopathy
Crystal-storing
histiocytosis
Cryocrystalloglobulin
-GN
Monoclonal IG
deposition disease
(MIDD)
Proliferative GN with
monoclonal IG deposits
(PGNMID)
C3GN with monoclonal
gammopathy
TMA
Organised deposits
70. C3G with monoclonal gammopathy
C3 deposition without IG deposition
Paraproteins act as inhibitory antibodies against the alternative
complement pathway regulators (anti-Factor-H-activity) or possess a C3-
nephritis-factor activity >> uncontrolled stimulation of alternative
complement pathway >>IG negative C3 deposition
C3GN is more common than DDD in association with monoclonal
gammopathy.
71. C3GN with monoclonal gammopathy
Pt >49 yrs with C3GN>> monoclonal gammopathy is found in 80% (Lloyd et
al., 2016)
Upon diagnosis of C3GN >> perform IF on paraffin tissue with pronase
(unmasks hidden Ig)>> if monoclonal Ig are identified>>PGNMID, if IG not
identified>> serum electrophoresis, immunofix, and free light chains>>
positive>> C3GN with monoclonal gammopathy
If C3GN without monoclonal Ig in biopsy and without monoclonal Igs in
serum>> evaluate alternative pathway
72. MGRS
No monoclonal
IG deposition
MONOCLONAL
IG deposition
Non-organised
deposits
Fibrillary Microtubular
Inclusion or
crystalline
deposits
IG-associated
amyloidosis
Monoclonal
fibrillary GN
Immunotactoid GN
Cryoglobulinemic
GN I and II
LC assoc. proximal
tubulopathy
Crystal-storing
histiocytosis
Cryocrystalloglobulin
-GN
Monoclonal IG
deposition disease
(MIDD)
Proliferative GN with
monoclonal IG deposits
(PGNMID)
C3GN with monoclonal
gammopathy
TMA
Organised deposits
73. TMA with monoclonal gammopathy
Monoclonal immunoglobulin acts as auto-antibody against complement-
regulators.
May be associated with POEMS
74. Diagnosis of Monoclonal Gammopathy
Laboratory methods for analyzing monoclonal proteins
Kieney Biopsy
Hematological workup
75. Diagnosis of Monoclonal Gammopathy
Laboratory methods for analyzing monoclonal proteins
Kieney Biopsy
Hematological workup
78. SPEP
Inexpensive and easy
Used to detect and quantify M-protein using a densitometer tracing of the
gel
Drawbacks:
- Not sensitive for small amount of M-protein (False negative result!!)
- Cannot distinguish the type of monoclonal Ig (IgG, IgM, IgA, kappa,
lambda)
79. SPEP
Indications:
• Unexplained anemia, bachpain, fatigue
• Osteopenia, osteolytic lesions, or spontaneous fractures
• Renal insufficiency with a bland urine sediment
• Heavy proteinuria in a patient over age 40 years
• Hypercalcemia
• Hypergammaglobulinemia
• Immunoglobulin deficiency
• Bence Jones proteinuria
• Unexplained peripheral neuropathy
• Recurrent infections
• Elevated erythrocyte sedimentation rate or serum viscosity
80. SPEP Findings:
Monoclonal Gammopathy: a single narrow peak in in the gamma (most
common), beta, or alpha-2 region of the densitometer tracing or as a
dense, discrete band on the agarose gel.
Biclonal Gammopathy: two different monoclonal proteins (5% of sera with
M-protein), 2 different heavy or light chain classes (eg IgA lambda, IgG
kappa).
- May be malignant or premalignant
Polyclonal Gammopathy:
-Polyclonal increase of Ig
-Broad based band of gamma mobility
- Occurs with infectious, inflamm, and reactive processes (chr. Hepatitis)
83. Kyle RA, Rajkumar SV. Plasma cell disorders. In: Cecil textbook of medicine, 22nd ed
84. SPEP
False -ve
• Bence Jones proteinemia as the
only monoclonal protein (conc.
Too low to cause a spike)
• IgD and IgE myeloma (small
protein and can be overlooked)
False +ve
• Hb-haptoglobin complexes
(band in alpha 2 region)
• Nephrotic synd (prominent
alpha 2 and beta regions)
86. Serum Immunofixation
Important for differentiation of a monoclonal from a polyclonal increase in
immunoglobulins.
Serum is electrophoresed and separated into 5 separate lanes >> each
layer is overlaid with a different monospecific Ab; 3 for heavy chains (anti
gamma, anti mu, anti alpha) and 2 for light chains (kappa and lambda)
M-protein gives a single sharp band associated with a single heavy chain
and a single well-defined band with similar mobility characteristics that
react with either anti lambda or kappa in sera but not with both.
87. Kyle RA, Rajkumar SV. Plasma cell disorders. In: Cecil textbook of medicine, 22nd ed
88. Serum Immunofixation
Advantages:
more sensitive than SPEP
Determination of type of monoclonal Ig
Disadvantages:
Cannot determine the amount of M-protein
SPEP should be combined with serum Immunofixation
90. Serum free light chains
Importance of the test:
16% of patients with MM produce only Bence-Jones protein
Free serum kappa light chains – 3.3 to 19.4 mg/L
Free serum lambda light chains – 5.7 to 26.3 mg/L
Ratio of kappa to lambda FLCs – 0.26 to 1.65 (GFR >60)
Serum FLC is more sensitive than urine immunofixation for detection of
light chains
91. Serum free light chains
In pts with GFR<60 ml/min, normal kappa/lambda ratio 0.3-3.1
Uses: Diagnosis and monitoring of progress of non-secretory and
oligosecretory myeloma, light chain myeloma, primary amyloidosis, MGUS,
and smouldering myeloma, monitoring of treatment
93. UPEP
Essential to detect the presence of potentially nephrotoxic concentrations
of urinary light chains.
Estimate amount of M-protein in urine
Serum free light chains can be used as an alternative
96. Urine Immunofixation
More sensitive than UPEP
assess and document complete response to therapy
Serum free light chains can be used as alternative
97. Diagnosis of Monoclonal Gammopathy
Laboratory methods for analyzing monoclonal proteins
Kieney Biopsy
Hematological workup
98. Diagnosis of Monoclonal Gammopathy
Laboratory methods for analyzing monoclonal proteins
Kieney Biopsy
Hematological workup
99. Renal Biopsy
In most cases is needed to show causal association between presence of
monoclonal Igs in serum and/or urine and renal lesions.
Renal biopsy can be refrained if:
- Highly probable light chain cast nephropathy
- Nephrotic syndrome or proteinuria and confirmed amyloidosis ( rectal
or fatty tissue)
- Monoclonal gammopathy or MM + Fanconi syndrome
Indication for biopsy if: sFLC <500 mg/l, predominant albumin in UPEP +
Urine Immunofix
100. Renal Biopsy
Do not forget the important role of IF on paraffin sections with pronase to
unmask immunoglobulins
EM is indespensible for diagnosis
Kidney biopsy is the only possibility to prove the nephrotoxicity of a
monoclonal protein.
101. Diagnosis of Monoclonal Gammopathy
Laboratory methods for analyzing monoclonal proteins
Kieney Biopsy
Hematological workup
102. Diagnosis of Monoclonal Gammopathy
Laboratory methods for analyzing monoclonal proteins
Kieney Biopsy
Hematological workup
103. Hematological Workup
BM biopsy or aspiration: including immunohistochemistry and flow
cytometry, staining for kappa and lambda to show whether they are
similar to the light chain restriction in the kidney or not (same clone!!)
CT whole body +/- PET or MRI: if no detectable clone with BM or in pts
with monoclonal IgM (more likely to have B cell or lymphoplasmacytic
clone)
Flow cytometry of peripheral blood lymphocytes: detect small low-grade
clones such as those in CLL
105. Treatment of Paraproteinemia with kidney
affection
Depends primarily on:
Pathological entity of kidney injury
Nature of the clone producing monoclonal Ig (plasma cell, B cells,
lymphoplasmacytic)
Probability of reversing existing kidney damage or preventing further
damage
106. Since MGRS do not meet the criteria of MM of lymphoproliferative
diseases, many hematologists do not treat them!
The renal outcomes of MGRS are associated with the hematologic
response to chemotherapy
107. Light chain cast Nephropathy
Acute measures:
- Stop Nephrotoxic drugs: NSAIDs, ACEi, ARBs, diuretics (only if
hypervolemia)
- TTT hypercalcemia if present
- Fluid therapy: target 3 L urine /day (100-150 ml/h isotonic saline) unless
contraindicated (HF, oliguanuric AKI)
- NaHco3 :controversial (useful if acidic pH, Target pH>7, avoid with
hypercalcemia>>risk of Ca-phosph precipitation)
- Initiate bortezomib-based chemo + high dose dexa to reduce light chain
concentration as soon as possible
108. Light chain cast Nephropathy (cont’d)
Anti-myeloma ttt:
- Bortezomib + high dose Dexa +/- Cyclophosphamide
o Triplet regimen is better for young fit pts with severe AKI
o Doublet regimen (Bortezomib+ Dexa): standard for old frail pts
- Bortezomib does not require dose adjustment with renal impairment or
with dialysis.
o Other proteasom inhibitors (carfilzomib, ixazomib)> less evidence on
efficacy and safety N.B. No dose adjustment with Carfilzomib, risk of AKI
and TMA!!
109. Light chain cast Nephropathy (cont’d)
o If autologous HCT not available>> Bortezomib+melphalan+Dexa (data in
dialysis pt are not available)
o Thalidomide: effective in pts with renal impairment , no dose adjustment
(N.B. in some case reports>>life threatening hyperkalemia)
o Lenalidomide: needs dose adjustment, dialysable (give after HD)
110. Light chain cast Nephropathy (cont’d)
High dose melphalan+ Autologous hematopoeitic cell transplantation
Standard treatment
111. Light chain cast Nephropathy (cont’d)
Extracorporeal methods of light chain removal:
1) High-cutoff dialyzer: pores larger than high-flux dialyzers
- When to use? 8h during first 5 d, then every other day for another 12 d
- Then 6h Dialyses 3x week
- Histologically confirmed light cchain cast nephropathy
- sFLC >500 mg/l
- should be only conducted parallel with chemotherapy!
- After each dialysis> 3-6 g albumin /dialysis hour
Target:reduction of FLC around 50-60%
Effect: controversial (MYRE, Eulite)
2) Plasmapheresis (with albumin)
- 5-7 times in 10 days
- Target: reduction of sFLC around 50%
112. Management of MGRS
Treatment target: suppression of B-cell clone with chemotherapy even if the
clone itself is not malignant!!
Rules of chemotherapy selection:
- Attention should be paid to renal metabolism as well as renal and
extrarenal toxicities.
- Alkylating agents: cyclophosphamide should be preferred to melphalan
due to lower toxicity when GFR is low.
- Immunomodulatory substances: thalidomide should be preferred to
lenalidomide (lenalidomide is excreted through kidneys and can cause
worsening of kidney function!)
- Bortezomib: no dose adjustment in ESKD
113. Management of MGRS (cont'd)
- Autologous HCT is not contraindicated in dialysis pts.
- Kidney Tx is not contraindicated in pts with MGRS (low risk to die because
of plasma cells, however high recurrence rate in kidney Tx, if the B-cell clone
is not controlled!!)
114. TTT of AL-amyloidosis
Determine Tx elegibility (pt ≤70yrs, RR ≥90, TNT<0.06
ng/ml,GFR ≥30, ≤2 organ involvement,etc)
- Eligible for Tx (autologous hematopoietic cell Tx):
Induction: with Bortezomib+Dexa+Cycloph ± daratumumab
Preoperative: high dose melphalan (200 mg/m2), pts who cannot get high
dose melphalan> better consider non-eligible for Tx, except pts on chr.stable
dialysis>melphalan 140 mg/m2.
Maintenance: with overt MM or without overt MM but at least 20% plasma
cells in BM and/or high risk findings in FISH
N.B. high risk transplant related mortality (sepsis, GIB,arrythmias,multiorgan
failure)
116. TTT of AL-amyloidosis cont'd
-Ineligible for Tx: different combinations
• Bortezomib+Dexa+Cycloph+ Daratumumab
• Bortezomib+Dexa+Cycloph
• Bortezomib or cycloph+Dexa+ melphalan
117. TTT of LCDD or HCDD
CKD Stage 1-3: Bortezomib-containing regimens are recommended
Some pts without significant extrarenal manifestations can be candidates for
high dose melphalan+ autologous HCT
- Some case studies showed resolution of light chain deposits, regression of
proteinuria and improvement of GFR after HCT (petrakis et al., 2010)
CKD 4-5: bortezomib-regimens (e.g. Borte+Dexa+cycloph)
- consider HCT only if kidney Tx is planned.
118. TTT of PGNMID
- PGNMID with a detectable plasma or B cell clone: clone-directed therapy
• Plasma cell clone: ttt similar to MM: bortezomib-regimens
(Bortezomib+Dexa+Cycloph± daratumumab)
• B cell clone: ttt as Waldenström: Rituximab ± cyclophosphamide and Dexa
or Rituxi+bendamustine (IgM-producing cells are CD20 positive)
- PGNMID without a detectable plasma or B cell clone: depends on presence
or absence of monoclonal protein in serum or urine
• Presence of monoclonal Ig of same isotype in both kidney and serum or
urine> causal relationship >ttt with chemo (non IgM>ttt like MM with
bortezomib, IgM> ttt like Waldenström ith Rituxi)
119. TTT of PGNMID (cont'd)
- PGNMID without a detectable plasma or B cell clone: depends on presence
or absence of monoclonal protein in serum or urine
• Absent monoclonal Ig in serum or urine:controversial (evidence is scarce),
ttt based on expert opinions>> based on kidney function and proteinuria
Acute or subacute kidney injury and/or proteinuria >1 g/d >> clone-
directed chemo (according to the clone of Ig in kidney)> if non-IgM in
kidney biopsy>> cannot differentiate B from plasma cells>empiric ttt with
either Rituxi or Bortezomib. Considering low side effects with Rituxi> can
start with it, switch to Bortezomib if no response!, if IgM in biopsy>
rituximab.
Normal renal function and proteinuria <1 g/d > ACEi or ARBs, follow up
with electrophoresis, immunfix, light chains, if progression > chemo
120. TTT of immunotactoid and fibrillary GN
associated with monoclonal gammopathy
TTT similar to PGNMID
N.B. In pts with immunotactoid GN associated
with monoclonal gammopathy but no detectable plasma cell or B cells clone
>> ttt with rituximab-based regimen (higher incidence of underlying B
cell disorders in immunotactoid GN)
121. TTT of C3GN with monoclonal gammopathy
Chemotherapy depending on the underling pathological clone (if detected)
or based on the isotype of circulating monoclonal protein (urine or serum) if
no pathologic clone is detected > similar to PGNMID (expert opinions)
Causal relationship between monoclonal Ig and C3GN is difficult to
establish!! (no monoclonal deposits in kidney), genetic testing (complement
mutations) might be helpful
122. TTT of type 1 cryoglobulinemia
Type 1 cryoglobulins consist of solitary monoclonal Ig, mostly either IgM or
IgG.
Pts with no or mild symptoms: observations
Pts with symptoms (symptoms related to underlying malignancy,
hyperviscosity, associated conditions as cryoglobulinemia, hemolytic
anemia, and paraneoplastic neuropathy > TTT
- If IgG>> Bortezomib-and cycloph-regimens
- If IgM >> rituximab-regimen (eg. Rituxi+ bendamustine or
rituxi+Cycloph+Dexa)
- hyperviscosity or severe symptoms >> plasmapheresis (albumin)