1 tuesday case conference. 2 multiple myeloma myeloma related renal failure treatment
TRANSCRIPT
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Tuesday Case Tuesday Case ConferenceConference
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Multiple Myeloma
Multiple Myeloma Myeloma related renal failure Treatment
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Myeloma
A clonal disorder of plasma cells Affects 1 in 300,000
1% of all new malignancies (16,000 per year)
10% of all new hematologic malignancies 2% of all cancer deaths (11,3000 per year)
Median age of onset: 66 Most common hematologic malignancy
in African Americans
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Development of Myeloma Cells
Transformation of a normal B cell into a malignant plasma cell Environmental/
occupational exposures have been implicated
Cytokines IL-6, RANK, TNF
VEGF
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Multiple Myeloma - diagnosis
Clonal plasma cells >10% on bone marrow biopsy or (in any quantity) in a biopsy from other tissues (plasmacytoma)
A monoclonal protein (paraprotein) in either serum or urine
Evidence of end-organ damage
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Structure of immunoglobulin
Nelson DL, Cox MM. Lehninger principles of biochemistry, 4th ed. WH Freeman pub. New York 2005.
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Serum Protein Electrophoresis
Astion ML, Rank J, Wener MH, Torvik P, Schneider JB, Killingworth LM. Electrophoresis-tutor: an image-based personal computer program that teaches clinical interpretation of protein electrophoresis patterns of serum, urine and CSF. Clin chem. 1995 Sep;41(9):1328-32
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Immunofixation Electrophoresis (IFE)
Astion ML, Rank J, Wener MH, Torvik P, Schneider JB, Killingsworth LM. Electrophoresis-tutor: an image based personal computer program that teaches clinical interpretation of protein electrophoresis patterns of serum, urine, and CSF. Clin Chem. 1995 Sep;41(9):1328-32.
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Frequency of isotypes of heavy and light chains produced by
non–immunoglobulin (Ig) M myelomas
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Staging and Prognostic Factors
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Epidemiology
In two large multiple myeloma studies, 43% (of 998 pts) had a creatinine > 1.5 and 22% (of 423 pts) had a Cr > 2.0
The one-year survival was 80% in pts with Cr < 1.5 compared to 50% in pts with a Cr > 2.3
5, 10, and 20 year survivals 31, 10, and 4% respectively
Prognosis is especially poor in pts who require dialysis
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Types of renal involvement in
dysproteinemias
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Pathogenesis of the different types of renal
lesions in dysproteinemias
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Myeloma Kidney
Most common Dx by demonstration of tubular casts
in the distal nephron
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Myeloma Kidney Two main pathogenetic mechanisms:
Intracellular cast formation Direct tubular toxicity by light chains
Contributing factors to presence of renal failure due to multiple myeloma: High rate of light chain excretion (tumor load) Concurrent volume depletion
PrognosisSerum creatine
(mg/dL)Median survival
<1.4 44 mo
1.4-2 18 mo
>2 <4Rayner HC, Haynes AP, Thompson JR, Russell N, Fletcher J: Perspectives in multiple myeloma: Survival, prognostic factors and disease complications in a single center between 1975
and 1988. Q J Med 79: 517–525, 1991
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Light Chain Deposition Disease
Most commonly presents with both renal insufficiency and nephrotic syndrome
Usually due to kappa immunoglobulin fragments which deposit in kidneys (basement membrane)
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Amyloidosis
Usually due to lambda light chains (AL)
Light chains are taken up and partially metabolized by macrophages and then secreted – then precipitate to form fibrils that are Congo red positive, -pleated
Like LCDD, due to tubular injury and also presents as nephrotic syndrome
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Hypercalcemia
Hypercalcemia occurs in multiple myeloma due to bone resorption from lytic lesions
Serum calcium > 11.0 mg/dL occurs in 15% of pts with multiple myeloma
Hypercalcemia commonly contributes to renal failure by renal vasoconstriction, leading to intratubular calcium deposition
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Renal Tubular Dysfunction – Acquired Fanconi
syndrome On occasion, light chains cause tubular
dysfunction without renal insufficiency Most commonly occurs with kappa
light chains This presents as Fanconi syndrome –
proximal renal tubular acidosis with wasting of potassium, phosphate, uric acid, and bicarbonate
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Renal Insufficieny
Fang LS. Light-chain nephropathy. Kidney Int. 1985 Mar;27(3):582-592.
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Presentation and outcome in myeloma-
associated renal disease
Multiple Myeloma_Korbet_JASN_2006
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Plasmapheresis in MM Theoretical benefit in removing the toxic
circulating light chains to spare renal function
Would seem to be most effective when circulating light chains in serum are present (i.e. significant M-spike on SPEP)
Limited data to support efficacy Treatment of choice if hyperviscosity
symptoms are present
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Plasmapheresis in MM
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Plasmapheresis studies
Johnson et al., Arch Intern Med. 1990
Forced diuresis /
chemo
Plasmapheresis / diuresis /
chemo
N 10 11
Improvement of renal function
7/11 (64%) 5/10 (50%)
Recovery from dialysis
3/7 (43%) 0/5
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Plasmapheresis studies
Zuchelli et al., Kidney Int 1988
Plasmapheresis / chemo /
HD
Chemo with PD
N 15 14
Recovery from dialysis
11/13 (84%) 2/14 (14%)
One year survival
66% 28%
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Plasmapheresis studies –Limitations
Few prospective trials done Available trials have small numbers of
patients enrolled
A larger prospective, randomized trial would be beneficial in establishing the clinical utility of plasmapheresis in preventing ESRD in MM
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Multiple Myeloma - treatment
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Novel Therapies
Velcade (bortezomib) Proteasome inhibitor Induces apoptosis via
caspase-8, 9 Anti-myeloma effects
by blocking NF-kB Revamid
IMiD Induce G1 growth
arrest
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Revlimid (lenalidomide)
First of new class of drugs called IMiDs
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Alkylating agents, Bortemozid, corticosteroids inhibit cell growth and induce apoptosis
Bortemozid inhibits NF-kB Thalidomide and
Bortemozid inhibit interaction between myeloma cells & stromal cells as well as cytokine production (TNF-alpha, IL-6)
Thalidomide inhibits angiogenesis and enhances CD8+ and NK cell functions
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Incidence of renal
involvement in dysproteinemia
s
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Causes of renal failure in MM
Cast nephropathy Light chain deposition disease Primary amyloidosis Hypercalcemia Renal tubular dysfunction Volume depletion IV contrast dye, nephrotoxic meds
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Treatment of renal failure in MM
Hydration with IV fluids Treatment of hypercalcemia
Loop diuretics Caution with bisphosphonates
Treatment of myeloma Pulse steroids +/- thalidomide VAD chemotherapy
Possible role for plasmapheresis Dialysis, as necessary
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Multiple Myeloma - treatment
Arsenic trioxide Thalidomide +/- Melphalan Cyclosporin A nonimmunosuppresive
analogs Anti-IL-6 and anti-IL-6R antibodies Bortezomid (Velcade)
Proteasome inhibitor Bone marrow transplantation
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