Renal Disorders in Multiple Myeloma

1
Renal Disordersin Multiple Myeloma

• Hematology Grand Rounds
• Tom Fong, MD
• September 9, 2005

2
Case Report

• 61 yo BF with no significant PMH except for
  hyperlipidemia presents with cough/ sinus
  congestion to her primary MD. She is prescribed
  an antibiotic (Ketek), and develops nausea,
  diarrhea, and weakness in the next few days. She
  returns to her PCP, and is found to have a Cr
  level of 5.2 (normal 5 mo. earlier).

3
Case Report

• PMH Hyperlipidemia
• Meds Estradiol, Ketek
• Allergies PCN, cefepime, sulfa
• Family Hx Non-contributory
• Social Hx Tob 25 pk-yrs, no ETOH
• ROS otherwise negative

4
Case Report

• Physical exam
• Vitals T 37, HR 80, BP 140/70, 96 RA
• Gen alert, NAD
• HEENT anicteric, PERRL, O/P clear
• Lungs CTA
• CV regular
• Abd - soft, NT, ND, no HSM
• Extr no edema

5
Case Report

• Labs
• WBC 6.8, Hgb 9.5, Plt 176
• Na 138, K 5.0, Cl- 101, HCO3- 25, BUN 39, Cr
  6.0, Glucose 87, Ca 11.3
• LFTs Protein 8.3, Albumin 5.0, Alk phos 139,
  Bili 0.4, AST 24, ALT 31
• Urine eosinophils negative

6
Case Report

• Labs
• SPEP 0.3, 0.4 gm gamma restricted peaks
• Serum immunofix IgG kappa, free kappa LC
• UPEP 73.5 gamma restricted peak
• Urine immunofix free kappa light chain
• 24 hour urine protein 5.085 gms
• IgA lt24, IgG 644, IgM 19 (all low)

7
Case Report

• Bone marrow biopsy 70 cellularity, increased
  atypical plasma cells comprising 60 of
  cellularity, c/w multiple myeloma

8
Case Report

• Skeletal survey no lytic lesions
• Renal ultrasound increased bilateral cortical
  echogenicity consistent with renal parenchymal
  disease
• Kidney biopsy cast nephropathy, IF
  kappa light chain deposits c/w cast nephropathy
  due to multiple myeloma

9
Case Report

• Hospital course Pt. was given IVF for acute
  renal failure, and pulse decadron (40 mg qday x 4
  days) was begun for new diagnosis of multiple
  myeloma. There was consideration of initiating
  plasmapheresis, which was ultimately not pursued.
  Her serum Cr improved to 3.8 (from 6.0) at the
  time of discharge, and she did not require
  hemodialysis.

10
Epidemiology

• In two large multiple myeloma studies, 43 (of
  998 pts) had a creatinine gt 1.5 and 22 (of 423
  pts) had a Cr gt 2.0
• The one-year survival was 80 in pts with Cr lt
  1.5 compared to 50 in pts with a Cr gt 2.3
• Prognosis is especially poor in pts who require
  dialysis

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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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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)
• Biochemical characteristics of light chain
• Concurrent volume depletion

13
Cast Nephropathy

• Most common pathological diagnosis on renal
  biopsy in multiple myeloma
• Due to light chains binding with Tamm-Horsfall
  mucoprotein, which is secreted by tubular cells
  in ascending loop of Henle, forming casts
• Multinucleated giant cells surround the casts
• Dehydration worsens cast nephropathy due to
  decreased flow in tubules, increased
  concentration of light chains

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Cast Nephropathy
15
Cast Nephropathy
16
Cast Nephropathy
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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
• Circulating light chains are taken up and
  partially metabolized by macrophages, and then
  secreted and precipitate, causing tubular injury
  and thus, proteinuria

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Amyloidosis

• Usually due to lambda light chains (AL)
• Pathogenesis is similar to LCDD, in that light
  chains are taken up and partially metabolized by
  macrophages and then secreted then precipitate
  to form fibrils that are Congo red positive,
  b-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 gt 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

21
Renal Tubular Dysfunction Acquired Fanconi
syndrome

• Light chains are resistant to protease
  degradation and have tendency to accumulate in
  tubule epithelial cells and form crystals
• Tubular damage due to light chain toxic effects
  or indirectly from the release of intracellular
  lysosomal enzymes

22
Role of IL-6

• IL-6 is an important growth factor for plasma
  cells in multiple myeloma, and may play a role in
  myeloma kidney
• IL-6 stimulates acute phase reactants from liver,
  promoting cast formation and possibly impairing
  light chain resorption
• IL-6 also contributes to hypercalcemia by
  stimulating osteoclasts

23
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

24
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
• Potential risk for bleeding if renal bx done due
  to pheresis-induced removal of coagulation factors

25
Plasmapheresis in MM
26
Plasmapheresis studies

• Johnson et al., Arch Intern Med. 1990
• Group 1 forced diuresis and chemotherapy (10
  patients)
• Group 2 plasmapheresis (3x/wk for 1-4 wks),
  diuresis, and chemo (11 patients)
• 7/11 pts (Group 2) and 5/10 pts (Group 1) had an
  improvement in renal function
• 3/7 pts (Group 2) and 0/5 pts (Group 1) recovered
  from dialysis needs
• Main predictor of irreversible renal failure was
  degree of myeloma cast formation on renal biopsy
• Concluded that plasmapheresis unlikely to be
  beneficial if severe cast formation, amyloidosis,
  or other irreversible changes are present

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Plasmapheresis studies

• Zuchelli et al., Kidney Int 1988
• Group 1 plasmapheresis (daily x 5 days), chemo,
  HD only as needed (15 pts)
• Group 2 chemotherapy with PD (14 pts)
• 11/13 pts from Group 1 improved renal function
  sufficiently to stop dialysis
• Only 2/14 pts from Group 2 improved renal
  function sufficiently to stop dialysis
• One year survival 66 in Group 1 vs. 28 in
  Group 2, p-value lt0.01

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Plasmapheresis studies Limitations

• Few prospective trials done
• Available trials have small numbers of patients
  enrolled
• Zuchelli study Pheresis group received HD as
  opposed to PD, ? significance of this
• A larger prospective, randomized trial would be
  beneficial in establishing the clinical utility
  of plasmapheresis in preventing ESRD in MM

29
Prevention of renal failure in MM

• IVF hydration
• Discontinuation of nephrotoxic drugs (i.e.
  NSAIDs, etc.)
• Chemotherapy/steroids treatment of multiple
  myeloma to decrease the filtered light chain load

30
Prevention of renal failure in MM Strategies of
theoretical benefit

• Avoid loop diuretics unless hypercalcemic may
  promote cast formation by volume depletion
• Alkalinizing the urine - makes light chains
  neutral or anionic, thus decreasing interaction
  with anionic Tamm-Horsfall protein
• Colchicine - decreases THP secretion into lumen
  and partially impairs binding of THP to light
  chains in animal studies

31
Case Report follow up

• Pt with multiple myeloma with peak Cr 6.0 d/c
  from hospital after IVF hydration, pulse decadron
  with Cr 3.8
• Had kappa light chain, cast nephropathy
• Plasmapheresis, HD were not done in hospital
• Currently has Cr 2.5, remains independent of
  dialysis after two cycles of Thal/Dex

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References

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• Blade J et al. Renal failure in multiple myeloma.
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• Basic-Jukic N et al. Myeloma kidney pathogenesis
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• Picken M. Pathology of Plasma Cell Dyscrasia. How
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• Pozzi C et al. Light chain deposition disease
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  and prognostic factors. Am J Kidney Dis 2003 42
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• Chow CC et al. Renal impairment in patients with
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• Johnson WJ et al. Treatment of renal failure
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