myeloma and renal disease paul cockwell consultant physician and nephrologist, clinical lead renal...
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Myeloma and Renal Disease
Paul Cockwell
Consultant Physician and Nephrologist, Clinical Lead Renal Medicine, Department of Nephrology, Queen
Elizabeth Hospital Birmingham.
Hon Senior Research Fellow, University of Birmingham.
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7500.15<15Kidney Failure5
1,5000.315-29Severe decrease in GFR4
22,5004.530-59Mild-moderate decrease in GFR
3A&B
15,0003.060-89Maintained eGFR + other evidence of kidney
damage
2
16,5003.3>90normal or increasedGFR with evidence of
kidney damage
1
No in UBC (estimate)
Prevalence(%)
eGFRml/min/1.73m2
DescriptionStage*
The stages of Chronic Kidney Disease
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Job
bag
nu
mb
er:
131/
UK
/11-
01/N
MA
R/2
727
Pre
par
atio
n d
ate:
Jan
uar
y 20
11
Calculating estimated GFR
• The different equations used for calculating estimated (e)GFR are not equivalent
• aMDRD – current internationally accepted standard for reporting kidney function when the eGFR is abnormal– aMDRD factors 4 variables – age, sex, ethnicity and creatinine – to
provide an eGFR
• CG eGFR – the equation used in most drug dose adjustment algorithms in renal disease– CG and eGFR are not equivalent
aMDRD: abbreviated modification of diet in renal disease; CG: Cockcroft-Gault; (e)GFR: (estimated) glomerular filtration 3
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Job
bag
nu
mb
er:
131/
UK
/11-
01/N
MA
R/2
727
Pre
par
atio
n d
ate:
Jan
uar
y 20
11
Acute Kidney Injury Network (AKIN) staging
Mehta RL et al. Crit Care 2007; 11: 1 – 8
Stage Serum creatinine criteria Urine output criteria
Stage 1 Increased serum creatinine of ≥0.3 mg/dL (≥26.4 μmol/L) or ≥1.5-2 times from baseline
<0.5 mL/kg/ hour for >6 hours
Stage 2 Increased serum creatinine to ≥2-3 times from baseline
<0.5 mL/kg/ hour for >12 hours
Stage 3 Increased serum creatinine to >3 times from baseline
or ≥4.0 mg/dL (≥354 μmol/L) with an acute increase of at least 0.5mg/dL (44 μmol/L)
or renal replacement therapy
<0.3 mL/kg/ hour for 24 hours or anuria for 12 hours
Only one criterion is required to qualify for stage
4
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Multiple myeloma
• Renal function a major determinant of Morbidity/Mortality
• Around 50% have significant renal impairment at presentation
– At new presentation around 4 pmp require dialysis
– Myeloma and dialysis survival poor
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Disease specific kidney injury in Myeloma
• Cast Nephropathy (Myeloma Kidney)
• Tubular epithelial cell injury +/- interstitial inflammation and fibrosis
• AL Amyloidosis
• Light Chain Deposition Disease
• Fibrillary GN
• Heavy Chain Deposition Disease
• Cryoglobulinaemic glomerulonephritis
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Co-factors for Acute Kidney Injury in Myeloma
• Drugs– NSAIDS– Diuretics
• Hypercalcaemia
• Sepsis
• Volume depletion/dehydration
• Operative stress
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Disease specific kidney injury in Myeloma
• Cast Nephropathy (Myeloma Kidney)
• Tubular epithelial cell injury +/- interstitial inflammation and fibrosis
• AL Amyloidosis
• Light Chain Deposition Disease
• Heavy Chain Deposition Disease
• Cryoglobulinaemic glomerulonephritis
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Intact Ig and Ig Free light chain (FLC) production by plasma cells
Lambda- Dimeric- 45 kd- 20% renal clearance- 4-6 hr serum half life
Kappa- Monomeric- 22.5 kd- 40% renal clearance- 2-3 hr serum half life
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0.1
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100000
0.1 1 10 100 1000 10000 100000
Serum Kappa FLC (mg/L)
Se
rum
La
mb
da
F
LC
(m
g/L
)
Lancet 2003; 361: 489-491
Normal range – serum FLC
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0.1
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Normal sera
Kappa BJ
Lambda BJ
NSMM
k FLC (mg/L)
lF
LC
(m
g/L
)
Blood.2001: 97: 2900-02
Immunoglobulin FLC levels in myeloma
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Comprehensive Clinical Nephrology (Johnson & Feehally); p238
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Presentation Biopsy Repeat Biopsy
6 weeks
Rapid renal scarring in Myeloma Kidney
Basnayake et al: J Clin Path
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NDT 2010: 25: 419-26
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Severe AKI and myeloma is a medical emergency
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Approach to AKI and suspected cast nephropathy
• Screen ASAP with SPE and sFLC or UPE
• Suspect cast nephropathy if sFLC>500mg/l or UPE BJP+ve
• High quality supportive care
• Prompt commencement of chemotherapy
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Supportive Care• Optimise urine output
• Correct hypercalcaemia
• Correct acidosis
• Avoid diuretics
• Avoid nephrotoxic drugs
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Chemotherapy
• Start ASAP
• Use dexamethasone and novel agents
• There is increasing experience in bortezomib in severe renal failure
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Early sFLC responses are a major determinant of renal
recovery
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Renal recovery from cast nephropathy and changes in sFLC levels in the first 21 days
For an 80% chance of renal recovery there must be a 60% reduction in
sFLC by day 21
39 patients with cast nephropathy: Birmingham + Mayo
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What about extra-corporeal removal of FLC?
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Plasma exchange can remove intravascular FLC
But does this translate into clinical benefit??
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Plasma Exchange When Myeloma Presents as Acute Renal FailureA Randomized, Controlled Trial.
Clark et al: Ann Intern Med. 2005;143:777-784.
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MERIT – primary end-point(thanks to J Behrens and M Drayson)
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~15%
~ 85%
Myeloma Load- FLC
generation
intravascular
extravascular
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Does High Cut-Off (protein-permeable) dialysis provide an alternative approach to plasma exchange for the removal of FLC?
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Convective permeability
HCO Membrane - increased permeability for mid-molecules
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Gambro HCO 1100 –6 hour dialysis – FLC removal kinetics – myeloma patient
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Refractory Myeloma and Acute Renal Failure – recovery from dialysis
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Renal recovery rates in study population and a case matched control population (P<0.001)
17 Control patients
17 Study patients
Hutchison et al, EDTA 2008.
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Survival relates to recovery of renal function
No renal recovery (n-5)
Renal recovery (n-14)
P<0.001
Hutchison et al, cJASN 2009
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90 Patient recruitment target
Randomisation
Control Arm HD45 Patients
Standard high-flux HD
‘Modified PAD regimen’ Chemotherapy (P) VELCADE™ (bortezomib) iv 1.0 mg/m2
(A) Adriamycin (Doxorubicin) iv 9.0 mg/m2
(D) Dexamethasone oral 40 mg
primary outcome = independence of dialysis at 3 months
Research Arm HD45 Patients
Extended HD on HCO 1100
EuLITE study design
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Ideal timelines – personal view
• Patient identified as at risk (AKI – unknown cause)
• SPE and sFLC – urgent (same day)
• Renal Biopsy if clinically suitable – urgent report
• Urgent marrow if indicated by SPE/sFLC/Renal Biopsy
• Immediate commencement of Dexamethasone followed by prompt addition of novel agent (e.g. Bortezomib)
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Determinants of recovery from dialysis dependent renal failure: an international study
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AKI secondary to cast nephropathy is a medical emergency analogous to RPGN secondary to vasculitis
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Conclusions
• Cast nephropathy secondary to myeloma and AKI is a medical emergency
• Coordinated MDT working is required to optimise patient outcome
• Early responses in serum FLC are required for a renal recovery
• Effective chemotherapy is essential
• The role of extra-corporeal removal of FLC is under evaluation
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AcknowledgementsUniversity Hospital Birmingham:Colin Hutchison, Mark Cook, Lesley Fifer, Koli Basnayake, Steph Stringer,
Consultant Nephrologists
Binding Site (University of Birmingham):Jo Bradwell, Graham Mead, Stephen Harding
Gambro-Hechingen: Markus Storr; Hermann Goehl; Ulrike Haug; Werner Beck
Gambro-Lund: Andrew Gill
Tubingen: Nils Heyne; Katja Weisel
OrthoBiotech: Rod Murphy; Caroline Stanton, Paula Stubbs
Conficts of interests: Gambro; The Binding Site; OrthoBiotech