myeloma and renal disease
DESCRIPTION
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. Stage*. Description. eGFR ml/min/ 1.73m 2. Prevalence (%). - PowerPoint PPT PresentationTRANSCRIPT
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.
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
Job
bag
num
ber:
131
/UK
/11-
01/N
MA
R/2
727
Pre
para
tion
date
: Jan
uary
201
1
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
Job
bag
num
ber:
131
/UK
/11-
01/N
MA
R/2
727
Pre
para
tion
date
: Jan
uary
201
1
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
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
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
Co-factors for Acute Kidney Injury in Myeloma
• Drugs– NSAIDS– Diuretics
• Hypercalcaemia
• Sepsis
• Volume depletion/dehydration
• Operative stress
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
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
0.1
1
10
100
1000
10000
100000
0.1 1 10 100 1000 10000 100000Serum Kappa FLC (mg/L)
Seru
m L
ambd
a F
LC (m
g/L)
Lancet 2003; 361: 489-491
Normal range – serum FLC
0.1
1
10
100
1000
10000
100000
0.1 1 10 100 1000 10000 100000
Normal sera
Kappa BJ
Lambda BJ
NSMM
k FLC (mg/L)
l FL
C (m
g/L)
Blood.2001: 97: 2900-02
Immunoglobulin FLC levels in myeloma
Comprehensive Clinical Nephrology (Johnson & Feehally); p238
Presentation Biopsy Repeat Biopsy
6 weeks
Rapid renal scarring in Myeloma Kidney
Basnayake et al: J Clin Path
NDT 2010: 25: 419-26
Severe AKI and myeloma is a medical emergency
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
Supportive Care• Optimise urine output
• Correct hypercalcaemia
• Correct acidosis
• Avoid diuretics
• Avoid nephrotoxic drugs
Chemotherapy
• Start ASAP
• Use dexamethasone and novel agents
• There is increasing experience in bortezomib in severe renal failure
Early sFLC responses are a major determinant of renal
recovery
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
What about extra-corporeal removal of FLC?
Plasma exchange can remove intravascular FLC
But does this translate into clinical benefit??
Plasma Exchange When Myeloma Presents as Acute Renal FailureA Randomized, Controlled Trial.
Clark et al: Ann Intern Med. 2005;143:777-784.
MERIT – primary end-point(thanks to J Behrens and M Drayson)
~15% ~ 85%
Myeloma Load- FLC
generation
intravascular
extravascular
Does High Cut-Off (protein-permeable) dialysis provide an alternative approach to plasma exchange for the removal of FLC?
Convective permeability
HCO Membrane - increased permeability for mid-molecules
Gambro HCO 1100 –6 hour dialysis – FLC removal kinetics – myeloma patient
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
0 30 60 90 120 150 180 210 240 270 300 3300
100
200
300
400
500
600
700
800
Serum free lambda Dialysate free lambda
Seru
m fr
ee la
mbd
a (m
g/L)
Lam
bda
in d
ialy
sate
(mg/
L)
Time (mins)
30
Refractory Myeloma and Acute Renal Failure – recovery from dialysis
0
500
1000
1500
2000
2500
3000
0 5 10 15 20 25 30
Days
Seru
m la
mbd
a (m
g/L)
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.
Survival relates to recovery of renal function
No renal recovery (n-5)
Renal recovery (n-14)
P<0.001
Hutchison et al, cJASN 2009
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
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)
Determinants of recovery from dialysis dependent renal failure: an international study
AKI secondary to cast nephropathy is a medical emergency analogous to RPGN secondary to vasculitis
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
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