Myeloma and Renal Disease Paul Cockwell Consultant Physician and Nephrologist, Clinical Lead Renal...

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

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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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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

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Serum Kappa FLC (mg/L)

Se

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Lancet 2003; 361: 489-491

Normal range – serum FLC

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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

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

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Serum free lambda Dialysate free lambda

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mg

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Time (mins)

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Refractory Myeloma and Acute Renal Failure – recovery from dialysis

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Days

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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.

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