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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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The stages of Chronic Kidney Disease
750 0.15 <15 Kidney Failure 5 1,500 0.3 15-29 Severe decrease in GFR 4 22,500 4.5 30-59 Mild-moderate decrease in GFR 3A&B 15,000 3.0 60-89 Maintained eGFR + other evidence of kidney damage 2 16,500 3.3 >90 normal or increased GFR with evidence of kidney damage 1 No in UBC (estimate) Prevalence (%) eGFR ml/min/ 1.73m2 Description Stage* 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
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Acute Kidney Injury Network (AKIN) staging
Only one criterion is required to qualify for stage 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 Mehta RL et al. Crit Care 2007; 11: 1 – 8
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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 kd - 40% renal clearance - 2-3 hr serum half life
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Normal range – serum FLC
Lancet 2003; 361: 10
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Immunoglobulin FLC levels in myeloma
k FLC (mg/L) l FLC (mg/L) Blood.2001: 97: Immunoglobulin FLC levels in myeloma
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Comprehensive Clinical Nephrology (Johnson & Feehally); p238
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Rapid renal scarring in Myeloma Kidney Basnayake et al: J Clin Path
Presentation Biopsy Repeat Biopsy 6 weeks Basnayake et al: J Clin Path
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NDT 2010: 25:
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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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39 patients with cast nephropathy: Birmingham + Mayo
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 Failure A Randomized, Controlled Trial. Clark et al: Ann Intern Med. 2005;143:
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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 Convective permeability
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Gambro HCO 1100 –6 hour dialysis – FLC removal kinetics – myeloma patient
Serum free lambda (mg/L) Lambda in dialysate (mg/L) Time (mins)
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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
Renal recovery (n-14) P<0.001 No renal recovery (n-5) Hutchison et al, cJASN 2009
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EuLITE study design 90 Patient recruitment target Randomisation
Control Arm HD 45 Patients Standard high-flux HD Research Arm HD 45 Patients Extended HD on HCO 1100 ‘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
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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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Acknowledgements University 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
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