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.

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

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

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

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

Normal range – serum FLC Lancet 2003; 361: 489-491 10

Immunoglobulin FLC levels in myeloma k FLC (mg/L) l FLC (mg/L) Blood.2001: 97: 2900-02 Immunoglobulin FLC levels in myeloma

Comprehensive Clinical Nephrology (Johnson & Feehally); p238

Rapid renal scarring in Myeloma Kidney Basnayake et al: J Clin Path Presentation Biopsy Repeat Biopsy 6 weeks 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

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

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 Failure A 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 Convective permeability

Gambro HCO 1100 –6 hour dialysis – FLC removal kinetics – myeloma patient Serum free lambda (mg/L) Lambda in dialysate (mg/L) Time (mins)

Refractory Myeloma and Acute Renal Failure – recovery from dialysis 30

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 Renal recovery (n-14) P<0.001 No renal recovery (n-5) Hutchison et al, cJASN 2009

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

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

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