Presentation on theme: "Myeloma and Renal Disease Paul Cockwell Consultant Physician and Nephrologist, Clinical Lead Renal Medicine, Department of Nephrology, Queen Elizabeth."— Presentation transcript:
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.
<15 Kidney Failure 5 1, Severe decrease in GFR 4 22, Mild-moderate decrease in GFR 3A&B 15, Maintained eGFR + other evidence of kidney damage 2 16,5003.3>90 normal or increased GFR with evidence of kidney damage 1 No in UBC (estimate) Prevalence (%) eGFR ml/min/ 1.73m 2 DescriptionStage* The stages of Chronic Kidney Disease
Job bag number: 131/UK/11-01/NMAR/2727 Preparation date: January 2011 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 number: 131/UK/11-01/NMAR/2727 Preparation date: January 2011 Acute Kidney Injury Network (AKIN) staging Mehta RL et al. Crit Care 2007; 11: 1 – 8 StageSerum creatinine criteriaUrine output criteria Stage 1Increased serum creatinine of ≥0.3 mg/dL (≥26.4 μmol/L) or ≥1.5-2 times from baseline 6 hours Stage 2Increased serum creatinine to ≥2-3 times from baseline 12 hours Stage 3Increased 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/MortalityRenal function a major determinant of Morbidity/Mortality Around 50% have significant renal impairment at presentationAround 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 hr serum half life Kappa - Monomeric kd - 40% renal clearance hr serum half life
Presentation Biopsy Repeat Biopsy 6 weeks Rapid renal scarring in Myeloma Kidney Basnayake et al: J Clin Path
NDT 2010: 25:
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
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 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:
MERIT – primary end-point (thanks to J Behrens and M Drayson)
30 Refractory Myeloma and Acute Renal Failure – recovery from dialysis
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 HD 45 Patients Standard high-flux HD ‘Modified PAD regimen’ Chemotherapy (P) VELCADE™ (bortezomib) iv1.0 mg/m 2 (A) Adriamycin (Doxorubicin)iv9.0 mg/m 2 (D) Dexamethasoneoral40 mg primary outcome = independence of dialysis at 3 months Research Arm HD 45 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
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