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Myeloma and Renal Disease

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 (%).

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Myeloma and Renal Disease

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  1. 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.

  2. Stage* Description eGFR ml/min/ 1.73m2 Prevalence (%) No in UBC (estimate) 1 normal or increased GFR with evidence of kidney damage >90 3.3 16,500 2 Maintained eGFR + other evidence of kidney damage 60-89 3.0 15,000 3A&B Mild-moderate decrease in GFR 30-59 4.5 22,500 4 Severe decrease in GFR 15-29 0.3 1,500 5 Kidney Failure <15 0.15 750 The stages of Chronic Kidney Disease

  3. 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

  4. Acute Kidney Injury Network (AKIN) staging Only one criterion is required to qualify for stage Mehta RL et al. Crit Care 2007; 11: 1 – 8

  5. 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

  6. 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

  7. Co-factors for Acute Kidney Injury in Myeloma • Drugs • NSAIDS • Diuretics • Hypercalcaemia • Sepsis • Volume depletion/dehydration • Operative stress

  8. 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

  9. Intact Ig and Ig Free light chain (FLC) production by plasma cells Kappa - Monomeric - 22.5 kd - 40% renal clearance - 2-3 hr serum half life Lambda - Dimeric - 45 kd - 20% renal clearance - 4-6 hr serum half life

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

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

  12. Comprehensive Clinical Nephrology (Johnson & Feehally); p238

  13. 6 weeks Rapid renal scarring in Myeloma Kidney Repeat Biopsy Presentation Biopsy Basnayake et al: J Clin Path

  14. NDT 2010: 25: 419-26

  15. Severe AKI and myeloma is a medical emergency

  16. 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

  17. Supportive Care • Optimise urine output • Correct hypercalcaemia • Correct acidosis • Avoid diuretics • Avoid nephrotoxic drugs

  18. Chemotherapy • Start ASAP • Use dexamethasone and novel agents • There is increasing experience in bortezomib in severe renal failure

  19. Early sFLC responses are a major determinant of renal recovery

  20. 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

  21. What about extra-corporeal removal of FLC?

  22. Plasma exchange can remove intravascular FLC But does this translate into clinical benefit??

  23. Plasma Exchange When Myeloma Presents as Acute Renal FailureA Randomized, Controlled Trial.Clark et al: Ann Intern Med. 2005;143:777-784.

  24. MERIT – primary end-point(thanks to J Behrens and M Drayson)

  25. ~ 85% Myeloma Load - FLC generation extravascular ~15% intravascular

  26. Does High Cut-Off (protein-permeable) dialysis provide an alternative approach to plasma exchange for the removal of FLC?

  27. HCO Membrane - increased permeability for mid-molecules Convective permeability

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

  29. Refractory Myeloma and Acute Renal Failure – recovery from dialysis

  30. 17 Study patients 17 Control patients Renal recovery rates in study population and a case matched control population (P<0.001) Hutchison et al, EDTA 2008.

  31. Survival relates to recovery of renal function Renal recovery (n-14) P<0.001 No renal recovery (n-5) Hutchison et al, cJASN 2009

  32. 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

  33. 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)

  34. Determinants of recovery from dialysis dependent renal failure: an international study

  35. AKI secondary to cast nephropathy is a medical emergency analogous to RPGN secondary to vasculitis

  36. 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

  37. 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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