High cut off dialysis and multiple myeloma


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High cut off dialysis and multiple myeloma

  1. 1. High cut off dialysis - Basics Dr. Sandeep G Huilgol MBBS, DNB (Internal Medicine), MMedSci (Nephrology)
  2. 2. Basics • The cure for this plasma cell dyscrasia remains elusive. • The outcomes of patients have improved considerably over the past decade. • Renal impairment has been associated with substantially reduced survival in patients with multiple myeloma. • The survival of this population improves when there is an early improvement in renal function. • Renal impairment remains a common problem at presentation in patients with multiple myeloma, affecting up to 40%. • Approximately 8% require renal replacement therapy to support patients with severe acute kidney injury.
  3. 3. • The mechanism of kidney injury in multiple myeloma differs considerably. • Most severe form is cast nephropathy caused due to serum free light chains.
  4. 4. • Normal plasma cells produce FLCs in slight excess to heavy chains to enable the correct assembly of intact immunoglobulins. • These excess FLCs are released into the circulation, filtered by the glomerulus and then catabolized in the proximal tubules. • In multiple myeloma, however, the clonal proliferation of plasma cells can increase the production rate of FLCs several 1,000-fold and a spectrum of renal injuries can occur as the FLCs reach the kidneys.
  5. 5. • Overall, clonal production of FLCs occurs in 96% of all patients at presentation of multiple myeloma.
  6. 6. • The presence of monoclonal immunoglobulin light chains is essential for the pathogenesis of myeloma kidney. • In order to be pathological the light chains must be free from the intact immunoglobulin to enable filtration at the glomerulus.
  7. 7. • When the FLCs enter the proximal tubules in high concentrations, the absorptive capacity of the multiligand endocytic receptor complex is overwhelmed and the FLCs pass through the tubules and into the urine.
  8. 8. • Two sites of injury predominate in myeloma kidney: • First, excessive endocytosis of FLCs in the proximal tubule creates a cascade of inflammatory pathways, which result in apoptotic and profibrotic transitions. • Second, the distal tubules are the site where FLCs encounter and bind to Tamm-Horsfall glycoprotein with differing degrees of affinity, resulting in co-precipitation.
  9. 9. • In normal individuals, sFLCs are rapidly cleared by the kidneys depending upon their molecular size. • Monomeric FLCs, characteristically κ, are cleared in 2-4 hours at 40% of the glomerular filtration rate (GFR). • Dimeric FLCs, typically λ, are cleared in 3-6 hours at 20% of the GFR, while larger polymers are cleared more slowly. • Removal is prolonged to 2-3 days in MM patients who are in complete renal failure, in which case FLCs are removed by the liver and other tissues.
  10. 10. • After filtration by the glomeruli, FLCs enter the proximal tubules and bind to brush border membranes via low-affinity, high-capacity receptors called cubulins and megalins. • Binding provokes internalisation of the FLCs, subsequent proteolysis into smaller peptides and finally their excretion into the urine flow. • The concentration of FLCs leaving the proximal tubules depends therefore upon the amount in the glomerular filtrate, competition for binding uptake from other proteins and the absorptive capacity of the tubular cells.
  11. 11. • A reduction in GFR, due to loss of nephrons, increases sFLC concentrations so that more are filtered by the remaining functioning nephrons. • Subsequently, and with increasing renal failure, hyperfiltering glomeruli leak albumin and other proteins, which compete with FLCs for absorption thereby causing more to enter the distal tubules.
  12. 12. • FLCs entering distal tubules can bind to TammHorsfall protein (uromucoid). • This is the predominant protein in normal urine and is thought to be important in preventing ascending urinary infections. • It is a glycoprotein (85kDa) that aggregates into high molecular weight polymers of 20-30 units. Interestingly, it contains a short peptide motif that has a high affinity for FLCs.
  13. 13. • The main renal pathology in the context of MM and ARF is myeloma kidney (cast nephropathy). • This is caused by precipitation of FLCs with uromucoid as waxy casts and is characteristically found in ARF associated with MM . • The casts obstruct tubular fluid flow, leading to disruption of the basement membrane and interstitial damage.
  14. 14. • Rising concentrations of sFLCs are filtered by the remaining functioning nephrons which become blocked, leading to a vicious cycle of further increases in sFLC concentrations and progressive renal damage. • This may explain why some MM patients, without apparent pre-existing renal impairment, suddenly develop catastrophic and irreversible renal failure. • The process is aggravated by other factors such as dehydration, diuretics, hypercalcaemia, infections and nephrotoxic drugs.
  15. 15. • Monoclonal FLCs cause renal impairment by several mechanisms, a variety of which may contribute to both acute and chronic renal failure.
  16. 16. Mechanisms of renal FLC toxicity • Activation of inflammatory mediators in the proximal tubule epithelium. • Proximal tubule necrosis. • Fanconi syndrome (renal tubule acidosis) with FLC crystal deposition. • Cast nephropathy. • AL amyloidosis • Light chain deposition disease
  17. 17. • So the key step in treatment is FLC removal
  18. 18. • Chemotherapy Plus • Plasmapheresis • High cut off dialysis
  19. 19. High Cut off diaysis • sFLCs can be removed more effectively by haemodialysis, provided the pore sizes of the membranes are large enough. • • Conventional dialysers have a molecular weight cut-off around 15-20kDa so the filtration efficiency for FLCs is very low. • However, some of the new “protein-leaking” dialysers have much larger pores.
  20. 20. • Haemo-diafiltration is more effective at removing small protein molecules than haemodialysis. • There are sporadic reports of patients with AL amyloidosis and end-stage renal failure who appear to have improved survival when haemodiafiltration is instigated. • But, there is currently inadequate clinical data to provide a clear conclusion in amyloidosis patients.
  21. 21. • 67 patients with AKI due to cast nephropathy who received HCO-HD with modern chemotherapy. • The majority of patients had sustained reductions in serum FLC concentrations (76%) and a high rate of independence of dialysis (63%). • The HD regime used Gambro HCO 1100 dialyzers and was aggressive, with almost daily 8-hour sessions for 12 days. • After this, alternate days and finally to three 6-hour sessions per week after day 21.
  22. 22. Conclusion • Obviously HCO-HD will only remove FLC and will not stop their production. • Therefore, for a sustained response, patients need to be a on a chemo-sensitive regime. • The above studies have demonstrated that patients who need a break in chemotherapy do worse, as do those with signs of chronicity on renal biopsy.
  23. 23. The following criteria are suggested before considering HCO-HD in patients with AKI due to cast nephropathy: • Chemo-sensitive regime; bortezomib is frequently employed. • High serum FLC levels (>500mg/l; usually much higher) • Low levels of interstitial fibrosis & tubular dropout on biopsy (i.e. evidence of salvageable kidneys)
  24. 24. Thank you