High cut off dialysis - Basics
Dr. Sandeep G Huilgol
MBBS, DNB (Internal Medicine), MMedSci (Nephrology)
• 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.
• The mechanism of kidney injury in multiple
myeloma differs considerably.
• Most severe form is cast nephropathy caused
due to serum free light chains.
• Normal plasma cells produce FLCs in slight excess to
heavy chains to enable the correct assembly of intact
• These excess FLCs are released into the circulation,
filtered by the glomerulus and then catabolized in the
• 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.
• Overall, clonal production of FLCs occurs in
96% of all patients at presentation of multiple
• The presence of monoclonal immunoglobulin
light chains is essential for the pathogenesis of
• In order to be pathological the light chains
must be free from the intact immunoglobulin
to enable filtration at the glomerulus.
• 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.
• Two sites of injury predominate in myeloma
• 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.
• 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
• 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.
• After filtration by the glomeruli, FLCs enter the
proximal tubules and bind to brush border membranes
via low-affinity, high-capacity receptors called cubulins
• 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
• A reduction in GFR, due to loss of nephrons,
increases sFLC concentrations so that more
are filtered by the remaining functioning
• 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.
• 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.
• 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
• 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
• Monoclonal FLCs cause renal impairment by
several mechanisms, a variety of which may
contribute to both acute and chronic renal
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
• High cut off dialysis
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.
• 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
• 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
• After this, alternate days and finally to three 6-hour
sessions per week after day 21.
• 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.
The following criteria are suggested before
considering HCO-HD in patients with AKI due to
• Chemo-sensitive regime; bortezomib is
• High serum FLC levels (>500mg/l; usually much
• Low levels of interstitial fibrosis & tubular
dropout on biopsy (i.e. evidence of salvageable