Slide 1
High cut off dialysis - BasicsDr. Sandeep G HuilgolMBBS, DNB
(Internal Medicine), MMedSci (Nephrology)
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.
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
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.
Overall, clonal production of FLCs occurs in 96% of all patients
at presentation of multiple myeloma.
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.
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 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.
In normal individuals, sFLCs are rapidly cleared by the kidneys
depending upon their molecular size. Monomeric FLCs,
characteristically , are cleared in 2-4 hours at 40% of the
glomerular filtration rate (GFR).
Dimeric FLCs, typically , 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.
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.
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.
FLCs entering distal tubules can bind to Tamm-Horsfall 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 interstitial damage.
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.
Monoclonal FLCs cause renal impairment by several mechanisms, a
variety of which may contribute to both acute and chronic renal
failure.
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
amyloidosisLight chain deposition disease
So the key step in treatment is
FLC removal
ChemotherapyPlusPlasmapheresisHigh cut off dialysis
High Cut off diaysissFLCs 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
haemo-diafiltration is instigated.
But, there is currently inadequate clinical data to provide a
clear conclusion in amyloidosis patients.
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 ahighrate of independence ofdialysis
(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.
ConclusionObviously 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 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)
Thank you
