**
‘Optimal
Haemodialysis’**

**Is
‘adequate’ still good enough?**

__
Haemodialysis ‘adequacy’__

__
__

**
1.
The current ‘measure’ of haemodialysis adequacy is a mathematical
‘concept’ called Kt/V* – more of this later …**

**
**

**
2.
A ‘poor-man’s’ Kt/V called the Urea Reduction Ratio (URR)* is also used
as it provides a good approximation to the Kt/V**

**
**

**
We **__talk__ of a dialysis treatment being ‘adequate’ if this measure, the
Kt/V*, can reach 1.3 per treatment … regardless of dialysis duration (time) or
frequency.

**
**

**
For those who use the URR, adequacy is achieved if the reduction in urea for any
given treatment is >65%. **

**
**

**
Kt/V and URR will be described later in this section**

**
Most dialysis units/services measure Kt/V or URR once every 2-3 months on a
random mid-week dialysis. They ‘assume’ that the result obtained is
representative of ‘all’ dialysis treatments in that measurement period.**

**
That seems a naïve assumption at best … !**

__
__

__
The inadequacies of ‘adequacy’__
…

**
‘Adequate’ is defined as … ***

*
‘sufficient’*
… but sufficient for what?

**
to remove all symptoms of disease?**

**
to normalise all biochemistry**

**
or**

**
to simply enable ‘activity of daily living’?**

**
to simply extend life/stay alive?**

*
‘satisfactory’*
… but this implies ‘barely so’

*
‘enough’*
… but ‘enough’ proportionate to what?

**
The Australian Concise Oxford Dictionary**

__
Adequate adequacy__
…

__
__

**
Haemodialysis can only be adequate when:**

**
all symptoms and signs of uraemia are eradicated**

**
the patient is fully rehabilitated**

**
dialysis does not interrupt activities of daily living**

**
**

**
… thus, true ‘haemodialysis adequacy’ is, in practice, rarely **__if ever__
reached

**
**

**
**

**
But …**

**
**

**
We **__talk__ of our current measures of haemodialysis ‘adequacy’ as if we
think that what we do now is ‘optimal’, that these measures somehow, magically,
confer all these benefits ... and confer them in such a way that the treatment
is deemed ‘good’ dialysis’.

**
**

**
But ...**

**
**

**
Current adequate dialysis is NOT good dialysis**

**
**

**
Current ‘adequacy’ measures are restricted to the measurement of the clearance
(removal) by dialysis of one, small and very **__un__representative solute
(waste), urea

**
**

**
… and good dialysis **__should be__ and __is__ far more than that!

__
__

__
__

__
The ideal ‘marker’ of adequacy__
…

__
__

**
A marker of ‘adequacy’ to determine ‘***how much dialysis is enough dialysis*’
has long been sought.

**
**

**
As ‘clearance’ is (essentially) synonymous with ‘renal function’, a measure of ‘***dialysis*
*clearance’* seemed to be a good way to assess ‘dialysis function’

**
This, of course, begs the question that clearance is the ‘be-all’ and ‘end-all’
marker of ‘goodness’**

**
**

**
Vanholder has defined that an ‘ideal marker of adequacy’ should be:-**

**
Retained in renal failure**

**
Eliminated completely by dialysis**

**
Proven to have dose-related toxicity**

**
Furthermore …**

**
Its generation/removal should be accurately representative of other toxins**

**
It should be easily and reliably measured**

__
__

__
Uraemic toxins and possible markers__

__
__

**
Some potential candidate toxins considered as **__the__ marker have include:

**
**

**
Small Soluble molecules**

**
Urea**

**
Guanidines**

**
Polyols**

**
**

**
Protein-bound molecules**

**
AGE**

**
Indoles and phenols**

**
Polyanions**

**
**

**
‘Middle’ Molecules**

**
Endothelin**

**
β**_{2}
microglobulin

**
Leptin**

**
**

**
And the winner was … urea !**

__
Urea – the ‘practical’ marker...__

**
Urea reflects **

**
the efficiency of removal of other small molecular weight uraemic toxins…
**

**
but ...**

**
importantly, urea does not always reflect the clearance of larger solutes**

**
It also reflects the dietary protein intake**

**
Urea
losses through dialysis and in the faeces also usefully allow the calculation of
a nutritional constant – the Protein Catabolic Rate (PCR)**

**
But ...**

**
Urea has, in my view sadly, become the ‘surrogate marker’ of dialysis adequacy,
despite many critics and criticisms **

__
__

__
__

__
Should adequacy be more than this?__

**
**

**
Beyond the simplistic concept of efficient small solute clearance, I believe
that **__optimal__ haemodialysis should include the:

**
Resolution of all **__overt__ disease

**
Regression of **__covert__ (hidden) CKD pathology

**
Avoidance/abolition of dialysis-related side-effects**

**
Reduction in the ultrafiltration rate to less than the equilibration rate**

**
Allowance for a normal diet and fluid intake**

**
Rehabilitation of lifestyle and employment capacity**

**
Reversal of all adverse morbidity/mortality**

**
… and, for the provider, even cost efficiency**

**
**

**
To exclude all of these markers of ‘good dialysis’ **

**
from an assessment of dialysis adequacy is**

** **

**
inexcusable**

** **

**
yet that is exactly what we do!**

** **

__
__

__
__

__
Kt/V and the URR … (ugh!) … and the
origins of adequacy__

**
**

**
It all began with the NCDS study in 1981. **

**
**

**
This study was designed to test the relative toxicity and importance of small
(and middle) molecules.**

**
In brief, it showed that the clearance of small solutes (eg urea) correlated
‘best’ with outcome.**

**
It ‘conceived and birthed’ the concept of ‘Kt/V’ as a mathematical measure of
dialysis adequacy.**

**
**

**
**

__
Kt/V__

**
K = clearance of urea (ml/min)**

**
t = time (minutes)**

**
V = volume of body water (litres)**

**
**

**
Kt/V depends upon**

**
dialyser surface area**

**
dialyser membrane characteristics**

**
the blood flow rate (Q**_{b}) and dialysate flow rate (Q_{d})

**
the convective component of ultrafiltration**

**
… in brief, Kt/V became the mathematicians dream!**

__
__

__
The ‘purists’ approach ...__

**
**

**
There are several formulae to calculate Kt/V (groan!)**

**
**

Kt/V = - log(R - 0.03) + [(4 - 3.5 R) x (UF/W)]

**
**

**
Or ...**

**
**

Kt/V = [- log((post BUN/pre BUN) - 0.008 x HD hrs)] + ((4 - 3.5 x
post BUN/pre BUN) x (wt loss/post wt))

**
Where ... **

**
UF = UF volume (in litres)**

**
W = post dialysis weight (in kgm)**

**
R = ratio of post-dialysis to pre-dialysis BUN**

**
**

__
The ‘simpletons’ approach …__

**
**

**
For the ‘mathematically challenged’, Kt/V can be thought of as:**

**
K = Membrane characteristics & flow rates**

**
t = Time**

**
V =
Body water as proportion of
body weight**

**
**

**
These three factors – in the prevailing view – are the key determinants of
dialysis adequacy but, to me, this reliance on a mathematical formula based
solely on the dialysis process fails my key determinants of patient outcome …
**

**
**

**
well-being of the individual**

**
**

**
relief of symptoms**

**
**

**
return to work and family-related pursuits**

**
**

**
individual self-determination. **

**
**

**
None of these are represented by the Kt/V formula.**

__
__

__
Interpreting Kt/V__
…

__
__

**
In addition, Kt/V is diminished by a multitude of confounding factors. These
confirm Kt/V as a far too simplistic expression of ‘adequacy’. **

**
**

**
These include:**

**
The ‘in-parallel’ nature of haemodialysis**

**
The inescapable facts of cardio-pulmonary and access recirculation**

**
The diminished reliability of Kt/V as a ‘true’ measure of urea clearance without
making allowances for ‘equilibration time’.**

**
The inaccuracy of dialyser specifications and dialysis machine estimates of
blood (Q**_{b}) and dialysate (Q_{d}) rates

**
The inevitability of hollow fibre clotting and consequent ‘non-contribution’**

**
The ‘cribbing’ of dialysis time - far commoner than we admit … **

**
Errors in post dialysis urea measurement – the complex issues of single
pool v double pool kinetics (not an issue for detailed discussion here)**

**
**

**
In addition … early interpretations of Kt/V were misleading:**

**
Initially, Sargeant and Gotch divided the NCDS dialysis population into two
groups, those with a Kt/V of < 0.8 and those > 0.8. They concluded that:**

*
A Kt/V < 0.8 was associated with high morbidity/mortality*

*
A Kt/V > 0.8 was associated with a lower morbidity/mortality*

**
Early on, a Kt/V > 0.8 became the 1**^{st} ‘Holy Grail’

**
The ‘80’s & ‘90’s were controversial decades with a gradual acceptance that
higher Kt/V’s were needed for ‘adequate’ dialysis.**

**
**

**
In 1998, Held first clearly showed a decline in mortality with increasing
dialysis ‘dose’ and re-drew the Sargeant and Gotch graph. **

**
**

**
He showed that morbidity and mortality clearly lessened as the Kt/V rose and
that this advantage appeared to continue ‘ad infinitum’**

**
**

**
Meanwhile, along came ‘easy adequacy’ - the URR**

**
**

**
**

**
**

__
The URR__

**
**

**
Daugirdas proposed a simpler measure of adequacy – the urea reduction ratio (URR)**

**
URR = **__pre-dialysis urea - post-dialysis urea__

**
pre-dialysis urea**

**
or...**

**
The percent reduction urea (PRU) ... which simply expresses the URR as a
percentage**

**
**

**
The URR ...**

**
Is easily calculated**

**
Is epidemiologically useful**

**
But ... **

**
It contains **__all__ Kt/V’s inaccuracies, __plus some__

*
*

*
URR variations are primarily due to:*

**
urea removal with ultrafiltration (which is not considered in Kt/V)**

**
timing inaccuracies of post dialysis blood samples **

**
single v double pool (urea equilibration time)**

**
intra-dialytic urea generation**

__
Kt/V derived from the URR …__

**
Several equations have been developed to convert Kt/V to URR:**

**
Kt/V = (0.026 x URR) - 0.460**

**
Kt/V = (0.024 x URR) - 0.276**

**
Kt/V - URR = (0.04 x URR) - 1.2**

*
But … a URR-derived Kt/V is significantly inaccurate
and imports *__and__ compounds __all__ the variabilities of both
measurements

__
In addition, there are other ‘chemistries’ to consider …__

**
Chemistries other than urea clearly have an influence on adequacy …**

**
The
protein catabolic rate (PCR) and nutritional adequacy is an important
contributor to overall dialysis adequacy but is, in part, confounded by intra-dialytic
urea generation**

**
The
serum albumin has long been regarded as a major determinant of outcome … if not
the most important of all (Lowrie)**

**
Acute phase reactants – CRP, ferritin and ? others have gained believers as
important factors in determining outcome**

**
Then there are …**

**
B2 microglobulin**

**
Oxidation end products**

**
AGE **

**
etc …**

*
If you have been confused by all this … welcome to my nightmare*

*
At the end of the day, a mathematical representation of dialysis adequacy is, in
my view, far too simplistic and fails to include many of the things that matter
most.*

*
Adequacy *__IS__ clearly more than Kt/V.

*
*

*
To
think that haemodialysis adequacy can ‘adequately’ modeled simply by measuring
(badly) the clearance of a one small solute (urea) as the lone determinant is,
at best, naïve and, at worst …*

*
*

*
… but then, I had better not say!*

__
So … what DOES seem to matter__
… ?

**
**

**
Is it flow
rate (Q**_{b}), membrane area (m^{2}),^{ }membrane
permeability (flux) … or is it time?

**
**

**
In the 90’s, emphasis (especially in the**^{ }US) was placed on:

**
Higher and higher flow rates (Q**_{b})

**
Bigger and bigger (m**^{2}) dialysers

**
Leakier and leakier (flux) dialysers**

**
**

**
But ...**

**
Shorter and shorter (t) time**

**
**

**
In the ‘90’s, major survival differences surfaced - US v ‘the rest’. **

**
**

**
Even after taking into consideration differences between patient populations, US
patient outcomes did not appear as good as those of patients in Japan and
Europe. **

**
**

**
This stimulated an international study to look at dialysis outcomes and practice
profiles (DOPPS), a study followed by even more extensive studies involving an
even more countries and dialysis services (DOPPS II, DOPPS III and DOPPS IV) to
attempt to identify those practices which were associated with poor outcomes and
those with better outcomes. **

**
**

__
All that seems clear so far is that__
...*
*

*
1.
Mortality correlates inversely with delivered dialysis dose*

*
2.
Dialysis dose = a factor of clearance *__and__ time

__
The HEMO study__

__
__

**
In 1994, a 7 yr multi-centre US study, the HEMO study, was initiated.
**

**
**

**
Sadly and in retrospect, I think it asked the wrong questions.**

**
It aimed to identify whether **

**
membrane type – high flux (leaky) or low flux (less leaky) **

**
the amount of dialysis (as measured by delivered Kt/V) **

**
or both **

**
… affected outcome**

**
**

**
HEMO compared 4 groups:**

*
Low flux + low Kt/V }*

*
High flux + low Kt/V } *__no direct comparison of__

*
Low flux + high Kt/V } *__dose with time__

*
High flux + high Kt/V }*

*
*

**
The initial results were released in late 2002**

__
__

__
__

__
Outcomes of the HEMO trial__
…

**
High flux did **__not__ improve average patient survival

**
Higher dose ‘tended to’ significance only**

_{
e}Kt/V_{(sp)}
1.25 ‘as good as’ 1.65 (but it __only__ used urea kinetics)

**
Unfortunately, there are lots and lots of confounders**

**
And ... importantly, it did not ask the KEY question – is TIME ON DIALYSIS, (ie:
dialysis membrane contact time) what **__really__ matters?

__
__

__
__

__
Time and the dialysis syndrome __

__
__

**
Longer dialysis duration permits:**

**
Slower ultrafiltration rates and less intra-dialytic hypotension**

**
Proportionately greater middle molecular v small solute clearance**

**
Better (reaching ideal) volume and BP control**

**
More easily achieved ‘dry weight’**

**
Slower/lesser intra-dialytic biochemical ‘assault’**

**
Intra-dialytic v post-dialytic compartmental equilibration**

**
Reduced cardiovascular ‘turmoil’ and morbidity**

**
**

__
Frequency - is this the key?__

__
__

**
Daily short hour dialysis**

*
Increased frequency *__without__ increased time

*
Better clearances*

*
... and some volume advantage*

**
**

**
The following graph schematically represents the rate of removal of, for
example, urea over a 4hr dialysis treatment.**