‘Optimal Haemodialysis’

Is ‘adequate’ still good enough?

Haemodialysis ‘adequacy’

We talk of haemodialysis adequacy as though dialysis treatment is ‘adequate’ if the Kt/V* is 1.3 per treatment (regardless of time or frequency) or if the Urea Reduction Ratio (URR)* is >65% for any random treatment.

* 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 … *

n    ‘sufficient’ …  but sufficient for what?

n    to remove all symptoms of disease?

n    to normalise all biochemistry

or

n    to simply enable ‘activity of daily living’?

n    to simply extend life/stay alive?

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

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

* The Australian Concise Oxford Dictionary

Adequate adequacy …

Haemodialysis can only be adequate when:

n     all symptoms and signs of uraemia are eradicated

n     the patient is fully rehabilitated

n     dialysis does not interrupt activities of daily living

… thus, true ‘haemodialysis adequacy’ is, in practice, rarely if ever reached

But …

·        We talk of current haemodialysis ‘adequacy’ as if we think that what we do now is ‘optimal’

·        Current ‘adequacy’ is restricted to the measurement the dialysis clearance (removal) of a small solute (waste), urea

… and good dialysis 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 an ideal way to assess ‘dialysis function’

·        This, however, 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 include:

Small Soluble molecules

·        Urea

·        Guanidines

·        Polyols

Protein-bound molecules

·        AGE

·        Indoles and phenols

·        Polyanions

‘Middle’ Molecules

·        Endothelin

·        β₂ microglobulin

·        Leptin

And the winner has been … … … urea !

Urea – the ‘practical’ marker...

·        Urea reflects the efficiency of removal of other small molecular weight uraemic toxins… but, importantly, it is not always reflective of larger solutes

·        It reflects dietary protein intake

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

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

But – should adequacy be more than this?

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

·        Resolution of all overt disease

·        Regression of) covert (hidden) ESRF pathology

·        Avoidance/abolition of dialysis-related side-effects

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

·        Normal diet and fluid allowances

·        Rehabilitation of lifestyle and employment capacity

·        Reversal of all adverse morbidity/mortality

·        … and, for the provider, even cost efficiency

To exclude these markers of ‘good dialysis’ from any assessment of dialysis adequacy is, again in my view, inexcusable …

… and yet, that’s exactly what we do!

Kt/V (… ugh), the URR and the origins of adequacy ...

It all began with the NCDS study in 1981

·        This study was designed to test the relative toxicity/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/membrane characteristics

·        blood (Q_b) and dialysate (Q_d) flow rates

·        the convectivity 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 (litres)

                  W  = post dialysis weight (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.

To me, however, 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 and 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’. They 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’ 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:

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

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

Meanwhile, along came ‘easy adequacy’ - 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 from the URR …
 

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

o       Kt/V = (0.026 x URR) - 0.460

o       Kt/V = (0.024 x URR) - 0.276

o       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 …

o       B2 microglobulin

o       oxidation end products

o       AGE

o       etc …

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

At day’s end, 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 – and to think that haemodialysis adequacy can ‘adequately’ modeled simply by the 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 (m²), membrane permeability (flux) … or time?

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

n    Higher and higher flow rates (Q_b)

n    Bigger and bigger (m²) dialysers

n    Leakier and leakier (flux) dialysers

But

n    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) and a second, more extensive study involving an even larger study (DOPPS II) to attempt to identify those practices which were associated with poor outcomes and those with better outcomes. DOPPS II (to which the Geelong Unit contributes) will be completed in 2004

All that seems clear so far is that ...

·        Mortality correlates inversely with delivered dialysis dose

·        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, 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 …

·        It compared 4 groups:

o       Low flux + low Kt/V            }

o       High flux + low Kt/V           }         none directly compare

o       Low flux + high Kt/V          }                dose with time

o       High flux + high Kt/V         }

·        The initial results were released in late 2002

Its outcomes …

·        High flux did not improve average patient survival

·        Higher dose ‘tended to’ significance only

·        _eKt/V_(sp) 1.25 ‘as good as’ 1.65 (but it only used urea kinetics)

The full data has still not been released … and there are lots and lots of confounders

Importantly though, it did not ask the KEY question – is TIME ON DIALYSIS, dialysis membrane contact time, what really matters?

Time and the dialysis syndrome

Longer time has been shown to allow for:

·        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?

1.      Daily short hour dialysis

1.      Increased frequency without increased time

2.      Better clearances

3.  Some volume advantage

This graph schematically represents the rate of removal of, for example, urea over a 4hr dialysis treatment. As can be seen, the rate of removal is fastest at the start and slowest at the end of dialysis. By having 6 x 2hr treatments/week, waste removal is maximised when compared to 3 x 4hr treatments/week. This is the ‘rationale’ behind short hour daily dialysis. Long nightly dialysis removes even more waste than a short daily regime, but does so at a far slower and gentler rate, thus maximising waste and fluid removal but at the same time, minimising the speed of change and thus minimising the symptoms associated with dialysis

 2.      Nightly long hour dialysis

·        Increased frequency with increased time

·        Provides maximum solute and fluid management

·        Uses minimum ultrafiltration rates

·        Attains maximum Kt/V (1.7-1.8)

… so, is this the ‘Holy Grail’ we seek?

The Haemodialysis Product (HDP)

·        In January 2002, Scribner & Oreopoulos published a new concept – the haemodialysis Product (HDP) – in Dialysis and Transplantation

·        They proposed adequacy be determined solely by the HDP – based only on time (t) and frequency (f) and expressed as

The ‘haemodialysis Product’ = Hours/session x (Sessions/week)²

HDP = t x (f)²

·        They believed ‘f’ more important than ‘t’, though recognised that both are important, inter-related and are the primary determinants of good dialysis

·        They, too, ‘debunked’ Kt/V and URR and recommended haemodialysis adequacy be simply expressed simply as t x (f)²

Modified from Scribner and Oreopoulos: Dial & Transpl. Jan 2002: 13-15

HDP – an attractive concept but …

As the HDP embraces ONLY time and frequency (consistent with my own beliefs) and was proposed by 2 of the ‘greats’ – Scribner and Oreopoulos

… why am I still uneasy that HDP is the right answer?

Optimum dialysis is and must be more …

·        Optimum HD can only be modeled by including:

o       Better clearance data – but more than just urea

o       Inclusion of morbidity data – diabetes, age, CV disease, Ca/PO₄ product etc

o       Inclusion of functional data – activity capacity, rehabilitation

  … and, the unmentionable – expenditure impact!

 Towards a more inclusive index …

·        The HDP depends only on time and frequency

·        The URR and/or Kt/V ± models selective parts of ‘process’ efficiency

·        Adequacy is more than time, frequency and selective clearance

… but

·        as yet,  there is no simple functional status index (FSI) nor outcome measure index (OMI)

·        Is an ‘FSI’ and/or an ‘OMI’ possible?

·        … and what of middle and other molecular clearances?

Could the HDP be modified by adding:

·        Additional efficiency data

·        Middle molecular and/or other clearance information

·        A functional status index (FSI) 

·        An range of outcome measures (OMI)

We need to learn …

·        How to incorporate each potential variable

·        How to decide what flexible ‘weight’ to assign to each variable

·        How to modify Scribner and Oreopoulos’ HDP using outcome data

Towards optimum haemodialysis …

·        Abandon ‘adequate’ and aim for ‘optimum’

·        Recognise the flaws of Kt/V and URR

·        Accept the lack of a true measure of optimum HD

·        Focus on time and frequency rather than simply on process

·        Consider using ‘smart’ computing modelling software on accumulated databases (eg: multi-variate analysis or, possibly better yet, artificial intelligence through ‘machine learning’ programs)

·        Incorporate functional (FSI) and outcome measure (OMI) data

Conclusion

Have I answered the question – “What is ‘optimal’ haemodialysis?” …

·        Sadly, I don’t think I have …

·        Moreover, I don’t think I yet can …

… but, this discussion may have rattled a few old skeletons, have provided some food for thought and have suggested a more inclusory process to develop for the future.

… if so, it has been a useful exercise

 Authored by A/Prof John Agar.
Copyright © 2005 Nocturnal Haemodialysis Program, Barwon Health.  All rights reserved.
Revised: 28th September 2006.