Possibly, a composite marker
As ever, Bill, from you, a thoughtful post – and one I doubt I can come up with an answer for – but, ‘oh, that it could be so’.
As Hamlet opines in his ‘To be or not to be’ soliloquy … ‘T’is a consummation devoutly to be wished’
Your search for a cell whose lifespan (a) is easily accessible to repeated analysis,(b) is affected by CKD and/or uraemia, and © … and here you make a leap of faith … is so sensitively affected by the level of metabolic ‘derangement’ that even small differences in the ‘goodness’ or ‘badness’ of dialysis might make it into a measurable indicator of dialysis efficacy … is going to be an unrequited search!
I’m afraid it just ain’t gonna happen.
While a great thought … and I mean that … and while the lifespan of an RBC might seem a potential candidate, the means by which we can measure sensitive and small decrements in RBC lifespan just aren’t there.
First, they are not accurate enough to measure the small changes (and they would be small) that might accurately grade levels of uraemic impact.
Second, too many extraneous factors also impact on RBC lifespan: iron status is one … but so, too, are ESA responsiveness and dose, folate levels - and many more.
To fulfill the ‘easily accessible to repeated measurement’ criteria, any measurable ‘factor’ would have to be a blood element. No dialysis patient is going to accept the regular and repeated taking of an ‘attached tissue’ sample … nor can I envisage one that would possibly fulfill the 3rd criteria of being so sensitively affected by uraemia as to be of use, even if sampling were possible.
So, no, I don’t think that would work. Nor would the white cell or platelet population be useful either – for similar as well as other ‘won’t work’ reasons. Much as it seems a nice idea, I just don’t see a cell, or the life of one - attractive though the idea may seem - working. Until such time as far more accurate and sensitive estimates of red cell survival that are also separable from other significant ‘uraemic influences’ - like EPO, ESAs and iron - it will always come back to a biochemical measure.
And, if biochemical, then what measure? And, here, I am again tempted to stick my neck out (badly) … why do I always end up doing this? …
I have long been tempted to consider the possibility of a ‘composite’ marker. So much has this been a temptation, that I have been patiently accumulating post-dialysis data in the hope that, one day, I might get the chance to potter around with it with this very thought in mind: a better biochemical aggregate by which to measure and guide ‘good dialysis’.
While you know my views about Kt/V, so I won’t expand here other than to say that its’ use as a ‘marker’ of effective dialysis is – in my view – seriously flawed … it is (likely) a fair marker of urea clearance (and some of the other smaller metabolic beasties) removed by dialysis. It just doesn’t represent all the other stuff that dialysis must remove (clear) – especially the middle molecule ‘group’.
But, as phosphate moves, acts, and behaves as a middle molecule even though it seems small (see my earlier post in this thread), then might not its’ clearance be used in conjugation with the urea clearance to give a combined or composite measure of small and middle molecule removal.
To this end, we have amassed at my unit over the past 6+ years a data-set of pre- and post-dialysis biochemical markers by routinely drawing not only pre- and post-dialysis urea and creatinine but also pre- and post- phosphate and calcium.
In Australia, few (if any) use Kt/V … but we all routinely measure the URR (ie: the urea reduction ratio … or, if expressed as a %, the PRU = the percentage reduction in urea … as was proposed by John Daugirdas as a ‘poor man’s Kt/V’).
The URR (or PRU) is a national measure in our ANZDATA registry – we all collect it.
The PRU is the pre-dialysis urea minus the post-dialysis urea, divided by the pre-dialysis urea, and expressed as a percentage – and is a measure of the degree (the %) by which the urea has been lowered by that dialysis treatment. While >65% is regarded as ‘adequate’, we shoot for >70% in all patients. Pump speed, dialyser surface area, dialysate flow rate and time (ie: dialysis sessional duration) can all be up-sized (surprise, surprise that time yields the biggest impact) to achieve a ‘better’ PRU.
Urea reflects small molecules (well, at least some of them) while phosphate is a ‘surrogate’ marker for middle (or larger) sized molecules.
Sure, other 'middle molecules exist: vitamin B12, B2-microglobulin, homocysteine are three that come easily to mind … but none of these is cheap to measure and none have the instantaneous ‘get a result in minutes’ value that phosphate offers.
We (or, at least, some of us) seem to ‘accept’ the PRU as a marker … why not, then, a “PPO4” equivalent … ie: a phosphate-based, PRU look-alike … the percentage reduction in phosphate.
We have >6 years of accumulated pre-and post- data in both conventional and home NHHD patient populations - all sequential and in all patients (with outcome data too) - waiting for me to potter with – if and when I get the time.
Then, maybe, some combination like the average of (PRU + PPO4) might emerge to better reflect both small and middle molecular clearance.
All that may be pure rubbish … but I haven’t yet put it out of mind to try.
We have this data on our NHHD’s going back >10 years. Our conventional dialysis group data goes back 6+ years … we only began to collect the conventional group data as a comparator group when it occurred that it might be useful. Now, I need the time …
Of course, PO4 may be be-devilled (as a marker) by the potential effect(s) of binder agents and their impact on the serum phosphate level (both pre- and post-dialysis) … and would this matter? To tell the truth, I am not sure how to rationalise this … though when eyeballing our pre- and post-dialysis data-sets for long, slow extended hour and high frequency dialysis for binder-free patients versus the data-sets for our ‘bound’ conventional dialysis patients, I don’t think it would make the numbers unusable.
The temptation is to think that if we (or, at least, some) put so much store by the PRU (or Kt/V), then it is not too far a stretch to think that similar devotion might accord to a composite measure which in-builds that pesky set of bigger beasts we call middle molecules. If the clearance of PO4 is a ‘fair’ marker of the clearance of these (and PO4 is certainly easy, quick and cheap to measure), then why have we left it - for so long - out in the cold.
Finally, while on the topic of markers - and composite markers at that … wouldn’t it be good to in-build into our ‘composite’ a marker which might ‘mark’ volume. That would yield a marker reflecting small molecule clearance (urea), bigger molecule clearance (phosphate) and the dimension of intravascular volume contraction during dialysis. What might work, here, is the serum albumin.
I have published a few peer-review papers and abstracts about this … see my last effort (this one with Andreas Pierratos) which deal with this area: Agar JWM and Pierratos A. The serum albumin and hemoglobin: Behavior patterns in nocturnal hemodialysis. Hemodialysis International 11(3): 303-308, June 2007.
In simplistic terms, the serum albumin rises in “wham, bam, thank-you ma’am” dialysis as albumin stays within the intravascular volume and, as it is contracted by rapid fluid removal during conventional dialysis, it becomes increasingly concentrated.
In other words, the measured concentration (of albumin) will rise if the rate of fluid removal from the intravascular volume constantly exceeds the rate at which fluid can flow from tissue and cellular fluid stores to replace that which is being removed by dialysis. The more rapid the dialysis, the greater the impact on blood volume and the greater the hyperconcentration of albumin.
But, as the dialysis treatment lengthens and slows, the rate of replacement from tissue and cellular fluid stores can keep pace with the rate of fluid removal, and the serum albumin concentration will change less, and less, until - at the point of equality where the rate of fluid removal by dialysis is no greater than the rate capacity of the tissues and cells to replace that which is being removed - the serum albumin will no longer be concentrated during dialysis and remain unaltered. The longer and slower (ie: the more physiological) the dialysis, the less the pre- to post- change in the serum albumin … until there is no change at all.
Measuring the pre- and post-dialysis albumin should, therefore, give a measure of the impact of the dialysis process on the blood volume. the less the change, the less the impact and (arguably) the ‘better’ the dialysis - from a volume aspect.
That’s complex - so if you don’t follow, say so … though you may need to re-read a few times.
In the end, a composite small molecule + large molecule + volume ‘measure’ might be possible … where each is accorded a measure and the summation equates to a biochemical and volume yardstick of the ‘goodness’ - or ‘badness’ - of the treatment process.
I still think more than just biochemistry and volume matter. The ‘good dialysis index’ … see http://www.nocturnaldialysis.org … assesses far more than just biochemistry and volume … but as a measure of these parameters, urea, phosphate and volume in a tripartite composite might be better than Kt/V (or PRU) alone.
Food for thought …