Stimulated by Ben's problem (see last thread): Vascular reactivity and dialysis

The issue of heightened vascular reactivity during dialysis is an interesting and somewhat vexed one but, unfortunately, it is an area we know precious little about – in part due to the difficulties of studying it reliably within a milieu (dialysis) where there are co-existing and dramatic volume and biochemical changes as an enforced – indeed, an essential – part of the process.

So many intra-dialytic factors impact on and inter-relate to blood vessel (vascular) tone – the capacity for blood vessels to normally contract or expand – that to ‘tease out’ exactly what matters and what is due to what, is a minefield for the researcher. This is even more difficult to do in any one individual patient. So much of the data in this area is conflicting that a clear understanding of what might push the blood pressure up (vasoconstrictive influences) vs what might lower it (vasodilatory influences) … all within the dialysis milieu … remains elusive. As we still don’t understand the mechanisms well in the normal state – let alone those with renal failure and who, to make matters even more complex, are on dialysis – it is an area where there is conjecture, possibility … but no proof or certainty.

There has been much interest in the role of oxidative stress end products and the balance (or [im]balance) between pro-oxidant and antioxidant ‘forces’ … if you like, the ‘promoters of’ and ‘defenders against’ blood vessel (mal)function. We do know that the cells - called endothelial cells - which line all our blood vessels are potent makers of hormonally active molecules … indeed, a slew of such substances. These endothelial cells make an absolute ‘soup’ of constrictor and dilator substances (the cells make both), the balance between the activity or suppression of these constrictor and relaxor molecules determining whether the blood vessels that they line constrict … get smaller … (thus biasing to a blood pressure raising – or hypertensive – response) or relax … get bigger … (thus biasing to a blood pressure lowering – or hypotensive – response).

Much/most of this research seems to have come out of Japan over the past decade or so … the Japanese having taken a keen interest in trying to tease out this almost un-teasable area.

Their work with Vitamin E coated dialysers looked interesting – at least for a while – but my understanding is that the results in this niche area of interest, in the end, have been rather inconclusive – or at least not sufficiently strong to suggest the widespread use or recommendation for Vitamin E-coated dialysers.

Here, it starts to get very complicated … …

Antioxidant enzymes, made within the endothelial cells (and some of these substances include such highly unpronounceable things as ‘superoxide dismutase’, ‘catalase’, and ‘glutathione peroxidase’) are known to help suppress or ‘convert’ some of the most potent and damaging products of cellular metabolism … superoxide radicals (nasty critters) … as well as hydrogen peroxide (also a nasty beast), to less reactive and damaging forms and, in so doing, help to reduce or suppress hyper-reactivity in the blood vessel walls.

Several other well known but circulating ‘extracellular’ antioxidants, such as albumin, bilirubin and urate, also help to prevent these free radical superoxides from reacting harmfully within the body (and within small blood vessels in particular) by ‘sequestering’ or ‘chelating’ (in simple terms, this means by ‘locking away’) these nasty vascular-reactive substances in the blood plasma itself.

Oxidative stress seems to be particularly detrimental in patients having haemodialysis as, possibly due to interactions between the blood and the dialysis membrane, a chronic defect develops in the antioxidant defense mechanisms of some patients. In this, nitric oxide may be a key and pivotal substance, but it is difficult to study as it is difficult to measure, other than indirectly.

The use, more recently, of more bio-compatible membranes has been a step forward.

The adoption of more stringent water standards for the production of water for use in the manufacture of dialysate than the currently accepted AAMI standards which still remain the standard for the US (see the Australian CARI guidelines at ) has further reduced the risk of water-induced inflammatory stimuli. Equipment – such as NxStage – which uses pre-prepared dialysate should yield near-ultra-pure water standards … but, then again, in the pre-packaged dialysate (bag-form), there remains a risk that plasticizers from the plastic bag that holds the dialysate may leech into the fluid – especially if stored for a period or if the bags have been subject to temperature or conditional change during transit and/or storage. This aspect, however, remains unknown and/or unproven – to my knowledge. As for the water quality provided by the Pureflow on-line dialysate ‘generator’, I am not sufficiently aware of the water quality test outcomes of the Pureflow to pass further comment.

One of the potential benefits (or curses) of haemodiafiltration (HDF) … a technique rapidly gaining in popularity in Europe and Australia though which is yet to make inroads into chronic dialytic care in the US … has been the requirement of (and provision for) ultrapure water for the HDF process. Ultra-pure dialysate (as is essential for HDF) has the clear benefit of further significantly reducing water-induced inflammatory stimuli … stimuli with the potential to induce superoxide radicals and oxidative end products and their circulatory effects.

Whether these are likely to be primarily hypertensive or hypotensive in nature … that remains uncertain … though the bulk of data would suggest that, in most patients, hypotension is the more likely outcome and not hypertension.

One thing, however, seems certain - water quality (or, perhaps more accurately, the lack of it) is a key factor in the chronic inflammatory state that is the base underlying state of many/most dialysis patients. If one thing occurs in the next decade that might make a real difference, then it is attention to and improvements in the quality of the water with which the machine ‘makes’ the final dialysate.

HDF but heightens the importance of this. HDF with the current AAMI-accepted standards extant in the US at present would be inappropriate and disasterous. HDF demands ultra-pure dialysate … as during HDF, replacement fluid passes from the dialysate into the patient across the membrane - this process occurs within the dialyser - and if the water quality is poor (and AAMI is orders of magnitude less ‘pure’ than is the water demanded by the European standards) - the circulation stands as an open target for the risks of endotoxin and other impurity exposure. Added filters (at a cost and changed frequently) assist but are not fail-safe devices. The water itself must be generated to an ultra-pure standard to ensure patient protection.

One interesting paper (again from Japan in 2006) alerted to the influence of light – in particular, fluorescent light – on blood. I was drawn to this paper by Miriam Lippel Blum, a dialysis patient - and I must say I was unaware until she pointed it out - and to make matters worse, it was hidden, not in the nephrology/dialysis literature but in Clinical Chemistry! In most dialysis patients – who dialyse during the day – the blood circulates outside the body to the dialyser and back within circuits of plastic tubing exposed to strong light. Light has been shown by these researchers to be a potent stimulant of vasoactive substances which, in their work, was shown to destabilize the blood pressure and the circulation and cause hypotension … a response which was blunted/abolished by light-shielding … or, to invoke my own interest, presumably by overnight (light-less) dialysis. But, again, light was, in this work, a promoter of a lowering of the blood pressure, not of the raising of it.

This last work is highly intriguing and needs to be repeated and teased out. If I had the time – it’d be me doing the repeating and the teasing. We have discussed this avenue of research but, to date, I have not had the research funds or staff to allow us to repeat the Japanese work or take this tantalizing thought further.

What all this says is – that we still know far too little about the factors that influence blood vessels – not only in health but also in disease … let alone when something as potent an additional factor as is dialysis is thrown into the mix.

None of this helps Ben’s problems (see the previous ‘thread’ posted by Gordon)… but some of these factors may be playing a part – especially as we have been told his history of ‘reactivity’ and ‘hypersensitivity’ to a range of stimuli.

While I feel for Ben and for his problems, I have no easy-fix solution for him and I doubt any of this offers that solution … with the exception (perhaps) of a trial of HDF.

I might be tempted to try HDF for Ben – if only to see if his blood pressure issues stabilized with ultra-pure water HDF. HDF is now being performed more commonly here in Australia – and, what’s more, this includes HDF in the home. HDF is also increasingly now being used in the UK, France and Germany and elsewhere in Europe.

It’s a tantalizing thought that this might be the method of choice for Ben.

But … do I know that? … no, I don’t! Far from it! … it is just but ‘a thought’.

However, in the spirit of the educative role of this site, I thought it may be of some interest to some readers of this site. It is not intended that this ‘post’ should stimulate wide speculation … and much of this area is exactly that … speculation … but more to alert you to some of the known unknowns (who was that recent ‘Washingtonian’ who said that?!). The problem is that there is so much we do NOT know about dialysis, about what we do and the responses of the body to those interventions.

I post this for your interest … rather than to induce interminable discussion.

Dr. Agar,

Very interesting thoughts regarding plastic leeching from dialysate bags; effect of light on blood; and transitioning to hemodiafiltratioin. Is it possible to perform hemodiafiltration with a NxStage PureFlow machine? If no, what machine may be utilized for the administration of such?

Thanks you,

Gordon for Ben

RE: Haemodiafiltration

In a word, no. The NxStage is not designed for nor performs HDF. It can’t.

The two machines that are use here in Australia and which are most commonly used in Europe as well are the Fresenius 5008 HDF system … you can see representative press releases from Fresenius on this machine and the process at

and at

or at

… while the Gambro Ultra can be seen in image at

while, if you want to chase the Gambro and HDF (as a process) further, Ingrid Ledebo wrote a nice paper on HDF in NDT

Both are state of the art machines.

As for home HDF, now that’s only just being played around with by devotee units … its not mainstream home therapy yet … though there are several self-dialysing at home here on daytime HDF.

Again, water is the thing. Diasafes x 2 (not x 1) changed at least 6th weekly seem to offer a good measure of added water certainty but this is very much a matter for the local services to scope and determine.

But, no … the NxStage can’t do HDF. It’s not designed for it. It’s not its purpose.

Dr. Agar,

Thank you for the info and links. I spent much of the morning calling both Fresenious and Gambro inquiring about the availability of hemodiafiltration machines available for purchase in the USA. It appears neither company sells machines capable of hemodiafiltrationin the USA–they are available in Canada and Mexico. I do not know if it is an FDA approval situation or no demand for the technology. The area sales reps were lacking in their knowledge of hemodiafiltration and did no know why the technology is not being sold in the USA…they guess it is lack of demand. I will continue inquire as to the reason.