2004/1 EDTNA/ERCA Journal Club Discussion Summary

The March 2004 EDTNA/ERCA Renal Care Journal Club discussed the paper entitled 'Technological advances in renal care' by Nicholas HOENICH, Elizabeth LINDLEY and John STOVES. This paper can be downloaded here .

The paper was discussed and circulated in a group of 545 JC members within the world. Anyone interested in Renal Care can simply become a JC member by subscribing for free at the Journal Club section at: www.edtna-erca.org

The paper has been actively discussed between André STRAGIER (Belgium), John STOVES (UK), Hans POLASCHEGG ( Austria), Liz LINDLEY (UK), Nic HOENICH (UK), Elisheva MILO (Israel), Prof. Stanley SHALDON (Monaco), Waltraud KÜNTZLE ( Germany), Anne MURPHY (Ireland), Bo RASMUSSON (Czech Republic), Ray TREVITT (UK), Prof. Jörg VIENKEN (Germany) and Marylou WRATTEN (Italy).

MESSAGES FROM THE DISCUSSIONS

I would like to mention some additional issues on transplantation:

Intravenous immunoglobulin induces a profound and sustained reduction in anti-HLA antibodies, thereby desensitising the patient and allowing transplantation. The success rate is about 80% and should lead to increasing transplantation of patients with high levels of antibodies. A similar success rate has been attained with blood group incompatible donors in Sweden, using IVIG after using rituximab (monoclonal antibody to B cells) and an antigen-specific adsorption column to remove blood group antibodies .

These two measures could make a significant impact on transplant waiting lists, they will certainly be significant for the previously untransplantable or long-waiting patients who can now be offered a transplant.

There is a growing body of evidence that supports the approach of pre-transplant PRA

( Panel Reactive Antibody ) reduction using IVIG in highly sensitised patients (HSPs).

There has been anecdotal success in our unit ( Leeds, UK ) with this approach in living donor transplantation. We have also performed in vitro studies to examine the relative efficacy of different IVIG preparations in reducing PRA titres ( Clark et al, Transplantation 2003 75(2):242-5 ).

Another somewhat controversial approach to increasing the opportunity for transplantation in HSPs is to place less emphasis on PRAs that are present in “historical” serum but absent from “current” serum.

As far as survival is accepted as measure of clinical benefit, technological advances have not resulted in any improvement.

The adjusted patient survival curves published by the EDTA-ERA registry at the congress 2000 overlap for the cohorts beginning 1980-84, 1985-89, 1990-94 and 1995-99. The 1 and 2 year adjusted survival data from the 2001 conference show the same.

Dialysers have made an enormous progress but this is not reflected by the mortality statistics.

Technological advances introduced between 1980 and 1995 have not resulted in better survival.

Next to patient survival comes patient wellbeing.The benefit of most of the technological novelties is highly questionable especially when compared to the benefits of more frequent dialysis. I would further like to point out that daily or nocturnal dialysis is more efficient in reducing pre-dialysis Beta-2-M levels than any known high efficiency treatment.

Although the number of patients treated with daily or nocturnal dialysis is still small the improvement of patient well being is undisputed. Patients should have the option to dialyse more frequently than 3 times per week, preferably at home. Technically, machines for  nocturnal dialysis can be simpler and smaller than existing standard machines and can be made  using proven technology.

When we talk about progress we should clearly refer it to goals. For myself I have defined the goals a long time ago : progress should serve the patient ; the patient care personnel and the technical support people.

The newer machines are praised for controlled UF ( now 20 years old ) and this has definitely contributed to a better life for patients and patient care personnel.

I agree fully on the big value of controlled ultrafiltration, which is often forgoten as being an important improvement over the last 20 years, and thus never experienced by our younger Renal Care Staff as such.

I am convinced that patient survival on hemodialysis – in which treatment is evolved towards dialysing older and older populations with more and more multiple comorbidities -  is importantly positive influenced by this application.

But we have seen other « progress » that makes machines more and more complicated without any apparent benefit for patients, e.g. « sodium profiles » or « ultrafiltration profiles » that are not backed by any sound physiological hypothesis and that have never been tested rigorously by double-blind protective studies over an adequate time.

Dialysis fluid supply systems accomodating conventional concentrates, cartridges and central delivery systems that have resulted in loss of compatibility and in much more complicated machines.

As a centre that trialed subcutaneous ports, my personal opinion is that they are unlikely to take over from the native AV fistula as the access of choice in the near future. However, they do have some important advantages over catheters and I do believe that for the subset of patients who have run out of peripheral access, the ports could become the access of choice.

Probably we need to spend more time working out how to optimize refilling rates for an individual patient. But in practice we probably do need to increase times for some patients.

As for the sensors monitoring the patient's refilling,in my unit we have some experience with this device. It comes with the RBV (relative blood volume). The machine measures the RBV and according to this adapts the fluid removal rate. You need to adjust the limit of the percentage of RBV before starting the dialysis session, it can go down to 70%, for example if you need to remove 4 Kg in 4 hours of treatment and you adjust it to the minimum limit of 90%, the patient will not remove all the 4Kg in this time, you will need to add dialysis hours, but if you start with RBV 70%, the patient will remove in the first hour of the dialysis session more fluids and then the rest of the dialysis will be relatively moderate, with periods of refilling according to measurements of BV.

When we start dialysis with this device, the recommendation of the company was to start slowly and do not go down to 70% because the patient do not feel well. From our experience for almost 2 years, we saw that patients do feel well even if in the first hour of dialysis the UF rate is high (2-2.5 Kg/H), after all this is the time the patient is overloaded with fluids The rest if the dialysis is really moderate, in the last hour most of the fluids are already out, and most of the patients feel very good, not tired, and say that they feel better at home too. Of course not every patient has the same refilling rate and some time you need more hours, but in most cases, at least from our experience, it works and we succeed to remove more extra fluids then in regular dialysis.

Why re-design dialysers? Our understanding of the treatment of uraemia is changing. For many years adequacy of dialysis has been confined to the removal of small molecular weight non protein bound solutes such as urea.  A variety of other compounds also need to be removed , e.g low molecular weight proteins or peptides which interfere with cell function, and as these are identified, so the requirements change.  It is virtually impossible to enhance the removal of small molecules any further without  a major cost implication, hence the future is likely to rely on hybrid therapies which involve different approaches.  Dialysis also needs to address some of the complex and contentious issues associated with outcomes or mortality.  Cardiovascular mortality is a common cause of death in patients receiving dialysis, it is even higher in patients with co existing disease such as diabetes. Both renal failure patients and patients with diabetes have elevated of advanced glycation end products (AGEs), AGEs arise from the production and inadequate removal during dialysis of modified proteins through advanced glycation and oxidation.  Advanced glycation end-product modified low density lipoprotein (AGE-LDL) and other AGE-modified proteins as well as oxidized LDL (oxLDL) are able to interact with a variety of cells and induce cell dysfunction and the release of pro-inflammatory mediators which contribute to the development of cardiovascular disease.  Current dialytic therapies ( even highflux treatments) are inadequate in their ability to normalize levels of AGE compounds such as N (epsilon) – (carboxymethyl) lysine (CML) and thus alternate rather than redesign approaches may be necessary.

One condition for optimal clearance in a dialyser is a homogeneous entry of dialysate water into the inner space of the membrane bundle.
A simple change in the geometry of the housing of a dialyser alone would not be sufficient for this purpose.  
Capillary membranes need to be separated from each other by either spacer yarns or through an ondulation of the fibers. Ondulation would allow for a non-parallel arrangement of the fibers and would thus facilitate the entry of dialysate water. A close observation of the membrane bundle through the transparent housing shows that capillaries are standardly not assembled in parallel, although this might look nicer if realized.
Some dialyser series contains micro-ondulated  membranes (also called Moiré-structures). They offer an improved dialysate entry to the bundle-center as compared to the standardly ondulated series.
Micro-ondulation and ondulation of capillary membranes is done in a separate manufacturing step during membrane production. The technique follows the experience of ondulating hair in figaro´s shop.

Sorbents are emerging as a potential method to remove some of the compounds discussed above. The potential exists to deplete the patient of important compounds by the use of sorbents, as sorbents are non selective.

Sorbents represent an interesting method to remove uremic toxins.  While it is true that most sorbents for renal replacement therapies are non-selective, they usually adsorb a basic class of molecules based on the chemical structure of the resin and the pore size within the resin.  For example, if you use a styrenic resin, it tends to be hydrophobic and adsorbs “hydrophobic” uremic toxins. Many uremic toxins are hydrophobic.  In addition many damaged proteins (oxidized, modified), also become more hydrophobic due to conformational changes. In this way, you can favor adsorption of toxins by choosing resins that have higher affinity towards the toxin and only low interactions with physiological molecules.

Resins often have an enormous surface area and the binding capacity of the resin depends on whether the uremic toxin can access the many pores contained within the bead. If the toxin is too large, it will only be able to bind to the external part of the resin bead (and you will lose most of the surface area of the resin).  The binding capacity also depends on the sorbent cartridge geometry, the quantity of sorbent and the linear velocity of the blood, plasma or ultrafiltrate. 

While it is true that it is difficult to adsorb “only toxins” and not adsorb “useful substances”, this also has to be taken into context of the treatment.  High convective treatments such as HDF would still have a greater loss than techniques that incorporate adsorption with subsequent reinfusion.  

Having worked more on the anticoagulation aspects of dialysis patients in the last months, I am asking myself, why we do not have more demands from our colleagues for better extracorporeal system with less air contact areas, optimised flow dynamic design, etc… Even if heparin is not expensive, it has major side effects – not all of them are really explored or taken into consideration in dialysis treatment.

I have read this article with interest and looking back over the past three decades whereby the patients were on dialysis for 10 hours and more, going through short treatments to ever increasing times again. I ask have we moved on and I would say yes and no. The 3 areas that have improved patients well being and quality are the introduction of erthopoetin (EPO), excellent membrane technology  (ongoing) and peritoneal dialysis (from 1986). All that I mentioned have the opportunity to allow the patient to have energy, increased post dialysis clearances and freedom from the unit (PD). All this has to be with the patients input, but I see more increased non-adherence and low compliance to treatment of any sorts in the last few years. Are we educating them enough, is it too much education they have and so feel empowered to think they know best? Are there too many patients to give proper input and support as we used to do, with fewer patients and more staff in the past?

The cardiac status of the young patient seems to have got worse even with better dialysis and EPO, maybe due to fluid overload. I agree we should look at the basics such as sodium balance, blood pressure control. I am a firm believer in that the patient, who adheres to a good dietary and fluid balance, has optimum blood pressure control and good health. These are the key success factors and all the technology in the world will not help without them.

It may well be that we have reached the summit of “the removal technology” and that better understanding of the retention of sodium will resolve many of the problems with which we are currently faced.

The only other area of improvement that I foresee is the universal adoption of endotoxin free dialysate by 100% usage of ultrafiltrated dialysate as opposed to the less than 50% currently employed.

In a recent seminar in Budapest, I learned about a new theory linking vascular calcification to inflammation. This adds to the reasons why we should aim to have ultrapure water for all patients.

It maybe that the failure to improve survival data in ESRD despite all the technical developments of the last 30 years would suggest that we need to improve the dietary care of these patients more intensively.

CLOSING WORDS by the authors

Closing remarks from Nic Hoenich:

Ideas about the technology that should become mainstream for the care of dialysis patients - below is a sort of wish list.

1. The ability to monitor vascular access performance on a routine basis. ( this is already available on some machines)
2. Clean dialysis fluid - - this is potentially possible to achieve by the use of extra filters, but requires some thought about making the hydraulic pathway more elegant
3. The ability to individualize individual electrolytes within the dialysis fluid.
4. The potential to measure dry weight and link it to blood pressure or more importantly vascular refilling rates.

I appreciate that most of these ideas are already in use is some units, but future developments need to be evidence based to justify inclusion and clinical application. Unfortunately such an evidence base in haemodialysis is not strong because units that try new ideas often don’t publish their findings.

Closing ideas from Lizzi Lindley:

In the future, I’d like to see a revolutionary new form of permanent vascular access – perhaps something like a port but with better protection from infection.

I’d also like to see HD machines that are small enough for patients to carry around so that they can work away from home and enjoy more holidays. And it would be good if these machines could be more selective and mimic more of the functions of the kidney.

Closing remarks from John Stoves:

The major issues in renal transplantation are achievement of immunotolerance and improvement in long-term transplant and patient survival. There is an inevitable trade off between the beneficial and detrimental effects of chronic immunosuppressive therapy, and whilst we aspire to the Holy Grail of immunotolerance it is imperative that we continue to explore different immunosuppressive strategies to maximise transplant performance and reduce patient morbidity and mortality. There is generally a movement away from corticosteroids and long-term use of calcineurin inhibitors such as cyclosporine and tacrolimus.

In the UK there is also a great deal of interest in reducing patient waiting times for renal transplantation through promotion of living donation and non-heart beating donation programmes. A recent nationwide Potential Donor Audit of heart beating donors revealed that consent for solid organ donation was given by the next of kin in only 52% of cases and it is hoped that this proportion will increase as a result of education and awareness programmes directed at the general population.

 Advances in the detection and characterisation of anti-HLA antibodies (PRAs) have increased the likelihood of a negative pre-transplant crossmatch investigation and this should lead to shorter cold ischaemia times for cadaveric transplants. One of the contributors to the JC discussion has also alluded to pre-transplant PRA reduction using IvIg and this may well be the key to improving opportunities for highly sensitised patients (typically those who have had previous pregnancy/ blood transfusions/ allogeneic transplants).  

Jean-Yves DE VOS (Belgium)
EDTNA/ERCA JC Manager