Progress in dialysis technology—clinical benefit vs increased complexity and risk. Report on the Dialysis Opinion Symposium at the ERA–EDTA Congress, 7 June 1998, Rimini

Ingrid Ledebo1, on behalf of: Claudio Ronco2, Ralph Schindler3, Roger Greenwood4, Antonio Santoro5 and Fernando Valderrábano6

1 Gambro Research, Lund, Sweden, 2 St Bartolo Hospital, Vicenza, Italy, 3 Charité/Virchow Klinik, Berlin, Germany, 4 Lister Hospital, Stevenage, UK, 5 Policlinico S.Orsola-Malpighi, Bologna, Italy, and 6 Hospital Gregorio Maranon, Madrid, Spain

Correspondence and offprint requests to: Ingrid Ledebo PhD, Gambro Research, Box 10101, S-220 10 Lund, Sweden.

Introduction

During the 1997 ERA–EDTA Congress and ASN meeting, held in Geneva and San Antonio respectively, a questionnaire was distributed to the participants asking their opinion on a number of issues relating to dialysis machine functions. Close to 2500 responses were collected, the majority from European nephrologists (Table 1Go).


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Table 1. Nationalities of the doctors responding to the Dialysis Opinion poll during the ERA–EDTA Congress and the ASN meeting in 1997
 
The results were presented during the ERA–EDTA Congress in Rimini in June 1998, in the Dialysis Opinion Symposium, chaired by E. Ritz. An invited group of experts presented their personal opinion on the different technological issues and the scientific evidence upon which it was based.

Backfiltration in dialysis

Question.
Volume control is a feature of modern dialysis machines that allows predictable weight loss. However, in most haemodialysis procedures it also involves some backfiltration of dialysis fluid. When standard dialysis fluid is used what is your opinion about such uncontrolled backfiltration?

Answer.
See Figure 1aGo.



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Fig. 1. Responses from 2475 doctors at the 1997 ERA–EDTA Congress and ASN meeting to questions about technical issues related to dialysis machine functions. (a) Backfiltration in dialysis; (b) ultrapure dialysis fluid; (c) on-line preparation of substitution fluid; (d) continuously measured parameters; (e) biofeedback.

 
Comments by C. Ronco:
During the 80s, backfiltration in dialysis was a highly controversial issue and by judging from this question, it has not been resolved [1]. Backfiltration is defined as the reverse flux of water across the dialysis membrane from dialysate into the blood, in response to a local negative TMP, which can be hydrostatic as well as osmotic in nature. We normally associate backfiltration with high-flux dialysis i.e. high-flux membranes used with volume-control and limited ultrafiltration. However, it can be shown that local backfiltration may take place also when the UF rate exceeds the so-called critical ultrafiltration [2]. Thus it is practically impossible to avoid backfiltration.

The concern about backfiltration is mainly associated with the risk of contaminants from the dialysis fluid reaching the blood. Standard dialysis fluid contains microbial contaminants, which may come into contact with the blood via backtransport. Larger molecules are carried across the membrane by backconvection in connection with backfiltration, while smaller molecules are transported by backdiffusion. Thus the risk of microbial contaminants reaching the blood is not limited to situations where backfiltration occurs. Even if we try to limit the backfiltration as much as possible, by maintaining a positive TMP, we may have some backtransport of pyrogens. This makes dialysis fluid quality the key issue.

Having accepted that backfiltration cannot be avoided, we should instead make use of it to increase the convective transport. Our group has shown that the clearance of large solutes increased significantly when we applied a constrictor to the fibre bundle, thus increasing the pressure drop and the backfiltration [3].

My personal answer to the question agrees with the majority in that backfiltration should be avoided when standard dialysis fluid is used. However, knowing that this is practically impossible we should first make sure that we are using ultrapure fluid and then benefit from backfiltration as a good way to increase the convective transport.

Ultrapure dialysis fluid

Question.
Standard dialysis fluid contains bacteria and endotoxin. As there is evidence that bacterial products in the fluid may activate the blood cells, when low-flux as well as high-flux membranes are used, demands are raised to improve the fluid quality. What is your opinion about using ultrapure dialysis fluid in haemodialysis?

Answer.
See Figure 1bGo.

Comments by R. Schindler:
Ultrapure dialysis fluid, usually obtained by ultrafiltration, is characterized by a bacterial count of <1 c.f.u./ml in contrast to the European Pharmacopoeia that recommends <100 c.f.u./ml. The major biological consequence of contaminated dialysis fluid is the induction of cytokines and a subsequent inflammatory reaction in the patient. Based on this I feel that dialysis fluid should be as clean as possible and the importance of using an ultrapure fluid must not be neglected. It is interesting to ask what the reason could be for anyone to disagree with this.

First, some may think that cellulosic, low-flux membranes are safe barriers against bacterial products. This is certainly not the case; there are several studies demonstrating that during contaminated in vitro dialysis, all tested dialysis membranes are permeable for cytokine-inducing substances. There appears to be even more permeation of bacterial products through cellulosic, low-flux membranes than through synthetic, high-flux membranes [4]. Second, some may argue that the European Pharmacopoeia standards are sufficient and that it is not necessary to purify the dialysis fluid further. However, the level of bacterial contamination depends on the culture conditions. If suboptimal culture conditions are used the bacterial count may underestimate the true contamination by a factor of 103 to 104 [5]. Moreover, we observed no correlation between bacterial counts and IL-6 induction by dialysate samples; i.e. even dialysate samples containing only few bacteria/ml may contain large amounts of IL-6-inducing substances [6]. Ultrafiltration removes these cytokine-inducing substances effectively. Third, some may argue that there are no prospective studies demonstrating an effect of ultrapure dialysis fluid on morbidity and mortality in dialysis patients. This is certainly true, but there are studies demonstrating a reduction of cell-associated cytokines and therefore an inflammatory process by the use of ultrapure dialysis fluid in vivo [7]. Evidence that an inflammatory process may contribute significantly to morbidity, such as accelerated atherosclerosis comes from animal studies in which the chronic administration of IL-1 leads to neointimal proliferation and vasospasm of coronary arteries [8]. Furthermore, several studies demonstrated that elevated levels of C-reactive protein predict cardiovascular events [9,10]. Thus, a link between inflammation and cardiovascular morbidity has been established that makes a possible induction of the inflammatory process by contaminated dialysate highly undesirable.

It is reassuring to see that such a large majority among the respondents also finds the use of ultrapure dialysis fluid in all forms of dialysis to be important.

On-line preparation of substitution fluid

Question.
To remove large solutes from blood during dialysis, convective transport should be applied. This requires highly permeable membranes and large ultrafiltration volumes. The need for replacement fluid can be fulfilled by on-line preparation, i.e. stepwise ultrafiltration of dialysis fluid. What is your opinion about on-line preparation as a way of preparing a sterile and pyrogen-free fluid for infusion?

Answer.
See Figure 1cGo.

Comments by R. Greenwood:
The main reason for wanting to use convective dialysis methods such as haemodiafiltration, is to be able to reduce the plasma levels of ß2-microglobulin, the 12 kDa molecule that is intimately associated with long-term complications in dialysis patients. With high-volume haemodiafiltration we and others have shown that the plasma level of ß2-microglobulin can be reduced by half, which may contribute to delayed appearance of dialysis-related amyloidosis [11]. To achieve this the convective transport needs to be maximized in relation to blood flow rate and treatment time, and UF volumes of at least 20 litres should be applied. This clearly makes the use of commercially available substitution solution in bags too expensive and on-line fluid preparation is the only realistic possibility. In comparison to backfiltration, on-line preparation of infusion solution is a highly controlled procedure that requires attention to standards and disciplined disinfection routines. Having access to practically unlimited volumes of this fluid we can use it to replace saline and also for regular flushing in heparin-free dialysis. The fluid composition is safeguarded by the principle of double systems in the dialysis machine, the probability of both failing at the same time being infinitesimal. The microbiological quality of the fluid is assured by the use of redundant retention capacity of ultrafilters that are quality-controlled in production and that are exposed to a calculated burden of bacterial products. Our own experience from over 55 000 treatments involving infusion of over one million litres of on-line prepared solution, shows that this works very well, as long as the routines for disinfection are followed. We have had eight pyrogenic reactions and all of them could be associated to breakdown of manual procedures. The answer to this must be automated disinfection. My personal opinion is that on-line fluid preparation is possible, desirable, and creates flexibility in dialysis therapy. It is a valuable new technique, which can be safely performed with modern machines designed for the purpose. I am pleasantly surprised to learn that there is such a widespread opinion in favour of on-line fluid preparation and hope that this will help overcome the barriers put up by regulatory authorities to this new technique which cannot be judged using old guidelines.

Continuously measured parameters

Question.
Having access to the extracorporeal circuit, the dialysis process can be followed by measuring different parameters. The following functions could be integrated in your dialysis machine and be measured accurately and continuously during the treatment. Which function would you choose to have first?

Answer.
See Figure 1dGo.

Comments by A. Santoro:
From a bioengineering perspective, conventional haemodialysis (HD) could be considered as a process in which a controller, the dialysis machine, works on a system, the patient, by using some actuators that can be different from one case to another, but always referring to the same principles—diffusion and convection. During the treatment the patient is considered like a black box because the clinical surveillance is limited to occasional measurements of body weight and blood pressure. On the other hand, over the past few years the progressive increase in the mean age of chronic dialysis patients along with the growing conditions of co-morbidity such as cardiovascular diseases and diabetes, have significantly increased the clinical critical status of the patients undergoing dialysis. The major repercussions of this clinical complexity can be observed in terms of the symptoms and inadequacy of the HD sessions, which have witnessed the recrudescence of haemodynamically unstable events and a greater incidence of morbidity.

The technological response to ensure an adequate dialysis even to susceptible patients may be the development of systems and sensors aimed at continuous measurement of various physiological patient parameters. But the indispensable pre-requisites for a sensor to be used in HD are: its absolute non-invasiveness, the tolerability on the part of the patient, the continuity and the accuracy of the measure, and an acceptable cost that will no further inflate dialysis treatment costs. In the recent past, some applications and studies on the concept of on-line monitoring have been described, all of them aimed at control of some patient parameters, such as blood volume [12], urea removal [13], ionic dialysance [14], temperature [15]. The on-line monitoring systems have been most useful in high efficiency, short-lasting dialysis procedures, since the risk of being `unphysiological' is so much greater when the treatment times are shortened [16]. The greater the depurative efficiency, the shorter the treatment time, the more accurate the control of dialysis adequacy will have to be. However, besides on-line monitoring there is another ambitious target in the HD technology—moving from a standard HD machine to a biofeedback machine with some additional blocks: biosensors, a physiological adaptive controller (which properly drives the dialysis machine in order to respect the medical prescription and patient tolerance), and a safety system extension.

As a first step towards this goal, I feel that continuous measurement of blood volume is the most valuable. We can use it for determining the individual threshold for ultrafiltration, in particular in volume-sensitive patients, to better define the patient dry body-weight, to prevent the appearance of hypovolaemic hypotension. Moreover, the automatic control of blood volume may be easily obtained by appropriate algorithms [17]. Furthermore in high-efficiency dialysis a continuous measure of urea removal or an indirect measurement of urea clearance obtained by ionic dialysance [14] could avoid the risk of major discrepancies between the prescribed and the delivered dialysis dose.

Looking at the response from my fellow nephrologists around the world, I note that sensors for blood flow rate, blood volume, and urea are of similar high interest, but there are considerable geographical differences. It is clear that the availability of different sensors governs the interest and this may indicate, not the refusal of the technological innovations, but that only when we get access to a certain technique can we appreciate what it can be used for.

Biofeedback

Question.
Biofeedback is the term used about automatic control of different dialysis parameters by a measured clinical value and an algorithm, e.g. letting the change in blood volume control the UF rate and the sodium concentration during dialysis. What is your opinion about such automatic actions by the dialysis machine, where no operator is involved?

Answer.
See Figure 1eGo.

Comments by F. Valderrabano:
This is a question for the future. We have witnessed many advances in haemodialysis technology during the past couple of years, such as volume control, ultrapure dialysis fluid, on-line fluid preparation, and on-line monitoring of various parameters. There are two processes that I would like to use in my discussion of biofeedback. The first is on-line urea kinetic monitoring, which means that some component of urea removal is continuously measured, and based on this the urea kinetics are calculated [18,19]. This enables us to adjust the dialysis parameters so that the prescribed dose of dialysis can be delivered. If we take a step beyond the on-line monitoring, the machine should make the necessary adjustments in flow rates or treatment time automatically and we could always be sure that the prescribed dose of dialysis is delivered.

The second example is on-line monitoring of blood volume, often based on measurement of haemoglobin concentration or haematocrit. This is helping us to achieve dry weight, avoid hypotensive episodes, improve tolerance of the dialysis session, and improve the control of hypertension [20]. Again, if we could programme the dialysis machine with the right information, it could automatically adjust the UF rate and the sodium concentration to achieve dry weight without symptoms. In my opinion both these examples of biofeedback would be very useful and would represent a major advance in dialysis technique during the next decade. To go from on-line monitoring to biofeedback should represent a minor incremental cost, as no extra disposable materials are needed. Still, the additional cost must not be large, since it is difficult to demonstrate direct savings. I am happy to see that the majority of the respondents share my belief in progress.

Discussion

During the concluding discussion the majority of the panel members expressed strong confidence in future technology. It was emphasized that new technology, although complex in nature, should be used to achieve simplicity in operation.

Dr Greenwood cautioned about the optimism expressed by other panel members in biofeedback, although he recognized this was a worthwhile goal. The closed-loop control of dialysis has remained elusive for years, chiefly because of the complexity of the physiological response to dialysis. At the moment the doctor and the nurse remain the most important instruments of biofeedback.

References

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