Progress in dialysis technology: membrane selection and patient outcome

Francesco Locatelli1,, Fernando Valderrábano2, Nicholas Hoenich3, Jürgen Bommer4, Karel Leunissen5 and Vincenzo Cambi6

1 Azienda Ospedale di Lecco, Lecco, Italy, 2 University Hospital Gregorio Marañon, Madrid, Spain, 3 Department of Nephrology, School of Clinical Medical Sciences, University of Newcastle, UK, 4 University Hospital, Heidelberg, Germany, 5 University Hospital, Maastricht, The Netherlands, and 6 Department of Clinical Medicine, Nephrology and Preventive Medicine, University of Parma, Italy

Introduction

Locatelli: When the need for dialysis arises, there are many different ways to treat patients, none of them necessarily wrong, but more agreement is needed on some of the basic techniques. In particular, there is still no consensus on the quality of dialysis treatment.

National differences

Locatelli: Let us start with an overview on possible national differences in the prevalence of patients with chronic renal insufficiency (CRI) on substitutive treatment by dialysis, in the distribution of treated patients among public, private and no profit centres, hospital centres, limited care, and home haemodialysis and in the percentage of patients treated by haemodialysis or peritoneal dialysis (either CAPD or CCPD).

Bommer (see also appendix, section 1): The total number of dialysis patients in Germany is increasing by about 8% per year and the latest figure of 48 000 is probably an underestimate. The underlying renal diseases are changing in the population, in particular the number of diabetics is continuously increasing [1]. Patients are getting older and these should be treated as effectively as the others, because data show that the most striking benefit of adequate dialysis is achieved in this age group [2]. Previously, patients were predominantly treated in hospitals. At present the split is one third in hospital centres, one third in private centres and one third in non-profit centres. This may also influence treatment strategies in the future. Approximately 40% of patients are dialysed with low flux membranes, despite recent data suggesting that high flux membranes prevent several complications in long-term haemodialysis [35]. Price considerations play a role in the decision making process.

Leunissen (see also appendix, section 2): In the Netherlands we are trying to establish guidelines in order to reach a cost-effective, evidence-based treatment strategy. The Registratie Nierfunctievervanging Nederland (RENINE) has provided much valuable information. The vast majority of patients up to 44 years of age are transplanted, with only 30% remaining on dialysis. In the age group of 45–64 years most patients are transplanted, using either a living donor or a cadaveric donor. There has also been a marked increase in elderly patients and about 20% are transplanted with a cadaveric donor kidney. About 15% are on peritoneal dialysis but most patients are on centre haemodialysis. The number of patients on haemofiltration is small (about 2% or 3%) because there is no special reimbursement for patients treated with haemofiltration. There is an increase in cardiovascular diseases and diabetes as primary causes of renal failure, especially for the older age groups.

Hoenich (see also appendix, section 3): The picture in the United Kingdom (UK) is incomplete. Under the reorganization of the National Health Service (NHS), agreement has had to be reached with district health authorities as to how many new patients should be treated; any increases in numbers have to be funded from resources allocated to the district health authorities. There are considerable differences between the different regions in the UK in their acceptance rates. In 1997 for a 60 million population there were 56 main units centred in large teaching hospitals or district general hospitals. The total number of dialysis stations in these centres was 1520 (median 23 in each dialysis unit) and the median shift per week was 18. There were also 63 satellite units in England and Wales treating a further 1540 patients utilizing a further 500 dialysis stations. In 1993, 19 212 patients received renal replacement therapy (RRT) compared to 23 115 in 1995. The treatment distribution was 20% on hospital haemodialysis, 4% on home haemodialysis, 23% on CAPD, with nearly half of the patients receiving transplantation. The median age for acceptance in 1995 was 61 years; 43% of the patients were older than 65 years and 15% were older than 75 years. The male : female ratio was 1.6 : 1.

Valderrábano (see also appendix, section 4): The total number of chronic dialysis patients in Spain is now 17 800 (more than 16 000 patients are treated by haemodialysis) representing around 454 per million population (pmp). The number of transplants performed per year is around 50 pmp (the highest rate in Europe). The estimated number of patients living with a functioning graft is around 14 000; thus about 60% of the patients are being treated by dialysis and 40% with a functioning graft. Both the number of transplants and the total number of dialysis patients have been increasing by about 5% per year. There are two types of centres: 50% public and 50% private. The rate of reimbursement for the private centres allows them to perform only bicarbonate or acetate haemodialysis (about US$140 per treatment at present). High flux haemodialysis and haemodiafiltration are not reimbursed, therefore these techniques are only performed in hospitals, with the exception of one company.

Cambi (see also appendix, section 5): There is no uniformity in treatment between northern and southern Italy. The average transplantation rate in northern Italy is similar to the rest of Europe but is more than 50% lower in the south; this is why the total number of transplants is relatively low and why haemodialysis is so well developed in Italy (a prevalence of 593 patients pmp, even higher than in Germany). Peritoneal dialysis has always been stagnant in Italy; some units still perform CAPD or automated APD in about 50% of their patients but the average has not changed over the last 15 years. The number of new dialysis patients is less than 8% per annum but there is a problem in northern Italy in providing treatment for new patients. There is an average of between four and six patients per station and patients are often treated up to midnight.

Membrane selection and patient outcome

Locatelli: The other topic of this forum is the selection of an adequate dialysis membrane. When considering membrane selection, dialyser membrane area, biocompatibility, sieving coefficient and the flux have to be taken into account. We have to discuss the theoretical advantages of different types of membrane according to a number of factors, including cardiovascular stability [68], preservation of residual renal function [9,10], nutritional aspects [11], lipid profile [1215], infection, anaemia [16], ß2-microglobulin (ß2M) removal [17,18] and morbidity and mortality (in general terms as well as specifically related to ß2M deposition) [5,1922]. Perhaps we could start by discussing the surface area of the membrane.

Valderrábano: The importance of the surface area depends on the type of membrane. In my unit the recent trend has been to use large surface area membranes in general.

Cambi: Once, there was only one type of membrane (Cuprophan). The subsequent introduction of many variables decreased the importance of the membrane surface area. I feel that we should not worry too much about it (historically, the area was between 1 and 1.5 m2).

Hoenich: I agree the historic preoccupation with surface area is no longer relevant. Perhaps we ought to be deciding on a new parameter which combines the surface area with the membrane sieving coefficient, because we are interested in removing a wide range of metabolites. The increase in surface area, whilst beneficial in respect of large molecule removal, does not necessarily mean optimally increased small molecule removal.

Bommer: There is an earlier flattening of clearance with increasing blood flow velocity in dialysers of small surface area, in comparison to larger dialysers. We have to discuss whether it is better to increase blood flow or dialyser size. I favour larger dialyser areas because the use of large surfaces increases not only urea removal, but also the removal of other compounds.

Locatelli: What type of membranes do you think is important regarding morbidity and mortality? I would first like to discuss the study by Hakim et al. [19] on the effects of different types of membrane, showing a 20% lower mortality in patients treated with modified cellulosic and synthetic membranes in comparison with cellulosic membranes. I would like to point out that this report was not based on a prospective randomized trial, but was a Registry study (a so called ‘historical prospective’ study).

Hoenich: The data reflects the delivery of dialysis in the United States in 1994. There is a problem in extrapolating differences in membranes to clinical outcome and it might be more appropriate to focus on the overall quality of treatment, of which biocompatibility represents one factor.

Locatelli: We did not find any difference in mortality and morbidity in our study among 380 patients who were randomized to either low flux haemodialysis with biocompatible and bioincompatible membranes or to high flux haemodialysis and haemodiafiltration [18]. However, the trial was not designed to evaluate a possible difference in morbidity and mortality, and the observation period of 24 months did not allow us to obtain any significant evaluation of possible long-term differences. In another study [5] of 6440 patients treated in Lombardy between 1983 and 1995 we found that the relative risk for mortality, although not significant, was lower when convective membranes were used (-10%). However we observed, in agreement with a Japanese study [4], that the relative risk for carpal tunnel syndrome surgery was 44% lower in the patients treated with haemodiafiltration or haemofiltration than in those treated with standard haemodialysis, thus supporting the importance of convective treatment in reducing morbidity from ß2M deposition.

Valderrábano: I would like to remind you that low flux polysulfone and high flux polysulfone membranes differ not only in efficiency but also in biocompatibility.

Leunissen: The relative effect of biocompatibility is so small that it is hard to prove its importance in preventing morbidity or mortality. I have been a member of the working party on the ‘Best European Guidelines for Anaemia’ and we found it difficult to develop an evidence-based consensus. Consensus-based guidelines should also be set up for doctors working in the field on the use of membranes in relation to surface area, high flux, low flux and biocompatibility. There have been more than 3000 papers published on biocompatibility. It is impossible for a doctor in everyday clinical practice to oversee this.

Bommer: We were all ‘biocompatibility believers’ but we now realise that it didn't take us much further forward. Cost effectiveness will be the main issue in the future. In my opinion it is also important to develop membranes which reduce activation of coagulation, thus reducing the use of heparin. In addition it may also be important to increase the ß2M flux across the membrane, in order possibly to reduce carpal tunnel syndrome.

Valderrábano: The use of high flux biocompatible membranes has not been shown to reduce the production of ß2M.

Locatelli: Despite the large number of published papers on the biological effects of bioincompatibility of dialytic membranes and their consequences, which stress the biological superiority of synthetic membranes, proof of a causal relationship with clinical diseases and biological reactions is scarce and the real impact of biological effects on clinical status is still debatable [18,23]. Moreover, it still needs to be clarified whether improvements in dialytic treatment are only due to membrane biocompatibility, or also to the difference in clearance of medium-sized molecules, the increasingly recognised clinical importance of high flux treatment, or possible interactions between biocompatibility and membrane flux.

Technology versus price

Cambi: I feel companies are making life unnecessarily complicated with their technology and commercial considerations. If it is true that really we do not need special membranes, if it is true that simple, non-biocompatible cellulosic membranes in everyday use can give you a much better or at least a similar result than all the complicated membranes, then I think that we should reconsider what we need from a company. If you consider that millions of people need this treatment, this is the real issue. Technology should concentrate on producing inexpensive equipment. We must think about a new way to treat patients, for instance abolishing the use of personnel and the use of dialysis centres. This is a new way to consider the problem. I would like to compare the search for intelligent membranes to the production of Ferraris, good for the rich few but of no use to the millions who drive ‘cheap’ Japanese cars.

Valderrábano: I disagree. It is true that in the past Cuprophan saved the lives of hundreds and thousands of patients [2] but this was not a reason to stop research into membranes. We still do not know exactly what we are going to extract from the patient during dialysis and we do not know enough about other rare or low-molecular weight toxins. New membranes are necessary to improve performance and to achieve better treatment for patients.

Hoenich: The priority seems to be to focus on the adequate removal of small molecules. The overriding need is to develop dialysers which are capable of adequately removing both small and large molecules [24]. This raises the question of whether you believe in small molecule removal or large molecule removal being the most important issue. A second approach might be to go right back to basics. If you say to yourself today: ‘I know nothing about renal failure, how should I treat this patient?’, I suspect that we would probably select a highly diffusive membrane. I think we would probably go for the same type of system that the human kidney utilizes, namely filtration. Our conception of dialysis treatment has evolved out of a historic approach and we need to review this. I accept Vincenzo Cambi's comments on unnecessary technology, but I would like to know if we would really like to go back to dialysing patients with a Kolff dialyser just because it was cheaper and simpler. What we have done is moved along, but at a price that we cannot really afford.

Bommer: I think that there should be a two-step approach. My information from India (where only 3% of the people with end-stage renal disease (ESRD) can be treated because of lack of money) [25,26] have convinced me that the most simple treatment is necessary, to keep these patients alive and to treat as many as possible in the cheapest way. But this does not mean that we should be satisfied with the way we are treating our patients at this moment. I agree with Nicholas Hoenich that we should try to improve dialysis therapy by looking at the function of the native kidney: this works much better than dialysis therapy today, removing more substances more efficiently. I don't know what kind of substances these are and what the harm is of them remaining in the blood, but I think that we should try to mimic the native kidney by more convective transport.

Locatelli: Thus we are looking now at the other side of the problem: if a patient is dying, what can be done to keep him alive?

Valderrábano: I suggest that, whilst patients in the Third World would be very happy with the possibility of two dialyses per week and to live with conventional dialysis using Cuprophan, the question remains: in what direction is haemodialysis going in the future?

Locatelli: I completely agree with the opinion of the panellists that we should be looking for the simplest and cheapest treatment possible to keep alive the patients that are dying at present, and, unfortunately, they are the majority. However, at the same time we should try to improve treatment quality as much as possible, or at least to find the best technical and clinical solutions and discuss the price only thereafter. Then we can decide whether or not to use it in everyday clinical practice and whether or not we can afford it.

We should try to summarize the treatment considerations as far as biocompatibility of membrane in relation to cardiovascular stability is concerned. I think, according to our discussion today, that the argument that biocompatibility improves the cardiovascular stability and well-being of patients is a weak one [6,7,11,18,27]. However, I would like to underline that atherosclerosis is one of the most important problems in our divisions [28,29], with common lower limb amputations, not only amongst diabetic patients but also in many non-diabetic patients.

Hoenich: I think it is puzzling that there are no important effects from membranes from the clinical point of view. However, there are a number of biological effects and the question is, can we translate these into a clinical outcome, for example, an increased incidence of infection?

Leunissen: Biocompatibility may be related to infection, inflammation and long-term cardiovascular atherosclerosis [3034].

Cambi: The concept of atherosclerosis as an inflammatory disease is a relatively new one [34], but increasingly important.

Valderrábano: It is clear that haemodialysis induces an inflammatory response [31]. What is not clear is the clinical significance of this inflammatory response in the different complications of dialysis patients.

Locatelli: I would like to invite all the panellists to give their opinions on what the dialysis industry should do to improve patient care and satisfy the needs of both patients and physicians.

Bommer: I think that price plays a major role in the selection of high or low flux dialysers. In parts of Germany there is no longer additional reimbursement for high flux dialysers, therefore the use of these will decrease.

Valderrábano: The Spanish Society of Nephrology has been trying to get the health administration to pay a supplement for high flux membrane usage. To date, only one region has accepted this concept but is placing limitations on the percentage of patients using high flux membranes.

Leunissen: In the Netherlands reimbursement is fixed. However, we are trying to get a real cost price reimbursement. We have defined quality control in dialysis treatment and according to the quality of the treatment and to the recommendations given, the government will pay for the cost of this treatment. If evidence-based medicine shows that using a high flux membrane is better in terms of morbidity for the patient, the government will provide additional money.

Hoenich: It is very obvious, from what we have heard and discussed, what industry should be doing to improve patient care. They need to look at their pricing structures, reduce the difference between standard and high flux membranes and perhaps introduce prospective controlled studies to establish whether there are benefits in using high flux membranes.

Valderrábano: I would urge the industry to support research and studies.

Bommer: There is little evidence that many of the new modalities, machines and membranes on the market have significant advantages over existing products. The pharmaceutical companies have to prove that a drug works before bringing it to market. I suggest that dialysis equipment manufacturers should adopt similar strict policies, and clearly document the benefits of new developments.

Locatelli: I would like to conclude by pointing out that proving efficacy and advantage of any kind of treatment requires clinical trials [35,36]. These are very costly and can only be carried out with the support of the industry, because public support is lacking. Perhaps we should try to ask the European Community to support such research programmes but I guess that it will be very difficult to obtain funding.

Consensus on membrane selection and patient outcome

Locatelli: It is time to summarize the areas of agreement in membrane selection. The points of agreement are the following.

(i) Surface: is not really important any more (at least over 1.2–1.5 m2, depending on the blood flow of each patient).
(ii) Biocompatibility (and high flux): no marked advantages known at present, unless new ones are detected from the clinical point of view (well-known biological effects).

Let me thank very much all the panellists for their active and productive discussion and above all for having made a tremendous effort in overcoming their personal opinions to try to reach a general consensus.

Appendix

National differences in renal dialysis
The following data have been taken from these sources: EDTA registry returns, Perilon database, RENINE, Membrana GmbH market research report, Unpublished data. They record the following for the latest available year, 1998: total patients under treatment for each modality in a given country, total patients under treatment as a rate per million population, new patients during the year as a rate per million population. The notes under each table compare the relative situations in the countries covered. Data on France (Section 6) are included, although these were not discussed by the faculty in the Accord Workshop. There may be some minor variations with the information supplied by the faculty in the first part of the Accord Workshop

Section 1: Germany
Population: 81.7 million

Modality Patients under Treated New
treatment patients patients




pmp

pmp

Transplantation 15 441 (24%) 189 30
Haemodialysis 45 766 (71%) 560 145
Peritoneal dialysis 3473 (5%) 42 17
Total 64 680 (100%) 791 162*

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

Notes

Germany has the highest number of patients under treatment for ESRD in Europe.

This is mainly due to the very large population of haemodialysis patients, supported with a strong transplantation sector, although the proportion of PD patients remains low at 5%.

The number of new patients remains high for both haemodialysis and transplantation.

Section 2: The Netherlands
Population: 15.5 million

Modality Patients under Treated New
treatment patients patients




pmp

pmp

Transplantation 4290 (50%) 277 29
Haemodialysis 3053 (36%) 197 57
Peritoneal dialysis 1246 (14%) 80 24
Total 8589 (100%) 554 81*

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

Notes

Statistics for ESRD treatment are carefully documented in the Netherlands.

The overall treatment rate is relatively low.

Transplantation plays the largest part, although the new patient rate is only average.

The peritoneal dialysis sector is proportionately larger.

Haemodialysis has not developed as far as might be anticipated (the number of new patients is lower than in the UK).

Regulations do not allow private sector dialysis facilities.

Section 3: United Kingdom
Population: 58.6 million

Modality Patients under Treated New
treatment patients patients




pmp

pmp

Transplantation 15 689 (54%) 268 25
Haemodialysis 8162 (28%) 139 55
Peritoneal dialysis 5322 (18%) 91 32
Total 29 173 (100%) 498 87*

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

Notes

The UK was one of the forerunners in Europe of ESRD treatment.

However, in recent years there has been a lack of resources devoted to the therapy and thus, inadequate treatment rates have been noted.

The overall treatment rate is only 2/3 that of Italy, Spain and Germany, and the previous high transplantation rate has decreased to below average.

Due to cost, the haemodialysis sector has been neglected in favour of peritoneal dialysis, which until recently accounted for half of the patients on chronic dialysis.

However, lack of long-term adequacy of peritoneal dialysis has prompted an increase in haemodialysis facilities, although the number of new patients is still less than half of that of other large countries.

Section 4: Spain
Population: 39.1 million

Modality Patients under Treated New
treatment patients patients




pmp

pmp

Transplantation 11 142 (39%) 285 45
Haemodialysis 16 327 (56%) 418 104
Peritoneal dialysis 1477 (5%) 38 16
Total 28 946 (100%) 741 120*

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

Notes

Spain has increased the treatment of ESRD in recent years and is now running close behind Germany in overall treatment and new patient rates.

Most notable is the large number of transplant patients and the continuing high number of new patients of 45 pmp, a result of the conscious decision some years ago to concentrate on organ replacement.

Haemodialysis therapy has been developed and the new patient rate is now similar to that in Italy.

Section 5: Italy
Population: 57.7 million

Modality Patients under Treated New
treatment patients patients




pmp

pmp

Transplantation 9856 (20%) 171 24
Haemodialysis 34 214 (69%) 593 104
Peritoneal dialysis 5203 (11%) 90 26
Total 49 273 (100%) 854 130*

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

Notes

The overall treatment rate in Italy for ESRD is the highest in Europe, mainly due to a high concentration on hemodialysis (at 593 pmp, this is even higher than that of Germany).

This is augmented by a peritoneal dialysis penetration rate of 11%.

Whilst the transplantation rate is lower than average, the peritoneal dialysis sector is more developed.

Section 6: France
Population: 58.1 million

Modality Patients under Treated New
treatment patients patients




pmp

pmp

Transplantation 12 255 (33%) 211 28
Haemodialysis 21 950 (60%) 378 89
Peritoneal dialysis 2603 (7%) 45 22
Total 36 808 (100%) 634 111*

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

*The total does not include the new transplanted patients pmp (who almost all come from the existing pool of RRT patients).

Notes

France has a fairly high overall treatment rate of 634 pmp, predominantly from the haemodialysis sector.

The overall new patient rate is not particularly high at 139 pmp.

For haemodialysis, the new patient rate is 89 pmp, significantly lower than in both Spain and Italy.

The transplantation rate is now only 28 pmp.

Acknowledgments

This report comes from the first ‘Accord Workshop’ which took place in Stresa (Italy) in June 1999. The other topic discussed—objectives in the pre-dialysis phase—will be reported in a subsequent issue of Nephrology Dialysis Transplantation. The Accord programme is an independent initiative supported by Membrana GmbH, seeking to bring about European consensus on important treatment and management issues in nephrology and dialysis, to help optimize clinical outcomes for patients. (More information can be found at the Accord website: www.accord-online.com) We would like to thank Kadija Roudi, Helen Wright, Lucia Del Vecchio, Marco D'Amico, Fanny Dell'Oro and Daniela Ravasio for their help in editing the manuscript.

Notes

Correspondence and offprint requests to: Prof. Dr Francesco Locatelli, Department of Nephrology and Dialysis, Azienda Ospedale di Lecco, Via Ghislanzoni 22, I-23900 Lecco, Italy. Back

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