2006/3 EDTNA/ERCA Journal Club Discussion Summary 

Should we provide ultrapure dialysis fluid?

An Edtna-Erca Journal Club (Winter 2006) discussion based on "Ultrapure dialysis fluid - how pure is it and do we need it" by Dr Ingrid Ledebo PhD of Gambro Corporate Research, Sweden.

Compiled by: Gareth Murcutt¹, based on contributions from Stanley Shaldon², Jean-Yves De Vos³, Elizabeth Lindley⁴, Robert Greening⁵, Susan K Hansen⁶, André Stragier³, Ray James⁴, Nic Hoenich⁴, Simon Brooke⁴, John Mahalko⁶, Ingrid Ledebo⁷

Abstract

The paper discussed during winter 2006 was an editorial in Nephrology, Dialysis and Transplantation (NDT) entitled "Ultrapure dialysis fluid - how pure is it and do we need it" by Dr Ingrid Ledebo PhD of Gambro Corporate Research, Sweden. Thirteen people from seven different countries contributed to the wide-ranging discussion whose topics ranged from the most cost effective way of producing ultrapure dialysis fluid (UPDF) to the environmental impact of heat sanitisation and the industrial-scale bleeding of the Limulus horseshoe crab. Different methods of disinfection such as heat and UV light were discussed as well as the requirement and funding for microbial detection assays and their various sensitivities.

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Keywords

Ultrapure, dialysis fluid, water treatment, environmental impact.

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Introduction

The paper selected for discussion by the EDTNA-ERCA Journal Club (JC) in Winter 2006 was “Ultrapure dialysis fluid - how pure is it and do we need it” by Dr Ingrid Ledebo PhD, of Gambro Corporate Research, Sweden [1]. In the paper, Dr Ledebo examined what is meant by the term ultrapure dialysis fluid (UPDF), how its definition has changed, and whether there is a clinical requirement to provide UPDF. The author also examined some of the cost issues and testing methodologies involved. Dr Ledebo concluded that UPDF should be included in clinical guidelines and identified the perceived costs, rather than the science, as the main barrier to its universal acceptance. All of these issues were visited and expanded upon during the JC discussion, which also examined some differences in reimbursement schemes and the potential environmental impact of providing and maintaining UPDF.

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Do we need ultrapure dialysis fluid?

Overall, there seemed to be a broad agreement that UPDF is desirable as the standard for dialysis fluid. This was expressed by Jean-Yves De Vos, from Belgium “In present day dialysis it should not be a question of whether we need UPDF for our patients, whatever technique is used (HD or HDF – low flux, mid-flux or high-flux). We simply should use it!”  Evidence to support this view was received from a number of contributors, including Prof. Stanley Shaldon who wrote: “The most evident clinical benefit that the routine use of UPDF has produced has been the virtual disappearance of the destructive bone and joint lesions associated with the inflammatory changes in haemodialysis patients. The explanation followed several years after the classic observational study from Hannover by Schwalbe and colleagues who showed that the introduction of reverse osmosis water treatment virtually eliminated the bone and joint lesions associated with β2M-amyloidosis [2]. More recently we demonstrated that advanced glycation of proteins (AGE) whilst inducing transcription of inflammatory genes required a second signal to produce the proteins necessary for the inflammatory cascade to occur [3]. The second signal was derived from endotoxin or smaller cytokine inducing substances (CIS).” A Canadian contributor (anon) added, “During the majority of high-flux dialysis there will be backfiltration because of the relatively low ultrafiltration rate. If a blood leak occurs it is possible the dialysis machine may not detect this because the pressure on the (venous) dialysate side may be greater than on the blood side. In this instance blood won't flow into the dialysate, to be detected by the blood leak detector of the machine, rather, the patient’s blood would be contaminated by any bacterial fragments in the dialysis fluid”.

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How may UPDF be produced and maintained?

This issue was at the center of the discussion. Should the water treatment system produce ultrapure water? Should the HD machines pass the dialysis fluid through a point-of-use ultrafilter? Perhaps both of these steps should be used to provide a greater degree of protection though these questions can’t be answered without also examining the associated costs.
Robert Greening from Canada commented, “We can’t rely solely on ultrafiltration just prior to the dialyser. We must at the same time do monthly bacteria and endotoxin testing to monitor the water quality. Disinfection of the entire water system on a regular basis is crucial to control the proliferation of biofilm and I would personally use Ozone in as much of the water loop as possible for the control of biofilm.”
From Jean-Yves De Vos, “The use of ultrafilters can be kept low if companies don’t produce them with special (proprietary) couplings. My criticism is that ultrafilters are often sold as being a special membrane at 5 to 10 times the price of a normal dialyser!” This excellent observation attracted the following response from Stanley Shaldon, “Lee Henderson first published a paper on the history of the medical use of ultrafilters in water treatment over 30 years ago using an Amicon ultrafilter. These devices were essentially made of hydrophobic polysulphone fibres and were excellent at producing ultrapure water but very poor as dialysers as they were not at all hydrophilic. With the advent of highflux dialysis, polysulphone was treated to vary the degree of hydrophobicity by, amongst other techniques, the amount of PVP added. Today most high flux dialysers can be used as ultrafilters but are less reliable than pure ultrafilters and there is the catch. To exploit the ultrapure dialysis market machine manufacturers have tended to incorporate special couplings [on ultrafilters] to allow them to sell expensive ultrafilters. The filters life span, particularly if cleaned by back filtration, is far longer than advertised and certainly months rather weeks. The limiting factor is often the resistance to flow when they tend to clog up as bit. If the question is money, then UF on the cheap with prolonged use of the ultrafilter is better than no ultrafilter but ideally, and probably for a medico-legal viewpoint today, it is better to invest in the proper device.” Ray James from London added, “We have found that having high quality water (typically <10 CFU/ml and <0.03 EU/ml or better) to start with, can extend the life of ultrafilters.” 
Dr Ledebo responded by pointing out that “Endotoxin filters close to the dialyser are a good insurance but it must be realized that the more contaminated the fluid that reaches the filter, the shorter the life time of the filter. Even if the filters are disinfected together with the flow path of the machine it does not mean that adsorbed endotoxins are desorbed. It is the available binding capacity for bacterial products that determines the effectiveness. When it comes to water quality, you should be able to rest on the European Pharmacopoeia and the EBPG guidelines [4, 5]. Everybody conducting dialysis should have water with <102 cfu/ml and <0.25 EU/ml and that should not have to be argued or supported by evidence. Striving to achieve a further improvement of the microbiological quality of the water for dialysis may actually be vain, because there are so many sources of contamination and growth possibilities along the path to the patient. It is better to make sure that the water quality is OK, safeguard its passage through the distribution system and use an endotoxin filter near the patient. A realistic ambition is to have standard water quality and ultrapure dialysis fluid.”

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Maintaining Water Quality

Thus we return to water quality and Gareth Murcutt made the following point “At the Royal Free Hospital we have invested in two stage (RO-RO) units with both the membranes and ringmain being regularly heat disinfected. I’m aware that chemical disinfection is still popular, and I wouldn’t question its efficacy, but the ease of use of heat disinfection (automatic programming, no residuals) was seen as a distinct advantage. We have a growing body of evidence from our regular sampling program to show that on occasions the first set of membranes have allowed some bacteria and endotoxin to pass, but these have been removed by the second stage. A very rough estimate of the extra cost associated with these units is about 25% on top of the cost of a standard plant and installation. If this is amortised over ten years it can be argued to offer good value for money”. André Stragier added that “Smeets et al. [6] demonstrated that a new, double RO with regular disinfection of the water treatment system significantly reduced biofilm formation, bacterial growth and endotoxin in the delivered RO water when compared with their previous single RO water treatment system. They clearly demonstrated this improvement in the tubing segment connecting the water loop with the dialysis machines; this segment was chosen because in their unit it was not included in the disinfection procedure of either the water treatment system or dialysis module and, therefore, is particularly vulnerable to bacterial contamination. In my opinion, before investing in a double-pass RO, we should invest in regular disinfection of the complete water loop. This should include the RO, the distribution loop and especially all the connections to the dialysis machines and any tanks inside them.  Regularly performing a complete disinfection should be the priority over any discussion about disinfection methods or agents, providing they are compatible with the machines. We should accept a monthly, complete disinfection as our minimum quality standard though there is of course no objection to doing this more frequently”. 

The heat disinfection of water treatment systems has some obvious benefits, however, as Jean-Yves pointed out “heat-disinfection in Belgium is considered to be high cost because of the high price of electricity. Perhaps this is not the case in other countries?”

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Environmental Impact of Maintaining and Testing Fluid Quality
Ray James from London provided an environmental view of this process: “Having recently carried out a study into some of the environmental aspects related to haemodialysis I think there are few points to consider. We have both RO-RO, systems with heat sanitisation of the ring, and dual RO in parallel, with chemical sanitisation. We have found that we can generally maintain quality levels with monthly sanitisation, including our older chemical systems. With this level of quality readily achievable, and with most dialysers effectively being ultrafilters anyway, I would question whether it is necessary to have point of use filters other than for on-line production of re-infusion fluid in HDF. The drive toward the use of heat sanitisation of RO membranes and ringmains is also another area that may warrant reviewing. Heating the water to >90°C uses a lot of energy and, certainly in the UK, this energy is provided to a large extent by burning fossil fuels. This means that it is costly both in terms of paying for the energy and in CO2 emissions. It is very easy to use heat disinfection and it is commonly advocated that this is carried out nightly. Is this really necessary? Cold water systems can and do produce good water quality, which can be readily maintained. There are chemicals available that break down into natural substances, and only small amounts are required to achieve good results. Should we not at least re-evaluate their use?”
Nic Hoenich from the UK also pointed out the concerns for the welfare of the Limulus horseshoe crab. “In order to produce LAL reagent, large horseshoe crabs are caught, examined for health, and bled. The crab's blood is centrifuged to separate the liquid plasma from the amoebocytes that are then freeze-dried. Whilst the crabs are not seriously harmed during this process, recent studies have indicated that bled horseshoe crabs have a mortality rate of 15%. In addition, there is a further decline in the population due to the harvesting of crabs as fishing bait. A conference to discuss the science and conservation of horseshoe crabs and to formulate plans for their conservation is due in 2007. Such action is already in place along the eastern coast of the US and this raises doubts about the long-term use of this test. Alternatives such as the Tachypleus amoebocyte lysate, which functions similarly to LAL, are being examined and geneticists are looking to clone the endotoxin-detecting gene in the horseshoe crab blood.”
André Stragier pointed out “When we designed our renal unit in 1993, we did not believe in bacterial filtration in the RO pure-water outlet to the distribution ring as an adequate option. Fortunately, our pharmacy reported very positive results using UV irradiation in their distilled water storage tank. As this proved adequate for their ultrapure pharmaceutical applications, we tried this alternative. With few exceptions this system produced AAMI quality water (<200 cfu/ml and <0.25 EU/ml) until in 1999, we decided to add a second UV lamp. The result was rewarding, keeping bacterial levels of the RO water at <1 cfu/ml over the 6 following years. Water quality assessment was regularly monitored with endotoxin tests, performed by our pharmacy (limit <0.125 EU) and all tests proved to be negative. The results of 12 years experience with this system have been published [7, 8]. 
We believe that UV irradiation is more efficient than ultrafiltration to prevent bacterial growth in infrequently (monthly) disinfected RO water distribution systems [9]; however, more research investigating this hypothesis would be very welcome. Our experience demonstrates it is possible to improve RO water quality in a conventional distribution system, without making big investments.
One of the benefits of the multiprofessional, international nature of the JC is that points of view from outside of the normal range are expressed. These comments from Susan K Hansen fall into this category “There is another option becoming available again (after an absence of 13 years) - sorbent regenerative hemodialysis. Continuously filtering the dialysate through the sorbent cartridge prior to sending it to the dialyser may obviate the need of expensive ultrafilters. The sorbent cartridge is capable of maintaining bacteria and endotoxin levels in the dialysate well below international standards and nearer those for true ultrapurity. Current sorbent cartridges routinely maintain dialysate bacteria levels at ~ 1 cfu/ml and endotoxin levels at < 0.3 EU/ml using ISO standard tap water for making the initial dialysate, without requiring any additional cost or effort on the part of the user. In addition, because in sorbent dialysis the total dialysate volume is only 6l (plus the ultrafiltrate) which is continuously regenerated, the cumulative toxin exposure risk may be even lower.”

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Fluid Testing Regimes

Nic Hoenich of Newcastle, UK made the following points about the LAL assay for quantifying the endotoxin content of water. “Whilst the LAL test is widely used it does not detect contamination by microbial degradation products other than intact lipopolysaccharide (LPS). Second, there is some evidence in the literature that the sensitivity of the test may be sub optimal when dealing with gram-positive bacteria. This issue has never really been addressed, but its’ importance should not be underestimated particularly in view of the recent paper by Gomila et al [10] who demonstrated a wide diversity of bacterial compounds in dialysis fluids. At the recent ASN meeting, Glorieux and colleagues from Gent presented what appears to be a more accurate method for quantifying bacterial contamination in dialysis fluids, based on the monocytic THP 1 cell line [11]. This assay incubates the cells with a dialysis fluid sample, and measures the IL-1, B response and was shown to detect microbial material which was not present using the classical LAL technique".
The following response came from Stanley Shaldon: “Undoubtedly a monocyte activation test is the most sensitive way of determining the presence of cytokine producing bacterial remnants that are considerably smaller than the endotoxin molecule. Indeed they can be as small as 200 Daltons (e.g. muramyl dipeptide). However, the big problem is that the test can easily be contaminated. Donor white cells need to be harvested and the incubation has to be done under vacuum conditions and takes several hours. False positives are not uncommon, I doubt whether this test could be applied in a routine fashion in a dialysis unit. For routine use a well-done LAL test is acceptable if the fluid has past through a membrane containing hydrophobic binding sites such as an ultrafilter. It does not work by pore size rejection as proven by the use of a positive control which is a very potent cytokine stimulator, staphylococcal protein A or toxic shock protein which whistles through an ultrafilter as it is positively charged and not retained by the hydrophobic sites.”
Dr Ledebo commented, “As a microbiologist I can sympathize with all comments about more careful testing for different bacterial strains and different endotoxins, but as a pragmatic clinical dialysis representative I strongly advocate not to make these routine activities too complicated. The result will only be that nobody follows the guidelines. We must know what the minimum requirements are and we need to be realistic.”

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Replacing an Aging Water Treatment Plant

Like all equipment, as a water treatment plant ages, so the output quality and reliability are likely to decrease. Lizzi Lindley of Sheffield, UK made the following point “Our unit has a huge water distribution system (it feeds 11 Wards on three floors) that is at least 14 years old and has no provision for disinfection because it was considered to be a 'closed system'. This is despite the 70 or so dialysis machines outlets! It does include a UV filter on the outlet of the RO water storage tank and until recently, we have been very lucky. Swabbing the outlets showed there is a biofilm throughout the system, but the water itself had <10 cfu/ml and <0.05 IU/ml for many years, despite the complete lack of disinfection. We've now had a couple of incidents where the endotoxin levels have increased dramatically to about 10 IU/ml. The first time, the levels fell again over about 6 weeks but remained slightly higher than in the past. So far, this time the levels have come down to about 0.8 IU/ml. In both incidents, there was no increase in the C-reactive protein levels in the patients and the staff managing anaemia did not report any increase in EPO use. We probably don't see a short-term effects because of the ultrafilters fitted to the HD machines, so the dialysis fluid continues to meet the ultrapure standard, and we use polysulphone dialysers.” Lizzi went on to ask, “How can we convince the business manager that the water treatment and distribution system needs to be replaced when we can't show any adverse results?” This raised the question: Do other units have old water plants? Simon Brooke from the UK replied, “Our main water plant is almost 16 years old and I believe it to be the cause of the water quality problems we have experienced recently. The plant is maintained by the works department and has been disinfected annually with peroxide. With modern plants automatically heat-disinfecting weekly I don't think an annual disinfect is frequent enough. I would be surprised if biofilm hasn’t formed somewhere. I'd like to see this old plant replaced but getting the funding will be very difficult." Ray James said, "Regarding the age of water plant, our oldest is 11 years and still producing good quality water. I see no reason why, with good maintenance, it should not continue for several years yet” and Gareth Murcutt added, “Our main water plant is now over 12 years old and I am about to start to develop a case to renew it.” Stanley Shaldon commented “There is literature available and if the business managers need convincing they should take a trip to Tassin la demi lune to see some of the crippled β2M-amyloid survivors who can still hobble around. Prevention is surely the key word.”  Ingrid Ledebo added “I understand that many of you need to justify the investment in new water systems and in endotoxin filters by using evidence of improved quality at least in fluid microbiology but preferably also in some patient-related data. You may ask what a safe flow-path is and this is where the new water plants offering automated disinfection fill an important role. If you cannot disinfect your distribution system you can be sure that it harbours a well-established biofilm. One problem with showing the impact of this may be that biofilms often do not contribute large numbers of free-flowing cells. Still, to impress upon the non-believers you may need to put their finger in a pipe and feel the slimy inside and then ask whether they would like to have this in close contact with their blood.”

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Water Quality Monitoring and Reimbursements

The issue of funding also relates to testing regimes, the only means with which to demonstrate compliance with the standards for fluid quality. Jean-Yves said, “The European Pharmacopoeia for dialysis water [4] does not apply to dialysis fluid. Due to this, dialysis fluid quality is not observed nor controlled by Health Authorities in Belgium. Endotoxin levels are rarely monitored as they are costly and not funded, unlike cultures for TVC, which are taken regularly as they are reimbursed. As such you can imagine it is difficult to improve fluid quality by much as there is no pressure [on management] to do so. Most Belgian units use ultrafilters as good practice.
John Mahalko, from New York, added, “In the US, there is technically no reimbursement for water testing. There is a reimbursement rate from Medicare or private insurance that covers the treatment consumables, staff labour, and specific patient lab testing. It is up to the facility determine how the reimbursement monies are actually spent. Hence, programs such as the reuse of dialysers are utilized for its cost reducing attributes. Some, AAMI recommendations are adopted into law and listed in the Code of the Federal Register (CFR)[12]. Not all AAMI recommendations are [currently] adopted into law and some facilities will just follow the CFR and what the individual State Health Departments adopts. So there is a diverse difference in what, where and how facilities test water and dialysate. The federal government also takes into account the financial burden that will be placed on facilities when standards are adopted. Providing UPDF may be beneficial to patients, but the cost of providing it may preclude the standard from being adopted. This means local personnel have to determine how much more than the minimum standards will be incorporated. This directly carries into the design, purchase, maintenance and testing of water treatment and dialysis delivery systems.”

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Conclusions

Haemodialysis patients are exposed, via the non-selective, semi-permeable membrane used in haemodialysis treatments, to approximately 25,000l of dialysis fluid every year. All contributors felt that this fluid should be of the highest available standard and evidence was presented of the long-term harm that poorer quality fluid can have on patients. The discussion of Dr Ledebo’s paper identified many different factors that play a role in determining the quality of dialysis fluid, as well as exposing some of the issues that limit it. Financial reimbursement systems vary between countries and whilst all participants felt that UPDF was desirable, the ability to deliver was dependant upon the resources available. Increased environmental awareness is also beginning to influence thinking on the subject. Wide variations in the funding for water and fluid testing were found to occur and some contributors found it difficult to garner the necessary local support for the capital purchases required to replace ageing water treatment plants.

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References

1. Ledebo I; Ultrapure dialysis fluid - how pure is it and do we need it?  Nephrol Dial Transplant 2007 22(1):20-23.
   
   
2. Schwalbe S, Holzhauer M, Schaeffer J, et al; Beta 2-microglobulin associated amyloidosis: a vanishing complication of long-term hemodialysis? Kidney Int. 1997 Oct; 52(4):1077-83.
   
   
3. Reznikov LL, Waksman J, Azam T, et al; Effect of advanced glycation end products on endotoxin-induced TNF-alpha, IL-1beta and IL-8 in human peripheral blood mononuclear cells. Clin Nephrol. 2004 May; 61(5):324-36.
   
   
4. European Pharmacopoeia 3rd Edition, Strasbourg, Council of Europe. 1997; 283–285
   
   
5. European Best Practice Guidelines for Haemodialysis (Part 1), SECTION IV. Dialysis fluid purity. Nephrol Dial Transplant 2002; 17 [Suppl 7]: 46–62
   
   
6. Smeets E, Kooman J, van de Sande F, et al; Prevention of biofilm formation in dialysis water treatment systems. Kidney Int 2003; 63:1574-1576)
   
   
7. Stragier A, Jadoul M; Preserving high Reverse Osmosis water quality. Clinical Nephrology 2005; 63: 35-40
   
   
8. Stragier A; Is Ultraviolet Irradiation on haemodialysis RO water beneficial? EDTNA/ERCA J 2005, 31:194-198
   
   
9. Träger H; The influence of bacteria in dialysis water on its endotoxin level. EDTNA/ERCA J 2002, 28: 121-124.
   
   
10. Gomila M, Gasco J, Gil J et al; A molecular microbial ecology approach to studying hemodialysis water and fluid.  Kidney Int. 2006 Nov; 70(9):1539-40.
    
    
11. Glorieux G, Schepers E, Schindler R, Lameire N, Vanholder R: A Novel Bio-Assay To Monitor Bacteriological Purity of Dialysate. Unpublished.
    
    
12. [12] Association for the Advancement of Medical Instrumentation: American National Standard. Water Treatment Equipment for Hemodialysis Applications: ANSI/AAMI RD62:2001. Arlington,VA: AAMI 2001

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