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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2001  |  Volume : 12  |  Issue : 3  |  Page : 406-412
Ultrapure Dialysate and its Effect on Patients Outcome

1 Servicio de Nefrología, Hospital Universitario Valdecilla, Santander, Spain
2 Servicio de Nefrología, Hospital Universitario Gregorio Marañón, Madrid, Spain

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How to cite this article:
de Francisco AL, Perez-Garcia R. Ultrapure Dialysate and its Effect on Patients Outcome. Saudi J Kidney Dis Transpl 2001;12:406-12

How to cite this URL:
de Francisco AL, Perez-Garcia R. Ultrapure Dialysate and its Effect on Patients Outcome. Saudi J Kidney Dis Transpl [serial online] 2001 [cited 2022 Jan 18];12:406-12. Available from: https://www.sjkdt.org/text.asp?2001/12/3/406/33565
Bacteriological quality of the dialysate fluid plays a role in the "biocompatibility" of hemodialysis (HD) [1],[2],[3] and therein lies the importance of treating the water used in its preparation properly to reach an adequate level of quality. [1],[2],[3],[4] The initial goal was to prevent acute intoxications, such as hard water syndrome, [5] eliminate contaminants, such as aluminum, which causes encephalo­pathy and osteomalacia [6],[7] or the chloramines, which can cause epidemics of worsening anemia through haemolysis. [8] Later more importance has been given to the endotoxins (Ets), which are responsible not only for the so-called reactions to pyrogens but also for the development of a chronic inflammatory state with long-term consequences on various clinical aspects of the patient. [9],[10],[11] In the future, our objective will be to achieve an ultrapure hemodialysis fluid containing only water and the necessary solutes, with a degree of purity similar to that required for solutions used in intravenous infusions. Accordingly, the dialysate fluid (DF) will be considered as a medication administered to the patient.

Biological contamination of dialysate

Hemodialysis units are subject to certain operational regulations in regards to the quality of the treated water and dialysate. [12],[13],[14],[15],[16],[17] These vary from one country to another [18] and are evolving towards the requirement for a higher quality of both. There are various multi-center epidemiological studies, which evaluate the quality of water and DF. [19],[20],[21] The first of these was carried out in the Central U.S. [19] in 51 hemodialysis centers complying with the Association for Advancement of Medical Instrumentation (AAMI) guidelines. In randomly obtained samples, 35.5% of the cases of treated water and 19% of the dialysis fluid showed conta­mination. Six percent showed more than 5 UE/ml of detectable endotoxins. Fungi and yeast were detected in the water treatment systems of 76% and 30% of the centers.

Treatment plant and distribution system may be sources of contamination. The risk is less when modern methods of water treatment are used, i.e. double reverse osmosis or deionizer and reverse osmosis. [22] However, currently popular HD modalities, e.g. the use of bicarbonate dialysis and high-flux dialysers predispose towards bacterial contamination of the dialysate fluid and the transfer of endotoxins from the dialysis fluid to blood causing more frequent pyrogen reactions. [23],[24],[25] Other factors, which increase the risk are the reutilization of dialysers and centralized dialysate production, specifically production of bicarbonate-containing dialysate. [2],[23] The degree of contamination is not equal in the different commercial concentrates and depends to a large degree on the form of preparation and the manner in which it is handled. [24]

Endotoxins (pyrogenic substances, monocyte activating substances)

Endotoxins in the dialysate fluid may enter the blood compartment and potentialy activate monocytes to produce pro-inflammatory cytokines. [1],[4],[23] Endotoxins can enter the blood through the dialyser. This passage depends not only on the quantity but also the quality of the endotoxins. Although their transport is basically affected by back filtration, [26] those endotoxins with a low molecular weight may pass through back diffusion. The endotoxins can pass through any type of membrane without exception. It has been proven that they do so more easily through high permeability membranes, in which back filtration is more common and reactions to pyrogens more frequent than with low permeability membranes. Some synthetic membranes, such as polysulfone and polyamide, have shown certain capacity to adsorb endotoxins, decreasing their passage into the blood.

Increased production of cytokines, mainly interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), is thought to be causally related to several distinct acute and chronic problems of HD patients [Table - 1]. [2],[23] These cytokines trigger a series of acute phase reactants and consequently, the patients exhibit a state of chronic micro-inflammation. [25],[27] Some studies have found a relation between these acute phase reactants and mortality of patients on HD. [ 27]

Despite a clear causal relationship, there is little statistical relation between (i) the average degree of bacterial contamination in terms of colony-forming units per ml (CFU/ml), (ii) the concentrations of endotoxin detectable by limulus assay lysate (LAL) and (iii) the production of cytokines by monocytes of patients exposed to such dialysate. [20],[22],[23]

What controls are necessary and treatment strategies advisable? On a practical level, the clinician has the obligation to control bacterial contamination of the dialysate in order to avoid the entire pathogenic sequence. This does not imply that it is not sensible to control other aspects of the pathogenic sequence as well: endotoxins, cytokines, acute phase reactants and clinical signs and symptoms, e.g. pyrogenic reactions [Table - 1]. Sampling of water for bacteria should be done at least monthly. Basic issue of how and when to take bacteriological samples is discussed elsewhere. [28] Endotoxin testing, specifically of the dialysis fluid, should be part of the regular quality control in dialysis. Endotoxin determination in dialysis fluid is obligatory in some countries and is recom­mended by the European Pharmacopoeia. [29]

The best system in preventing the existence of ETs in the DF is to avoid bacterial contamination. At present, filters made of polysulfone or polyamide membranes [1] are used to eliminate the endotoxins from dialysis fluid. They can achieve their effect by adsorption; since their cutting point of mass transfer is 60 KD, which is higher than the molecular weight of many endotoxins; this makes their frequent replacement important. Dialysate filtration with these polysulfone filters is effective and produces fluid with a minimal ETs level, which implies lower cytokine production in our experience [1] and others. [2],[3] We were able to show, in six out of seven hemodialysis patients that filtering the DF through polysulfone filters decreased the blood levels of TNF- α and IL-6. [1],[30]

Ultrapure dialysate and clinical outcome

The theoretical objective is to obtain highly ultrapure water with resistivity above 5 Mn/cm, < 0.5 mg/l of total solids, less than 10 CFU/ml and 0.25 UE/ml LAL. For the moment, we must probably be content with purified water according to the guidelines of the "European & US Pharmacopoeia": with less than 100 CFU/ml and < 10 mg/L of total solids. The trend towards maintaining high quality DF implies a system of periodic control and maintenance and close monitoring of the limits of the level of contamination and the ultimate limit according to a draft from the AAMI would be 50 CFU/ml and 1 UE/ml and the admissible limits of 200 CFU/ml and 2 UE/ml. In all instances, measures should be taken in order not to exceed the admissible levels. These levels contrast with those required recently in France for the infusion liquid made from the DF in On-Line hemodiafiltration, which require less than 0.05 UE/ml. Currently, the ultrafiltration of a high quality dialysis fluid, as well as sterilization and dis-infection systems for HD machinery is becoming a necessity.

Morbidity and mortality of dialysis patients may be related to the production of cytokines by peripheral blood mononuclear cells. Many clinical manifestations often observed in dialysis patients may be related to this specific action namely: chronic inflammation, anemia, malnutrition, conse­quences of oxidative stress, cardiovascular and bone disease, immunological dysfunction and some other acute complications such as fever, hypotension and sleep disorders.

Clinical data suggest that reduction of this clinical inflammation may prevent or decrease the severity of chronic comp­lications related to long-term hemodialysis.

Dialysis related amyloidosis

Contaminated dialysate may cause mono­cyte activation and consequently enhanced tissue inflammation and progressive beta2 microglobulin amyloidosis. The ultrapure dialysate, compared to the moderately contaminated one, reduced the prevalence of carpal tunnel syndrome at mean six years follow-up (3% versus 23%) in 187 patients under cuprophan hemodialysis. [31] In retros­pective studies, some investigators have suggested that improved water and dialysate quality as well as the more frequent use of synthetic dialyser memb­ranes may be associated with a decreased prevalence of dialysis amyloidosis. [32]

   Malnutrition Top

Chronic cytokine activation causes a chronic inflammatory state. [9],[10],[11],[26] Recent studies in dialysis patients have shown that albumin generation and serum albumin levels are negatively correlated with several markers of inflammation such as serum C-reactive protein, other acute phase proteins and IL-6. Proinflammatory cytokines contribute to malnutrition by decreasing albumin synthesis, appetite and catabolic degradation of muscle proteins. [33]

   Anemia Top

Cytokine production in dialysis may also interfere with normal erythropoiesis. Goicoechea et al found a significant corre­lation between IL6 and TNF-α, concen­trations from cultured peripheral blood monocytes (PBMCs), and the erythropoietin dose in patients under hemodialysis. [34] In a retrospective analysis of 399 patients using ultrapure dialysis, Kleophas et al noted that low doses of erythropoietin were needed. [35] These data are in accordance with the clinical observations describing acute-phase proteins as the best indicators for erythro­poietin resistance in uremic patients. [9],[36] In a recent prospective study, Sitter et al compared the effect of the potentially microbiologically contaminated dialysate and ultrapure dialysate on the response to rHuEpo. They demonstrated that low bacterial contamination can induce the activation of monocytes resulting in elevated serum levels of IL-6. They also showed that the use of pyrogen free ultrapure dialysate resulted in a better response to rHuEpo. [37] Erythro­poietin resistance in the absence of iron depletion, hyperparathyroidism, aluminum overload or other comorbid conditions may be related to chronic cytokine activation induced by contaminated dialysate.

   Consequences of Oxidative Stress Top

The antioxidant system is severely impaired in hemodialysis patients mainly by uremia­associated factors, bio-incompatibility of the dialysis system and also by the presence of trace amounts of endotoxins. The existence of an increased oxidative stress in chronic renal failure is supported by evidence of increased lipid, carbohydrate and protein oxidation products in plasma and cell membrane. Clinical consequences of this oxidative stress are accelerated atherosclerosis, amyloidosis and anemia.

Since evidence exists showing that trace amounts of endotoxin in dialysate is a potent trigger of deleterious reactive oxygen species, [38] the use of ultrapure, sterile nonpyrogenic dialysate is considered, together with antioxidant supplementation, in order to prevent or decrease oxidative stress in hemodialysis patients. [39]

   Cardiovascular Complications Top

Cardiovascular complications caused by accelerated atherosclerosis are the main cause of mortality in dialysis patients. Recent data tend to prove that athero­sclerosis is mediated by inflammatory mechanisms. [40] Several in vitro studies as well as clinical investigations support the concept of monocyte activation and cytokine production as important mediators of endothelial damage and consequent atherosclerosis. [41],[42] Clinical studies confirm that cardiovascular mortality in hemo­dialysis patients is associated with high plasma C-reactive protein. [43] Whether ultrapure dialysate reduces inflammation and consequently cardiovascular mortality needs to be confirmed in prospective randomized studies.

   Dialytic Strategy Top

Since back filtration and back diffusion of contaminated dialysate are driving forces for the passage of endotoxin and other cytokine-inducing substances different dialytic strategies have been developed to reduce or eliminate this effect. The abrogation of back filtration by high volume hemo­diafiltration or double-chamber hemodiafil­tration reduces cytokine production. Panichi et al demonstrated that hemodiafiltration with back filtration was associated with a significant increase of IL-1Ra and IL-beta in comparison to those found in patients treated with a modified hemodiafiltration modality without back-filtration (paired filtration dialysis). [44] Hemodiafiltration with on line endogenous reinfusion, [45] on line hemodiafiltration [46] and double chamber online hemodiafiltration [47] are procedures with optimal clinical out-comes and lower cytokine production.

In order to reduce the activation of circulating mononuclear cells by bacteria­derived substances, the production of proinflammatory cytokines and consequently their contribution to complications such as beta2 microglobulin amyloidosis, protein catabolism and accelerated atherosclerosis, the use of ultrapure, sterile nonpyrogenic dialysate is an absolute need in hemodialysis.

   References Top

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26.Panichi V, Migliore M, De Pietro S, et al. Plasma C-reactive protein in hemodialysis patients: a cross-sectional, longitudinal clinical survey. Blood Purif 2000;18:30-6.  Back to cited text no. 26    
27.Bergstrom J, Heimburger O, Lindholm B, Qureshi AR. C-reactive protein as predictor for serum albumin and mortality in hemo­dialysis. J Am Soc Nephrol 1995;6:573.  Back to cited text no. 27    
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32.Schwalbe S, Holzhauer M, Schaeffer J, Galanski M, Koch KM, Floege J. Beta 2­microglobulin associated amyloidosis: a vanishing complication of long term hemo­dialysis? Kidney Int 1997;52:1077-3.  Back to cited text no. 32  [PUBMED]  
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34.Goicoechea M, Martin J, de Sequera P, et al. Role of cytokines in the response to erythropoietin in hemodialysis patients. Kidney Int 1998;54:1337-43.  Back to cited text no. 34  [PUBMED]  [FULLTEXT]
35.Kleophas W, Haastert B, Backus G, Hilgers P, Westhoff A, van Endert G. Long-term experience with an ultrapure individual dialysis fluid with a batch type machine. Nephrol Dial Trasplant 1998; 13:3118-25.  Back to cited text no. 35    
36.Gunnell J, Yeun JY, Depner TA, Kaysen GA. Acute-phase response predicts erythropoietin resistance in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis 1999;33:63-72.  Back to cited text no. 36  [PUBMED]  
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38.De Leo FR, Renee J, McCormick S, et al. Neutrophils exposed to bacterial lipo­polysaccharide upregulate NADPH oxidase assembly. J Clin Invest 1998;101:455-63.  Back to cited text no. 38    
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42.Shimokawa H, Ito A, Fukumoto Y, et al. Chronic treatment with interleukin-1 beta induces coronary intimal lesions and vasospastic responses in pigs in vivo. The role of platelet-derived growth factor. J Clin Invest 1996;97:769-76.  Back to cited text no. 42    
43.Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 1999; 55:648-58.  Back to cited text no. 43  [PUBMED]  [FULLTEXT]
44.Panichi V, de Pietro S, Andreini B, et al. Cytokine production in hemodiafiltration: a multicentre study. Nephrol Dial Trasplant 1998;13:1737-44.  Back to cited text no. 44    
45.Marinez-D Francisco AL, Ghezzi PM, Brendolan A, et al. Hemodiafiltration with on line regeneration of the ultrafiltrate. Kidney Int 2000;58:S66-S71.  Back to cited text no. 45    
46.Canaud B, Bosc JY, Leray H, et al. On line hemodiafiltration: state of the art. Nephrol Dial Transplant 1998;13:3-11.  Back to cited text no. 46    
47.Pizzarelli F, Tetta C, Cerrai T, Maggiore Q. Double-chamber on line hemodiafiltration: a novel technique with intra treatment monitoring of dialysate ultrafilter integrity. Blood Purif 2000;18:237-41.  Back to cited text no. 47  [PUBMED]  [FULLTEXT]

Correspondence Address:
Angel L.M de Francisco
Servicio de Nefrología, Departamento de Medicina, Universidad de Cantabria, Hospital Universitario Valdecilla, Santander
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