8

WATER TREATMENT FOR CONTEMPORARY HEMODIALYSIS

BERNARD J.M. CANAUD and CHARLES M. MION

Rationale for water treatment in iiemodialysis 231 Water and dialysate distribution system 246 Water contaminants 232 Final filtration 246 Water treatment devices 234 Water treatment system maintenance and Activated carbon filters 234 hygiene of dialysis 247 Distillation 236 Disinfection 247 Softening 237 Filter and resin changes 247 Filtration 238 Biofilm synthesis and destruction 247 Ultrafiltration 239 Water treatment quality control 249 Reverse osmosis (RO) 239 Chemical purity 249 Deionization 240 Microbiological purity 250 Ultraviolet radiation treatment 242 Water standards for contemporary dialysis 250 Water treatment system concept 242 Conclusions 251 Water pre-treatment and purification systems 243 References 251 Water storage 245

RATIONALE FOR WATER TREATMENT IN has introduced new risks directly related to the quality HEMODIALYSIS and purity of water used in dialysis (8-11). Hemodialy­ sis using highly permeable membrane and ultrafiltration Maintenance hemodialysis is an accepted life support sys­ controller is responsible for backfiltration and/or backdif- tem ensuring long term survival of half a million end stage fusion from dialysate (12-17). On the one hand, such an renal failure patients worldwide. Hemodialysis patients unapparent convective transport phenomenon is capable are regularly exposed to 300-400 liters of hemodialy­ of transferring toxic and/or pyrogenic substances from sis fluids per week during dialysis. The quality of water dialysate to blood resulting in febrile reaction (18-21). used to dilute the concentrated dialysate fluid is important On the other hand, dialysate contaminants may contribute because of the nature of the contact between dialysate and to the activation of various protein systems, enzymes and the patient's blood. The end stage renal failure patient is cells circulating in the blood compartment (22, 23). In­ the last link of a complex chain leading to the hemodialy­ line production of substitution fluid used in some dialysis sis process, where patient's blood is exposed to dialysate. modalities (e.g., in-line hemofiltration, HF or hemodi- One can look at the hemodialysis system as the end point afiltration, HDF) infuse a large fraction of dialysate fluid of an hydraulic circuit where city water is changed in dhectly into the patient's blood stream enhancing risks water for HD through municipal water supply, water treat­ for direct toxicity and/or pyrogenicity (24, 25). Dialyz­ ment system, distribution system and delivering dialysate er reconditioning using water from the dialysis unit is through the artificial kidney (Figure 1). associated with hazards of introducing pyrogenic materi­ From the early days of dialysis it is known that water al and/or bacteria within the lumen of the dialyzer fibers used for hemodialysis must be purified in order to prevent (26-35). Water treatment system therefore must provide clinical side effects due to contamination of water (1-4). the dialysis facility and the hemodialysis machine with a Water for dialysis must be considered as a pharmaceuti­ pure water which has been cleared from all contaminants cal product exposed to patient's blood system requiring a (36-38), specific and more stringent purification approach (5-7). Water purity requirements have changed over the past Drinking regulation standards for water are based on a three decades. Hemodialysis has been used routinely as weekly exposure of 14 liters with a selective gut barri­ maintenance therapy in end stage renal disease patients for er. Hemodialysis patients are exposed to 300-400 liters thirty years. Schematically, water purity has considerably per week through a non-selective artificial dialyzer mem­ improved according to a three stage periods. brane. Furthermore, dialysis patients having non urinary The first decade (1960-1970) was a pioneering period. excretion capacity are exposed to higher risk of toxic The objectives were essentially the development of dialy­ substances accumulation particularly for those who are sis program in order to ensure survival of end stage renal bound to protein and/or tissue. Contemporary dialysis failure patients. Water treatment system used during this 232 Bernard J.M. Canaud and Charles M. Mion

1. Water supply Municipal water supply

Charcoal r-Pm-treatmmt Fllteriii|»SoftenerMJ|. jj^^^ Ji-iMcrofliter

2. Water L Primary Reverse treatment treatment Ultrafllter Delontzer ' osmosis

Sabmicronic L. PosMreatment storage tank filter charged*

3. Distribution system

4. Dialfsate w H li IP delivery

Hemodialysis tacility

Figure 1. Schematic representation of the different steps of the water purification system, starting from the municipal water supply and ending at the dialysate delivery system.

period was basically designed to remove colloid particu­ hypothesis was the starting point of a new research area in lates, calcium, magnesium, chlorine and toxic substances water and dialysate purity leading to the use of ultrapure in order to prevent mainly 'haxd water syndrome' and water and dialysate in hemodialysis (22), also to prevent pyrogenic reactions. Indeed, from the ear­ In this chapter, the various water puriication options ly Seattle experience, it was shown that the bacteriologic available to the dialysis practionner will be described. contamination of the dialysis iuid was a potential risk for Details will be provided concerning the nature of water the hemodialysis patient (39). treatment systems, the physical principles involved, and The second decade (1970^1980) revealed the hazards the monitoring approach necessary to optimize water of various substances added to city water to control tur­ treatment production for hemodialysis. The quality stan­ bidity (aluminium sulfate) or bacteriologic contamination dards required to satisfy contemporary dialysis needs and (chlorine, chloramine). Aluminium intoxication revealed to ensure patient's safety on a long term basis will also be by the epidemic occurrence of 'dialysis dementia' was discussed. particularly stressed (40-44), Water treatment system improvement consisted in generalizing the use of reverse osmosis system and/or the deionizers (mixed beds) to WATER CONTAMINAHTS prevent the rislc of aluminium intoxication, and activat­ ed charcoal to remove chlorine and chloramine from city There are three major groups of water contaminants: par­ water (45-49). ticulates, dissolved substances and microorganisms which The third decade (1980-1990) was characterized by the are presented in Figure 2. introduction of major changes in hemodialysis technolo­ Depending on the source, water will contain varying gy. Bicarbonate dialysis, highly permeable membranes, amounts of particulates, TTiese particulates are responsible ultrafiltration controllers were soon identified as new haz­ for water turbidity: they include minerals (clay, sand, iron) ards requiring a higher degree of water purity with reduced or coUoids (silica soluble or polymerised). bacteriologic and endotoxin contamination (8). In this Dissolved substances are inorganics or organics, context, water became a component of the complex prob­ microorganisms and pyrogens. lem hemodialysis hemocompatibility. The Interleukin-i 8: Water Treatment for Hemodialysis 233

Water contaminants

Reteitale

Permeate

Heyerse osmosis yitiBliltraliOtt Submicronic MIcroiltratlon M'daftons fiifration i.45jinti 0.22 - 0.04|jiii

Figure 2. Water contaminants. Efficacy of several water purification devices cuirently used in water treatment system.

The main inorganic species are represented by ions, salts, Ca, Fe, Zn. Among the organic substances, the Table 1. Contaminants of water and tlieir toxic effects as docu­ main commoa species are by-product from natural sub­ mented in hemodialysis patients stances (tannin, lignine) or from agricultural (pesticide, insecticide, fertilizer) or industrial (oil, mining, munici­ Contaminants Toxic effects pal dumps) processes. Contaminants of water which have Aluminium Dialysis encephalopathy, bone documented toxicity in hemodialysis have been listed in disease, microcytic anemia Table 1. Calcium-Magnesium Hard water syndrome: nausea, Microorganisms are mainly represented by bacte­ vomiting, muscular wealcness. ria, although fungi, yinises, protozoan are occasionally headache, hypertension, malaise encountered. Bacteria contamination with living organ­ Chloramines Hemolysis, anemia. isms lead also to release of degradation products (endo­ methemoglobinemia toxin, peptidoglycanes) (50, 51). The main microorgan­ Copper Mausea, chills, headaclie, severe isms observed in city and/or dialysis water are listed in hemolysis, hepatitis Table 2. Fluoride Bone disease: osteomalacia Water treatment options should take into account the Nitrate Methemoglobinemia, cyanosis, degree of contamination of the incoming water and hypotension, nausea requirements for purity grade of the final water prod­ Sodium Hypertension, pulmonary oedema. uct. Furthermore, it must be emphasized that municipal confusion, headache, thirst, water supplies may have seasonal yaiiations (52). Chem­ tachycardia, seizures, coma ical substances, such as aluminum, chlorine, chloramine, Sulfate Nausea, vomiting, metabolic iuoride, that are added by municipal authorhies to clear acidosis or to make water safe for drinking make unsafe the water Zinc Anemia, nausea, vomiting, fever for hemodialysis (53-74). In addition, the distribution Microbial Chills, fever, nausea, septicemia piping system may itself contribute to water contamina­ tion: toxic material such as copper, brass, zinc and lead Pyrogen Pyrogenic reaction, hypotension. may leach into the water supply during distribution or cyanosis, shock prolonged stagnation; poorly designed hydraulic systems will facilitate bacterial growth. 234 Bernard J.M. Canaud and Charles M. Mion

Table 2. Waterbome bacteria usually identified in water treatment system

Bacteria Tap water Softeners Dialysate Deionizers Activated charcoal

Gram positive Bacillus sp. Bacillus sp. Bacillus sp. Corynebacterium sp. Micrococcus sp. Staphylococcus sp. Streptococcus sp. Gram negative Pseudomonas sp. Eschericia coli Pseudomonas spt {P. aeruginosa, P. mattophilia, P. cepacia) Pseudomonas sp. Flavobacter sp. Flavobacterium sp. Flavobacter sp. Acinetobacter sp. Serratia sp. Alcaligenes sp. Achromobacter sp. Erwinia sp. Aerobacter sp. Achromobacter $p. Alcaligenes sp. Aeromononas sp. Xamhomononas sp. Serratia sp. Moraxella sp. Klebsiella sp. Enterobacter cloacae Anaerobic Mycobacteria Clostridium sp. M. chelonei M. chelonei Mycobacter sp. M. chelonei-like M. xenopi M. gordonae M. scrofulaceum

WATER TREATMENT DEVICES particle sizing, source, nature and degree of activation of charcoal. Overall efficacy of charcoal filter, is depending Activated carbon filters upon cartridge geometry, incoming water flow ind con­ tent of chlorine and chloramines. Regarding thf proper Activated carbon filter is usually used as pre-treatment for configuration of carbon filter the most critical factor is removing dissolved organic contaminants and chlorine, the water contact time with the charcoal bed. The choice chloramines from water supply (75-78). of a carbon filter must be appropriately sized according Granular activated carbon is embedded in cartridge. to water contamination degree and volume to b0 treated. Carbon filter may be utilized both as an adsorptive device Periodic backwashing of carbon filter will permilt cleans­ and a pre-treatment clearing media filter. However, it has ing of accumulated organic substances while restoring to be mentioned that activated carbon is not an efficient adsorptive capacity by unpacking media and pneventing media filter since the equally sized carbon particles tend chaimeling occurrence. to occlude at the top of the media causing rapid increases When adsorptive capacity is exceeded and activated in delta pressure drop in turbid water situations. Carbon carbon exhausted, 'spill-over' of chlorine, chloramines filter should be used for first stage oxident removal and and dissolved organics may occur in the effluent water. not as media filter. Permanent monitoring of the concentration of chlorine in Activated carbon has a microporous structure offer­ the effluent is therefore a convenient and easy method for ing a very large surface area to weight ratio that facili­ monitoring the efficacy of activated carbon. Carbon fil­ tates surface adsorption of chlorine, chloramine utilized ter may not be regenerated effectively and must be used to sanitize water distribution system and organic removal as a disposable cartridge or repackable with fr$sh gran­ (Figure 3). ular activated charcoal. Periodic replacement of carbon The adsorption capacity and the rate of removal varies filter cartridge is therefore necessary to maintain optimal with the carbon used. The activated charcoal efficiency functioning of the device. is function of various parameters: volume of charcoal, 8: Water Treatment for Hemodialysis 235

Table 3. Advantages and drawbacks of the different water treatment modules

Activated carbon Advantages Drawbacks • Remove adequately organic contaminants • Release abrasive particles (fines) chloride, chloramine • Limitation in adsorptive capacity (spill-over) • Large adsorptive capacity • Facilitate bacterial proliferation • Low cost • Difficult to sanitize

Distillation Advantages Drawbacks • Remove all type of contaminants • High consumption of energy • Indefinite reusability • Non effective on volatile contaminants • Prevent using chemical agent • Require strict attention • Spare environment from polution

Softeners Advantages Drawbacks • Reduce effectively 'water hardness' • Non effective for removing particles, organic components, or other ions • Regenerable at ease • Salt release is a function of hardness of water degree • Low cost • Facilitate growth of bacteria • Difficult to sanitize • Aging of softener and exhaustion of resins is associated with • Risk of 'hard water syndrome'

Mixed bed of deionlzation Advantages Drawbacks • Eliminate ions • Non effective in organic components, nor micro-oganisms • Regenerable without limitations • Potentiate bacterial growth • Low cost in use • Release of particles • Exhaustion of resins

Continuous Electric Deionlzer Advantages Drawbacks • Eliminate adequately ions • Non effective for organic components, particles and micro-organisms • Permanent regeneration • Sensitivity of membranes • Low cost of maintenance • Aging and loss of efficacy with time • Not source for bacterial growth

MicrofiUration Advantages Drawbacks • Eliminate all micro-organisms, particles according to • No regeneration permeability of the membrane • Non effective for dissolved mineral, pyrogens, nor colloids • Limited maintenance • Saturation and release risks • Bacterial growth and contamination risk

Reverse osmosis Advantages Drawbacks • Remove most ions dissolved • Require a pre-treatment system • Eliminate lipopolysaccharides and part of incoming bacterial • Consumption of large quantity of water • Wearing of the RO membrane 236 Bernard J.M. Canaud and Charles M. Mion

Figure 3. Activated carbon module (left part) and its mode of action in water purification (right and enlarged part).

Carbon filter, because of its granular structure, tends to release abrasive particles called fines. MIcrofilters are Doflector therefore placed in series with carbon filter to prevent Condensator downstream plugging and deleterious effects of fines on reverse osmosis membrane. Microporous structure of activated carbon and organic substances accumulation represent a perfect media favor­ Heater Cooling ing microbial contamination. Furthermore, removal of water chlorine by activated carbon facilitates bacterial growth. Carbon titer contributes largely to increase levels of bac­ teria and endotoxins in treated water. Periodic sanitization Distillation Distilled of carbon filter is therefore necessary to prevent reaching water critical levels of bacteria proliferation (10^ to 10^ CFU/ml) with major risk of downstream seeding. Flushing car- Figure 4. Water distillation system used in an industrial or boa filter with high concentration chlorine may be used pharmaceutical setting. to reduce level of bacterial contamination without alter­ ing activated carbon functionality. Advantages and draw­ backs of activated carbon filtration are summarized in vapor phase with a subsequent condensation of the vapor Table 3. to water by cooling (Figure 4). Distillation is effective in removing non volatile organ­ Distillation ic and inorganic substances, particulate, colloids sub­ stances, microorganisms and pyrogens. On the opposite Distillation is the oldest approach and the reference it is not effective for volatile substances which may be method used for water purification by the pharmaceuti­ found in distillate. cal industry (9). Two stage distillation remains the Euro­ Although distillation is an effective modality, it is not pean Pharmacopoeia standard method to produce water commonly used in water treatment for hemodialysis. Two for injection (WFI), main reasons for that: first, it requires an expensive chain Distillation is based on change of water state with large of production (tubing system, stainless steel storage tanks) consumption of energy: liquid water is converted to the which is prone to recontamination; second, it consumes large amount of energy both for heating and cooling water; 8: Water Treatment for Hemodialysis 237

Figure 5. Water softener module (left part) and its mode of action in water purification (right and enlarged part). although recent technological improvement have substan­ process. Regular softener regeneration is accomplished tially reduced these expenses. Advantages and drawbacks on site with brine sodium chloride solution by reverting of distillation are summarized in Table 3. the ion exchange process. Na-t- ions are then reinstated on the resin by exchange with divalent ions fixed. Regenera­ Softening tion of exhausted resins may be done industrially outside from site. Water softening is necessary to reduce total hardness of Softener performances optimization have been incoming municipal supply water (< 1 ppm). It consists achieved by using monodispersed resin beads: the homo­ in removing calcium and magnesium from water by ion­ geneity of such resin particles improves the softener ion ic exchange with cation fixed on resin beads (9). Water exchange capacity resulting in a reduced volume of resin softeners are used commonly in the pre-treatment stage of required for water softening. water to reduce divalent ion charge and to protect mem­ Calcium release from exhausted resin may lead to' hard brane of equipment downstream from build up and scal­ water syndrome'. This must be prevented by continuous or ing. It is essential to prevent 'hard water syndrome'. daily hardness monitoring (Testomat®) and by frequent Water softeners are ion exchangers (Figure 5). The automated regeneration cycles ensuring a safety reserve resin of the module is a cationic form that exchanges two in softening capacity of the resin. Na+ ions for Ca+"^ and Mg^^ as well as other cation ions Softener resin, favoring water stagnation, is prone (iron, manganese). to bacterial growth with seeding downstream. Frequent Volume of resins (15-75 1) determines roughly the regeneration cycles with back washing will reduce bacteri­ volume of softened water available for consumption (1- al proliferation as well as the accumulation of particulates 4 m^). Effectiveness of softeners is a function of total in resin bed. Continuous chlorine infusion upstream is hardness of incoming water, flow production and/or con­ effective in preventing bacterial proliferation within resin sumption ratio, functional quality of resins used and fre­ beads. Periodic sanitization performed either by flushing quency of regeneration cycles. When all Na+ ions have the softener with a highly concentrated sodium hypochlo­ been exchanged the resin is exhausted and has to be rite solution or the peracetic acid may be helpful to reduce regenerated to prevent hard water syndrome. Regener­ the level of bacterial contamination without altering resin ation cycles are programmed to start automatically out of functionality. Advantages and drawbacks of softening are dialysis running hours. Softeners must be equipped with a summarized in Table 3. by-pass, shunting the water flow during the regeneration 238 Bernard JM. Cmmd and Charles M. Mion Conwentional Filtration Depth filter Screen filter

Figure 8. Microfilter types: depth filters are made of an anange- ment of packed fiiiers knot-works in bundle; Screen filter are Cross-Flow Filtration mads of porous inert :ind homogenous maaix.

Food III f?*^ ^^ o^ o o, ^ "="0 ll| Bettntate witer size in the range of 0.45 ^m down to 0,1 (im are com­ mercially available wifli surface areas large enough n Flltrato n to reduce hydraulic resistance to a minimum and in various fittings (i.e., cartridges, fiat disks). Microbial filtration is defined as absolute with 0.22 ^m pore size membranes. It has been shown, however, that some figure 6^ Water filtrationprinciples : conventional filtration bacterial species of minute size can cross 0.22 pm (perpendicular) favoring built-up and accumulatioa of contami­ pores, and will be removed only with 0.1 ^m pore nants at the membrane surface; cross-flow (tangential) prevent­ size membranes. ing accumiiiatiori of contairdnants at tlie membrane surface. Except for the removal of microorganisms, filtration never reach the efficacy of reverse osmosis (RO) or ultra­ Mlcmfilter mmfilter filtration (UF) that work at molecular size filtration. Mlcroporous filter Molecylar filter Filters commercially available are of two main types: depth filter (packed fibers); surface or screen filter (porous matrix) (Figure 8): - Depth filters are made of an arrangement of close­ ly packed fibers knot-works in a bundle determin­ ing a variable thickness. Particulates are excluded by hazard retention (inertial impacting to media) or by adsorption into ibers. Figure 7. Illustration of the retentive capacity of microfilter - Screen filters are made of porous, inert and homo­ compared to ultrafilter. geneous matrix sieving incoming particulates. Reten­ tion on matrix surface is then absolute for particulates larger than medium pore diameter. Filtration Stability of filtering media is most helpful from a clini­ cian point of view to ensure the safety of filtering process. Sediment filtration, as the name states, is a membrane Filters are then best classified either in stable or unstable ilter process, used to remove particulate of large size from media according to pressure flow regimen changes. the water supply (79-84). It prevents plugging and fouling - Unstable media structure are characterized by a poros­ of water treatment equipment downstream. Filtration is ity size that increases with filtration pressure forbid­ accomplished by particulate size exclusion while water ding nominal retention rating. Such a condition facil­ percolates through porous medium with nominal porosity itates the release of medium and permeation of par­ less than that particulate one (Figure 6). According to size ticulates above the nominal porosity of filter. This is particulate removed there are three stages of iltration: pre- mainly observed with depth and fiber filters. filtration, micro-filtration and sub-micronic filtration: - Stable media means that the pore size determined dur­ - Pre-iltration is a crude process designed to clarify raw ing the manufacturing process remains stable whatev­ supply water. It eliminates the large size particulate er pressure regimen flow is used. Such filters ensure (5-5{X) ,um) from incoming water preventing fouling an absolute retentive capacity for particulates larger of equipment downstream; than the pore size. This is obtained mainly with screen - Micro-filtration is a more refined process, removing filters. smaller size particulate (1-5 ^m diameter) (Figure 7); The choice of a filter depends on its planned use: - Sub-micronic filtration is used to exclude lower size - In-depth or unstable filters used for prefiltration water particulate and bacteria. Membranes with pore remove in an inexpensive way 90-98% of suspend- 8: Water Treatment for Hemodialysis 239

ed particulates and prevent fouling and build up in water in two streams: on one side permeating the mem­ equipment downstream. brane is the ultrafiltrate cleared of contaminants; on the - Screen filters (surface filters) on the contrary are used other side excluding from the membrane is the retentate a for post-treatment to exclude small size contaminants concentrate of rejected particulates (Figure 6). UF is effec­ (resin fragments, particulate of activated charcoal, tive in removing microorganisms, pyrogens, colloids and colloidal substances ...) particulates (submicronic) with a molecular size higher than cut off point of the membrane (88-95). Combining filters of different retentive capacity in Ultrafilters are made from highly permeable membrane series permits to optimize and to improve the overall effec­ usually synthetic (polyamide, polysulfone ...) arranged tiveness of the filtering system: serial association with and packed in a plate or hollow fiber unit. down rating filtering capacity is designed to enhance final liie performances of an ultrafilter depend on the char­ purity of water: parallel association of filters is designed acteristics of the membrane, including hydraulic perme­ to increase the production capacity while maintaining the ability, sieving molecular cut off, surface electric charges loss of pressure charge at a low level. and surface area. Performances are also influenced by flow Functional performances of a filter are usually defined rate regimen, purity of incoming water and transmem­ according to their retentive capacity rating. However two brane pressure. Membrane adsorption, due to the chemical major points must be underlined. First, from a terminolo­ reactivity and zeta potential of the synthetic membranes, gy standpoint it is important to differentiate absolute and may also contribute significantly in removing charged par­ nominal retentive rating. Absolute retentive rating repre­ ticles of inflowing water. Such property extending func­ sents the diameter of the largest particulates that caimot tional capacity of ultrafilter to reactive species have been pass through a filter in fixed conditions. Nominal reten­ clearly demonstrated for lipopolysaccharides (87-95). tive rating is determined by the manufacturing process The nature of the membrane is a critical factor deter­ and corresponds to the media pore size thai is supposed mining efficacy and resistance of UF to water contami­ to exclude incoming particulates with a larger diameter. nants and corrosive action of chemical disinfectant. As a Second, from an effective efficacy standpoint, a filtration membrane filtration process, ultrafiltration reduces conta­ process is defined as a reduction percentage of incoming minant titer of inlet water, meaning that effectiveness of contaminants. Therefore, the efficacy of a filtering system UF is also a function of purity of incoming water. Optimal will also depend upon the purity of the feeding water. functioning of UF requires permanent tangential filtration Charge-modified filter is a new and promising approach flux and/or intermittent flushing preventing plugging and enlarging filter properties by adding a removal capaci­ build up at the membrane surface. Association of ultra- ty for pyrogens. Based on the positive zeta potential of filters in series enhances the overall efficacy of the UF their membrane surface, such filters are able to remove system by reducing hazards of permeating contaminants. negatively charged lipopolysaccharide from deionized, Programmed changes of ultrafilters is also a safe and nec­ reverse-osmosis treated, and distilled water (85-86). essary way to prevent unexpected passage of contaminants Filter fouling may be monitored by differential pres­ in case of ultrafilter saturation. sure changes occurring from pre- to post-filter in fixed Ultrafilters are particularly useful and highly effective functional conditions. Periodic filter changes are therefore in removing pyrogens at a reasonable cost. Ultrafilter necessary to prevent reduction of filtering capacity. may also be used to protect RO membranes or to ensure Bacterial growth is a major problem with filters. This final ultrapurity of water produced. Ultrafilters are usually is due to colloid and organic substances accumulation and placed in water posttreatment. Regeneration of industrial to water stagnation, both conditions favoring bacterial ultrafilter may be performed on site by chemical cleaning proliferation. and back flushing. Advantages and disadvantages of UF Filters are usually not regenerable meaning that with are summarized in Table 3. time progressive build up of particulate matter is occurring within the membrane. When filter membrane is saturat­ Reverse osmosis (RO) ed, retention capacity may be exceeded and particulates break-through may occur. Retentive capacity is then over­ Reverse osmosis is a membrane filtration process based flowed. Filter must be replaced periodically to ensure on molecular sieving (« 300 Daltons) and ionic exclu­ optimal functioning and to prevent unexpected release of sion with 90-99% rejection (9) (Figure 9). RO is the particulates from saturated membrane. Advantages and more cost competitive effective method to purify water drawbacks of filtration are summarized in Table 3. from dissolved organic and inorganic particulates includ­ ing bacteria and endotoxins (96-101). Ultrafiltration Osmosis occurs when two solutions of different ionic concentrations are separated by a semi permeable mem­ Ultrafiltration (UF) is a membrane filtration process based brane. Osmosis describes the phenomenon of solvent mainly on a molecular sieving exclusion (Figure 7). It has flowing from the less concentrated to the more concentrat­ a molecular cut off higher than reverse osmosis but low­ ed side. The driving force responsible for this movement er than submicronic filtration. Ultrafilter splits incoming 240 Bernard J.M. Canaud and Charles M. Mion

Permeate

Reverse Osmosis Osmosis Soft water

Rejection

RO Membrana Permeate

A. Reverse osmosis principle B. Reverse osmosis module

Figure 9. Reverse osmosis (RO). A. Physic principle of reverse osmosis. B. Reverse osmosis module and its mode of action (enlarged part). RO splits incoming soft water in two fluxes, permeate (purified water) and retentate (rejected and concentrated watei). being known as the osmotic pressure as shown on Fig­ The performance of the RO system is monitored by ure 9 (left panel). If the hydraulic pressure applied on continuous measurement of resistivity of both product the concentrated side is higher than the osmotic pressure, water and of rejected water. A production/rejection ratio then the solvent flow is reverse and move from the more of 0.85-0.95 is obtained with an efficient RO sysfiem while concentrated to the less concentrated side. The process is a value below 0.80 indicates the need to change the mem­ then called reverse osmosis. The RO acts as a selective brane module. RO water quality can deteriorate with time sieving filter rejecting solute above the membrane cut off. because of fouling and/or scaling of membraine. Such RO separates incoming water flow in two fluxes:R O water problems depend mainly on the purity of the inflowing (permeate) on one side; rejected water (concentrate) con­ pretreated water. Periodic flushing of membrane is then tains 90-99% of water contaminants as shown on Figure 9 required for scrubbing concentrated particles at the mem­ (right panel). brane surface and then to restore optimal functioning of RO membranes include two major types: cellulosic RO. (cellulose acetate) and synthetic (polyamide, polysul- The RO process is effective in decontaminating water, fone). Thin composite membranes, recently developed for if membrane integrity is preserved: RO removes bacteria clinical use, seem more promising as they ally high per­ (provided the bacterial load of affluent water is limited formance and strong resistance. RO membranes are fitted and the tightness of the frame is adequate), viruses and in modules with various geometrical configuration: plate lipopolysaccharides (LPS) (47, 48). It must be empha­ membrane frame, spiral wound and hollow fibers. sized however that its efficiency is highly dependent of RO performances depend upon different factors: mem­ nature of the RO membrane and its interaction with the brane and module characteristics (structure, surface area, chemical and/or bacteria species of water. nature), inflowing water temperature, pH, water contam­ Overall efficacy of RO may be overwhelmed in case of inant concentration and production/rejection ratio. Opti­ incoming water of high ionic strength. A deionizer may mal performances and life span of RO are function both of be added downstream of the RO system to 'polish' water: the pretreatment system efficacy and of the RO membrane this approach introduces a major risk of microbiological maintenance (flushing, cleaning, disinfecting) (101). contamination of the purified RO water by the resins of the Resistance of the RO membranes to the destructive deionizer. Advantages and drawbacks of reverse osmosis action of chemical species (pH, chlorine, chloramine), are summarized in Table 3. disinfectant (peracetic acid, formaldehyde ...) or bacte­ ria is directly related to the nature of the membrane: cel­ Deionization lulose acetate is highly sensitive to the bacteria destruc­ tive action; synthetic membranes are more sensitive to Water deionization consists in removing dissolved inor­ the corrosive action of chemical species; thin compos­ ganic ions using their electrical and charged properties. ite membranes appears conversely highly resistant to all It is based on a ion-exchange process. According to the agents. nature of the media used for exchange, deionjizers may be classified in two types: solid phase deionizer (mixed bed) 8: Water Treatment for Hemodialysis 241

Figure 10. Mixed bed deionizer module (left part) and its mode of action (riglit and enlarged part) as a ion resin exchanger (cationic and anionic resins).

i 6©Ci ¥V 3t©f

Pernieabic Perrai*a&fe Cation MeiTibFSM Cj" Na" Membrane Anson Fsfmeebie s Meir.brar* i * IJJXSM I'' - Membrane

:' Magnetic Fieic rff^«ja''

Figure 11, CoBlinuous Electric Deionizer (CDI) module combines electrodialysis (magnetic ield, arrow) and ion exchange (resin and membrane) to produce high quality water. 242 Bernard J.M. Canaud and Charles M. Mion

(Figure 10); Continuous Electric Deionizer (Figure II) The resin facilitates ion transfer by providing a lo\v resis­ (CDI) (102-104). tance path for the transfer of ions. In addition as the water Deionizer in solid phase consists in a percolation product become very pure, the current applied in excess of water in resin of cationic and anionic types (mixed splits water into hydrogen and hydroxyl ions regenerating bed) (Figure 10). Dissolved ion particles of water are continuously the resin. exchanged with the ions fixed on the resins, cationic CDI provides high quality water with resistivity up to resins (styrene, divinylbenzene) bearing sulfuric radical 20 megOhm/cm. Monitoring of CDI performances may exchange hydrogens ions for cations (Na, Ca, Al ...), be checked by continuous measurement of resistivity on anionic resins (styrene, divinylbenzene) bearing ammoni­ outflowing water with temperature compensated conduc- um radical exchanges OH hydroxyl ion for anions (Cl~). timeter. The exchanged hydrogen and hydroxyl ions combine Overall efficacy depends upon geometrical and func­ together to form water. tional characteristics of CDI (surface area exchange, num­ A deionizer consists either in a dual bed (two sep­ ber of compartment, membranes, dilute/concentrate flow arate beds one each, for cationic and anionic resin in ratio), incoming water composition (ionic strength, tem­ series) or mixed bed (mixture of cationic and anionic perature, pH) and intensity of electrical field acting on resins in the same bed). Resins consist in a mixture of the module. The continuous regeneration of the resins styrene/divinylbenzene bed to form a polystyrene matrix. by electrodialysis prevents their exhaustion and does not Deionizer produce water of high quality and high resistiv­ require the use of chemical reagents. ity (> 1 megOhm/cm). Continuous in line monitoring of In addition, the permanent water flux within CDI lim­ deionizer efficacy insured by on-line resistivity measure­ its bacterial growth and reduces the hazards of pyrogen ment with temperature compensated resistivimeter. release downstream. Advantages and drawbacks of deion- Efficacy of resin is correlated with its overall exchange ization are summarized in Table 3. capacity. Deionizer retentive capacity depends upon vol­ ume and resin exchange capability, ionic strength of Ultraviolet radiation treatment inflowing water and consumption flow. When saturation of exchange sites is reached, the resin is exhausted. Regen­ Ultraviolet (UV) radiation is a ionization process that is eration is then necessary to prevent release of fixed cations able to destroy all types of waterborne bacteria whatev­ (Ca+^, Mg++) and anions (NO3, SO4 ...). Effluent er their state, vegetative or sporulated. Microorganisms water may also become acidic because of the imbalance withstand considerably more to UV in water than in dry between cations and anions exchange capacities. Regener­ air. Bactericidal effects of UV in water is depending on the ation of deionizer may be scheduled automatically or ini­ amount of energy delivered to suspended organisms and tiated manually when resistivity has declined to less than is function of the own resistance of waterborne microor­ 1 megOhm/cm. It consists in a reverse ion exchange based ganism to the UV radiations. The degree of penetration of on a two step procedure: first, back washing to remove UV (water depth layer) and the flow rate of water through particulates; second, regeneration of cationic resins with the UV source are major factors of germicidal effective­ strong acid (HCl) and anionic resins with strong alcali ness. The variation of degree of absorption is function of (NaOH, bleach) to eluate fixed ions. mineral and organic content of water. The redaction of Deionizers are subject to fouling and bacterial prolifer­ UV spreading through the source is observed with scaling ation which results in microbial contamination of down­ of the lamp. The intensity of U V output of a lamp depends stream equipment. on the voltage, water temperature and burning hours of a Continuous Electric Deionizer (CDI), a more recently lamp. developed process, combines the advantages of electro- Commercial UV source are provided through mercury dialysis and ion exchange to produce a high quality water lamp (cold vapour of mercury) enclosed in a quartz protec­ (Figure 11). It combines ion exchange membranes and tive sleeve allowing for higher lamp temperatures required resins to remove ions from water under the influence of for optimum output of UV. Germicide UV lamps have lim­ an electrical field. CDI module consists in a series of ited life time (5-10000 h) based on a continuous flow. thin parallel compartments separated by selective cation­ UV is an effective and practical alternative for disin­ ic and anionic membranes; in this arrangement every fecting water, but it increases the lipopolysaccharide and second compartment is filled with a mixture of cation­ peptidoglycane content of treated water due to process of ic and anionic resins. The incoming water is separated in iDacterial killing. two fluxes: the main fraction of water is flowing through mixed resins defined as the diluting or product compart­ ment, while a small fraction is flowing co-currently in the WATER TREATMENT SYSTEM CONCEPT adjacent compartments designed as concentrate compart­ ments. Electrical field force ions to migrate from product None of the individual water treatment devices described compartment to dilute pathway according to polarity of above offers the possibility of producing high purity water field and selectivity of membranes as shown in Figure 11. on a long term basis. The association of several water 8: Water Treatment for Hemodialysis 243

Water pre-treatment and purification systems Table 4. Purified water according to European and US Phar­ macopeia. Highly purified water (ultrapure water) according to semiconductor industry needs Chemical purification is the first stage of the water treat­ ment system. It is one of the most important since con­ Constituent Purified water Ultrapure ditioning the final purity grade of the water distributed. (European &) water Water purification consists in three steps which includes: US pharmacopoeia) 5 A/n cm (1) pre-treatment consisting in filters, softener, carbon filter, microfilters; (2) primary treatment consisting in a PH 5.0-7.0 5.0-7.0 reverse osmosis (one or two RO) and deionizer for 'pol­ CWoride, mg/1 <0.50 <0.06 ishing' water; (3) post-treatment consisting in ultrafiltra­ Sulfate, mg/1 <0.10 <0.08 tion and submicronic filtration with or without storage Ammonia, mg/1 <0.10 <0.03 tank. Various grades of water may be achieved depend­ Calcium, mg/1 < 1.00 <0.04 ing directly upon complexity and cost of water purifica­ Carbon dioxide, mg/1 <5.00 <0.20 tion options used. According to our present knowledge, Heavy metals, mg/1 <0.10 <0.01 pharmaceutical quality grade water appears as a new and Total solids, mg/1 < 10.0 <0.50 generalized standard for contemporary hemodialysis. Of Total bacteria count, CFU/ml < 100 < 10.0 these waters two types are suitable for hemodialysis as presented in Table 4: (1) purified water; (2) highly purified Pyrogen Endotoxin, MEJmX 7 <0.25 water (ultrapure water). The chemical specifications for hemodialysis water are similar to those of water for injec­ tion. Absence of bacteria and endotoxin and a resistivity superior to 5 megOhm/cm are the main characteristic of the latter. treatment options is required to achieve a regular and constant production of high grade quality water. A water a. Purified water may be obtained from a relatively simple treatment system in all cases will be a chain associating water purification system made of a pretreatment (soft­ several units assembled either in series or in parallel, each ener) and reverse osmosis (RO) module assembled in one having a specific function. The major contribution of series. Such water treatment system should represent now, water engineering should be to optimize the performance the basic and common denominator for all conventional of each component to enhance the quality of final prod­ hemodialysis system. uct (105-108). The assemblage of various components According to the quality of the municipal water supply to make a water treatment chain results frequently in an different options of filtration may be proposed. Basically, antagonism between the chemical and microbiologic cri­ such water treatment purification system consists of a pre- teria of ultrapure water. For example, the improvement of treatment followed by a deionization by RO with straight ion removal by adding resins to a RO system enhances and direct distribution system. Microfiltration may be bacterial proliferation with a deleterious effect on micro­ occasionally associated as a final quality insurance. A biological purity. flow diagram of such water purification treatment show­ Water treatment is a complex process that starts from ing the different components is given in Figure 12. water mains and ends at patient bed-side in the dialysate The pretreatment consists in series of filters for large production. Final purity of water distributed to the particulate removal, a cation exchange softener, an activat­ hemodialysis machine will therefore integrate all imper­ ed charcoal cartridge and a filtrationdow n to 1.0-0.45 /xm. fections in the water treatment chain. Permanent sanitization of resins may achieved by contin­ Water treatment systems for hemodialysis include usu­ uous chlorine injection in tap water. ally four sections assembled in series, which include: (1) water pre-treatment; (2) water purification system; b. Highly purified water (ultrapure water). Chemical and (3) water storage (reserve) and distribution system (pip­ microbiological (bacteria viable organisms and endotox­ ing, net delivery system); (4) dialysate preparation and ins) limits are most stringent in this case. Quality stan­ delivery system (dialysis machine) (Figure 1). Most dialy­ dards are those required for water for injection with the sis machines are also a final filtration device (submicronic only difference that conditions of production and instanta­ filter and/or ultrafilter) to ensure the microbial purity of neous consumption preclude any microbiological control the water feeding dialysis machine and/or the dialysate to be performed (Table 4). delivered to the patient's dialyzer. Highly purified water may be produced using different The complexity of such water treatment chain explain treatment options. Schematically, three different types of easily the difficulties in maintaining high quality grade water treatment chains are presented that seem to offer the standards for water. It is also important to remind that best quality insurance consisting in: the final quality of the delivered water will be negative­ ly influenced by the worst quality segment of the water 1. The first type presented in Figure 13, consists in a chain. pretreatment system followed by two stage deioniza- 244 Bernard J.M. Canaud and Charles M. Mion

MIcroflttM'

MicroflKar

Distribution Raw Water Loop

Figure 12. Basic water treatment chain for hemodialysis consists in a pre-treatment (microfiltration, activated carbon, softener) completed by a RO module and a direct production of treated water to the dialysis unit through a recirculating loop.

Distribution Loop Miaofllter Microfiiter MIcrofilter Reverss Osmosis

Raw Water

til iJf

Pum,>1l!p t Submicronic 0.1 p Filter +

Figure 13. Water treatment chain designed to produce highly purified water. It consists in a pre-treatment followed by a two stages RO treatment. Storage tank is used in this case to prevent any imbalance due to peak flow consomption. Microbiologit purity of water is insured by a permanent recirculation through two serial positively charged submicronic (0.1 /jm) filter.

tion by RO completed by a final filtration using a 2. The second type of chain shown in Figure 14, consists 0.1 /xm pore size filter membrane. The treated water in a pretreatment system followed by primary deion- is distributed to the dialysis machines through a recir­ ization by RO, completed by polishing deionization culation loop. The pretreatment uses a series of filters by CDI and a final ultrafiltration or mictofiltration for large particulate removal (5-1 /xm), a dual soften­ (0.22 or 0.1 ^m positively charged). Pretrtatment is er and activated carbon filter followed by a filtration the same as previously described. RO unit; uses syn­ down to 0.45 /xm. The water treatment consists in two thetic or composite membrane. RO is operated at 50- RO units placed in series. An intermediary storage 60% rejection to reduce the rate of fouling. The CDI tank may be useful to prevent any RO dysfunction by unit is a single stage, 30 parallel plate cell designed fluid imbalancing. Rejection flow is discarded on the to produce a nominal product flow of 20 Ifmin. CDI first RO module while it is recirculated and mixed with is operated at 80-85% recovery. The ultrkfilter unit softened water on the second RO module. RO modules is made of a spiral synthetic membrane or a hollow use cellulose acetate or composite membrane. fiber used at a low rejection rate and/or with periodi- 8: Water Treatment for Hemodialysis 245

Distribution Loop MIcrotilter Mlaodlter

Raw Water

Submlcronic Oltar -r Drain

Figure 14. Water treatment chain designed to produce highly purified water. It consists in a pre-treatment completed by RO treatment then polished by Continuous Electric Deionizing (CDI). Storage tank is used in this case to prevent any imbalance due to peak flow consumption. Microbiologic purity of water is insured by a permanent recirculation through serial positively charged submicronic (0.1 /im) filter.

cal flushing of the membrane. The RO, CDI and UF flow exceeding the instantaneous production capacity of should be sanitized at regular intervals at least monthly the water treatment system; it is also requisite to keep and preferably weekly. Chemical disinfection may be a water safety reserve in a large dialysis unit or to pre­ performed, according to the manufacturer recommen­ vent flow and hydrostatic pressure imbalances between dations, using appropriate concentrations of formalde­ the various components of the water treatment system. hyde or peracetic acid or chlorine. Simplification of In practice, water storage can be dispensed with in small sanitization has been made possible through the use dialysis units (e.g., self dialysis or limited care facilities) of a single and common chemical agent both for RO, or in home hemodialysis, while it becomes mandatory in CDI and ultrafilters. large dialysis facilities. When water storage is required, 3. The third type of chain shown in Figure 15 consists in a reservoir should be designed specifically and integrated a pretreatment system followed by a primary deion- into the water distribution system (Figures 13-15). Closed ization (mixed bed) then enhancing microbiological stainless steel storage tank offers the best choice for this quality by final filtration (ultrafiltration or preferably purpose. Vessel design is important to prevent water stag­ microfiltration); RO can be used for that purpose, but nation. The interior of the reservoir is concave at both the rejection flow should be recirculated and mixed ends. The internal surface is polished to discourage bacte­ with the afferent water feeding the deionizer. Deioniz- rial adhesion. Water arrives at the upper entry point of the er consists in a mixed anionic cationic resin exchange reservoir, impinges into a concave badffle which directs the unit. RO unit uses a synthetic or a composite mem­ water stream along the inner surface of the vessel, thus brane. Ultrafiltration unit or submicronic filtration assuring permanent lavage of the wall. Water is continual­ insure the final purity of water produced to the dialysis ly pumped into the circuit from the bottom of the reservoir unit by eliminating endotoxins and bacteria. either forward in the distribution loop for dialysis use or backward in the water treatment system when dialysis unit is not rurming. Water storage Reservoir is maintained under pressure of water sup­ ply circuit when placed before RO. Event of the reser­ A water tank is not always required in a water distribution voir are protected from bacterial contamination by micro- circuit: whenever possible, it is preferable to avoid it, as filters (0.1 /xm). Level probes (max and min) are also water stagnation in a reservoir favors bacterial growth. A necessary to check filling state and action automatically tank can be avoided when the production capacity of the filling/emptying cycles. water treatment system exceeds at all times the consump­ tion needs of the dialysis units (Figure 12). A reservoir will be necessary when water consumption in the dial­ ysis unit varies during the day with peak consumption 246 Bernard J.M. Canaud and Charles M. Mion

Microflttar Mlcfotitter Mlcfotllter MIcrofltter Reverse "^ Osmosis Delonlzer mixed bed Distribution i^ Raw Water Loop I

UF

Submicronic P Filter* Drain ^

Figure 15. Water treatment chain to produce highly purified water. It consists in a pre-treatment completed by RO treatment then polished by mixed bed deionizing. Treated water is directly flowed to the dialysis unit without storage then recirculated. Microbiologic purity of water is insured by a permanent recirculation through serial submicronic (0.1 /xm) filter and/or ultrafilter.

Water and dialysate distribution system arms whose length does not exceed the diameter of the principal circuit. The hydraulic circuit starts from the water mains, sup­ Second, to prevent bacterial adhesion to the ianer sur­ plying the dialysis unit and leads into the dialysate com­ face of the piping, high water velocity and shear rate partment of the dialyzer. It forms a complex path that should be obtained by selecting a pipe with the smallest comprises three major segments: irmer diameter compatible with the required flbw. The - The first segment includes the pretreatment and treat­ material chosen should have a smooth and polished inner ment water systems. As indicated above, it is the most surface and joints that disrupt piping continuity should be complex part of the hydrostatic circuit and it will not avoided. Stainless steel, that can be welded without crack be discussed further here. formation at the inner surface, thus preventing the forma­ tion of bacterial niches, is the ideal material. Its high cost, - The second segment, that should be linear, may however, has been an impediment to its routine use. High include a reservoir and ends into the various ports grade PVC is more commonly used, because of its low­ of utilisation in the dialysis center; it includes the er cost: high bacterial quality can be obtained provided tubes connecting the hemodialysis machines to the the piping installation is carefully designed and regularly main piping. disinfected. - The third segment consists of as many hydraulic cir­ Third, continuous water circulation is a basic neces­ cuits as they are HD machines. The complexity of sity to prevent water stagnation and bacterial growth. the hydraulic pathway inside the machines creates If possible, storage reservoir should be avoided. If this numerous niches facilitating bacterial adhesion and impossible, reservoir with a recirculating loop Including proliferation. To prevent bacterial contamination of a filtration system must be operated 24 h a day. dialysis water and of dialysate, the hydraulic circuit Fourth, dead space and lateral arms (manyfolds) must should be carefully designed by the manufacturer. be avoided or reduced to a minimum. Tubing connecting The design of the hydraulic installation is a critical the distribution loop to the dialysis machine should be as point that will have a major impact on the degree of bac­ short as possible as shown in Figure 16. terial contamination of water and thus of dialysate. Since the extra cost in this area is modest the greatest effort Final filtration should be made to obtain the best plumbing configura­ tion. Without entering into details of such technical points, When a storage tank is used, water flow in the recircu­ four principal criteria that must be adhered to should be lation loop is provided by dual centrifugal punlps which underscored. maintain the hydrostatic pressure at the level required First, hydraulic circuit requires a design that insures for proper functioning of the various systemsi fed with linear circulation of the water. Elimination of any by-pass ultrapure water. A cold sterilisation system, made of an creating stagnation zones. If valves are required on the ultrafilter or preferably a submicronic filters with posi­ water distribution piping, they should be placed on lateral tive zeta potential at the filter membrane surface (0.1 ^m 8: Water Treatment for Hemodialysis 247

Water Treatment Disinfection From System To Disinfection is necessary to reduce the degree of bacteri­ al contamination in a water treatment system production (109-112). It must be adapted to die segment of die water Recirculating treatment chain considered and to the level of contamina­ Loop tion (Figure 17). Bacteria lodging inside in depth filters, softeners resins iJiilriilnJ and activated charcoal are very difficult to remove. All . 1 these material, easily penetrated by water-borne bacte­ 3 ria, offer excellent niches facilitating bacterial growth. To 2 • reduce microbial multiplication in this critical sector of : the water treatment chain, several measures are required: 1 HD machines (1) permanent addition of bleach to raw water to enhance free chlorine level to reach 0.3 mg/1 within filters and soft­ Dialysis Unit ener resins; (2) pulse disinfection of activated charcoal by high bleach flushing once a week; (3) suppression of acti­ Figure 16. Tubing connecting the water distribution loop to vated charcoal if possible and free chlorine neutralization the dialysis machine must be as short as possible to reduce dead by downstream infusion of thiosulfate. space and water stagnation. This is illustrated by the 3 mode of Periodic disinfection of RO, CDI and ultrafilters may connection: 1. Conventional tubing. 2. Short tubing connecting be achieved by using a chemical disinfectant. The choice system. 3. Total suppression of tubing dead space with a specific of disinfectant must be done in accordance with material connecting device. specifications and manufacturer recommendations to pre­ vent any damaging effect. Periodicity, concentration and time exposure to the agent are dependent upon the nature of the disinfected material, the degree of contamination and the kinetics of recontamination. pore size, Posidyne®, Pall, NY, USA) is placed after the Filter and resin changes pumps, at the inlet of the recirculation loop. This system should eliminate all the bacteria that may have grown in the water stagnant into the reservoir. ITie recirculation Filters, softeners, activated charcoal and deionizers rep­ loop returns to the reservoir, the water not utilized in the resent an ideal support for microbial growth. On the one dialysis center. Optimal fiinctioning of such a distribution hand, porosity of these material facilitate adhesion and closed loop system is based on four major rules: first, per­ penetration by circulating water-borne bacteria. On the manent water flux and bacterial absolute filtration to lower other hand, presence of organic substances enhance bac­ bacterial growth in the reservoir and to eliminate bacteria teria growth by providing nutrient media. When bacteria and endotoxins from the water running into the loop; sec­ have colonized such material they are very difficult to ond, high flow rate to impede the bacterial colonization dislodge by a back-washing or to kill by disinfectants of the pipes; third, careful cleaning and disinfection of and/or chemical germicides. Moreover, heavily contami­ the hydraulic circuit at regular intervals to prevent biofilm nated filters overpassing their retentive capacity are sub­ formation and bacterial contamination; fourth, prevention ject to release with risk of downstream contamination of of back contamination through lateral arms by regular dis­ equipment. Disinfection permits to reduce bacterial con­ infection and physical disconnection of the HD machines tamination of a water treatment system in a limited and/or when they are not in use. an acceptable range. However disinfection alone cannot insure sterility for a prolonged period of time when filters or resins are contaminated. Therefore, periodical changes of filters and resins, combined with frequent disinfection WATER TREATMENT SYSTEM MAINTENANCE cycles, is the only way to optimize microbiological results AND HYGIENE OF DIALYSIS and to insure on the long term the production of ultrapure water (113). As discussed previously, both proper design of the hydraulic circuit and adequate hygienic measures are the BioiUm synthesis and destruction two key conditions to obtain high quality water for dial­ ysis. The careful maintenance of a water treatment sys­ Bacterial adhesion to inert surface material occurs tem is essential to insure the continuous production and inevitably in all water distribution piping network (114). distribution of ultrapure water. Thus maintenance relies Such adhesion is facilitated by reduced water flow and on three complementary measures: disinfection; filters low shear rates at the water-tubing interface by areas of and/or resins changes; biofilm destruction. 248 Bernard J.M. Canaudand Charles M. Mion

Dlslrtbution Raw Water Loop

Chlorine cantlmmtialf Pemcetlc add or FormaWehyele Perocetic acid or Formaldehyde or Steam sterilization porlodlcallf

Figure 17, Dinsiafection procedures. 1. Permanent clilomie infusion ia the pre-treatment part prevents bacterial growth, Chiorine is then removed by the activated csirbon. 2. Periodic disinfection r?)ay be realized with biocide (formaldehyde, pcracctic add, hypochlorite) with appropriate concentration and optimal periodicity. 3. Daily seam disinfection may be performed m die stainless steel recircttlating loop.

Figure 18. Bioilm, as it can be obser^'ed in the PVC water piping feeding a dialysis machine not regularly disinfected (courtesy of Remy Nicolle, Biocides Etepartment, SEITIC. Pajis-France). ' water and/or by defect and cracks at the inner surface production of the exopoly saccharide and the reproduction of the pipe walls (storage tank, vakes). However, water of bacteria leads to the production of a continuous Moilm borne bacteria may stick to surfaces even at high water at the irmer part of the colonized surface (Figure 18). fluxes. Moreover fixed bacteria facilitate the adhesion of Bioilm provides a protection from natural or synthetical­ other circulatiEg microorganisms leading to a progres­ ly produced antimicrobial agents (biocides). It facilitates sive bacterial build-up. Interaction of bacteria is initial­ bacterial proliferation in which in turn metabolic products ly reversible, hut it becomes eventually irreversible. In stimulate the growth of the other organisms. An aggregate nutrient poor environment such as ultrapure water most of microorganisms leads to molecular or proton exchanges bacteria grow attached to surfaces mainly because of their which in turn is associated with microbial corrosion. The hydrophobicity. Initially, sessile bacteria adhere randomly corrosion process can be initiated by formation of proton to tubing surfaces by means of flieir glycocalyx. Tlien, the concentration gradients inside and around the bacteria, 8: Water Treatment for Hemodialysis 249

Figure 19. Biofllm striping efffxt of a pcracetic acid solution (Dialox®"', CFPO, Paris-France). PVC tubing appears clean and germ4re.e. Only silicium deposits can be obsen-ed at the tubing surface (courtesy of R6iTiy Nicolle, Biocides Department, SEFPIC, Paiis-France). which generate electrochemical forces within the bioilm. above. Basic requirements for an adequate control of the High grade stainless steel is the only material resistant to chemical purity of the water produced are summarized in this corrosion phenomenon. this section (115). Most plastics contains synthetic polymers which are The effectiveness of the softener may be monitored resistant to microbial degradation with the exception for either periodically (daily or weekly) by measuring the low molecular weight polyethylene and polyesters. Plas­ hardness of the effluent water using suitable titration kits tics may also contains plasticizers, pigments, stabilizers, (resolution of less < 1 mg/l) or permanently by a sensitive lubricaats that may serre as nutrients for bacteria and fun­ automated probe (Testomat®) equipped with appropriate gi. Even though the plastic is not degraded, its resistance alarms which will inform the nursing personnel of the may be altered. Bacterial growth may cause plastic pipes dialysis center if tie hard water is not adequately soft­ to become brittle and crack. Fungi may grow inside plastic ened. material and on thefr surface modifying their aspect. The filters (sediment filters, ultrafilter) capability must Prevention and destruction of bioilm is therefore an be monitored to prevent plugging and sloughing risks. It essential aim in the hygiene of the water distribution sys­ is therefore important to monitor the pressure drop across tems. Few detergent agents can induce the hydrolysis of the filters by suitable pressure gauges; the ilters will be the exopolysaccharide shield. Bleach, sodium hydrox­ discarded and replaced when the pressure gradient across ide and peroxyacetic acid preparation which demonstrate the filler reaches the safety limits specified by the manu­ detergent properties, should be periodically employed to facturer. strip the bidfilm away from the inner surface of the pipe Chlorine removal by activated charcoal is important wall and disinfect adequately the water distribution pipes to prevent RO membrane damage. The effectiveness of (Figure 19). activated charcoal must be monitored by measuring chlo­ rine concentration in the effluent. This control can be performed periodically with appropriate dosage kits or WATEM TEEATMENT QUALITY CONTROL permanently monitored by an appropriate probe under automated control. Chemical purity The effectiveness of a desionizer (conventional mixed bed or CDI) and of a RO system can be monitored perma­ The methods used for monitoring the effectiveness of each nently by measuring the resistivity of the effluent water water treatment options have been discussed in paragraphs produced using an adequate resistivimeter. With RO the 250 Bernard J.M. Canaud and Charles M. Mion

Endotoxin, LAL-detectable, pg^ml Bacteriologic surveillance should concentrate on the 350- critical areas of the installation: after resins and activat­ 300- ed charcoal cartridges, at the entrance and at the outlet 250- of the cold sterilization system of the recirculating loop. 200. Monitoring should be more frequent when an installation 150. is put out of service in order to detect abnormalities in 11^ 100- the hydraulic circuit (126-139). The experience and data 50- gained provide to the user a bacteriologic and lipopolysac- Q t charide contamination profile of the water treatment sys­ Raw CtMicoal Siorad T UcraNlaradTf IcacuMng Malyaala water waMr 1 wataraiOf* | loop tem and can be used to establish the points and frequency sor1 M Id R.O. Storab Connacting Wlrapur i of subsequent monitoring (Figure 20). Endotoxin level in wati atvO.« watar watar tubing dialyaala r w P the water should be evaluated using the LAL test (134, 135). Under usual conditions of use this test has a detec­ Figure 20. Endotoxin concentration profi le of a water treatment chain from raw water to dialysate delivery system. tion limit of 0.1 EU/ml, but a sensitive automated assay using a chromogenic method lowers the detection thresh­ old down to 0,005 EU/ml. rejection/production ratio permits to adjust the quality of treated water according to ionic strength of affluent WATER STANDARDS FOR CONTEMPORARY water. DIALYSIS For monitoring the quality of the final water produced and to ensure compliance with water standards defined by pharmacopoeia, water contaminant concentrations have to Various grades of water may be used for hemodialysis. be determined at the end point of water treatment produc­ From the early days of dialysis, it is known that soft­ tion and at the inlet of the distribution system. Analytical ened water was necessary to prevent the occurrence of the methods complying with pharmacopoeia recommenda­ 'hard water syndrome'. Later on it was shown that puri­ tions should be used to control the chemical purity of fied water using reverse osmosis or deionizer was a basic water. requirement to prevent aluminium intoxication. Eventual­ ly, according to our present knowledge and conditions of contemporary dialysis, it became clear that highly purified Microbiological purity water was required (140-149). Water used for hemodial­ ysis must be close to pharmaceutical grade (i.e., water for To guarantee the reliable and reproducible production of injection) which is achievable with the moderri technol­ an ultrapure water, it is important to organize a surveil­ ogy of water treatment (143-144). Of these waters, two lance protocol documenting die degree of water contam­ are of primary interest for hemodialysis, purified water ination along the water chain (116-118). Water sampling and ultrapure water. In Table 4 a summary of the water devices should be placed in judiciously chosen sites to quality standards is presented permitting to differenti­ permit easy and efficient microbiologic surveillance of ate both type of water. The term 'ultrapure water' has the water treatment chain, reservoir and water delivery been coined mainly to satisfy the needs of the semicon­ system. Samples of water should be cultured regularly ductor industry. In this definition, a strong emphasis is once or twice a week to verify that the installation is given to a higher chemical purity expressed ia terms of operating properly and that adequate disinfection is being a water resistivity equal or superior to 5 megOhms/cm. implemented. This definition includes also stringent requirements con­ The most practical method for conducting the bacteri- cerning the degree of bacterial contamination, with less ologic surveillance of a water treatment production and than 100 CFU/liter and undetectable levels of lipopolysac- distribution system is to culture 0.45 /xm membranes fol­ charides. For dialysis purposes, RO treated water with a lowing filtration of adequate volume of the water to be resistivity in the range of 0.1-0.3 megOhm/cm is quite sat­ tested (from few milliliters up to one liter) according to isfactory; in this context, the term ultrapure water refers the expected degree of contamination. A convenient mem­ mainly to a very low level of bacterial and endotoxin brane support (Swinnex, Millipore, Bedford, MA, USA) contamination(i.e., < 100 CFU/liter; undetectable levels will simplify this operation (119-121). Following sam­ of endotoxin with a sensitive assay). This microbiolog­ ple filtration the membrane is placed on a culture medi­ ic purity is required particularly when high flmx dialysis um favoring the growth of water born bacteria; in spite methods (with high convection rates) are utilized or when of the recommendations of culturing on Q-ypticase-soya reuse of dialyzers is performed. media by various pharmacopoeia, the R2A poor nutrient medium will offer a more sensitive method to detect the presence of these bacteria and to quantify the degree of water contamination and to evaluate the risk of pyrogenic reactions (122-129). 8: Water Treatment for Hemodialysis 251

CONCLUSIONS tion and cytokines production). Time will tell wether this purified environment provided by ultrapure dialysate Contemporary dialysis has created new needs for the water delays (or prevents) the occurrence of late dialysis com­ purification system. Treated water utilized in hemodial­ plications such as /?2M-amyloidosis. Ultrapure water was ysis machine must satisfy more stringent constraints of developed mainly to satisfy the stringent specification of purity both for chemical and microbiological. the semiconductor industry. Due to increased awareness Pharmaceutical grade or highly purified water, so called of the biological hazards of extra-corporeal circulation ultra-pure water, has become a new standard for the dial­ and blood transmembrane contact with a polluted dialysis ysis of the 90s. Several reasons support this need. Limi­ fluid is a strong stimulus to provide hemodialysis patient tations of conventional dialysis as a long term treatment with a sterile endotoxin free dialysate (140). modality (> 10 years) has become largely evident over the last decade. A growing number of patients are suffer­ ing from the bone and joint long term dialysis syndrome REFERENCES induced by ^2-microglobulin amyloidosis. Hemoincompatibility of the hemodialysis system has 1. Man NK, Funck-Brentano JL: Dialyzers and water treat­ been regularly raised as a potential causal factor. ment, in Therapy of Renal Diseases and Related Disor­ Release of pro-inflammatory mediators from protein ders, edited by Suki WN, Massry SG, Boston, Martinus and cell system activation occuring through the blood- N'ijhoff Publishers, 1984, p 545 membrane interaction is enhanced by water contaminant 2. Easterling RE: Mechanical aspects of dialysis includ­ and/or by-products. 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