INTRODUCTION — Water used for the preparation of dialysis fluid is generally derived from a source of drinking water, such as a large municipal water supply, a small community water system, or from a well. The basic requirements for safe drinking water are set out in the World Health Organization (WHO) Guidelines for drinking water quality [1]. Those guidelines outline minimum standards of safe practice and set numerical "guideline values" for contaminants in drinking water and indicators of drinking water quality. Drinking water may also be subject to various statutory regulations, such as the Safe Drinking Water Act (SDWA) in the United States [2], and the European Drinking Water Directive in the European Union [3].

Drinking water is not always in compliance with these regulatory requirements [4-6]. As an example, in the municipal drinking water of several large cities in the United States, changes in water treatment practices and aging water distribution systems have resulted in levels of lead that were more than twice the Environmental Protection Agency action level [7]. Regulatory noncompliance is not limited to chemical contaminants, but can also occur for pathogens including bacteria, viruses, and parasites [8].

Drinking water is not safe for use in hemodialysis applications and must, therefore, be treated further at the point of use. Healthy individuals seldom have a weekly water intake of more than 14 liters (ie, 2 L/day). However, a typical hemodialysis prescription (thrice weekly for four hours per session with a dialysate flow rate of 800 mL/min) exposes the patient to more than 500 liters of water per week across the semi-permeable membrane of the hemodialyzer. Because of this substantially higher exposure to contaminants in water, additional treatment of water used for preparation of dialysis fluid is required.

This topic discusses contaminants that may be present in drinking water, the safe levels of those contaminants in water used for hemodialysis, and the clinical risks to hemodialysis patients associated with those contaminants. For the purpose of discussion in this topic, the term "dialysis water" refers to water that has completed the process of decontamination in preparation for hemodialysis and the term "dialysis fluid" refers to dialysate, which is dialysis water mixed with electrolytes and a buffer as per the hemodialysis prescription.

The main processes used for removal of contaminants from water intended for hemodialysis are summarized here (table 1). More detailed information on the design and operation of water treatment systems intended to protect patients from contaminants is discussed elsewhere. (See "Assuring water quality for hemodialysis".)

CLINICALLY RELEVANT CONTAMINANTS — Water used for hemodialysis should comply with the standards developed by the International Standards Organization (ISO) and adopted by many national agencies worldwide [9-13]. These standards define the maximum permissible levels of chemical contaminants (table 2) and microbial contaminants in dialysis water and make recommendations regarding methods for their quantification. (See 'Microbial contaminants' below.)  

Other guidelines issued by professional organizations provide support to clinical and technical staff and help ensure that a standardized approach is used across facilities. Although those guidelines differ in their scope, the permitted levels of chemical and microbiologic contaminants in dialysis water mirror the levels provided in the ISO standards (table 2) [12,14-17].

Contaminant exposure can be associated with clinical manifestations that are acute in onset (at the time of exposure) or that develop over time with chronic exposure (table 3 and table 4). Acute events related to water contamination generally occur in a cluster of patients while they are on hemodialysis. However, the severity of these events and their onset during a hemodialysis session can vary between patients. Patients' position on the water distribution loop and the timing of the hemodialysis treatment relative to the contamination event can also impact the clinical presentation. As an example, exposure to residual disinfectant in the water supply predominantly affects patients who are most proximal to the water supply during the first treatment session following disinfection. Chronic exposure to water contaminants is more difficult to identify. Water contamination should be suspected when multiple patients are affected while receiving hemodialysis at the same facility.

Chemical contaminants and trace elements with known toxicity in hemodialysis patients

Aluminum — Salts of aluminum, such as alum, are added to drinking water to facilitate chemical precipitation and flocculation of colloidal particles (turbidity) and microbes. Prior to the widespread use of reverse osmosis in the treatment of water, hemodialysis patients were at risk of chronic exposure to aluminum. The chronic exposure to aluminum led to neurologic injury including speech abnormalities, myoclonic muscle spasms, seizures, personality changes, and other manifestations (table 3) [18,19]. (See "Aluminum toxicity in chronic kidney disease" and "Seizures in patients undergoing hemodialysis".)

Today, aluminum toxicity is rare [20,21]. Nonetheless, occasional, sporadic outbreaks of aluminum intoxication associated with inadequately treated water continue to be reported [22-24].  

Historically, based on the risk of aluminum toxicity among patients on hemodialysis, routine measurements of plasma aluminum concentration were performed [25]. However, with improvements in hemodialysis technology, the utility and cost-effectiveness of such measurements have been questioned [26,27]. It is reasonable to monitor for patient exposure to aluminum during hemodialysis by regularly verifying the performance of the water treatment system. The measurement of plasma aluminum levels should be limited to patients in whom there is a high risk of overload or clinical evidence of toxicity [28]. This may include patients who are on over-the-counter medications containing aluminum or being treated with newer hemodialysis techniques, such as online hemodiafiltration (due to 25 to 35 L of water infused directly into the blood).

Copper and zinc — Copper and zinc can leach from metal pipes or plumbing. These metals have been associated with anemia and fatal hemolysis in patients on hemodialysis and are removed from water by reverse osmosis (table 3 and table 1) [29-31].

Fluoride — Fluoride is added to drinking water in low concentrations to prevent dental caries; it may also be naturally present in ground water. Over-fluoridation of drinking water has occurred [32,33].

Patients with reduced glomerular filtration rates (GFRs) have a decreased ability to excrete fluoride and may develop skeletal fluorosis even at 1 part per million (ppm) fluoride concentration that is normally present in the drinking water (table 2) [34]. Excess fluoride has been associated with increased osteoid parameters and decreased bone microhardness in patients with renal osteodystrophy [35]. It is unclear if there is any association between osteomalacia or osteoporosis and chronic exposure to low levels of fluoride that remain after reverse osmosis [20,36].

During the preparation of dialysis fluid, fluoride is removed either by reverse osmosis or by deionization (table 1). Deionizers have a limited capacity for anion removal. If operated to exhaustion, anions previously removed by the deionizer may be released back into the water. This can lead to intoxication from acute exposure to high levels of fluoride and can manifest as severe pruritus and fatal ventricular fibrillation (table 3) [37].

Lead — Lead can leach from metal plumbing or be present in public water from changes in water treatment practices. As an example, the introduction of monochloramine as a disinfectant for drinking water led to elevated lead levels from corrosion of lead piping [38]. Elevated levels of lead in hemodialysis patients have been linked to uremic pruritus (table 3) [39-41]. Lead is removed from water by reverse osmosis (table 1).

Clinical manifestations of lead toxicity are discussed elsewhere. (See "Lead exposure and poisoning in adults", section on 'Clinical manifestations'.)

Nitrates — Nitrates are commonly present in fertilizers and find their way into water sources. Violations in the maximum enforceable limit of nitrate (as nitrogen) for drinking water (10 mg/L [or 10 ppm]) are common (table 2) [42]. Elevated levels of nitrate can cause anemia and methemoglobinemia in hemodialysis patients (table 3) [43-45]. (See "Methemoglobinemia".)

Nitrates are removed from the drinking water by reverse osmosis (table 1).

Sulfate — Sulfate (SO₄) from industrial discharges or from naturally occurring minerals is found in many water supplies. It may also result from the use of iron sulfate as a flocculent for water treatment. At levels >200 mg/L in dialysis water (table 1), sulfate can cause nausea, vomiting, and metabolic acidosis (table 3) [46]. However, these effects have not been observed when the level remains <100 mg/L (that which is permitted in dialysis water).

Trace elements — Trace elements can enter the water supply from naturally occurring minerals or from industrial discharges. A deficiency of essential trace elements and an excess of potentially toxic trace elements are common in patients on hemodialysis [44,47,48]. They are removed from water by reverse osmosis (table 1). Apart from selenium and chromium, the permitted levels of barium, silver, cadmium, mercury, arsenic, thallium, and vanadium are set at 10 percent of the value permitted in drinking water by the United States Environmental Protection Agency (EPA) (table 2). For selenium and chromium, the zero-transfer level is set [10]. The zero-transfer level is the concentration of the element in the dialysis water at which no transfer (by diffusion down a concentration gradient) occurs between dialysis fluid and plasma. For selenium and chromium, a zero-transfer level is higher than 10 percent of the value permitted in drinking water.

Trace metals such as cadmium, arsenic, mercury, chromium, and aluminum may be toxic to bone cells even at low concentrations (table 2 and table 3) [49]. Despite the zero-transfer level, increased levels of chromium have been reported in the serum and bone of hemodialysis patients [50-52]. The most likely source of this chromium is dietary intake. Although there is no evidence of dialysis water being a potential source of chromium, intoxication is possible from the salts added to the dialysis fluid or from leaching of the hemodialysis machine [50,51].

Electrolytes present in dialysis fluid — Electrolytes such as sodium, potassium, calcium, and magnesium are present in drinking water at various concentrations and are removed during water treatment prior to its use for hemodialysis. This is to ensure that the residual electrolytes present in dialysis water do not contribute to clinically significant concentrations during the preparation of dialysis fluid. Electrolytes are generally well removed by reverse osmosis (table 1). Divalent cations, such as calcium and magnesium, are usually removed by water softening prior to reverse osmosis to prevent scaling of the reverse osmosis membrane (table 1).

Accidental softener malfunction during hemodialysis can lead to hypernatremia [53], while elevated levels of calcium from failure of a reverse osmosis unit or softener can lead to hard water syndrome, which manifests with nausea, vomiting, weakness, and hypertension (table 3) [54,55]. Hard water syndrome can also be associated with an increased risk of arteriovenous fistula thrombosis [55].

Disinfectants added to drinking water — Disinfectants are added to drinking water at the municipal level to ensure that the water complies with the national standard for total coliform bacteria in drinking water. Disinfectants commonly used for this purpose include chlorine, monochloramine, and chlorine dioxide.

Chlorine and monochloramine — In addition to disinfecting water, chlorine is also a strong oxidizing agent that can interact with contaminants in the water to form byproducts of disinfection, such as trichloromethane, chloroacetic acids, and chlorite. These substances are considered harmful and are regulated under the Safe Drinking Water Act [2]. Chlorine can also corrode copper pipes, leading to an increase in the copper level of water. Such an increase in copper can be mitigated by controlling the pH and/or adding orthophosphate to the water [56]. Chlorine also oxidizes iron, manganese, and taste and odor compounds present in water. In addition, it removes color from the water, decreases hydrogen sulfide levels, and aids in other water treatment processes, such as sedimentation and filtration. 

Chloramines are the reaction products of chlorine and ammonia, of which monochloramine is the most common. Monochloramine is widely chosen as a disinfectant for drinking water due to certain advantages compared with chlorine, such as: maintenance of its disinfectant activity for a prolonged period of time; lack of alteration of the taste or smell of drinking water; and a lower likelihood of reacting with organic matter to produce trihalomethanes that are associated with health risks [57]. Chlorine and monochloramine are removed by carbon filtration. The removal of chlorine and monochloramine is essential before the reverse osmosis step to prevent damage to the reverse osmosis membrane (table 1).

Monochloramine-contaminated dialysis fluid can cause hemolysis, hemolytic anemia, and methemoglobinemia [58-62], and has also been associated with erythropoietin resistance (table 3 and table 4) [63]. (See "Methemoglobinemia".)

Chlorine dioxide — Chlorine dioxide is used as a disinfectant by a small number of municipal water suppliers. Thus, residual chlorine dioxide and its oxychlorine byproducts, such as chlorite and chlorate, may be present in drinking water. In the United States, the permitted Mean Residual Disinfection Level of chlorine dioxide for drinking water is 0.8 mg/L, and the permitted Maximum Contaminant Level for the byproduct, chlorite, is 1.0 mg/L. In the United Kingdom, the maximum permitted level for the combined concentrations of residual chlorine dioxide and chlorite is 0.5 mg/L. Chlorine dioxide and its oxychlorine byproducts are removed by carbon filtration (table 1).

There is little information about the toxicity of chlorine dioxide and its byproducts to hemodialysis patients. A limited study of 17 patients unknowingly treated with dialysis water disinfected with chlorine dioxide showed no evidence of adverse effects [64]. The dialysis water contained 0.02 to 0.08 mg/L of chlorite and no detectable chlorate. However, the patient population was small and potentially important hematologic parameters were not measured. Despite a lack of clear evidence of harm, chloride dioxide should be considered a contaminant with similar clinical toxicity to chlorine and monochloramine until more information is available (table 3).

Disinfectants added by hospitals or hemodialysis facilities

Hydrogen peroxide and silver-stabilized peroxide — Hydrogen peroxide and silver-stabilized peroxide can be used to suppress growth of legionella in storage tanks and distribution systems of health care premises that include hemodialysis units. The presence of residual hydrogen peroxide and silver-stabilized hydrogen peroxide in dialysis water has been associated with cyanosis and methemoglobinemia, and can be removed by carbon filtration (table 1) [65-69]. (See "Methemoglobinemia".)

Peracetic acid and sodium hypochlorite (bleach) — Dialysis water treatment and distribution systems routinely undergo disinfection or descaling to prevent bacterial growth. (See "Assuring water quality for hemodialysis", section on 'Disinfection'.)

During disinfection, a cold sterilant such as peracetic acid or sodium hypochlorite is added to the water and circulated for a period of time. The sterilant is then flushed from the system using water produced by the water treatment system. The flushed water is then tested for the presence of residual sterilant using test strips.

However, if flushing of the system is inadequate, patients can be inadvertently exposed to the sterilant. Typically, the risk of exposure is the highest for patients treated on the first shift (after sterilization) who are in closest proximity to the water treatment system. Exposure to sodium hypochlorite can be serious and is usually manifested by hemolysis, hyperkalemia, hypoxia, and cardiac arrest (table 3) [70,71]. Exposure to peracetic acid can also result in hemolysis [72]. Peracetic acid and sodium hypochlorite are removed by carbon filtration (table 1).

Microbial contaminants

Bacteria and endotoxin — In addition to limits for chemical contaminants, the ISO standard also specifies maximum permitted levels for bacteria and endotoxins in the dialysis water. Adherence to these standards is particularly important when the ultimate use of the water is for the on-line preparation of sterile, non-pyrogenic substitution solution for hemodiafiltration. (See "Technical aspects of hemodiafiltration".)

Bacteria or endotoxins can also contaminate dialyzers that are reused. This is usually by way of the water that enters the blood compartment of the dialyzer when it is being processed for reuse. These contaminants can then travel from the blood compartment into the patient's bloodstream, causing bacteremia, endotoxinemia, and pyrogenic reactions [73-75]. (See "Reuse of dialyzers".)

Bacteriostatic agents, chlorine and monochloramine, that are added for disinfection of drinking water get removed from dialysis water (see "Assuring water quality for hemodialysis", section on 'Activated carbon beds or filters'). This makes the water susceptible to bacterial proliferation. If such proliferation goes unchecked, a biocide-resistant biofilm can develop and serve as an ongoing source of bacterial contaminants [76]. Improvements in membrane technology have led to development of dialyzer membranes that provide an effective barrier against bacteria and endotoxins. However, small bacterial fragments still have the potential to cross some dialyzer membranes [77-81]. The repeated exposure to such bacterial fragments is associated with a microinflammatory response, which is believed to contribute to the long-term morbidity among patients on hemodialysis [82].

Typical culture and colony count methods for detecting bacteria are limited in their ability to detect low concentrations of fastidious and slow-growing bacteria that are typically present in drinking water, and routinely used assays for bacterial fragments can only detect lipopolysaccharide and lipid A [83]. Sophisticated test systems are available for detection of additional microbes and microbial products, such as peptidoglycans, bacterial DNA, mycoplasma, fungi, and viruses [84,85]. However, there are no established standards for such testing.

Cyanobacterial toxins — Surface water can be contaminated by cyanobacteria. Cyanobacteria produce microcystins that are harmful to humans. Most municipal water treatment plants do not regularly screen for microcystins in the water supply, unless cyanobacteria are present in the source water. If identified, remedial action is taken so that the water complies with health advisory recommendations detailed by the World Health Organization (WHO) and the United States EPA [1,86]. However, complete removal of microcystins is challenging due to the possibility of dissolved extracellular toxin that can bypass the treatment process [87].

Hemodialysis patients exposed to dialysis water contaminated with cyanotoxins may develop fatal acute illness [3,88-91]. However, ensuring safety of hemodialysis patients from these toxins is complicated by a lack of monitoring and regulation of cyanotoxins in source drinking water, lack of established safe levels in dialysis water, and insufficient knowledge regarding the methods to eliminate them. Thus, hemodialysis centers should be aware of potential cyanotoxins in dialysis water, particularly when it is sourced from warm, slow-moving, nutrient-rich surface water, which is prone to cyanobacterial blooms. Hemodialysis facilities should establish a means of communication with their municipal water providers so that they are notified of any cyanobacterial blooms in the surface waters used for their supply.

In the absence of concentration-toxicity data, the United States and international standards for dialysis water set the maximum allowable levels of potentially toxic contaminants at 10 percent of the levels allowed in drinking water. On that basis, and using the WHO provisional drinking water guideline for the concentration of microcystin-LR at 1 microgram/L based on lifetime exposure, the maximum concentration for microcystins in dialysis water would be 10 percent of 1 microgram/L, or 0.1 microgram/L.

CONTAMINANTS WITH UNCERTAIN TOXICITY IN HEMODIALYSIS PATIENTS

Organic compounds — The World Health Organization drinking water guidelines list many organic contaminants, such as trichloroethylene and bisphenol A (BPA), which may be present in drinking water [1,92,93]. However, the long-term effects of these contaminants on hemodialysis patients are unknown.

BPA is used in the manufacture of plastics [93]. It is metabolized in the liver to form bisphenol A glucuronide, which plays a role in the pathogenesis of several endocrine disorders. BPA can be removed from water by nanofiltration and reverse osmosis [94]. However, BPA can be present in plastic components of the water distribution system downstream of the water treatment facility [95,96], so that patients who receive on-line hemodiafiltration can still be exposed to BPA and its chlorinated derivatives [95]. The level and impact of exposure for hemodialysis patients remains unknown.

Other organic compounds such as pesticides, herbicides, and polycyclic aromatic hydrocarbons can also be present in drinking water. Reverse osmosis and granular-activated carbon can remove organic compounds. However, adequate removal is highly dependent upon the size of the carbon beds and the availability of binding sites.

If the presence of an organic compound has been demonstrated in dialysis water, then routine monitoring is advised, and it is reasonable to aim for a concentration that is 10-fold lower than the requirement for drinking water.

Microplastics — There is widespread presence of microplastics (<5 mm in diameter) in drinking water [97]. Microplastics are unlikely to cross reverse osmosis or dialyzer membranes and, to date, there is no evidence to suggest that microplastics are harmful to hemodialysis patients [98].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dialysis".)

SUMMARY AND RECOMMENDATIONS

●Drinking water, which is usually sourced from a large municipal water supply, a small community water system, or a well, is not safe for hemodialysis and must, therefore, be treated further at the point of use. (See 'Introduction' above.)

●The International Standards Organization (ISO) and other agencies define the maximum permissible levels of chemical (table 2) and microbial contaminants present in dialysis water. Lack of adequate contaminant removal can result in clinical manifestations of toxicity among hemodialysis patients. Toxicity may be acute in onset (at the time of exposure) or may develop over time with chronic exposure (table 3 and table 4). Contamination should be suspected when multiple patients undergoing hemodialysis at the same facility develop similar symptoms. (See 'Clinically relevant contaminants' above.)

•Certain chemical contaminants, such as aluminum, copper, zinc, fluoride, lead, nitrates, sulfate, and trace elements may inadvertently enter the water supply from various environmental sources. These chemicals require removal by reverse osmosis (table 1). (See 'Chemical contaminants and trace elements with known toxicity in hemodialysis patients' above.)

•Dialysis water can also contain excess amounts of electrolytes (eg, calcium, magnesium) requiring removal (table 1). (See 'Electrolytes present in dialysis fluid' above.)

•Disinfectants, such as chlorine, monochloramine, and chlorine dioxide, are added to the water supply to limit growth of coliform bacteria. Exposure to these can result in hemolysis, hemolytic anemia, methemoglobinemia, and erythropoietin resistance (table 3 and table 4). They are removed by carbon filtration (table 1). (See 'Disinfectants added to drinking water' above.)

•Additional disinfectants (eg, hydrogen peroxide), which may be added by hospitals or hemodialysis units, need to be removed by carbon filtration (table 1). (See 'Disinfectants added by hospitals or hemodialysis facilities' above.)

•The ISO standard also specifies maximum permitted levels for bacteria and endotoxins in dialysis water. Failure to control these can result in bacteremia, endotoxinemia, and pyrogenic reactions. In addition, surface water can be contaminated by cyanobacteria that can produce microcystins, which can lead to fatal illness in humans. Hemodialysis facilities should establish a means of communication with their municipal water providers so that they are notified of any cyanobacterial blooms in the surface waters used for their supply. (See 'Microbial contaminants' above.)