Dialysis-Associated Complications and Their Control

Matthew J. Arduino

Priti R. Patel

INTRODUCTION

The number of patients who have end stage renal disease (ESRD) has increased dramatically in the past 40 years. Three major forms of renal replacement therapy (i.e., hemodialysis, peritoneal dialysis, and kidney transplantation) treat ESRD patients. Data from the U.S. Renal Data System (USRDS) suggests that by the end of 2010 there were approximately 593,086 patients with ESRD. Maintenance hemodialysis patients comprise approximately 65% (383,992) of the patients in this population. Approximately 5% (29,733) of ESRD patients are treated by one of the modes of peritoneal dialysis (1).

In 1967, approximately 1,000 patients were undergoing maintenance or chronic hemodialysis. In 1973, when full Medicare coverage was extended to ESRD patients, approximately 11,000 patients were undergoing dialysis. By the end of 2010, the program had grown markedly, and almost 400,000 patients were treated in 5,760 dialysis centers (free-standing for profit and nonprofit clinics, in addition to hospital-based units) and in homes. Most patients (63.4%) were treated in centers affiliated with one of the three large dialysis organizations (i.e., Fresenius Medical Care, DaVita, or DCI), 11.6% of patients were treated by small dialysis organizations, 10% by hospital-owned units, and 15% by independent providers. There were also 81,076 full and part-time staff members (i.e., Nurses, Technicians, Dieticians, Social Workers, and so on) employed by these facilities. Home hemodialysis represents a very small fraction of U.S. hemodialysis patients (1). The ESRD program is administered by the Centers for Medicare and Medicaid Services (CMS) of the Department of Health and Human Services and is the only Medicare entitlement that is based on the diagnosis of a medical condition. As such, participating healthcare facilities must meet CMS regulations as published in the CMS Conditions for Coverage for End-Stage Renal Disease Facilities, 2008 (2).

The technology for performing dialysis as well as the potential for complications has changed markedly over the years. In the early 1960s, hemodialysis was used almost exclusively for the treatment of acute renal failure. Subsequently, the development of the arteriovenous shunt and certain other ancillary technologic advances in dialysis equipment expanded the use of hemodialysis to maintenance therapy for ESRD. In the 1970s, the primary mode for dialysis treatment was hemodialysis performed with various types of dialysis machines and artificial kidneys.

The use of peritoneal dialysis, accomplished by automated machines (cycling), or manually, also increased. The three modes include continuous ambulatory peritoneal dialysis (CAPD), automated peritoneal dialysis (APD), and intermittent peritoneal dialysis (IPD) modality. Peritoneal dialysis is more popular among pediatric nephrology programs (approximately 40% of all pediatric dialysis patients) (1) than adult programs. One must also recognize that patients may change modality due to vascular access failure, or failure of the peritoneum to adequately perform dialysis (e.g., recurrent peritonitis or peritoneal transport issues).

All patients with chronic kidney disease, including dialysis patients, have a compromised immune system and other co-morbidities that place them at increased risk for infectious diseases. Patients on maintenance hemodialysis are at particular risk. In-center hemodialysis patients are at higher risk for infections and are at risk for other adverse events associated with the dialysis process. In this environment, multiple patients typically receive dialysis concurrently, and there are repeated opportunities for person-to-person transmission of infectious agents, directly or indirectly via contaminated devices, equipment and supplies (including medications), environmental surfaces, or the hands of healthcare personnel when recommended infection control practices are not followed. In addition, the dialysis process is not without risks either due to errors by personnel, failure of equipment, or vascular access complications.

The Centers for Disease Control and Prevention (CDC) compiled data of adverse outcomes among dialysis patients from two sources. The first includes outbreak investigations in dialysis settings reported to CDC and National Surveillance data. National surveillance data was collected by CDC beginning in the 1970s to study the incidence and prevalence of hepatitis B (HBV) in this population. These national surveys subsequently evolved into the National Surveillance of Dialysis-Associated Diseases in the United States performed by CDC in collaboration with CMS in 1976, 1980, 1982 to 1997, and 1999 to 2002 (3,4,5,6,7,8,9,10,11,12,13,14,15,16). Future surveillance data will be collected from facilities and providers through the use of the National Healthcare Safety Network (NHSN) surveillance system (17).

Over the past 40 years, the CDC also has investigated outbreaks in the dialysis setting; 24 outbreaks were infections (bacterial or fungal) or pyrogenic reactions, 28 outbreaks were due to viral infections, 11 were due to exposure to chemical contaminants, and two allergic-type complications during dialysis (Table 23.1). In addition, the CDC also investigated a cluster

of vascular access failures (18), cases of nephrogenic systemic fibrosis due to exposure to gadolinium (19), neurologic symptoms following use of aged dialyzers (20), adverse reactions and death associated with heparin contaminated with over-sulfated chondroitin sulfate (21), deaths following the use of dialyzers contaminated with a perfluorocarbon performance fluid (22,23), and hemolysis due to defective bloodlines (24). This chapter describes the major infectious diseases and other adverse patient reactions that can be acquired in the dialysis center setting, the important epidemiologic and environmental microbiologic considerations, and infection control strategies for their prevention.

TABLE 23.1 Outbreaks and Adverse Events in the Dialysis Setting Investigated by the Centers for Disease Control and Prevention (CDC) and State/Local Health Departments

Description (Reference)	Cause of the Events	Corrective Measures/Recommendations
CHEMICAL CONTAMINATION OF DIALYSATE
Aluminum intoxication and seizures in seven patients (281)	Exhausted deionization tanks unable to remove aluminum in incoming tap water	Monitor deionization tanks daily; install reverse osmosis unit
Aluminum intoxication, neurologic symptoms, dementia and elevated serum aluminum levels in 64 patients; three deaths (174)	Aluminum pump was used to transfer acid concentrate to the treatment area	Utilize components in the fluid distribution systems that are compatible and do not leach into the dialysate
Elevated serum aluminum levels detected in 10 patients during routine screening (176)	Replacement transfer pump used to pump acid concentrate from 55 gallon drum into jugs used at the machine contained aluminum components	Contact manufacturer of acid concentrate for a compatible pump; utilize components in the fluid distribution systems that are compatible and do not leach into the dialysate
16 patients developed nausea, vomiting, chills, some develop fever; two deaths (282)	Water used to prepare dialysate contained volatile organic compounds (CS₂, CH₃S, etc.); multiple causes: citric acid used to adjust incoming water pH to aid in removal of chlorine by carbon tanks; water treatment system not functioning properly; microbial quality of water above AAMI limits	Suspend injection of citric acid (use another pH additive); redesign and replace water treatment system
Hemolytic anemia in 41 patients (177)	Facility increased capacity of water treatment system without adjusting size of pretreatment carbon beds; potable water supplier uses monochloramine as residual disinfectant, which was not removed completely by the carbon tank	Use larger carbon beds to give adequate empty bed contact time to remove chloramines; monitor for total chlorine breakthrough after first carbon tank
Fluoride intoxication in eight patients; one death (46)	Accidental spill of hydrofluosilic acid at drinking water plant lead to excessive fluoride levels in water entering a dialysis unit; water treatment at the dialysis facility only included softening	Install reverse osmosis unit
Fluoride intoxication in nine patients; three deaths (45,283)	Exhausted deionization tanks discharged a bolus of fluoride	Deionization tanks should be monitored with temperature compensated resistivity alarms that include both visual and audible alarms
Formaldehyde intoxication in five patients; one death (178)	Disinfectant not properly rinsed from the distribution system	Eliminate stagnant flow areas; test for residual disinfectant
Decreased hemoglobin in three pediatric dialysis patients (284)	Hydrogen peroxide used to disinfect the system not adequately rinsed from the system; facility used flat bottom storage tank that could not be drained	Thoroughly rinse disinfectant from the system; use an appropriate residual test kit; installation of a storage tank with conical bottom and outflow at lowest point would allow for storage tank to empty completely
116 of 130 patients (89%) at a dialysis center in Brazil, had visual disturbances, nausea, and vomiting associated with hemodialysis and 50 died; following the initial investigation it was reported an additional 26 patients had died of liver failure (285,286)	Water contaminated with cyanobacterial toxins not removed by water treatment system; patients exposed to dialysate containing microcystin-LR	Have finished drinking water supplied to the facility; important to appropriately design (based on system feed water), install, monitor, and maintain water treatment systems
Severe hypotension in nine patients (287)	Dialysate contaminated with sodium azide used as a preservative from new ultrafilters (filters were labeled “not for medical use”)	Rinse system after modification or installation of new components
BACTEREMIA, FUNGEMIA, OR PYROGENIC REACTIONS NOT RELATED TO DIALYZER REUSE
Pyrogenic reactions in 49 patients (31)	Untreated tap water contained high levels of endotoxin	Install a reverse osmosis water treatment system
Pyrogenic reactions in 45 patients (30)	Inadequate disinfection of the fluid distribution system	Increase disinfection frequency and disinfectant contact time
Pyrogenic reactions and bacteremia in five patients; two patients had bacteremia (one with Klebsiella pneumonia, the other had both K. pneumonia and Pseudomonas aeruginosa) (288)	Two weeks before the outbreak a pump that pumped sodium hypochlorite through the distribution and machines failed; the distribution system and machines were inadequately disinfected; P. aeruginosa, K. pneumonia, and Pantoea (Enterobacter) agglomerans were recovered from water, dialysate, and other environmental sources	Routine disinfection of the fluid distribution system and dialysis machines following repair of the pump ended the outbreak
Pyrogenic reactions in 14 patients; two with bacteremia; one death (29)	Reverse osmosis water storage tank contaminated with bacteria	Remove or properly maintain and disinfect storage tank
Bacteremia in 35 (51.5%) patients with central venous catheters (CVCs) (142)	CVCs used as primary access; median duration of catheter use among affected patients was 311 days; improper aseptic techniques	Use CVCs only when necessary (i.e., bridge to maturing fistula or graft or as an access of last resort); use appropriate aseptic techniques when inserting CVC and performing catheter care
Three pyrogenic reactions and seven Enterobacter cloacae bloodstream infections…(111)	Incompetent check valves in the waste handling option (WHO-port) of one type of dialysis machine allowed backflow of spent dialysate into patient blood lines during circuit priming and dialysis initiation; Machines and ports were contaminated with E. cloacae	Routine maintenance, disinfection, and valve competency testing of the WHO should be carried out
Gram-negative bacteremia in 1 patient (6 E. cloacae, 4 P. aeruginosa, 2 Escherichia coli; 2 had polymicrobial bacteremia) (112)	Incompetent check valves in the waste handling option (WHO-port) of one type of dialysis machine allowed backflow of spent dialysate into patient blood lines during circuit priming and dialysis initiation; machines and ports were contaminated with E. cloacae and P. aeruginosa	Routine maintenance, disinfection, and valve competency testing of the WHO should be carried out
Outbreak of pyrogenic reactions and gram-negative bacteremia in 11 patients (4 had bacteremia) (28)	Water distribution system was not routinely disinfected and machines were not disinfected in accordance with manufacturer’s instructions; water and dialysate cultures were performed using a 10^-3 calibrated loop on blood agar plates—results were often reported as no growth	Disinfect machines according to manufacturer’s instructions; include water distribution system in the weekly disinfection of the RO system. Do not use calibrated loops. These are not sensitive to detect when AAMI limits have been reached; use spread plate or membrane filtration techniques and Trypticase Soy Agar (TSA) for testing (94)
Phialemonium curvatum access infections in four hemodialysis patients, two patients died of systemic disease (289,290).	Phialemonium species were only recovered from the condensation drip pans under the blowers of the HVAC system that supplied air to the dialysis center. Observations at the facility noted some irregularities with site prep for needle insertion; all infected patients had synthetic grafts.	Review infection control practices, clean and disinfect the HVAC system where water accumulates; perform surveillance on facility patients. Observe proper aseptic technique during access cannulation.
Fungemia with Phialemonium curvatum in two maintenance hemodialysis patients (291).	Both patients were dialyzed on the same machine. Facility used machines with a waste handling port; Phialemonium was isolated from reverse osmosis unit (WHO-port and valves were not available for culture)	WHO ports have been previously been associated with cases of bacteremia; remediation of water distribution system and maintenance and discontinuing use of WHO ports ended the outbreak.
ADVERSE EVENTS ASSOCIATED WITH HEMODIALYZER REUSE
Mycobacterial infections in 27 patients (292)	Inadequate concentration of dialyzer disinfectant	Increase concentration of formaldehyde used to disinfect dialyzers to 4%
Mycobacterium abscessus infection in five patients treated with high-flux hemodialyzers (38)	Inadequate dialyzer disinfection due to over diluted disinfectant; inadequate disinfection of water distribution system	Use higher concentration of dialyzer disinfectant; follow manufacturer’s label; more frequent disinfection of the water treatment system
Bacteremia and pyrogenic reactions in six patients (293)	Dialyzer disinfectant diluted to improper concentration	Use disinfectant at recommended dilution and verify concentration
Bacteremia in six patients (CDC, unpublished data)	Inadequate concentration of dialyzer disinfectant; water for reuse did not meet AAMI standards	Use AAMI quality water for reprocessing hemodialyzers; ensure proper disinfectant concentration in reprocessed dialyzers
Nine pyrogenic reactions and five gram-negative bacteremias in 11 patients undergoing dialysis (67)	Inadequate mixing of dialyzer disinfectant	Thoroughly mix dialyzer disinfectant and verify proper concentration
Bacteremia in 33 dialysis patients at two dialysis clinics (104,294)	New dialyzer disinfectant created holes in dialyzer membranes	Change disinfectant (manufacturer withdrew product from the market place)
Six chronic hemodialysis patients acquired bloodstream infections (BSIs) with Klebsiella pneumoniae of the same serotype and similar plasmid profile (72)	Dialyzers contaminated during removal and cleaning of headers with a common gauze pad; staff not routinely changing gloves; dialyzers not reprocessed for several hours after disassembly and cleaning	Do not use gauze or similar material to remove clots from header; rinse headers with treated water and disinfect header components before reassembly; change gloves frequently; reprocess dialyzers immediately after rinsing and cleaning
Pyrogenic reactions in three high-flux dialysis patients (295)	Dialyzers reprocessed with two different disinfectants; water used for reprocessing hemodialyzers did not meet AAMI standards	Do not disinfect dialyzers with multiple disinfectants; disinfect water treatment system more frequently
Pyrogenic reactions in 14 high-flux dialysis patients; one death (296)	Dialyzers rinsed with tap water; water for reuse did not meet AAMI standards	Do not rinse or clean dialyzers with city tap water; use treated water that has been maintained to meet AAMI standards
Pyrogenic reactions in 18 patients (69)	Dialyzers reprocessed with city tap water containing high levels of endotoxin; water did not meet AAMI standards	Do not rinse or clean dialyzers with city tap water; use treated water that has been maintained to meet AAMI standards
Pyrogenic reactions in 22 patients (71)	Water for reuse did not meet AAMI standards; improper microbial assay method was employed to monitor dialysis fluids	Use correct microbial assay procedure; disinfect water treatment system to maintain microbial quality of treated water and meet AAMI standards
Bacteremia with gram-negative water bacteria in 13 patients (297)	Water distribution system had flow and pressure problems; B. cepacia and Ralstonia spp. were isolated from water and dialysate. Water was sporadically above AAMI limits; no bacteremia in patients when reuse was suspended	Evidence that system had biofilm present; suggestions were made to consider replacing the distribution loop which would also help with the flow and pressure problems. Scrapings of section of pipe that was removed had evidence of biofilm.
*Acute hypersensitivity/allergic reactions*
Acute allergic reactions in hundreds of patients using reprocessed hemodialyzers in at least 31 dialysis centers (70,170).	Related to the use of angiotensin-converting-enzyme (ACE) inhibitors, and possibly to chemicals used in cleaning dialyzer or inadequate disinfectant rinse out.	No specific recommendations were made.
Nationwide outbreak of severe allergic-type reactions that were first detected in a single hemodialysis facility. 152 cases identified (21).	Use of heparin manufactured by Baxter Healthcare was the factor most strongly associated with reactions; heparin was found to be contaminated with over-sulfated chondroitin sulfate (OSCS)	Manufacturer recalled all lots implicated.
*Hemolysis and other miscellaneous investigations*
Severe hemolytic events among dialysis patients in dialysis facilities in five states; at least three deaths (24)	Three lots of bloodlines had a manufacturing defect that caused approximately 10% of the bloodlines to have occlusions; these inclusions blocked between 20% and 80% of the internal diameter of the lines	Manufacture recalled several lots of blood tubing sets
State medical examiner’s office notified CDC of a cluster of deaths due to vascular access hemorrhage (18)	Reviewed CMS and medical examiner records; Identified 88 confirmed cases; risk factors included: presence of an arteriovenous graft, access-related complications within 6 months of death, hypertension	Nephrologists should review primary and secondary prevention measures with their patients; particularly those who have had vascular access complications
CDC notified of 28 patients with nephrogenic systemic fibrosis (NSF) at one medical center (19).	14 of 19 confirmed cases had receipt of gadolinium-containing contrast solution the year before onset; gadolinium contrast exposure was associated with NSF in a dose dependent manner	Receipt of gadolinium-containing contrast solution should be avoided when possible in patients with end stage renal disease, particularly those receiving peritoneal dialysis.
TRANSMISSION OF VIRAL AGENTS
26 patients seroconvert to HBsAg-positive (185)	Blood leaks in coil dialyzers and use of recirculating bath dialysis machine	Separation of HBsAg-positive patients and equipment from susceptible patients; pressure-leak testing of reused dialyzers was inadequate
19 patients and one staff member seroconvert to HBsAg-positive in a 14-month time frame (182)	No specific cause identified; false-positive HBsAg test results caused some susceptible patients to be dialyzed with infected patients	Laboratory confirmation of HBsAg-positive results; strict adherence to glove use and use of separate (dedicated) equipment
40 patients (24 in-center, 12 home dialysis, and 4 home training) and 10 staff members convert to HBsAg-positive during a 10 month period (186)	Home patients were excluded from the investigation due to paucity of data; staff were not wearing gloves; environmental surfaces not routinely cleaned/disinfected; improper handling of sharps	Separation of HBsAg-positive patients and their dedicated equipment from susceptible patients; proper precautions by staff (e.g., gloving, handling of needles and sharps, and disinfection of environmental surfaces)
13 patients and one staff member convert to HBsAg-positive in a single month (180)	Extrinsic contamination of intravenous hypertonic glucose being prepared adjacent to an area where blood work was handled	Separate medication preparation area and blood processing for diagnostic tests
10 patients seroconvert to HBsAg-positive in a 1-month period (179)	Extrinsic contamination of bupivacaine that was shared between HBsAg-positive and susceptible patients	No sharing of equipment, supplies, and medications between patients
Eight patients seroconvert to HBsAg-positive over a five month period (CDC, unpublished data)	Sporadic screening for HBsAg; HBsAg-positive patient not isolated; major bleeding incident with environmental contamination	Perform monthly screening of patients for HBsAg; isolate HBsAg-positive patients with dedicated equipment and staff; vaccinate all susceptible patients
Seven patients seroconvert to HBsAg-positive during a 3-month period (184)	Same staff caring for HBsAg-positive and HBsAg-negative patients	Separate HBsAg-positive patients from HBsAg-negative patients; same staff should not care for both HBsAg-positive and negative patients on the same shift
Eight patients convert to HBsAg-positive during 1 month (187)	Not consistently using pressure transducer protectors; same staff members cared for both HBsAg-positive and negative patients on the same shift	User pressure transducer protectors and replace after each patient; same staff members should not care for both HBsAg-positive and -negative patients on the same shift
14 patients seroconverted to HBsAg-positive during a 6-week period (188)	Failure to review laboratory results of admission and monthly HBsAg testing; inconsistent hand hygiene and use of gloves; adjacent clean and contaminated areas; <20% of patients vaccinated	Proper infection control precautions for dialysis units; routine review of laboratory testing; hepatitis B vaccination of all dialysis patients
Seven patients seroconverted to HBsAg-positive during a 2-month period (188)	Staff members cared for both HBsAg-positive and negative patients on the same shift; common medication and supply carts were moved between stations, and multidose vials were shared; no patients were vaccinated	Dedicated staff for HBsAg-positive patients; no sharing of medications or supplies between patients; centralized medication and supply areas; vaccinate all patients against hepatitis B.
Four patients seroconverted to HBsAg-positive during a 3-month period (188)	Transmission appeared to occur during hospitalization at an acute care facility	Vaccinate all patients to protect against hepatitis B
11 patients seroconverted to HBsAg-positive during a 3-month period (188)	Staff, equipment, and supplies were shared between HBsAg-positive and -negative patients	Dedicate staff for HBsAg-positive patients; no sharing of supplies or medications between patients; vaccinate all patients to protect against hepatitis B
Two patients seroconvert to HBsAg-positive during a 4-month period (181)	Same staff members cared for HBsAg-positive and -negative patients; no patients were vaccinated	Dedication of staff for HBsAg-positive patients; hepatitis B vaccination for all patients
36 patients with elevated liver enzymes consistent with non-A non-B hepatitis (298)	Environmental contamination with blood	Monthly liver enzyme screening; use proper infection control precautions (e.g., gloving, environmental cleaning)
35 patients with elevated liver enzymes over a 22-month period; 82% of cases were anti-HCV positive (189)	Inconsistent use of infection control precautions, especially hand hygiene and glove use	Strict compliance with aseptic techniques and infection control precautions for all dialysis patients
Seven of 51 patients seroconvert to anti-HCV positive (239,242)	Dialysis on same machine immediately after patient with chronic HCV infection; preparation of multidose intravenous medication at the dialysis station; failure to routinely clean dialysis machine or dialysis station surfaces between patients	Strict compliance with aseptic techniques and infection control precautions for all dialysis patients; routine anti-HCV testing
HCV infection developed in 5/95 patients (239,242)	Dialysis on same machine immediately after patient with chronic HCV infection; preparation of multidose intravenous medication at the dialysis station; failure to routinely clean dialysis machine or dialysis station surfaces between patients; use of a mobile medication or supply cart that was moved between dialysis stations	Strict compliance with aseptic techniques and infection control precautions for all dialysis patients including environmental cleaning and disinfection of the dialysis machine and station, medication preparation in a separate clean area; and discontinue use of mobile carts to deliver supplies and medications between dialysis stations
Incident HCV infection in 3/24 patients (239,242)	Patients dialyzed at the station adjacent to that of patients with chronic HCV infection; use of a mobile medication or supply cart that was moved between dialysis stations	Do not use mobile medication or supply carts that move from station to station; deliver clean supplies and medications to each station individually; follow recommended infection control precautions for all dialysis patients
Incident HCV infection in 7/64 patients (239,242)	Patients dialyzed at the station adjacent to that of patients with chronic HCV infection; receipt of intravenous medication from vial (including single-dose vials) used for <1 patient; dialysis during the shift following that of patient with chronic HCV infection but not with the same machine; routine cleaning and disinfection of environmental surfaces not performed; mobile carts used for delivery of medications and supplies	Do not use mobile medication or supply carts that move from station to station; single-dose vials should not be shared; clean and disinfect dialysis machine surfaces (including prime buckets) between patients, clean and disinfect station area before setting up and priming next patient’s dialyzer and extracorporeal circuit; follow infection control precautions for all dialysis patients
11/75 patients develop HCV infection (239)	Preparation of injections in contaminated environment; failure to separate clean and contaminated areas; failure to change gloves and perform hand hygiene after handling contaminated dialysis equipment	Follow recommendations for infection control precautions for all dialysis patients, hand hygiene, and environmental infection control
7/183 patients develop HCV infection (239)	Use of mobile cart to deliver injectable medications to multiple patients; reuse of single-dose vials of epoetin alfa on multiple patients; failure to clean dialysis equipment between patients	Do not use mobile carts to deliver injectable medications or supplies; clean and disinfect external surfaces of the dialysis machine and patient station between each patient; follow recommendations for infection control precautions for all dialysis patients
HCV infections develop in nine patients (191)	Multiple breaches in infection control practices including inadequate cleaning and disinfection of the machine and station (visible blood was present on dialysis chairs, machines, and floor); inappropriate glove use, inconsistent hand hygiene; and deficiencies in training	Patients transferred to other facilities and dialysis center closed by the State regulatory agency, after several attempts made to correct infection control deficiencies
HCV infections in eight patients (240)	New infections were seen in patients dialyzed after or on the same machine a patient with chronic HCV infection. Infection control lapses in medication handling; lack of cleaning of access ports on CVCs; heparin and saline were prepared at dialysis stations; medications prepared and delivered using mobile carts. Patients were “bled on” to WHO-port and WHO-port was not disinfected between patients. Environmental cleaning and disinfection were suboptimal; routine disinfection of machines conducted with patient still in dialysis chair.	Follow recommended infection control precautions for dialysis setting; proper use of gloves; perform hand hygiene and use new pair of gloves before performing vascular access care; use antiseptic to disinfect CVC hubs and injection ports prior to accessing; prepare medications in an “clean” area dedicated for that purpose; parenteral medications should never be prepared at the dialysis station; if facility chooses to use medication and supply carts, these should remain stationary in a designated clean area; use an EPA-registered disinfectant for cleaning blood spills;
21 patients in a hospital-based outpatient dialysis unit develop HCV infection (192)	Breaches in infection control practices identified by the local health department included: medication preparation and delivery; suboptimal environmental cleaning and disinfection	Strict compliance with aseptic techniques and infection control precautions for all dialysis patients including environmental cleaning and disinfection of the dialysis machine and station, medication preparation in a separate clean area; and discontinue use of mobile carts to deliver supplies and medications between dialysis stations
Two HCV infections in an outpatient hemodialysis facility (193)	No breaches in infection control identified but epidemiologic and laboratory evidence suggested in-center transmission.	Follow recommendations for preventing infections
HCV infection in six dialysis patients (194)	Limited separation between “clean” and “contaminated” areas; lab specimens processed in the same location as medication preparation; overcrowding; significant lapses in cleaning and disinfection were observed; blood glucose meters and clamps were not routinely disinfected between patients; clean supplies obtained by staff wearing contaminated gloves; blood glucose meters returned after use to “clean” supply table; ports on blood tubing and catheters not routinely disinfected before accessing	Facility should identify a staff member responsible for infection control; conduct regular meetings to discuss infection control issues; insure that monthly serology results are reviewed promptly; segregate clean and contaminated areas; consider facility design and work flow; consider redesign of treatment area to provide sufficient space between stations, and clean and contaminated areas; insure proper use of gloves and hand hygiene; items used on more than one patient should be cleaned and disinfected between each patient; patient’s station (chair and machine) should be cleaned and disinfected with a EPA-registered disinfectant
13 patients at one dialysis center in Colombia tested positive for HIV in 12 months; 9/13 seroconverted from negative to positive during this period and 2/9 had other risk factors (195)	Facility reprocessed vascular access needles by soaking in a common container containing a low-level benzalkonium chloride disinfectant; needles could have been shared among patients	Access needles are single-use only; if they are to be reused then they should be cleaned and sterilized between uses.
HIV infection in 39 patients at two hemodialysis centers in Egypt (196)	Practices that resulted in sharing of syringes among patients were observed at both centers	Do not share syringes. Follow infection control recommendations for preventing infections among dialysis patients

BACTERIAL AND CHEMICAL CONTAMINANTS IN HEMODIALYSIS SYSTEMS

A typical hemodialysis system consists of a water supply, a system for mixing water and dialysis fluid concentrates, and a machine to pump the dialysis fluid through the artificial kidney (commonly referred to as the hemodialyzer or dialyzer). The dialyzer is connected to the patient’s circulatory system as part of an extracorporeal circuit. Blood is pumped through the dialyzer where dialysis is accomplished by means of a membrane to remove waste products from the patient’s blood by both diffusion and convection.

MICROBIAL CONTAMINATION OF WATER

Technical developments and clinical use of hemodialysis delivery systems improved dramatically in the late 1960s and early 1970s. However, a number of microbiologic parameters were not accounted for in the design of many hemodialysis machines and their respective water supply systems. In many situations, certain types of microorganisms such as gram-negative water bacteria, mycobacteria, and fungi can persist and actively multiply in aqueous environments associated with hemodialysis equipment under certain conditions. These organisms can adhere to surfaces and form biofilms, which are extremely difficult to eradicate (25,26,27,28). This can result in the production of massive levels of microbial contamination, which can directly or indirectly cause septicemia or endotoxemia in patients (29,30,31).

A number of factors can influence microbial contamination of fluids associated with hemodialysis systems (Table 23.2) (29,32,33). The waterborne microbes can be important contaminants in hemodialysis systems (Table 23.3), and virtually all disinfection strategies for fluid water distribution lines and dialysis machines are targeted to this group of bacteria. Gram-negative water bacteria are capable of multiplying rapidly in all types of waters, even those containing relatively small amounts of organic matter, such as water treated by distillation, softening, deionization, or reverse osmosis (34). These organisms can attain levels ranging from 10⁵ to 10⁷ colony forming units (CFU) mL^-1 of water without turbidity and, under certain circumstances, can be a health hazard for patients.

Nontuberculous or environmental mycobacteria also can multiply in water (Table 23.3). Although they do not contain bacterial endotoxin, they are comparatively resistant to chemical germicides and, as will be discussed later, have been responsible for patient infections due to inadequately disinfected dialyzers that are reprocessed and inadequately disinfected peritoneal dialysis machines (35,36,37,38).

The strategy for controlling massive accumulations of gram-negative water bacteria or nontuberculous mycobacteria in dialysis systems primarily involves preventing their growth. This can be accomplished by proper disinfection of water treatment systems and hemodialysis machines. Gram-negative water bacteria and their associated lipopolysaccharides (bacterial endotoxins) and nontuberculous mycobacteria ultimately come from the potable water supply, and levels of these bacteria can be amplified depending on the water treatment systems, dialysate distribution systems, type of dialysis machine, and method of disinfection (Table 23.2) (25,27,29,30,32). Each of these components is discussed separately in some detail.

Water Supply

Most dialysis centers use water from a public supply that may be derived from surface, ground, or blends of surface and ground waters. The source of the water may be important in terms of chemical, bacterial, and endotoxin content. Surface waters frequently contain endotoxin from gram-negative water bacteria and from certain types of blue-green algae (Cyanobacteria). Endotoxin levels are not substantially reduced by conventional municipal water treatment processes and can be high enough to cause pyrogenic reactions in patients undergoing dialysis (31).

Essentially all public water supplies are contaminated with water bacteria; consequently, a dialysis center’s water treatment and distribution systems and dialysis machines are challenged repeatedly with continuous inoculation of these ubiquitous bacteria. Even adequately chlorinated water supplies commonly contain low levels of these microorganisms. Whereas chlorine and other drinking water additives added to the city water may prevent high levels of contamination, the presence of these chemicals in dialysis fluids is undesirable because of adverse effects on patients undergoing dialysis (39,40,41,42,43,44,45,46). Furthermore, the dialysis water treatment systems described in the following section effectively remove chemical contaminants including drinking water disinfectants, allowing for the unrestricted growth of waterborne microorganisms.

Water Treatment Systems

Water used to produce dialysis fluid must be treated to remove chemical contaminants. Since 1981 the Association for the Advancement of Medical Instrumentation (AAMI) has published guidelines for the chemical and bacteriologic quality of water used to prepare dialysis fluid. These guidelines and recommended practices have recently been harmonized with the international community (47,48,49). However, CMS has adopted older AAMI standards covering water treatment, dialysate quality, and reuse of dialyzers as regulation to participate in the Medicare program (2,50,51,52).

Water systems are divided into three types of components based on function: pretreatment, treatment, and polishing. Some pretreatment components may vary based on the area of the United States and local water quality. Pretreatment serves several purposes, the most important is protecting the
downstream treatment components. A variety of different water treatment system components are used, but most of them are associated with amplification of water bacteria (Table 23.2). The most common treatment components are ion exchange devices including water softeners (pretreatment) and deionizers (DI; treatment or posttreatment polisher). However, these ion exchange components do not remove endotoxins or bacteria, and both softeners and DI tanks contain large surface areas and provide sites of significant bacterial multiplication (53,54). An effective means of treating water for dialysis is reverse osmosis. By 1997, reverse osmosis (RO) or deionization (DI) water treatment systems were being used by 99% of U.S. dialysis centers (13). RO possesses the singular advantage of being able to remove both bacterial endotoxins and bacteria from supply water. However, low numbers of gram-negative or nontuberculous mycobacteria water bacteria can either penetrate this barrier or colonize the downstream portion of the RO unit by other means. Consequently, reverse osmosis systems must be monitored and disinfected routinely.

TABLE 23.2 Factors Influencing Microbial Contamination in Hemodialysis Systems

Factors		Comments
WATER SUPPLY
Source of community water
	Ground	Contains endotoxin and bacteria
	Surface Water	Contains endotoxin and bacteria, may also contain cyanobacteria
WATER TREATMENT AT THE DIALYSIS CENTER
None		Not recommended
Pretreatment		Serves to remove residual drinking water disinfectants, some organics and protect downstream water treatment equipment from foulants, scale formation and oxidants
	Multimedia Depth Filters	Removes particles down to 15 microns, may act as significant reservoir of bacteria; these can be backwashed
	Water Softener	Ion exchange to remove ions associated with hard water; protects the reverse osmosis (RO) unit from buildup of scale on the membrane; significant cause of bacteria and endotoxin
	Granular Activated Carbon (GAC)	Two beds/tanks in series with total empty bed contact time of 12 minutes; essential to remove chlorine and chloramine; also removes some organics; mandatory if only using deionization for water purification; significant source of bacteria and endotoxin
	Cartridge Filter	Placed prewater treatment devices such as RO unit to protect the unit from carbon fines and other particulates in the pretreated water; may remove bacteria (depending on filter pore size); selection of filter based on RO manufacturer’s recommendations
Treatment
	Reverse Osmosis	Reduces inorganic chemical contaminants, bacteria, and endotoxin to safe levels; membranes must be maintained (cleaned and disinfected)
	Deionization (DI)	Removes cations and anions from water to create highest ionic quality water; does not remove bacteria or endotoxin; allows for significant bacterial growth and endotoxin production; if used as the only water treatment device (usually as an emergency backup) GAC should always be used as prefilter; DI tanks are often used to polish RO product water: highly dangerous when exhausted
	Ultraviolet (UV) irradiator	Kills bacteria and may create UV resistant forms when energy output from the lamp decreases
	Ultrafilter	Removes bacteria and endotoxin; last water treatment device; usually placed after storage tank; should be used in systems that have UV irradiators or DI tanks.
WATER AND DIALYSATE DISTRIBUTION
Distribution Pipes
	Size	Oversized diameter and length decrease fluid flow rate and increase bacterial reservoir for both treated water and centrally prepared dialysate.
	Construction	Pipe materials, presence of rough joints, dead ends, and unused branches influence microbial colonization and biofilm formation
	Elevation	Outlet taps should be located at highest elevation to prevent loss of disinfectant
	Storage Tanks	Can act as a reservoir for bacteria; if present, must be properly designed (including a tight fitting lid) and vented, and routinely cleaned and disinfected
DIALYSIS MACHINES
Single-pass		Disinfectant should have contact with all parts of the machine that are exposed to water or dialysis fluid; should be routinely disinfected
Recirculating machines/batch machines		Recirculating pumps and machine design may allow for massive contamination levels if not properly maintained and disinfected; must be rinsed and disinfected if a blood leak occurs; see manufacturer’s instructions

Various filters are marketed to control bacterial contamination in water and dialysis fluids. Most of these are inadequate, especially if they are not routinely disinfected or changed frequently. Particulate filters, commonly called prefilters, operate by depth filtration and do not remove bacteria or bacterial
endotoxins. These filters can become colonized with gram-negative water bacteria, resulting in amplification of the levels of both bacteria and endotoxin in the filter effluent. Absolute filters, including the membrane types, temporarily remove bacteria from passing water. However, some of these filters tend to clog, and gram-negative water bacteria can “grow through” the filter matrix and colonize the downstream surface of the filters within a couple of days. Furthermore, absolute filters do not reduce levels of endotoxin in the effluent water. These types of filters should be changed regularly in accordance with the manufacturer’s directions and disinfected in the same manner and at the same time as the dialysis system.

TABLE 23.3 Types of Microorganisms Associated with Hemodialysis Systems

Gram-Negative Bacteria

Gram-Positive Bacteria

Fungi

Nonfermenters/Oxidative

Brevundimonas diminuta

Burkholderia cepacia complex

Flavobacteria

Herbaspirillium spp.

Methylobacterium spp.

Pseudomonas aeruginosa

Pseudomonas fluorescens

Pseudomonas putida

Pseudomonas spp.

Ralstonia pickettii

Ralstonia mannitolilytica

Sphingomonas paucimobilis

Stenotrophomonas maltophila

Enterobacteriaceae

Enterobacter cloacae

Klebsiella pneumoniae

Serratia liquefaciens

Serratia marcescens

Gram-positive bacilli

Brevibacterium spp.

Paenibacillus spp.

Leifsonia aquatica

Nontuberculous mycobacteria

Mycobacterium abscessus

Mycobacterium chelonae

Mycobacterium fortuitum

Mycobacterium gordonae

Mycobacterium mucogenicum

Mycobacterium scrofulaceum

Aspergillus spp.

Penicillium spp.

Phialemonium curvatum

Trichothecium

Candida albicans

Candida parapsilosis

Candida spp.

Rhodoturula spp.

Trichosporon spp.

Granulated activated carbon (GAC) tanks remove certain organic chemicals and available chlorine (free and combined chlorine) from water by adsorption, but the filters also significantly increase the level of water bacteria and do not remove bacterial endotoxins. GAC readily removes free chlorine but is not as efficient in removing combined chlorine (chloramines) and is greatly affected by pH of the feed water. As pH increases, GAC becomes less efficient at removing chloramines. For removal of free chlorine an empty bed contact time (EBCT) (volume of carbon ft³ = (gallons per minute × EBCT)/7.48) of at least 6 minutes is required and at least 10 minutes for chloramines (55).

Ultraviolet germicidal irradiation (UVGI) lamps are sometimes used to reduce bacterial contamination in water. These lamps should operate at a wavelength of 254 nm and provide a radiant energy dose of 30 milliwatt (mW)-sec cm^-2. Several studies have demonstrated that a dose of 30 mW-sec cm^-2 will kill >99.99% of a variety of bacteria, including Pseudomonas species, in a flow-through device (56,57). However, certain gram-negative water bacteria appear to be more resistant to UVGI than others, and using sublethal doses of UVGI or exposing water for an insufficient contact time may lead to proliferation of these resistant bacteria in the water system (33,58). This problem may be accentuated in recirculating dialysis systems in which repeated exposures to sublethal doses of UVGI are used to ensure adequate disinfection. The multiplication of those microorganisms surviving initial exposure enhances resistance to UVGI. In addition, UVGI does not affect bacterial endotoxins. The use of high intensity UVGI in the pretreatment chain also may be used to destroy free and combined chlorine (59).

As mentioned, an effective means of treating water for dialysis is the correct use of a reverse osmosis unit. We recommend using a water treatment system that produces chemically adequate water with appropriately low levels of microbial contamination. Such systems also are well suited for hard water with appropriate pretreatment (e.g., using a softener to prevent scale formation on the RO membrane). Reverse osmosis is a membrane separation process for removing solvents from a solution using a semipermeable membrane. In this instance, water is forced against the membrane (overcoming osmotic pressure), which is highly permeable to water and rather impermeable to the dissolved contaminants. Thus, pure water is pushed through to form product water. Water and contaminants (concentrate) that do not pass through the membrane or “rejected water” can be recirculated and diluted with feed water or sent to drain. The RO is capable of removing a variety of contaminants (down to atomic nuclei in size) and will reject 95% to 98% of cations and 85% to 90% of anions, depending on the RO membrane used (55,60). It is possible for bacteria to eventually get from the feed water to contaminate the product water, which is why RO membranes should be cleaned and disinfected per manufacturers’ instructions.

Posttreatment, RO water may be polished to chemically purify water further by using an additional treatment step, DI. The DI unit also may serve as an emergency backup to the RO unit in case the RO fails. However, since DI units can become colonized and allow for microbial amplification, an ultrafilter should always be placed at the final treatment step to remove bacteria and endotoxins (49,50,53,54,61). The ultrafilter consists of similar types of membranes as in a RO unit, but it can be operated at ordinary water line pressure. Depending on system design, ultrafilters should always be used if any one or more of
the following devices is used after the water treatment step storage tank to remove bacterial and endotoxin: DI, UVGI.

Distribution Systems

Dialysis centers use one of two general systems configurations for delivering water or dialysis fluids to individual dialysis machines. The first type treats the incoming supply water and distributes it to individual free-standing dialysis stations either in a direct feed system or an indirect feed system (recirculating system). At each station, the water is mixed with dialysis concentrates to generate dialysate in the dialysis machine. Another type of system, usually found in some large dialysis centers, involves the automatic mixing of treated water and dialysis concentrate at a central location followed by distribution of the warmed dialysis fluid through pipes to individual dialysis stations. In some facilities the dialysis concentrates are prepared from powdered components and centrally delivered to each station by piping systems. In these system designs, the distribution system consists primarily of plastic piping (e.g., polyvinyl chloride [PVC], cross-linked polyethylene [PEX], polyvinylidene fluoride [PVDF], polypropylene [PP]) and valves, though some facilities use 316L stainless steel or glass for their distribution systems (49,50).

These distribution systems can contribute to microbial contamination in two ways; first, they sometimes use pipes that are larger in diameter and longer than necessary to handle the required fluid flow. This slows the fluid velocity and increases both the total fluid volume and the wetted surface area of the system. Gram-negative bacteria in fluids remaining in pipes may multiply rapidly and colonize these wetted surfaces of the pipes, producing bacterial populations and endotoxin quantities in proportion to the volume and surface area (62). Such colonization results in bacterial formation of protective biofilm, which is difficult to remove and protects the bacteria from disinfection (62).

Because pipes can constitute a source of water bacteria within a distribution system, routine disinfection should be performed at least weekly. To ensure that the disinfectant cannot drain from pipes by gravity before contact time is adequate, distribution systems should be designed with all outlet taps at equal elevation and at the highest point of the system. Furthermore, the system should be free of rough joints, dead-end pipes, and unused branches and taps. Fluid trapped in such stagnant areas can serve as reservoirs of bacteria capable of continuously inoculating the entire volume of the system (30,32,33,61).

Incorporation of a storage tank in a distribution system greatly increases the volume of fluid and surface area available to act as reservoirs for the multiplication of water bacteria. Storage tanks should not be used in dialysis systems unless they are properly designed, frequently drained, and adequately disinfected. This may include scrubbing the insides of the tank to physically remove bacterial biofilm. It is also recommended that an ultrafilter be used distal to the storage tank (61,63).

Hemodialysis Machines

Currently in the United States, virtually all centers use single-pass hemodialysis machines. In the 1970s, most machines were of the recirculating or recirculating single-pass type. The nature of their design contributed to a relatively high level of gram-negative bacterial contamination in dialysis fluid (25,26,27,29). Single-pass dialysis machines tend to respond to adequate cleaning and disinfection procedures and, in general, have lower levels of bacterial contamination in their dialysis fluid than do recirculating machines. Levels of contamination in single-pass machines depend primarily on the bacteriologic quality of the incoming water and on the method of machine disinfection (29,32,33).

A frequent error in disinfecting single-pass systems occurs when the disinfectant is introduced in the same manner and through the same port as the dialysate concentrates. By so doing, the pipes and tubing of the incoming water are not exposed to a disinfectant; thus, the environment is such that bacteria can readily colonize and proliferate, acting as a constant reservoir of contamination. To adequately disinfect a single-pass system, the disinfectant must reach all parts of the system’s fluid pathways (61,63).

Dialyzers

The dialyzer (artificial kidney) usually does not contribute significantly to bacterial contamination of the dialysate. Hemodialysis patients are treated using hollow-fiber dialyzers. These devices are classified as either low-flux or high-flux based on membrane characteristics (64,65). The percentage of centers that reported reuse of dialyzers on the same patient increased from 18% to 82% during the period from 1976 to 1997, but declined over the next 5 years to 63% in 2002 as one of the large dialysis providers moved from reuse to nonreuse (3,13,16,66). Improper reprocessing techniques have been associated with outbreaks of bacteremia and pyrogenic reactions in dialysis patients (38,67,68,69,70,71,72,73).

Disinfection of Hemodialysis Systems

The objective of a dialysis system disinfection procedure is to primarily inactivate bacteria and fungi in the fluid pathways associated with the dialysis system and to prevent these organisms from growing to significant levels once the system is in operation. Routine disinfection of isolated components of a dialysis system frequently produces inadequate results in which the hazard to the patient persists. Consequently, the total dialysis system (water treatment system, distribution system, and dialysis machine) needs to be considered when selecting and applying disinfection procedures.

Chlorine-based disinfectants (e.g., sodium hypochlorite solutions) are convenient and effective in most parts of the dialysis system when used at the manufacturer’s recommended concentration. Also, the test for residual available chlorine to confirm adequate rinsing is simple and sensitive. However, because of the corrosive nature of chlorine, the disinfectant normally is rinsed from the system after a short (20 to 30 minutes) exposure time. This practice commonly negates the disinfection procedure because the rinse water is not sterile and invariably contains waterborne microorganisms that immediately resume multiplication. If permitted to stand overnight, the water may contain significant microbial contamination levels. Therefore, chlorine disinfectants are most effective when applied just before the start-up of the dialysis system rather than at the end of the daily operation (74,75). In some large centers with multiple shifts, it may be reasonable to use sodium
hypochlorite disinfection between shifts (this may not be necessary with some single-pass machines, if the levels of bacterial contamination are below AAMI action limits) (2,47,48,50,51) and disinfection with peracetic acid, hydrogen peroxide, ozone, or hot water at the end of the day (75,76,77).

Hydrogen peroxide, ozone, hypochlorite solutions, heat and citric acid, and peracetic acid can produce good disinfection results (27,74,77,78,79,80,81,82,83,84). They are not as corrosive as hypo-chlorite solutions and can be allowed to remain in the dialysis system for long periods when it is not operational, thereby preventing the growth of bacteria in the system. Aqueous formaldehyde used to be commonly used as a disinfectant in the dialysis setting because it has good penetrating characteristics. However, it is considered an environmental hazard and potential carcinogen and is associated with irritating qualities that are objectionable to staff members. Formaldehyde is very rarely used today because of Environmental Protection Agency (EPA) regulations regarding wastewater discharges and its potential as an occupational hazard.

Some dialysis systems use hot-water disinfection (pasteurization) to control microbial contamination. In this type of system, water heated to >80°C (176°F) is passed through all proportioning, distribution, and patient-monitoring devices before use. This system is excellent for controlling bacterial contamination (27,84). Use of ozone also has been increasing as a means of sanitizing water treatment distribution loops and central bicarbonate delivery systems (77).

Monitoring Water and Dialysis Fluid

Bacteriologic assays of water and dialysis fluids should be performed at least once a month. Chemical analysis of water used for dialysis should be done before the system is designed and then at least seasonally (since feed water quality is not static and may change) to ensure that the water is of sufficient quality for hemodialysis applications (48). The current recommended maximum level of microbial contamination of water and standard dialysate used for hemodialysis is 100 CFU mL^-1 (47,49). These particular numbers are based, in part, on an increasing body of evidence indicating that dialysate may be partly responsible for the chronic inflammatory state in dialysis patients (85,86,87,88,89,90). In these new AAMI recommendations, water and conventional dialysate have the same maximum contaminant levels (MCLs) for microorganisms, however, maximum endotoxin levels are 0.5 endotoxin units (EU) mL^-1 for dialysate and 0.25 EU mL^-1 for water (47,49). Action levels also have been included and have been set to 50% of the MCL. They also have included standards for ultrapure dialysate and dialysate for infusion (Table 23.4) (47). However, in the United States, CMS (2) has adopted AAMI limits for water and dialysate based on the older standards with MCLs of 200 CFU mL^-1 and 2 EU mL^-1 (50

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