1. Introduction
The concept of renal replacement therapy (RRT) has evolved considerably over the last
2 decades. Dialysis, a key component of RRT intended to clear uremic toxins and periodically
restore the internal milieu composition, has benefited from considerable advances
in dialysis technology (bicarbonate-buffered dialysis fluid, ultrafiltration-controlled
systems, profiling systems, blood volume and temperature control, direct quantification,
and high-flux dialyzers) and innovative adjunctive drug therapies designed to correct
anemia (erythropoietinstimulating agents (ESA), IV iron, etc.), metabolic bone disease
(vitamin D and analogs, calcimimetics, etc.), and associated metabolic disorders (lipid-lowering
agents, antioxidants, etc.) (1). Such refinement in optimizing RRT would have not
been possible without intense and collaborative clinical research, which led to a
better understanding of uremic complications and improvement in the standards of care
for chronic kidney disease patients (2).
Despite these medical and technical advances, it is disappointing to note that morbidity
and mortality still remain high in dialysis-dependent chronic kidney disease patients
(3). Most recent studies have noted that the dialysis population has changed over
the last decade, characterized by patients who are older and suffer from multiple
comorbid conditions, including diabetes and cardiovascular diseases that compromise
patient outcomes (4). Indeed, it has also been shown that chronic microinflammation
represents the common link and amplifying factor to such dialysis-related pathology
(5, 6). In this interesting debate, it is strange to note that the nephrology community
has overlooked the microbial purity of dialysis fluid while technical solutions to
correct impure dialysis fluid have been available for 2 decades (7, 8). This study
is intent on supporting the use of ultrapure dialysis fluid (UPDF) in all hemodialysis
(HD) modalities and showing that UPDF is technically and economically feasible in
most dialysis facilities worldwide. (9, 10).
2. UPDF as a Surrogate for Sterile and Non-Pyrogenic Dialysis Fluid
The term “ultrapure” was coined in the early 80s to underline the fact that dialysis
fluid solutions (water and dialysis fluid) were highly purified in comparison to standard
procedures and were used as a surrogate for sterile and non-pyrogenic fluid (11).
UPDF was defined as containing < 0.1 colony-forming unit/ml (CFU/ml) using sensitive
microbiological methods and < 0.03 endotoxin unit/ml (EU/ml) using the limulus amoebocyte
lysate (lAl) assay. This definition is now widely accepted and used for UPDF determination
in international guidelines. A summary of microbiological standards for water and
dialysis fluids in HD is given in Table 1.
Table 1
Microbiological Standards for Water and Dialysis Fluid Purity
Standard Water
Standard Dialysate
Ultrapure Water
Ultrapure Dialysate
Sterile Dialysate
Bacterial limits a, CFU/mL
< 100-200
< 100-200
< 0.1
< 0.1
< 10-6
Endotoxin limits b, EU/mL
< 0.25-2
< 0.25
< 0.03
< 0.03
< 0.03
aAdequate monitoring and microbiological technique (i.e. UPDF,poor media TGEA, R2A,17-23ºC,7
days)
bSensitive LAL assay, threshold detection limit , 0.03 EU/mL
3. UPDF is Easily Produced by Online Cold Sterilization
Technical aspects of producing UPDF have been described in detail elsewhere (12).
UPDF relies on 3 basic principles: use of ultrapure water; installation of sterilizing
ultrafilters (1 or 2) in the dialysis fluid pathway on adequately designed HD machines;
and implementation of strict hygienic rules (disinfection procedures and ultrafilter
changes) and regular microbiological monitoring (13). Figure 1 presents the concept
of the cold sterilization process based on tangential ultrafiltration. Figure 2 shows
HD machines equipped with ultrafilters installed in series, designed to ensure a final
cold sterilization of the dialysis fluid flowing into the patient’s hemodialyzer.
Figure 1
Cold Sterilization Process Based on Ultrafiltration
Figure 2
HD Machine Equipped With Sterilizing Ultrafilters
4. UPDF is Justified by Operative Conditions of Contemporary Dialysis
HD has emerged as a leading component of this innovation. hemodialyzer membranes have
improved in performance, resulting in a major increase in solute removal capacities
for both small and middle molecules (high-flux membranes), and a significant improvement
in biocompatibility (synthetic high-flux membranes) (14). hemodialyzer performance
has also improved, thanks to new geometry designs favoring back-transport phenomena
and convective clearance imposed by ultrafiltration controller systems installed onto
dialysis machines (15). Along these lines, the microbiological purity of dialysis
fluid has become a critical component, recognized as a key element in the HD biocompatibility
network (16). Standards of purity for water and dialysis fluid established in the
70s were later recognized as being poorly adapted to the setting of contemporary HD
conditions (17). A recent transcontinental agreement (Europe, US, Japan) has recognized
the need to upgrade water and dialysis fluid purity for all dialysis modalities. For
this purpose, guidelines supporting the regular use of UPDF for all HD modalities
and editing handling and hygienic rules have been established (18-20). Beneficial
effects of regular use of UPDF are seen in intermediate and long-term outcomes in
dialysis patients (21).
5. UPDF Prevents Inflammation and Its Deleterious Biological and Clinical Consequences
Intermediate outcomes are mainly related to the preventive and/or anti-inflammatory
effects associated with the regular use of UPDF (22). Several controlled and/or randomized
studies have demonstrated that UPDF use was accompanied by a decrease in sensitive
inflammatory markers (21) and sustained reduction of chronic inflammation (23) in
HD patients. Interestingly, correction of the microinflammatory state is associated
with better correction of anemia and decreased requirements for ESA)(24-26), suggesting
better ESA responsiveness (27, 28).
In addition, the use of UPDF is associated with a reduction in plasma levels of beta-2
microglobulin and pentosidine (29). Myeloperoxidase activity and lipid profile tend
to improve in parallel with CRP reduction in patients exposed to UPDF (30-32). Monocyte
activation and apoptosis and the release of inflammatory factors are reduced with
the use of UPDF (33). In addition, oxidative stress is minimized with the combination
of high-flux membrane and UPDF (34). Residual renal function is better preserved over
a 24-month period in the UPDF-treated group, as shown in a randomized controlled trial
(35, 36). Nutritional status and visceral protein levels improved significantly in
a UPDF-treated group, compared to their counterparts treated with conventional (contaminated)
dialysis fluid (37, 38).
6. UPDF Reduces Morbidity and Mortality in HD Patients
Beneficial effects of UPDF on morbidity and mortality of dialysis patients are more
difficult to ascertain because there are several confounding factors (39). The use
of synthetic high-flux membranes and enhanced convective clearance by online hemodiafiltration
(ol-HDF) facilitating the removal of middle- and large-molecular-weight uremic toxins
are the two most prominent factors (40, 41). Indeed, using UPDF with more efficient
modalities (ol-HDF or high-flux HD) should not be considered exclusion criteria but
rather an incentive, and there is strong support for its generalization in dialysis
(21).
The use of UPDF is associated with significant reduction in morbidity (42) and cardiovascular
events (43). In addition, in a recent randomized controlled trial, locatelli et al.
have shown that by combining the use of UPDF and convective therapies (HF and HDF),
the incidence of hypotensive episodes could be significantly reduced (44).
Interestingly, 2 retrospective cohort studies have reported a dramatic reduction in
the prevalence of beta-2 microglobulin amyloidosis, as revealed by carpal tunnel syndrome
surgery, with extended use of UPDF and synthetic membranes (26, 45). One study also
reported significant improvement in the painful and disabling symptomatology of beta-2
microglobulin amyloidosis after switching conventional dialysate with UPDF (46). In
a retrospective cohort study, cardiovascular morbidity and mortality was decreased
(47) in dialysis patients mainly exposed to UPDF.
ol-HDF, which represents the most advanced dialysis modality and requires the use
of UPDF, is associated with better outcomes for dialysis patients. In most recent
cohort studies, the use of high-efficiency (high-volume) HDF was associated with a
relative risk reduction of all-cause mortality averaging 35% (48, 49). Interestingly,
cardiovascular mortality was particularly reduced in 2 recent studies underlining
the potential beneficial effects of UPDF and convective therapies on the vascular
disease of dialysis patients (50, 51). All these studies underlined the fact that
ultrapurity of the dialysis fluid was the common factor of improvement, mediated through
a reduction of the chronic microinflammatory status of dialysis patients.
7. UPDF is Technically and Economically Feasible for All Dialysis Facilities
Several reports have shown that UPDF was accessible and affordable in most dialysis
centers (52). In this perspective, the recent intermediary analysis of the CoN-TRAST
study is the most significant (53). Ten dialysis facilities were selected for conducting
the water and dialysis fluid microbiological audit. Precise and sensitive microbial
monitoring of water and dialysis fluid, including bacteriometry (nutrient-poor media
(R2A) culture over 7 days) and endotoxin content (limulus amoebocyte lysate using
a chromogenic method), were performed monthly over the 2-year period of follow-up.
of the 3961 dialysis fluid samples, 99.1% complied with the ultrapurity standard as
defined by European Best Practice Guidelines and Dutch guidelines. No side effects
or pyrogenic effects were noted in 97 patients who received 11258 ol-HDF sessions.
In brief, this study confirms that UPDF may be easily produced on a country-wide scale
and used in virtually all contemporary dialysis facilities.
Economic issues associated with the regular use of UPDF should not be ignored and
kept under a veil of silence. The production of ultrapure water requires a water treatment
system (WTS), including pretreatment (softener, activated carbon, microfiltration),
a water polishing system (based on a double reverse-osmosis system in series), and
a well-designed distribution loop (ensuring permanent circulation of water with immediate
delivery to dialysis machines). Disinfection processes (type, agent, and frequency)
and microbiological monitoring of WTS are established according to contamination levels
and facility practices. HD machines should be equipped with captive ultrafilters,
ensuring a final cold sterilization of the dialysis fluid produced. HD machines are
disinfected after each run and ultrafilters are replaced according to manufacturer
recommendations. Microbiological monitoring of dialysis fluid is performed periodically
according to local and regulatory practices. Considering the fact that ultrapure water
is a standard for newly created dialysis facilities in Europe, the only additional
cost is associated with the periodic changes of sterilizing ultrafilters installed
on the HD machines and the microbiological monitoring of dialysis fluids. Based on
a rigorous cost analysis conducted over the last 5 years in our units, we estimated
this extra cost at 5 euros per session. The additional costs generated by this high
standard of water and dialysis fluid purity are offset by direct and indirect clinical
benefits, including better correction of anemia with reduced ESA, and improved patient
outcomes with reduced morbidity and hospitalization rates (46). It would be interesting
to conduct an economic prospective study on HD patients treated with UPDF to precisely
evaluate cost savings in terms of ESA dose, nutritional improvement, and hospitalization
reduction.
8. UPDF Will Be the Basic Requirement for Developing Innovative Dialysis Modalities
for Future Renal Replacement Therapy
In the perspective of developing or improving future dialysis methods, such as ol-HDF
(enhanced internal HDF, hemofiltration, etc.), automated dialysis machines ensuring
dialyzer priming and rinsing (home and/or self-care machines), and biofeedback-controlled
machines (pulse IV infusion, volume control, etc.), it seems obvious that UPDF will
be a basic resource for such development. Considering the high-quality refinement
of dialysis fluids, we must deduce that UPDF offers a more efficient barrier against
proinflammatory biological reactions, at no risk to dialysis patients.
To conclude, UPDF must be considered a basic component of contemporary HD therapy
for preventing chronic inflammation and improving patient outcomes in high-flux HD.
The use of UPDF is an additional step required to develop ol-HDF and related innovative
renal replacement therapies (47).