Hemodialysis International 2007; 11:S39–S48

Beyond ultrapure hemodialysis: A necessary

and achievable goal

Carl M. KJELLSTRAND,1,2,3 Per KJELLSTRAND4,5

1
Loyola University Chicago, Chicago, Illinois; 2SUNY at Brooklyn, Brooklyn, New York; 3Karolinska Institute,
Stockholm, Sweden; 4Lund’s Universitet, Lund, Sweden; 5Senior Scientific Advisor, Gambro AB, Lund,
Sweden

Abstract
Survival of chronic hemodialysis patients is worse than that of many patients with cancers or severe
infections. An important cause of chronic inflammation is impurities infused into patients during
dialysis. Definitions of dialysis purity have been narrow and focused on metals in dialysate water and
on bacterial contaminants. There is no standard for priming fluids or toxins released directly into
blood from inside the extracorporeal circuit. We propose a much broader standard of dialysis purity
that also includes phthalate metabolites, bisphenols, spalled particles, and other contaminants from
dialysis machines, filters, and bloodlines. Standards must include new methods for measuring bac-
teriological contaminants in addition to colony-forming units and endotoxin determinations. These
include the sensitive silkworm larva plasma test that detects peptidoglycan that is missed by endo-
toxin tests and standards for newly detected small molecular bacterial detritus. Current levels for
‘‘standard’’ bacteriological contaminants are woefully inadequate and should be increased. New
standards for contamination with plasticizers and spallation are also necessary. Studies with ultra-
pure dialysis have shown almost immediate patient benefits with increased well-being and stabil-
ization of the cardiovascular system during and between dialyses. Intermediate effects include lower
C-reactive protein levels, better response to erythropoietin, increased appetite, and improved nu-
trition. Over the years, amyloidosis and carpal tunnel syndrome have become less common and
cardiovascular deaths have decreased. Standards for dialysis purity must be sharpened and expand-
ed and this becomes even more urgent with daily and long nightly hemodialysis. All contaminants
received by patients, whether biological, chemical, or physical, must be considered.

Key words: Hemodialysis, ultrapure, dialysis systems

INTRODUCTION AND PERSPECTIVE
When dialysis was introduced into clinical medicine in
the mid-1940s, scant attention was paid to the purity of
the dialysate. As the dialysis membranes in use then were
impermeable to molecules above a molecular weight of
1500 da, the membrane protected patients from biologi-
cal contaminants and as dialysis was only for acute renal
Correspondence to: C. M. Kjellstrand, MD, PhD, FACP,
FRCP(C), 965 Creekside Dr, College Place, WA 99324,
U.S.A.
E-mail: carl.kjellstrand@gmail.com
failure, the procedure usually was only necessary for 2 or
3 weeks. With the arrival of chronic hemodialysis in
1960, the need for dialysis was prolonged abruptly from
days to years. Since then, membranes made from syn-
thetic materials have come into use that may allow pas-
sage of molecules up to 20,000 da. An unavoidable
compromise is that as toxins are removed from blood,
any similarly sized contaminants in the dialysate can pass
into the patient.
On average, most patients in the United States begin-
ning dialysis today rarely survive more than 4 years.1
With an average of 150 dialyses per year, each for about
3 hr, patients will have only about 600 dialyses over
4 years for a total of about 1800 hr. With short daily

r 2007 The Authors. Journal compilation r 2007 International Society for Hemodialysis S39
Kjellstrand and Kjellstrand
and long nightly hemodialysis, things are different now:
survival is likely to be better and patients will live longer;
the extreme rarity of surviving for more than 40 years
may become more common.2 Patients dialyzing 6 times a
week now will undergo more than 300 dialyses a year and
be on dialysis for 900–1000 hr if on short daily dialysis
and for some 2500 hr if on long nightly dialysis. Assum-
ing that only 0.5 g of plasticizers, rubber, and spalled
particles are infused at each treatment, this results in a
load of at least 150 g/year and if a patient survives for 25
years some 4 kg.
Most considerations of purity in dialysis have focused
on metals, small organic and inorganic contaminants
such as chloramines in water, or bacterial growth and
endotoxin in dialysate, all on the outside of the dialysis
membrane. However, there is also the direct interaction
between blood and surfaces in the dialyzer and blood
tubing. The dialysis system has been described as a ‘‘bio-
reactor’’ where a patient’s blood interacts with foreign
surfaces and is exposed to contaminants in the dialysate,
some of which enter the body of the patient.3 Thus, dia-
lysis purity and biocompatibility are described generally
as effects of the membrane and the bacterial purity of the
dialysate.4
There are many other sources of contaminants in the
dialysis system, several from the inside. These include im-
purities from intravenous fluids used to prime and rinse
the circuit and for volume administration, and plasticiz-
ers, glues, fillings, bonding materials, spalled particles,
and other substances leached from the dialyzer and blood
tubing that are infused into patients’ blood. Plasticizers,
particularly phthalates in blood tubing, curing materials
used in membrane fabrication, chemicals used in dialyzer
reuse, spalled particles from blood tubing sets and pump
segments, potting compounds in the headers of hollow
fiber dialyzers, and phenols from dialyzer casings, have
all been associated with ill effects in dialysis patients.
These contaminants and their effects will increase as the
number of dialyses per week doubles and as patient sur-
vival is prolonged.
The clinical consequences of an ‘‘impure dialysis sys-
tem’’ have been thought to contribute to inflammation
and oxidative stress in hemodialysis patients and these in
Table 1 Standards of dialysate purity
U.S.A. Proposed U.S.A.
CFU/mL o2000 o200
Endotoxin EU/mL No limit o2.0
EURO = Europe; ST =standard; UP =ultrapure.
S40
turn are thought to contribute to malnutrition, amyloi-
dosis, and arteriosclerosis. This has been described as the
MIA-syndrome of dialysis: malnutrition-inflammation-ar-
teriosclerosis.5 These relationships have become of great
interest to investigators. A recent Gateway search cross-
referencing inflammation and dialysis over the last few
years yielded 1986 articles; cross-referencing oxidative
stress with dialysis resulted in 811 articles.
DEFINITIONS OF PURITY
Definitions or standards of purity in dialysis almost ex-
clusively refer to the bacteriological purity of the dialy-
sate. This review will not consider metals and small water
purification compounds such as chloramines. Purity is
defined by endotoxin levels (endotoxin units or EU) and
the number of colony-forming units (CFU) in the dialy-
sate. The present standards are shown in Table 1. These
differ considerably from country to country; in the United
States, the allowed number of CFU is 200,000 times and
the endotoxin level is 200 times those in Japan. As meth-
ods of measuring impurities improve, standards will
change. Thus, any of the current or proposed standards
are arbitrary and will probably become more stringent
with the discovery that even minute amounts of contam-
ination may lead to long-term disease in dialysis patients.
We are of the opinion that the standard should be no CFU
and no measurable level of endotoxin in dialysate. Purity
should be ‘‘beyond ultrapure.’’
There are presently no standards for plasticizers or
spallation.
TYPES OF IMPURITY
Bacteriological
Only CFU and endotoxin levels are considered today, but
the limulus amebocyte lysate assay detects only the lipo-
polysaccharide endotoxin of Gram-negative bacteria and
perhaps b-glycan from fungi. Only the silkworm larva
plasma test detects the peptidoglycan of the cell wall
of Gram-positive bacteria.6 Recent studies indicate that
there are small bacterial fragments or metabolites of
EURO ST EURO UP Japan
o100 o0.1 o0.001
o0.2 o0.03 o0.01
Hemodialysis International 2007; 11:S39–S48

Gram-negative bacteria with molecular weights between
1500 and 6000 da that are not detected by the limulus
test. Such fragments easily pass current dialysis mem-
branes and stimulate inflammatory responses in mono-
cytes such as increased IL-6 formation.7
There are also no standards for contamination by vir-
uses. However, hepatitis C virus has been suspected of
passing through dialysis membranes, perhaps in unde-
tectable small cracks, and so cross-infecting dialysis pa-
tients.8 This indicates that patients should have dedicated
machines. Dialysis machines are not particularly expen-
sive, but the costs of hospitalization and medical care are.
Plasticizers
Several harmful nonbiological substances have been
shown to be released from components in the dialysis
system. A workshop 30 years ago implicated rubberizers
and metals from the tubing and dialyzer membranes.9
Recently, most interest has focused on problems from plas-
tics used in modern dialysis. These are listed in Table 2.
Phthalates, used for softening polyvinylchloride (PVC),
are those most commonly used today and almost all rele-
vant studies are from Germany and Japan. Fairly large
quantities of di-(2-ethylhexyl)-phthalate (DEHP) are in-
fused from blood-tubing sets and from bags containing
intravenous fluids. Kambia and associates have estimated
Table 2 Contaminants of plasticizers, sterilizing agents, and
reuse chemicals
Compounds in polyvinylchloride
Di-(2-ethylhexyl) phthalate (DEHP)
Mono(2-ethylhexyl) phthalate (MEHP)
2-Ethylhexane (2-EH)
Phthalic acid (PA)
4-Hepatanone (4-H)
Bisphenol-A
And various metabolites
Ethylene oxide
Chemical for reuse
Peracetic acid
Formaldehyde
Glutaraldehyde
Unknown reactive contaminants
Glues
Epoxy compounds
Bonding
Filling
Potting
Cleaning
Products from incomplete bonding and hardening
Hemodialysis International 2007; 11:S39–S48
Beyond ultrapure hemodialysis
this to be of the order of 13 to 42 mg for each dialysis, and
the amount seems proportional to the fat content of the
patient’s blood.10 This translates to a potential burden of
more than 30 g over 5 years in patient on conventional
hemodialysis. While DEHP is relatively nontoxic in cell-
culture studies, it is transformed in the body into other
molecules, particularly mono-(2-ethylhexyl) phthalate
(MEHP), which is highly toxic. When this is added to
cell-culture media in concentrations relevant to human
exposure, almost no cells remain viable after 3 hr of
exposure.11 The potentially harmful effects in humans
are hotly debated, some calling for an immediate halt to
the use of PVC in medical devices, while others state that:
‘‘to question the safety of PVC is a major waste of time,
resources and human potential.’’12–14
Phthalates induce IL-1 production in vitro and their
potential toxic effects include necrotizing dermatitis, he-
patic inflammation, endocrine disturbances, and carcino-
genesis. Phthalates are excreted in the urine, and the
blood level of phthalates in both conventional hemodial-
ysis and peritoneal dialysis patients is 4–20 times that of
normal controls.15–17 Because of the very large exposure
to phthalates with long-term hemodialysis and especially
with more frequent hemodialysis, we believe that PVC
should be eliminated from hemodialysis devices.
Other potentially toxic additives in dialysis are bisphe-
nol-A and its metabolites. These are eluted from the
polycarbonate shell and polysulfone membrane of some
dialyzers.18–20 Again, almost all studies are from Japan.
These compounds are present in the blood of dialysis
patients in quantities 20 times that in normal controls.21
The toxic effects of bisphenols include hematopoietic
damage, sperm changes, and, perhaps most alarming, a
defect in gene transcription.22 This finding and the car-
cinogenesis described for phthalates are of particular con-
cern in dialysis patients who have an incidence of cancer
7 times that of the general population.23
The well-known first-use syndrome is related to eth-
ylene oxide used in dialyzer sterilization.24 Glutaralde-
hyde, peracetic acid, and formaldehyde used in chemical
reuse procedures of dialyzers are other poisonous and
oxidizing substances that are released into patients. Dur-
ing reuse, these agents bind to materials in the dialyzer,
cannot be completely rinsed out, and are slowly released
and infused into patients during the subsequent treat-
ment.25 Formaldehyde and glutaraldehyde have a strong
cross-linking capacity for nucleic acids and proteins and
so have been used as fixatives for biological tissues in
both light and electron microscopy. The cross-linking re-
actions are the mechanism for killing microbes and are
irreversible and so both substances have the potential for
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Kjellstrand and Kjellstrand
the build-up of irreversible long-term damage even at
concentrations that yield no acute effects. At present,
there are no reliable methods for the prediction of such
long-term damage and so no way to protect patients other
than to keep such substances completely away from their
equipment.26
New, unexpected and unknown compounds may be
introduced in dialysis manufacturing, some with imme-
diate lethal results. In a recent episode, more than 50
patients died worldwide when treated with dialyzers in
which a Freon-like compound had been introduced dur-
ing manufacturing.27 Such dramatic episodes are only the
tip of the iceberg, and lower but daily infusions of sub-
stances undoubtedly are damaging to long-term dialysis
patients. Very reactive substances from incomplete bond-
ing and hardening of 2-compound adhesives, bonds, fill-
ers, and glues used in dialysis material fabrication are also
infused into patients as it is very unlikely that a predia-
lysis rinse with 0.5 to 2 L of saline will completely wash
these undesirable substances out.
All medical devices and fluids have to be sterilized so
that no living microbes enter the patient. Killing microbes
can be achieved in several ways, including either breaking
or cross-linking the molecules in the living organism, a
‘‘stick in the wheel’’ approach. Nucleic acids and proteins
are the main targets of these processes. There are 3 main
methods for sterilization: heat, radiation, and reactive
chemicals. These means may be combined, while ma-
nipulation of pH may also be used to enhance killing ca-
pacity. These methods not only damage the molecules of
the microbes but also affect other molecules in the plas-
tics and the fluids. A serious problem with these ap-
proaches is that the molecular nature of many of the
reactive fragments that develop is unknown. These frag-
ments may not be detected by currently available meth-
ods, and there is no way of predicting their effects on
patients. Degradation of glucose during heat sterilization
of fluids for parenteral nutrition and peritoneal dialysis is
an example of how complex a seemingly simple chain of
events can be.28–32 The low sensitivity of existing animal
models means that such models have not proved to be
very useful.33,34
Spalled particles consisting of PVC, polyurethane, and
silastic, particularly from the pump segments in the ex-
tracorporeal circuit, have been found in the lungs, skin,
spleen, and liver of patients and have been associated
with signs of hepatic irritation and fibrosis and hypercal-
cemia.35–40 We could not find a single article on spalla-
tion in hemodialysis published after 1992. There is
presently no standard for spallation in dialysis, but there
is a standard for large volume intravenous fluid infusion
S42
in the U. S. Pharmacopoeia, 23, general chapter 788. This
standard allows up to 12,000 particles o10 mm in size
and 2000 particles o25 mm in size per liter to be infused.
A patient on parenteral nutrition could be infused with
24,000 small and 4000 larger particles each night, and
would have approximately 0.175 billion small and 30
million larger particles infused over a 20-year period of
treatment. This amount appears excessive, but the poten-
tial load of spalled particles for a patient on daily hemo-
dialysis dialyzing some 300 times a year and expected to
live possibly 10 to 20 years and possibly experiencing up
to 3000 to 6000 dialyses will be many times greater.
MEASURING CONTAMINANTS
A summary of the methods for measuring contaminants is
shown in Table 3.
Bacteriological
Bacteriological contaminants are studied by incubating
the suspected sample in or on various growth media. If
living microbes are present, they will eventually grow and
form colonies. There are considerable differences in the
number of CFUs detected, depending on the procedure
and what media and growth times are used.41,42 Endo-
toxin content is measured by the limulus amebocyte ly-
sate test or by chromogenic methods that are constantly
being made more sensitive; the lower limit of detection is
now in the neighborhood of 0.005 EU/mL or 1 ng/mL. As
discussed previously, peptidoglycan is not detected by
these methods but is detected with the silkworm larva
plasma test. No commercial test is available for detection
of smaller bacterial fragments at this time.
Plasticizers
Phthalate metabolites and bisphenols can be quantified
by several different physical methods, none easy or read-
ily available commercially.
Table 3 Ways to detect and measure contaminants
Physical: Chemical finger printing
1. UV spectro-photometry
2. NIR ‘‘near infra red’’ spectro-photometry
3. IR ‘‘infrared’’ spectro-photometry
4. HPLC-UV-DAD (diode array detector)
Cell testing: Biological fingerprinting
Clinical: Clinical fingerprinting
1. Quantitate ill-effects reported by patients
2. Temperature, vital signs
3. Oxidant and inflammatory markers
Hemodialysis International 2007; 11:S39–S48

There are 3 non-specific ways to quantify contamin-
ants, physical/chemical, biological, and clinical finger-
printing, and all can give estimates of the sum of
contaminants and their ill effects. In physical fingerprint-
ing, curves of the output from high-performance liquid
chromatography (HPLC) are made from dialysate and
predialysis and postdialysis blood samples and the peaks
and valleys compared among different dialysis systems.
This is similar to early studies of ‘‘middle molecule’’ toxins
in dialysis.43 Only when the chemical nature of the con-
taminant is known and it is available in a pure form
(which is usually not the case) can the amount of con-
tamination be estimated. In biological fingerprinting, the
fluids are added to cell cultures and damage is estimated
by cell viability or enzyme release.10–12,33,34 Clinical fin-
gerprinting refers to studies of the ill effects reported by
dialysis patients such as episodes of hypotension, ar-
rhythmias, cramps, headache, backache, itching, nausea,
and vomiting, together with measuring clinical effects
such as fall in blood pressure and changes in pulse rate
and body temperature. Studies of the effect of different
qualities of dialysate on inflammatory and oxidant stress
markers in patients also belong in this category.
Spallation is studied with in vitro techniques that in-
volve placing a filter or Coulter counter on the venous
return line from the dialyzer and counting the number of
particles collected. There are no methods for the study of
spallation in vivo.
BIOCOMPATIBLE MEMBRANES
Complement activation and leucopenia in dialysis was
first described more than 30 years ago and was found to
be highly dependent on the nature of the membrane.44
Cellophane was the least biocompatible membrane as de-
fined by complement activation and leucopenia; polysul-
fone, polyamide, and polyacrylonitrile membranes were
the most biocompatible, with other membranes in be-
tween. Other biological effects, such as elastase release
and thrombocytopenias, do not necessarily occur in tan-
dem with the more dramatic complement-leucopenia re-
sponse and there is considerable intrapatient variability in
the responses.45,46 Oddly, there are no detectable acute
clinical ill effects in patients paralleling the dramatic com-
plement activation-leucopenia changes in the blood.47,48
More recent data have shown no survival advantage
with open, biocompatible membranes over others.49
However, any subtle beneficial effects may have been
drowned out by the effect of present-day short, intermit-
tent dialysis with its poor patient survival. More than 60%
of hemodialysis patients in the United States are dead
Hemodialysis International 2007; 11:S39–S48
Beyond ultrapure hemodialysis
within 5 years and thus long-term observations are not
possible. Long-term problems including amyloidosis and
its complications and cardiovascular problems that de-
velop over time are discussed later. However, common
sense dictates that a membrane that does not activate the
clotting and complement cascades is to be preferred over
a membrane that causes violent biological activations in a
patient’s blood.
REMOVING IMPURITIES
There are 4 principal methods of removing contaminants:
filters, absorbers, chemical cleaning, and physical clean-
ing using large volumes and hot water. The methods used
differ on the outside and inside of the extracorporeal cir-
cuit. Filters have been used successfully to remove bac-
teria and endotoxin down to undetectable limits from
dialysate,50 but with the discovery of small bacterial tox-
ins, there may be a need to decrease pore size in order to
remove them.7 Recently, an absorber to bind endotoxin
has been described that can reduce the endotoxin content
of both dialysate and blood, but no clinical testing has
been reported.51 Filters and absorbers can be used to
produce a ‘‘beyond ultrapure’’ dialysate but they will not
produce an ultrapure dialysis system.
Phthalates and bisphenols, small molecules with a mo-
lecular weight of o1000 da, will pass through most filters
and are not bound to specific binding sites. It is also im-
portant to be aware that everything added to the extra-
corporeal circuit may be released and so introducing
more filters or absorbers may reduce one form of impur-
ity but add another. While reuse with chemicals probably
reduces both plasticizers and spallation because of the
volumes of fluids used in the washout, the chemicals
themselves can add toxicity. Moreover, these chemicals
often penetrate poorly into the organic debris left in a
used dialyzer where bacteria may hide. The best method
to clean the inside of the extracorporeal circuit appears to
be thorough physical washing with rinse volumes much
larger than the usual 0.5 to 2 L of saline, followed by
polishing with hot water. Water has the advantage of
being nontoxic, heat has the advantage that it penetrates
everywhere, and both are easy to dispose of.
Two modern dialysis systems designed to produce be-
yond ultrapure dialysis are the German Geniuss system
(Fresenius Medical Care Germany, Bod Homburg, Ger-
many) and the American Aksys PHDs system (Lincoln-
shire, IL, U.S.A.). Both use a tank of dialysate. In the
Genius system, an ultra-sterile, filtered bicarbonate dial-
ysate is constantly exposed to the bactericidal effect of
an ultraviolet light emanating from a light rod in the
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Kjellstrand and Kjellstrand

dialysate tank.52,53 In the Aksys system, the dialyzer and Table 4 Comparison of symptoms, as percent of dialyses
tubing set are part of the dialysis apparatus and are with symptom and changes in vital signs as patient changed
changed only monthly. After each dialysis, the entire sys- from conventionally clean dialysis to beyond ultrapure
tem, both inside and outside the extracorporeal circuit, is dialysis
scrubbed with 40 L of water and heat-sanitized with 8 L
Conventional Ultrapure
of water at 75 1C.54–56 Both these systems have under-
N=2819 N=1636 p
gone extensive clinical testing and appear to have brought
about improved patient outcomes. To us, the physical Hypotension 14% 9% o0.0001
Arrhythmia 2% 0.1% o0.0001
process of water and heat cleaning of both the inside and
Headache 7% 4% 0.004
outside of the extracorporeal circuit, together with ex-
Cramps 5% 3% 0.016
tended nonchemical reuse, appears to be the best method Nausea 2% 1% 0.012
presently available to clean out bacterial, plasticizers, and Backache 1.2% 0.2% 0.002
physical spallation contaminants simultaneously. Postdialysis PR 490 35% 24% o0.0001
Fall in systolic BP 17  21 8  21 o0.0001
mmHg
BENEFITS OF BEYOND ULTRAPURE Fall in diastolic BP 6  12 2  12 o0.0001
DIALYSIS mmHg
Increase in PR/min 2  13 0  12 o0.0001
Immediate beneficial effects
The symptoms declined by 50% to 95%, and the decline in blood
Immediate beneficial effects of ultrapure dialysate, usually pressures was much smaller when patients were dialyzed on the
seen within days or weeks, appear to include more stable ultrapure system.
cardiovascular status during dialysis with less hypoten-
sion and arrhythmias and an improved general well-being levels were significantly lower, and at 3 months, while
with fewer episodes of headache, backache, nausea, and hemoglobin levels were equal between the 2 groups, the
other clinical symptoms.55,57–61 In more than 4400 dial- need for erythropoietin was 26% lower in patients using
yses using 6 dialyses a week and the same patients, dia- the ultrapure dialysate.62,63 Bonforte et al., followed 32
lysis with conventional machines was compared with patients for 9 months and reported almost identical find-
slightly longer dialysis using the Aksys PHD. Cleanliness ings.64 Schiffel et al., randomly assigned 30 patients
was measured as the occurrence of any bacterial growth to conventional or ultrapure hemodialysis. During a 24-
and determination of endotoxin levels. In approximately month follow-up, they found lower levels of inflamma-
400 prime samples, conventional machines failed to meet tory markers and better preserved residual renal function
the intravenous fluid standard (o0.5 EU/mL) in a third in those dialyzed with ultrapure dialysate.65,66 In a fur-
of the samples and the old European standard (o0.25 ther study with 12 months of follow-up, inflammatory
EU/mL) in two-thirds of the samples. The PHD showed markers were significantly lower in patients on ultrapure
no detectable endotoxin when tested to the limit of the dialysate while dry body weight, mid-arm muscle cir-
method (o0.005 EU/mL). The patients reported signifi- cumference, serum albumin concentration, growth factor
cantly further improvement in well-being when using the 1, leptin, and protein catabolic rate increased. All these
beyond ultrapure dialysis system and vital signs were factors did not change in patients using conventional
better preserved. In multivariate analysis, the significant dialysate.65,66
factor associated with the improvements was the purity
of the dialysis, not differences in the time or the speed of Long-term benefits
dialysis. The results are summarized in Table 4.
Over decades, patients dialyzed with ultrapure dialysate
have fewer episodes of carpal tunnel syndrome, amyloi-
Intermediate effects dosis, and dialysis arthropathy. Cardiovascular mortality
Intermediate effects take months to detect and include a is also reported to be lower in patients on ultrapure
better response to erythropoietin, lower C-reactive pro- dialysate when compared with patients dialyzed against
tein (CRP) levels, and increased appetite with improved regular dialysate.67–69 Baz et al., followed 226 patients
nutrition. Sitter and coworkers randomized 30 hemodi- for up to 16 years. In 39 of those treated with ultrapure
alysis patients to either conventional or ultrapure dialy- dialysate, none had carpal tunnel symptoms at 10 years
sate. In the group using ultrapure dialysis, CRP and IL-6 compared with 40% of 103 patients treated with conven-

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tional dialysate.67 Similarly, Lonnemann and Koch com-
pared the incidence of carpal tunnel syndrome at 13 years
in patients treated with conventional dialysate (70%) with
those treated with filtered ultrapure dialysate (30%) and
with the Genius machine (15%).68
At least 3 groups have observed less cardiovascular
morbidity in patients treated with ultrapure dialysate
when compared with patients on conventional equip-
ment.52,70–72 In a 3-year investigation of 60 patients,
Lederer et al., found that CRP levels were significantly
lower in those on the ultrapure system and there were 11
cardiovascular events in the 38 patients by conventional
dialysis vs. 1 in 22 patients treated with ultrapure dial-
ysate (po0.0001).72
CONCLUSIONS
(1) Beyond ultrapure dialysis means ultrapure dialysate
on the outside of the dialyzer and also ultrapure
conditions inside the blood circuit.
(2) The benefits of ultrapure dialysate appear to include
a frequent decrease in symptoms during dialysis.
Intermediate effects manifesting themselves within
months include less inflammatory STIMULI, less
need for erythropoietin, better-preserved renal func-
tion, and improved nutrition. Over decades, amy-
loidosis, carpal tunnel syndrome, and perhaps
cardiovascular events are considerably less common.
(3) The long-term effects of spallation and plasticizer
contamination from dialyzers, blood tubing, intra-
venous fluids, and bags are not known, but many
common ill effects suffered by dialysis patients such
as skin disease, hepatic failure, endocrine dysfunc-
tion, hematopoietic damage, and marked increase in
cancer may be related to such contaminants.
We define beyond ultrapure, biocompatible hemodialysis
as follows:
1. Bacteriologically ultrapure dialysate: endotoxin levels
o0.0005 U/mL, CFU o 1/1000 mL, and silkworm
larva plasma test negative.
2. Toxicologically ultrapure dialysate: no PVC, bisphe-
nols, trace metals, or reactive compounds.
3. Biocompatible membrane in the dialyzer and bio-
compatible plastics in the blood tubing and
pump segments and no complement activation-leu-
copenia.
4. No PVC anywhere in the system and so no intraven-
ous fluids from PVC-containing bags should be used.
5. Ultraclean dialyzer and blood tubing: no toxic sub-
stances (PVC, bisphenols, reactive compounds).
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Beyond ultrapure hemodialysis
6. Minimal spallation: much less than the U.S. Pharma-
copoeia limits or o1000 particles of o10 mm in size
and o200 particles of o25 mm in size during each
dialysis.
7. Dedicated machine for each patient.
All current standards for purity of dialysis are woefully
inadequate as they mainly refer to fluids outside the
blood circuit. It is meaningless to use dialysate contain-
ing o0.005 EU/mL endotoxin and then use prime and
infusion fluids that contain 0.5 EU/mL and high concen-
trations of phthalate. All contaminants received by
patients, whether biological, chemical, or physical, need
consideration.
Some may scoff at our definitions and consider beyond
ultrapure dialysis as economically impossible. However,
several clinics have used this approach successfully for
decades. The savings from lower morbidity will exceed
the moderate cost.
Manuscript received October 2006; revised October 2006.
REFERENCES
1 U.S. Renal Data System. USRDS 2005 Annual Data Re-
port: Atlas of End-Stage Renal Disease in the United
States, National Institutes of Health, National Institute of
Diabetes and Digestive and Kidney Diseases, Bethesda,
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