ART

ADVANCED RENAL TECHNOLOGIES

Product Manual

®
CITRASATE
ADVANCED RENAL TECNOLOGIES

Citrasate®

© Advanced Renal Technologies

40 lake Bellevue, Suite 100
Bellevue, WA 98005
Table of Contents
Citrasate® (Dialzate with anticoagulant) 13

C HA P TER 1
Citrasate® and dialyzer Biocompatibility 15
Citrasate®
Innovative dialysis solution

Introduction 2
C HA P TER 4
Citric Acid 3 Citrasate®
Dialyzer reusability
Chemical composition 5

Citrasate® improves the reusability 18

C HA P TER 2
Citrasate®
Superior Therapeutic performance C HA P TER 5
Packages

Hemodialysis delivered dose 6

Citrasate® and dose adequacy 7 Packages 20

Citrasate® and metabolic acidosis 9

Citrasate® and calcium 10

C HA P TER 6
Reference
C HA P TER 3
Citrasate®
Local anticoagulant Reference 22

Adequate anticoagulant 12
 1
Chapter

Introduction
Citrasate® innovative dialysis solution

F
or many years, the composition
remained stable, until a decade
for acetate. Recently, Advanced
new chemical formulation of
treatment.
of the dialysate used in Haemodialysis
ago when bicarbonate was substituted
Renal Technologies (ART) introduced a
dialysate that can improve dialysis

Citrasate® is the first new dialysate formulation in decades, and DRYalysate®

is the dry version of this new formulation. The new formulation in Citrasate®
contains the natural substance citric acid in place of acetic acid, which all
other dialysates have.

Citric acid is a physiological acid that is rapidly metabolized in muscle, liver

and kidney. It is important as an intermediate in the citric acid cycle and
therefore occurs in the metabolism of almost all living cells. Citric acid also is
a well known anticoagulant it has a long and safe history of use in medicine,
most notably as an anticoagulant used in the collection and storage of blood
for transfusion.

2 CITRASATE®
Citric Acid

Citric acid is a physiological acid that is rapidly metabolized in muscle, liver

and kidney. It is important as an intermediate in the citric acid cycle and
therefore occurs in the
metabolism of almost
all living things.

The citric acid cycle

(also known as the
tricarboxylic acid cycle,
the TCA cycle, or the
Krebs cycle) is a series
of chemical reactions of
central importance in all
living cells.

Citric acid cycle is part

of a metabolic pathway
involved in the chemical
conversion of
carbohydrates, fats and
proteins into carbon
dioxide and water to
generate a form of
usable energy

Citric Acid and Krebs cycle (Citric Acid Cycle):

However, the TCA cycle also functions in biosynthetic pathways in which
intermediates leave the cycle to
be converted primarily to
glucose, fatty acids, or non-
essential amino.

Glutamate and aspartate are

synthesized from α-
ketoglutarate and oxaloacetate,
respectively, via transamination.

Glutamate is synthesized by the

reductive amination of
aketoglutarate catalyzed by
glutamate dehydrogenase; it is

3 CITRASATE®
thus a nitrogen-fixing reaction. In addition, glutamate arises by
aminotransferase reactions, with the amino nitrogen being donated by a
number of different amino acids. Thus, glutamate is a general collector of
amino nitrogen.

Aspartate is formed in a transamintion reaction catalyzed by aspartate

transaminase, AST. This reaction uses the aspartate a-keto acid analog,
oxaloacetate, and glutamate as the amino donor. Aspartate can also be
formed by deamination of asparagine catalyzed by asparaginase.

Asparagine synthetase and glutamine synthetase, catalyze the production of

asparagine and glutamine from their respective a-amino acids. Glutamine is
produced from glutamate by the direct incorporation of ammonia; and this
can be considered another nitrogen fixing reaction. Asparagine, however, is
formed by an amidotransferase reaction. Aminotransferase reactions are
readily reversible. The direction of any individual transamination depends
principally on the concentration ratio of reactants and products.

Systemic acid-base changes cause striking changes in citrate clearance and

metabolism. Recent evidence suggests that the effects of acid-base changes
are mediated by alteration in the pH gradient across the inner mitochondrial
membrane. Metabolic alkalosis causes cytoplasmic pH and bicarbonate to
increase, resulting in a decrease in the mitochondrial pH gradient. This
change inhibits the tricarboxylate carrier, slowing entry of citrate into the
mitochondrial matrix compartment. The level of citrate in the cytoplasm
increases, tubular and peritubular citrate uptake are reduced, and citrate
clearance increases. Opposite changes occur in acidosis. Change in the
mitochondrial pH gradient provides a sensitive mechanism for regulating renal
substrate metabolism.

The renal clearance of citrate is greatly increased during metabolic Alkalosis.

All of the citrate filtered through the glomerulus is reabsorbed in the nephron
with only small quantities escaping into the urine. In the presence of
metabolic alkalosis the tubular reabsorption of citrate is inhibited, and the
excretion of citrate increases manyfold with little concomitant change in the
plasma level. The physiologic characteristics of this phenomenon have been
described in numerous reports, but the cellular mechanism responsible for it
has not been defined.

Citrate Normal anticoagulant:

Citrate is a well known anticoagulant that functions by binding serum calcium

thereby reducing the calcium available to participate in the blood’s clotting
cascade. It has a long and safe history of use in medicine, most notably as an
anticoagulant used in the collection and storage of blood for transfusion.

4 CITRASATE®
Chemical composition
Citrasate®, a new acid concentrate for bicarbonate dialysis, in which the
primary acidifying agent is Citric acid instead of acetic acid.

Citrasate® Regular Dialysate

Sodium (mEg/L) 137.3 137

Chloride (mEg/L) 103.25 – 106.75 103.25 – 106.75

Calcium (mEg/L) 2.5 OR 3.0 2.5 OR 3.0

Magnesium (mEg/L) 0.75 0.75

Potassium (mEg/L) 0–3 0–3

Dextrose (g/L) 2 2

Bicarbonate (mEg/L) 37 37

Acetate (mEg/L) 0.3 4

Citrate (mEg/L) 2.4 None

The indications for use of Citrasate®:

• Citrasate® is suitable for all Haemodialysis patients:

o Aiming to achieve adequate dialysis dose, or have chronic
acidosis maintaining the normal body electrolyte level.
o patients with a risk of bleeding from the use of systemic anti-
coagulation (Heparin) (i.e., ICU and Post-operative patient) ;
o When it’s contraindicated to use Heparin (I.e., Patient with
heparin-induced thrombocytopenia ”HIT”),
o Patient with an antibody to (intolerance to) Heparin whose
dialyzers clot despite large amounts of heparin;
o Patient achieves limited dialyzer reuse due to extensive clotting
within the dialyzer during dialysis; increasing the effective
surface area and improving the dialyzer biocompatibility.

5 CITRASATE®
 2
Chapter

Citrasate®
Superior therapeutic performance

The dose of dialysis in terms of urea clearance is marginal in many

Hemodialysis patients, and metabolic acidosis as determined by the pre-
dialysis serum HCO3 level is common. CITRASATE® rather than acetic acid as
acidifying agent provides superior performance properties.1

Hemodialysis Delivered dose.

N
umerous studies outcomes have demonstrated a correlation between
the delivered dose of Hemodialysis and the patient's mortality and
morbidity.2,3. Evidences have shown that mortality among ESRD
patients is lower when sufficient Hemodialysis treatments are
provided. Clinical signs and symptoms alone are not reliable indicators of
Hemodialysis adequacy.4,5

To see whether dialysis is removing enough urea, the clinic should

periodically—normally once a month—test a patient's blood to measure
dialysis adequacy. Blood is sampled at the start of dialysis and at the end.
The levels of urea in the two blood samples are then compared. Two methods
are generally used to assess dialysis adequacy, URR and Kt/V.

6 CITRASATE®
Citrasate® and dose adequacy
Citrasate® increases the delivered dialysis dose for the patient. This
includes improved Kt/V and (Urea Reduction Rate) URR and increased
predialysis serum bicarbonate levels improving the dialysis outcomes
(minimize the Mortality and Morbidity).1

The significant increase in the delivered dose of dialysis seen at the end of a
twelve-week study was not a result of any increase in blood or dialysate
flows, dialysis time, or a change in dialyzers--known factors influencing the
dose. It is possible that the increased removal of urea (increased dose) may
be attributable to the presence of citrate in the dialysate. In the twelve-week
study the initial average urea reduction ratio (URR) was 68.5 ± 5.9%, and
after treatment with the citrate dialysate disclosed herein, this ratio had
increased to 73 ± 5.3% (p<0.03). SpKt/V, calculated using the Daugirdas II
formula, also increased from 1.23 ± 0.19 to 1.34 ± 0.2 (p=0.01).1

7 CITRASATE®
8 CITRASATE®
 Citrasate® and Metabolic Acidosis

Persistent metabolic acidosis in dialysis patients has been associated with

increased protein catabolism7, increased turnover of ß2 microglobulin8, bone
metabolism problems9 and abnormal muscle functions10. Correction of
metabolic acidosis has been attempted either by increasing dialysate
bicarbonate concentration11 or by prescribing oral bicarbonate12, but both
approaches have associated practical and clinical problems. Citrate is
metabolized in liver and muscle to produce bicarbonate, and patients getting
massive blood transfusions are known to develop alkalosis as a result of the
increased citrate load13.

Thus, citrate metabolism alone may explain the increase in serum bicarbonate
level. However, increased intradialytic bicarbonate transfer from the dialysate
to the blood might also be a factor as the result of a possible effect of citric
acid on the dialyzer membrane. The increase in pre-dialysis serum HCO3 may
be attributed to the increase of the delivered dose and the production of HCO3
from citric acid.1

Pre-dialysis mean serum HCO3 level mEq/L

9 CITRASATE®
Citrasate® and Calcium
The concentration of citrate in CITRASATE® is only 2.4 me/L; only about one-
fifth of the concentration used to achieve anticoagulation via traditional
regional citrate infusions. The use of CITRASATE® does not produce
measurable systemic anticoagulation, the anticoagulant effect is confined to
the dialyzer and the venous side of the dialysis set up.

CITRASATE® generally produces a clinically acceptable transitory reduction

(about 10%) in ionized calcium1. Ionized calcium begins to normalize to the
predialysis level as soon as the CITRASATE® dialysis session stops1. The
consistent treatment of chronic dialysis patients with CITRASATE® has
demonstrated no change over extended time periods in either total or ionized
serum calcium levels1.

We postulate that by binding with calcium, dialysate citrate provides a local

anticoagulant effect at the dialyzer membrane level. This effect may help to
preserve membrane permeability and keep the capillary fibers patent. This
could explain the observed increase in transfer of solutes such as urea and
bicarbonate between dialysate and blood.1

Using Citrasate® emphasizes and takes advantage of the localized anti-

coagulant property. These benefits include: increasing the blood flow through
the dialyzer, thereby increasing the dose of dialysis; keeping the dialyzer
cleaner, thereby allowing more extended reuse of the dialyzer; mitigating the
clogging of dialyzer pores, thereby allowing greater clearance of "middle
molecules" e.g., molecules having a molecular weight of about 12,000
Daltons; providing a significant source of additional bicarbonate to the blood,
thereby reducing the incidence of chronic acidosis; and reducing or
eliminating the need for the anti-coagulant “Heparin".1

1 0 CITRASATE®
1 1 CITRASATE®
 3
Chapter

Citrasate®
Local anticoagulant

Adequate anticoagulant

A
dequate anticoagulation is a precondition to prevent extracorporeal
blood clotting and to improve biocompatibility during
Hemodialysis14.

Heparin is widely used for prevention and treatment of thromboembolic

disorders and to prevent clotting within the extracorporeal circuit during
Hemodialysis. However, the systemic nature of heparin anticoagulation
increases the risk of bleeding complications and, therefore, cannot be
safely used in post-surgical patients or in those who are actively bleeding.
Some acutely ill patients develop severe thrombocytopenia with the use of
heparin. In these patient groups, if Hemodialysis is needed, heparin
cannot be safely used, and successful completion of the Hemodialysis
procedure can often become quite challenging, since without
anticoagulation the system frequently clots.

In recent years, Citrate has gained more popularity as an anticoagulant

during Hemodialysis especially in patients with increased bleeding risks,
because of the advantages of an efficient anticoagulation that is
exclusively confined to the extracorporeal circulation and also
improvement of the biocompatibility by inhibition of activation of blood
cells.15

1 2 CITRASATE®
Citrasate® (Dialysate with
Anticoagulant)
Citrasate® provides a local anticoagulant effect at the dialyzer membrane
level. This effect reduces dialyzer clotting and keep the capillary fibers
patent, thus improving membrane permeability and increased dialyzer
reusability. The rapid metabolism of citrate to bicarbonate releases
calcium and, therefore, does not confer systemic anticoagulation.

Using Regular Dialysate Using Citrasate

As Dialyzers clot during dialysis, this reduces effective dialyzer surface

area. Effective urea clearance is a combination of dialyzer membrane
permeability and surface area plus
blood and dialysate flow rates.

The use of citrate as anticoagulant

during Hemodialysis induces lower
activation of coagulation than both
conventional and unfractionated
Heparin (UFH) which might
contribute to an improvement of
biocompatibility of Hemodialysis
extracorporeal circulation.14

Citrasate®, a new acid concentrate for bicarbonate dialysis, is unique

because it uses citric acid rather than acetic acid for acidification. Citrate
is a well known anticoagulant that functions by binding serum calcium
thereby reducing the calcium available to participate in the blood’s clotting
cascade. This characteristic of Citrasate®, its ability to reduce clotting,
makes it very useful for treating patients that either can’t use Heparin or
for those for whom Heparin is ineffective.
Citrasate® provides an effective alternative for problem patients with: 16

1 3 CITRASATE®
 • a risk of bleeding from the use of systemic anti-coagulation
(Heparin) for example ICU and post operative patient;
• When it’s contraindicated to use Heparin (I.e., Patient with heparin-
induced thrombocytopenia ”HIT”),
• Patient with an antibody to Heparin (intolerance) whose dialyzers
clot despite large amounts of heparin;

CITRASATE® retaining the patient's ability to clot blood

Citrasate® is particularly useful in instances where patients should be

heparin-free during dialysis. For example, post-operative patients may
undergo acute kidney failure due to the kidney's response to the
anesthesia, and thereafter need dialysis treatment until kidney recovery
occurs. Heparin or other anti-coagulant should not be delivered
systemically to these patients because retaining the patient's ability to clot
blood is an important part of the healing process. With traditional
dialysate, undesirable blood clotting will occur within the dialyzer, unless
the patient receives some anti-coagulant. However, with the Citrasate®, a
patient with acute kidney failure can undergo successful dialysis without
systemic administration of anti-coagulant. A patient with acute kidney
failure may also experience more rapid recovery of kidney function upon
exposure to Citrasate®, in comparison to conventional dialysate, because
Citrasate® has fewer tendencies to activate complement formation, where
complement formation tends to slow down kidney recovery.1

Citrasate® Minimize the use of Systemic Anti-Coagulant

Citrasate® reduces or eliminates the need for the anti-coagulant “Heparin"

without adverse effects. 1

1 4 CITRASATE®
Citrasate® and Dialyzer Biocompatibility
The biocompatibility of the dialyzer membranes and whole blood is of
major concern. Both proteins and cells adhere to the membrane surface.
This contact, in turn, causes a number of deleterious responses, which
resemble those of assaults to the patient's immune system in the form of
severe allergic reactions. The responses are numerous and in some
instances life threatening. They include: Platelet adhesion, agglomeration
& damage, Thrombosis and erythrocyte adhesion. Complement activation
(C3/C.5) the clinical manifestations are also numerous and in some cases
lead to morbidity and mortalities.

Coagulation activation presents one of the main determinants of

biocompatibility. Coagulation activation is obviously one of the most
important barriers to adequacy of dialysis delivery. Recently, Shegal et al
analyzed patient-related and technical factors determining dialysis delivery
in 1836 treatments provided to 721 randomly selected patients on regular
Hemodialysis therapy17. Their study concluded that beside dialysis
prescription problems with vascular access and clotting are the most
important limits to dialysis adequacy.

1 5 CITRASATE®
Citrasate® inhibit blood coagulation locally at the dialyzer membrane
surface resulting in better dialyzer clearance, As Dialyzers clot during
dialysis, this reduces effective dialyzer surface area. Effective urea
clearance is a combination of dialyzer membrane permeability and surface
area plus blood and dialysate flow rates and improve the biocompatibility.
Clotting not only reduces the efficiency of dialysis therapy by mechanical
obstruction of the dialysis membrane, but causes activation of other
cascade systems activation of cellular elements besides platelets and
especially polymorphonuclear neutrophils, the release of vasoactive
hormones, such as thromboxane, of mediators such as tumor necrosis
factor α and enzymes such as elastase. 14

1 6 CITRASATE®
1 7 CITRASATE®
 4
Chapter

Citrasate®
Dialyzer reusability

Citrasate® Improves the reusability

Dialyzer reuse is limited by the clotting of blood, which blocks the fibers
and reduces the membrane surface area. Clotting during treatment may
also reduce dialysis efficiency and potentially decrease delivered dose,
Kt/Vurea. Citrasate® reduce clotting during acute dialysis treatments.18

Citrasate® raise average dialyzer reuse by

more than 60% on all patients, and by
over 100% on patients considered
"problem clotters." 1

Reuse outcome on Citrasate® was

compared with the reuse on the regular
acetic acid containing bicarbonate
dialysate (controls). The overall reuse
with citrate dialysate increased significantly from 15.1 ± 9.4 to 18 ± 10.0
(mean ± SD) on regular and citrate dialysate, respectively (p = 0.0003).
The most significant increase was seen in those patients who had limited
reuse before the switch to Citrasate®; 51, 59, and 134% increases
occurred in those with 10 to 15, 5 to 10, and < 5 reuses at controls,
respectively. Interestingly, the 10 patients with 10 or fewer reuses had
significantly lower Kt/Vurea at baseline (before the switch to Citrasate®)
than those with > 10 reuses (1.23 ± 0.23 vs. 1.47 ± 0.23, respectively,
p = 0.009). The Kt/Vurea increased to 1.41 ± 0.31 after the switch in the
low-reuse group but the increase did not reach statistical significance
(p = 0.07). The results from this study show that Citrasate® is associated
with increase in dialyzer reuse and appears to be related to reduced
clotting.18

1 8 CITRASATE®
1 9 CITRASATE®
 5
Chapter

Citrasate®
Packages

Citrasate®

• Citrasate® is ready to use liquid concentrate in convenient gallon jugs.

• Package information: 4.5 - 5 Liter bottle.
• The following concentrations are listed in mEq/L, except for Dextrose
which is in mg/dl, and represent the concentration in dialysate after
proper dilution before including the ionic contribution of the bicarbonate
concentrate.

Concentration Sodium Chloride Calcium Magnesium Potassium Dextrose Acetate Citrate

36.83X 81.3 84.5 2.5 1 0 200 0.3 2.4
36.83X 81.3 85.5 2.5 1 1 200 0.3 2.4
36.83X 81.3 86.5 2.5 1 2 200 0.3 2.4
36.83X 81.3 85 3 1 0 200 0.3 2.4
36.83X 81.3 86 3 1 1 200 0.3 2.4
36.83X 81.3 87 3 1 2 200 0.3 2.4
36.83X 81.3 85.5 3.5 1 0 200 0.3 2.4
45X 100.3 103.5 2.5 1 0 200 0.3 2.4
45X 100.3 104.5 2.5 1 1 200 0.3 2.4
45X 100.3 105.5 2.5 1 2 200 0.3 2.4
45X 100.3 104 3 1 0 200 0.3 2.4
45X 100.3 105 3 1 1 200 0.3 2.4
45X 100.3 106 3 1 2 200 0.3 2.4
45X 100.3 104.5 3.5 1 0 200 0.3 2.4
35X 100.3 103.5 2.5 1 0 200 0.3 2.4
35X 100.3 104.5 2.5 1 1 200 0.3 2.4
35X 100.3 105.5 2.5 1 2 200 0.3 2.4
35X 100.3 104 3 1 0 200 0.3 2.4
35X 100.3 105 3 1 1 200 0.3 2.4
35X 100.3 106 3 1 2 200 0.3 2.4
35X 100.3 104.5 3.5 1 0 200 0.3 2.4

2 0 CITRASATE®
 DRYalysate®

• A dry powdered acid concentrate that needs to be mixed with water prior
to use.
• Each box of DRYalysate® will reconstitute into fifty (50) liters of acid
concentrate.
• The following concentrations are listed in mEq/L, except for Dextrose
which is in mg/dl, and represent the concentration in dialysate after
proper dilution before including the ionic contribution of the bicarbonate
concentrate.

Concentration Sodium Chloride Calcium Magnesium Potassium Dextrose Acetate Citrate

45X 100.3 103.5 2.5 1 0 200 0.3 2.4
45X 100.3 104.5 2.5 1 1 200 0.3 2.4
45X 100.3 105.5 2.5 1 2 200 0.3 2.4
45X 100.3 104 3 1 0 200 0.3 2.4
45X 100.3 105 3 1 1 200 0.3 2.4
45X 100.3 106 3 1 2 200 0.3 2.4
45X 100.3 104.5 3.5 1 0 200 0.3 2.4
36.83X 81.3 84.5 2.5 1 0 200 0.3 2.4

2 1 CITRASATE®
 6
Chapter

Reference

1. A Ahmad S, Callan R, Cole JJ, Blagg CR. Dialysate made from dry chemicals using citric acid
increases dialysis dose. Am J Kidney Dis 2000; 35:493-499
2. Owen WF, Lew NL, Liu Y, Lowrie EG, Lazarus JM: The urea reduction ratio and serum albumin
concentration as predictors of mortality in patients undergoing Hemodialysis . N Engl J Med 329:1001-
1006, 1993
3. Owen WF, Chertow G, Lazarus JM, and Lowrie EG: The dose of Hemodialysis: Mortality responses by
race and gender. JAMA 280:1-6, 1998
4. Delmez JA, Windus DW, St. Louis Nephrology Study Group: Hemodialysis prescription and delivery in
a metropolitan community. Kidney Int 41:1023-1028, 1992
5. Lindsay RM, Heidenheim AP, Spanner E, Baird J, Simpson K, Allison ME: Urea monitoring during
dialysis: the wave of the future. A tale of two cities. ASAIO Trans 37:49-53, 1991
6. Hofbauer R, Moser D, Frass M, Oberbauer R, Kaye AD et al. Effect of anticoagulation on blood
membrane interactions during Hemodialysis . Kidney Int (Oct) 56:1578-1583 1999
7. Reaich et al., Am. J. Physiol. 265:E230-E235 (1993)
8. Sonikian et al., J. Am. Soc. Nephrol. 7:350-356 (1996)
9. Lin et al., ASAIO J. 40:M440-M444 (1994)
10. Guest et al., J. Am. Soc. Nephrol. 8:236A (1997)
11. Ahmad et al., Trans. Am. Soc. Artif Intem. Organs 26:318-321 (1980)
12. Brady and Hasbargen, Am. J. Kid. Dis. 31:35-40 (1998)
13. Dzik and Kirkley, Trans. Med. Rev. 2:76-94 (1988)
14. Hofbauer R, Moser D, Frass M, Oberbauer R, Kaye AD et al. Effect of anticoagulation on blood membrane
interactions during Hemodialysis. Kidney Int (Oct) 56:1578-1583 1999
15. BOEHLLER J. SCHOLLMYER P, DRESSL B, DOBOS G, HOERL WH: Reduction of granulocyte
activation during Hemodialysis with regional citrate anticoagulation: Dissociation of complement activation
and neutropenia from neutrophil degranulation. J Am Soc Nephrol 7:234-241, 1996
16. Annie Tu, MS, ARNP, CNN; Ahmad S.,: Heparin-free hemodialysis with citrate-containing dialysate in
intensive care patients. Dialysis & Trans. V.29, No. 10 Oct. 2000
17. SEHGAL AR, SNOW RJ, SINGER ME, AMINI SB, DEOREO PB, SILVER MR, CEBUL RD: Barriers to
adequate delivery of Hemodialysis. Am J Kidney Dis 31:593-601, 1998
18. Ahmad S, Callan R, Cole JJ, Blagg CR. Increased dialyzer reuse with citrate dialysate. Hemodialysis
International V. 9 Issue 3 Page 264 - July 2005 doi:10.1
ADVANCED RENAL TECNOLOGIES

© Advanced Renal Technologies

40 lake Bellevue, Suite 100
Bellevue, WA 98005