A pilot study regarding regional anticoagulation by a citrate containing dialysis fluid.

In hemodialysis, renal replacement is achieved by filtering blood of a
hemodialysis patient through an artificial kidney. The patient's blood is led
to a blood pump through a needle and subsequently pumped through hundreds
hollow fibers forming the artificial kidney. Exchange of waste products is
achieved by diffusion to the dialysis fluid which flows on the other side of
the hollow fibers. The purified blood is returned to the body. Hemodialysis is
typically performed twice or thrice weekly during 3 to 5 hours. If the patient
cannot receive a renal transplant, this regimen will remain for the rest of
his/her life. As blood is pumped through these very thin fibers, clotting can
occur. The clotting can necessitate termination of the dialysis session. To
prevent this, anticoagulation is created during hemodialysis, mostly by
administering low molecular weight heparin (LMWH) in a dose varying between
2500 and 10.000 U.

A disadvantage of the anticoagulation with LMWH is the simultaneous
anticoagulation of the patient, which poses a tenfold increased risk on a
subdural hematoma compared to the normal population. In the Albert Schweitzer
Ziekenhuis (ASz), two patients were lost similarly. This strongly increased
risk may be due to the simultaneous use of oral anticoagulation or antiplatelet
agents for other reasons. It is concluded that ideally only the artificial
kidney should be anticoagulated (regionally) and systemic anticoagulation of
the patient should be prevented.

This risk of bleeding has led the Nederlandse Federatie voor Nefrologie (NFN)
to formulate a guideline on the use of anticoagulants in hemodialysis in 2012.
This guideline advises to avoid the use of heparin or LMWH in case of a high
risk of bleeding as during active bleeding or dialysis within 2 to 3 days after
surgery or trauma. In case of moderate increased risk of bleeding, as during
use of other anticoagulants, adaptation of the anticoagulation is advised.

One of the options for achieving regional anticoagulation i.e. exclusively the
extracorporeal system is anticoagulated, is the use of citrate. Citrate is an
anticoagulant as it binds Factor IV (calcium = Ca) of the coagulation cascade.
Continuous veno-venous hemofiltration (CVVH) with citrate (a form of renal
replacement in the intensive care unit) is standard practice at the ASz .

Regional citrate anticoagulation (RCA) would be the ideal solution for
hemodialysis patient with a moderate increased or high risk of bleeding. Apart
from preventing anticoagulation of the patient, RCA results in less clotting of
the extracorporeal system than with LMWH (4). Unfortunately, RCA is a
technically demanding procedure. Citrate is administered with a syringe pump.
The dialysis fluid should be calcium (Ca)- and preferably, magnesium (Mg)-free,
while Ca en Mg are infused after the artificial kidney. When the blood pump
stops or has to be stopped due to technical problems, as happens frequently,
the syringe pump has to be stopped as well. If this is omitted, citrate will
accumulate. As soon as the blood pump is restarted, a flush of citrate will
reach the patient. This causes a passing hypocalciemia with complaints of
cramps and paresthesia, which can be frightening for a patient.

In case of an acute bleeding, the technically demanding RCA is used in several
hospitals in the Netherlands; several handbooks call it the first choice in
this setting. In cases of a moderate increased risk of bleeding, RCA is not
used due to the technically demanding procedure.

Would it be possible to simplify RCA in such a way that patients with a
moderate increased risk of bleeding don't have to be exposed to the
superimposed risk of bleeding due to LMWH?

Since some years a 0.8 mmol/l citrate containing dialysis fluid is used in the
United States (Citrasate® ). Also the Swedish firm Gambro produces a similar
dialysis fluid. This citrate containing dialysis fluid has not been marketed in
order to replace the use of LMWH or heparin. Nevertheless, there is a
publication in which it was used as substitution for heparin. Citrasate®
reduced clotting but 41% of the dialysis sessions had to be stopped
prematurely.

Citrasate®, which is commercially available in The Netherlands, has been used
in the ASz, Dordrecht, during the dialyses of 3 patients using acenocoumarol.
Dialysis had never to be stopped due to clotting in these 3 patients. There
were more clotting phenomena in the extracorporeal system than during standard
dialyses with LMWH. The explanation for the occurrence of clotting is that
Citrasate® contains Ca (1,25 mmol/l) en Mg (0,5 mmol/l). Part of the 0,8 mmol
citrate is bound to these cations and not available for anticoagulation (8).
Probably, only 0,42 mmol/l citrate is effectively avalable as anticoagulant in
Citrasate. Subsequently, in 3 patients using anti platelet agents, some
dialyses were performed using a 1,25 mmol/l Ca, 0,5 mmol/l Mg en 1,0 mmol/l
citraat (theoretically 0,62 mmol/l available free citraat) containing dialysis
fluid. In these sessions, clotting was not more frequent than with LMWH. Serum
Ca was lower compared with standard dialyses with LMWH because in LMWH a
dialysis fluid containing 1,5 mmol/l Ca is used.

This study envisions to simplify RCA. The current Dutch practice adding the
citrate to the arterial blood line by a pump will be replaced by adding the
citrate to a Ca- and Mg-free dialysis fluid. The substitution of the Ca and Mg
after the artificial kidney to the venous blood line will remain the same. Due
to the absence of Ca and Mg, a citrate concentration of 0.83 mmol/l in the
dialysis fluid will suffice. The study will be performed in hemodialysis
patients using oral anticoagulation or antiplatelet agents.

The study has 3 objectives:
1. Proving that this form of RCA does not increase the risk of bleeding while
achieving a degree of anticoagulation of the extracorporeal system that is
similar to that when using LMWH. When this study shows that citrate does not
increase the risk of bleeding and achieves a similar degree of anticoagulation
compared to LMWH, this form of RCA will be tested in a larger population of
hemodialysis patients to investigate non-inferiority to anticoagulation with
LMWH. 2. The simplification of the existing RCA in order to make it available
to patients receiving chronic hemodialysis with a moderate increased risk of
bleeding i.e. using oral anticoagulation or antiplatelet agents. 3. Investigate
whether serum values of Ca and Mg are similar to those during standard
anticoagulation with LMWH.

Dialyses

Each patient will function as its own control and will be treated with both
LMWH and citrate. Each patient will be treated with two consecutive citrate
dialyses (C1 and C2). These dialyses will be compared to two consecutive
standard dialyses with LMWH. (L1 en L2). The citrate- and standard dialyses
will be performed on the same day of the week. A possible third dialysis during
the week will not be a study session and therefore be a standard dialysis with
LMWH.

Regional citrate dialysis with calcium- and magnesium-free citrate dialysis
fluid.

The dialysis fluid is produced by mixing 9.75 liters of a Ca-, Mg-free, 3,0
mmol/l acetate containing concentrate (Dirinco ACC1208 ) with 250 ml of a 1500
mmol/l citrate solution (Dirinco Citralock 46.7%, CE 1275).

Ca- and Mg-suppletion with a solution containing Ca 54 mmol/100ml, Mg 14
mmol/100ml and 136 ml Cl/100 ml.

The burden will not be different to that of the regular thrice weekly
hemodialysis. Time expenditure for the patient will be unaltered. There will be
no additional punctures of veins or vascular access. In 2 weeks, an extra
amount of 120 ml of blood will be taken from the patient. The possible side
effects are known because citrate is often used as anticoagulantia with CVVH at
the intensive care departments. It has to be noted that the proposed citrate
concentration of 0.83 mmol/l in the dialysis fluid is 30% less than used with
CVVH. Excessive administraton (more than 4 times the proposed amount) of
citrate kan cause a metabolic alkalosis and symptoms of hypocalciemia. These
symptoms are divided according their incidence: seldom paresthesia, extremely
seldom muscle contractions, carpopedal spasm, insult, laryngospasm,
bronchospasm, increased QT interval, hypotenson, heart failure, arytmhia and
papil edema. The chance of these side effects are further diminished by the
used concentration of 0.83 mmol/l citrate, the separate administration of
calcium and magnesium, and the regular controls of the permanent present
dialysis nurse. The risk of clotting is similar to that of Citrasate that has
been registered and is used commercially. The expected side effects are less
than those seen with Citrasate. If by chance the proposed RCA with citrate does
not result in sufficient anticoagulantic effect, clotting may occur. The
results of clotting are minimal. At worst, in case of clotting of the
extracorporal system, patient will lose approximately 200 ml of blood.