Acute kidney injury (AKI) is a common and serious problem in critically ill patients, and is
known to be an independent risk factor for mortality. Renal replacement therapy (RRT) is the
mainstay of supportive treatment of patients with severe acute kidney injury. The goal of RRT
is to achieve adequate correction of uremia, electrolyte abnormalities, and volume overload
while ensuring good hemodynamic tolerance. The advantages of continuous renal replacement
therapy (CRRT) are increased time-averaged dialysis dose, less hemodynamic instability, and
possibly, removal of high molecular weight solutes, such as inflammatory cytokines. Solute
removal can occur by several different mechanisms in CRRT. For relatively small solutes, the
importance of diffusion and convection is emphasized, for solutes of larger molecular weight,
the importance of convection and adsorption is emphasized. The ability of a specific CRRT to
remove a certain solute is determined by membrane characteristics. But actual measurements of
middle molecule clearance in large clinical trials have not been available in most trials.
During CRRT, blood is conducted through an extracorporeal circuit, circuit clotting is a
major problem in daily practice of CRRT, increasing blood loss, workload, and costs. Early
clotting is related to bioincompatibility, critical illness, vascular access, CRRT circuit,
and modality. Therefore, one major intervention to influence circuit survival is
anticoagulation. However, systemic anticoagulation, usually with heparin, can produce
hemorrhagic complications in patients at high risk of bleeding. To minimize the risk of
bleeding, a number of alternative regimens has been proposed, however, each of those methods
has its own limitations and complication. Nafamostat mesilate, a serine proteinase inhibitor,
while inhibiting various clotting factors in filter circuit, is characterized by short half
life resulting in little systemic anticoagulation effect. A recently developed CRRT AN69ST
membrane® (Gambro Inc) is coated with a polyethylene imine (PEI, cationic biopolymer) on the
membrane surface. Once adsorbed onto the membrane, heparin keeps its anticoagulant
properties. Therefore CRRT has been managed without systemic administration of heparin.
The investigators will conduct a multicenter prospective randomized controlled open-label
trial which compares the difference in circuit survival between between nafamostat infusion
and heparinized saline priming as anticoagulation for CRRT. The primary end-point of this
study is circuit survival, the time of 1st membrane exchange. The secondary end-point is
clearance of small molecule (urea) and middle molecule (β2 microglobulin) at 0, 1, 6, 24h,
ACT(activated coagulation time) measurements after 1hr of the CRRT, Hemorrhagic complication.
This is a noninferiority trial. The aim is to demonstrate that nafamostat infusion is not
inferior to the heparinized saline priming. For this purpose, at least 80 subjects (a total
of 160) would be required for each group if type I error rate is 5% and type II error is 20%
given 20% of drop-out rate during the study period. Block randomization will be used by means
of a dedicated website.
There are still conflicting data on the effective exchange time of circuit membrane. Our
study may help to improve prognosis in patients with severe AKI.