Research Article: Middle molecule clearance with high cut-off dialyzer versus high-flux dialyzer using continuous veno-venous hemodialysis with regional citrate anticoagulation: A prospective randomized controlled trial

Date Published: April 26, 2019

Publisher: Public Library of Science

Author(s): Lorenz Weidhase, Elena Haussig, Stephan Haussig, Thorsten Kaiser, Jonathan de Fallois, Sirak Petros, Yoshitaka Isaka.


Regional anticoagulation with citrate during renal replacement therapy (RRT) reduces the risk of bleeding, extends dialyzer lifespan and is cost-effective. Therefore, current guidelines recommend its use if patients are not anticoagulated for another reason and if there are no contraindications against citrate. RRT with regional citrate anticoagulation has been established in critically ill patients as continuous veno-venous hemodialysis (CVVHD) to reduce citrate load. However, CVVHD is inferior regarding middle molecule clearance compared to continuous veno-venous hemofiltration (CVVH). The use of a high cut-off dialyzer in CVVHD may thus present an option for middle molecule clearance similar to CVVH. This may allow combining the advantages of both techniques.

In this prospective, randomized, single-blinded single-center-trial, sixty patients with acute renal failure and established indication for renal replacement therapy were randomized 1:1 into two groups. The control group was put on CVVHD using regional citrate anticoagulation and a high-flux dialyzer, while the intervention group was on CVVHD using regional citrate anticoagulation and a high-cut-off dialyzer. The concentrations of urea, creatinine, β2-microglobulin, myoglobin, interleukin 6 and albumin were measured pre- and post-dialyzer 1, 6, 12, 24 and 48 hours after initiating CVVHD.

Mean plasma clearance for β2-microglobulin was 19.6±5.8 ml/min in the intervention group vs. 12.2±3.6 ml/min in the control group (p<0.001). For myoglobin (8.0±4.5 ml/min vs. 0.2±3.6 ml/min, p<0.001) and IL-6 (1.5±4.3 vs. -2.5±3.5 ml/min, p = 0.002) a higher mean plasma clearance using high-cut-off dialyzer could be detected too, but no difference for urea, creatinine and albumin could be observed concerning this parameter between the two groups. CVVHD using a high cut-off dialyzer results in more effective middle molecule clearance than that with high-flux dialyzer. German Clinical Trials Register (DRKS00005254, registered 26th November 2013)

Partial Text

Acute kidney injury requiring renal replacement therapy (RRT) is associated with a high mortality [1, 2] and represents an independent risk factor besides the severity of the underlying disease [3]. Continuous renal replacement therapy (CRRT) offers better hemodynamic stability and gentle removal of solutes and fluids [4]. Nevertheless, a better survival could not be demonstrated with CRRT compared to intermittent hemodialysis (IHD) [5, 6]. Furthermore, there is a lack of evidence concerning optimal dose [7, 8, 4, 9, 10] and the best time point to start RRT [11, 12].

This study is a prospective, randomized, single-blinded single-center trial in a 28-bed medical intensive care unit (ICU) at the University Hospital Leipzig, Germany. The study was approved by the local ethics committee (University of Leipzig, reference number: 447-12-24092012), conducted in accordance with the German medical product law and registered in the German Clinical Trials Register (DRKS00005254, registered 26 November 2013). Informed consent was obtained from all participating subjects. Eligible patients were enrolled after informed consent by the patients themselves or their legal guardians. The trial was conducted between May 2014 and May 2015.

Baseline characteristics of the study groups are shown in Table 1, with no significant difference between the control group and the intervention group.(Table 1)

This prospective randomized trial compared the application of two different dialyzers during CVVHD with regional citrate anticoagulation in critically ill patients. A significantly better plasma clearance of middle molecules could be demonstrated with the high cut-off dialyzer compared with the standard high-flux dialyzer. Since both dialyzers are made of the same membrane surface and material, the differences in the plasma clearance of the investigated substances can be explained only by the difference in pore sizes. β2-microglobulin is a surrogate parameter for middle molecular uremic toxins. Elevated serum levels of this protein are associated with increased mortality and development of amyloidosis [29, 30, 31, 32]. A few reports showed that reduction in β2-microglobulin levels may have mortality benefit in end stage renal disease [29, 30]. Hemodialysis using high cut-off dialyzers was shown to effectively lower plasma β2-microglobulin levels [33]. A cross-over study in a small study population using sustained low efficiency daily dialysis (SLEDD) [28] demonstrated a superior elimination of β2-microglobulin using the high cut-off Ultraflux EMiC2 dialyzer than with the high-flux dialyzer Ultraflux AV 1000S (plasma clearance: 52 ± 1,7 ml/min vs. 41.7 ± 1.5 ml/min, p<0.001). The higher clearance rate in that study compared to ours is due to the higher volume exchange per time with SLEDD. Similar to that study, our trial also showed that there is no relevant albumin loss with the high cut-off dialyzer. Another investigation showed an enhanced elimination of glutamine and serine with the high cut-off Ultraflux EMiC2 [34], while circulating microRNAs were not eliminated by this dialyzer [35]. A recent study demonstrated a higher clearance of IL-6 and interleukin 10 using Ultraflux EMiC2 compared with AV 1000S in CVVHD with citrate anticoagulation [36]. Another recent trial revealed no differences in removing β2-microglobulin between continuous veno-venous hemodiafiltration (CVVHDF) using Ultraflux AV 1000S and CVVHD using Ultraflux EMiC2. However, the dialysis dose was in the CVVHDFgroup (36±4 ml/kg/h) much higher than in the CVVHD group (21±6 ml/kg/h) [37]. In summary, the available data indicate that Ultraflux EMiC2 allows an effective elimination of molecules up to a molecular weight of 40 kDa [38]. There is an effective elimination of β2-microglobulin in citrate anticoagulated CVVHD using the HCO-dialyzer Ultraflux EMiC2 in critical care patients. A significant removal of myoglobin and IL-6 also seems to be possible. Therefore this procedure could be useful in patients suffering from rhabdomyolysis and increased risk of bleeding as well as those with severe inflammation.   Source:


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