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18th ISAD

International Symposium on Albumin Dialysis

Extracorporeal Albumin Dialysis using OPAL® for albumin recycling is superior in detoxification to using MARS® - The OPAL®esce Study

Abstract Body:
In liver failure, albumin bound toxins (ABT) are associated with hepatic encephalopathy (HE), renal failure (RF) and pruritus (PR). Albumin dialysis using MARS® has been shown to remove albumin bound toxins, especially those binding to the benzodiazepine binding site of albumin (Sudlow II), which hosts many toxins of relevance for liver failure, such as bile acids, middle molecular fatty acids, tryptophane and metabolites, etc. The binding of a marker for the binding capacity of this site, dansylsarkosin, has been shown to be a reliable indicator for overall toxin load of ABT and correlated with validated prognostic Scores (MELD). Specifically, patients with MELD Scores >20 had a median ABiC of 39 (24-74) compared to the 100 of healthy subjects. Also, in a prospective, randomized trial investigating MARS® efficacy, survival of subjects with low MELDs (40) was strongly associated with improvement of ABiC, while failure to improve ABiC was associated with a mortality of over 80%.

In conclusion, only if ABiC can be improved, the efficacy of ECAD was sufficient to compensate for the rebound/reformation of albumin bound toxins. Especially in subjects with limited reserve hepatic function, a more effective ECAD procedure may be required to achieve improvement of ABiC and thereby survival.

In MARS®, efficacy is limited because of the limited capacity of the MARS® Activated Charcoal (AC250) to adsorb albumin stabilizer caprylate and other albumin bound toxins. The HepalbinTM adsorbent (HA) consists of micro particle charcoal embedded within a micromesh forming three dimensional scaffold, designed to improve the clearance of albumin bound molecules from albumin solutions, mostly due to reduction of the need for albumin to travel long distances by diffusion.

In a prior single center cross over study comparing 6 hours with the HepalbinTM adsorbent versus the MARS® adsorbents, in 12 patients, MARS® resulted in reduction of bile acids by 22.76 (+23.57)%, whereas HepalbinTM adsorbents resulted into a reduction by 34.21 (+22.73)%. With respect to total bilirubin, MARS® resulted in reduction of bile acids by 7.7 (+13.76)%, whereas HepalbinTM resulted into a reduction by 20.7 (+9.08)%. Patients ABiC at the binding site for phosphatidylcholine was non-significantly increased by 11.17 (+15.42)% for MARS®, while the improvement was significant (p<0.028; paired t-test) for the improvement observed for HepalbinTM by 16.44 (+19.6)%. Although a successful improvement, the study was single centered and had a small sample size (n=12), which might have been why MARS® improvements did not reach significance at all. Safety measurements were not clinically meaningful impacted (hemoglobin, platelets, MAP, prothrombine time index), with the exception that the Shock-Index and Clot formation time (thromboelastography) normalized on HepalbinTM AC but not on MARS® AC. Safety could be demonstrated so that a multicenter study (OPAL®esce) was appropriate.

The aim of this multicenter randomized cross over study was to compare in vivo the improvement of patient’s albumin binding function assessed by the ABiC test during ECAD using the HepalbinTM adsorbent implemented in an “open albumin dialysis - OPAL®”-kit versus the classical MARS® kit, containing the AC250 charcoal and the IE250 anion exchanger.

Methods:
In a multicenter prospective randomized controlled study, subjects with progressive jaundice and/or HE and/or RF and/or PR were treated first with one ECAD kit and afterwards crossed over for the second treatment to the other. Subjects were not made aware of which adsorbent they had been treated with, the machine platforms were identical (MARS®-monitor). Pre-and post-values of markers for ABT were measured. Safety and other clinical parameters were compared.

Results:
After obtaining consent, 29 subjects with acute or acute on chronic liver failure with progressive jaundice>8mg/l and/or secondary renal failure and/or hepatic encephalopathy and/or intractable pruritus were randomized consecutively. In 24 subjects samples for the measurement of ABiC could be obtained before and after MARS® or OPAL® treatment respectively. Out of these, 13 had MARS® as the first treatment and 11 OPAL®.

Despite the higher number of subjects, patient’s ABiC at the binding site II was non-significantly increased from 55.44+14.41% to 58.97+13.35% (paired t-test p=0.148) by a mean of 3.53+11.53% for MARS®, while the improvement was even more significant (paired t-test p<0.001) for the improvement observed for OPAL® from 52.94+11.96% to 62.29+11.39% by 9.35+7.4%. 

The difference between the upward trend in MARS® (3.53+11.53%) and the almost 3 times higher significant improvement observed in OPAL® (9.35+7.4%) was also significant in the unpaired t-test (p=0.046).

Conclusion:
If the concept of albumin binding capacity for dansylsarkosin as a good indicator for progression or regression of endogenous accumulation of albumin bound toxins is valid, the limited capacity of the classical MARS® kit with macroparticle adsorbents, insufficiently recycling the dialysate albumin and improving patients albumin binding function could explain the limited efficacy in survival trials, which is still under debate, although in narrowly defined populations, also MARS® could improve survival. Since the capacity of OPAL® to improve patient’s albumin binding function is almost three times as much as the capacity of MARS®, further survival studies should implement the HepalbinTM adsorbent or an equivalent for albumin recirculation.

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