Thermodynamic Considerations in Solid Adsorption of Bound Solutes for Patient Support in Liver Failure

Acute liver failure (ALF), defined as sudden onset with no previous history of liver disease, and acute-on-chronic liver failure (AcLF), resulting from sudden decompensation of existing liver disease, are life-threatening conditions that have poor prognosis1, 2. Despite differences in cause and pathophysiology of the underlying disease state, clinical presentation of the disease and its progression are similar, e.g., advancing encephalopathy, blood coagulopathy, elevated ammonia, lactate, and bilirubin levels, and frequently include hemodynamic instability, renal failure, and respiratory distress3. Hence standard medical therapy, primarily supportive in nature, is the same for both ALF and AcLF. Detoxification approaches have been developed for treatment of liver failure based upon the premises that (1) liver failure progresses because of the presence of toxic substances that continue to promote liver cell death; (2) removal of many toxic substances is problematic because the toxins bind tightly to proteins, such as albumin, limiting free solute concentration in the plasma, which in turn, severely limits the ability of conventional dialysis to remove the toxins; and (3) detoxification, i.e. removal of toxins, will allow the liver to exercise its regenerative capabilities, promoting recovery from liver failure. The detoxification approaches generally use one or more high affinity binders that can successfully compete with albumin to remove albumin-bound toxins. Based upon operating characteristics, detoxification approaches can be broadly classified into two categories: open-loop, in which the high affinity binder is continuously added and removed from the system, and closed-loop, in which toxins accumulate on binder without removal of binder from the system. The HemoCleanse-DT (formerly known as the Biologic-DT and Liver Dialysis Unit, HemoCleanse, Lafayette, IN) and single pass albumin dialysis (SPAD) are examples of open-loop dialysis systems based on adding a high affinity binder to the dialysate. The HemoCleanse-DT uses a finely divided, high surface area charcoal adsorbent as the toxin binder while SPAD uses albumin. Perfusion with the HemoCleanse-DT resulted in normalization of blood chemistries (clearance of aromatic amino acids, bilirubin, ammonia, and cytokines and increase in Fischer amino acid ratio), reduction in encephalopathy, and improvement in physiologic status in several small clinical studies4–7. However, the number of patients in any of the studies was insufficient to draw conclusions with respect to efficacy. Although no clinical trials of SPAD have been reported, several case reports have found significant removal of copper from a Wilson’s disease patient8, reductions in hepatic encephalopathy and bilirubin9, and no significant difference between 1.85% and 5.0% dialysate albumin concentration in bilirubin removal from a patient with hyperbilirubinemia10. Modeling predictions indicate that albumin concentrations as low as 0.5% would have been equally effective for these cases11–13. The Molecular Adsorbent Recirculating System (MARS, Gambro AB, Stockholm, Sweden) and Fractionated Plasma Separation, Adsorption, and Dialysis System (Prometheus, Fresenius AG, Bad Homburg, Germany) are examples of closed-loop systems. MARS uses an intermediate albumin dialysis step to transfer toxins from albumin in the plasma to solid adsorbents while Prometheus directly contacts the adsorbents with plasma. Regardless, the solid adsorbents remain in the system during patient perfusion. MARS perfusion has been used in over 4000 ALF or AcLF patients14 and is associated with significant clearance of bilirubin, bile acids, ammonia, and cytokines and reduction in encephalopathy15–18. The most recent entry into clinical evaluations, Prometheus has been associated with reduction in cerebral edema19, and reductions in albumin-bound toxins such as bilirubin, bile acids, and cholinesterase20–23. Although neither MARS nor Prometheus have not yet been shown to have clinical efficacy with respect to patient survival in an appropriately controlled, randomized study, several reports of direct comparison between the systems in support of liver failure patients have appeared24–27. The reports indicate that both MARS and Prometheus remove albumin-bound toxins with slight differences in the removal of different toxins. Although both MARS and Prometheus are based upon the well-founded principle that albumin-bound toxins in plasma, which are not amenable to removal by conventional dialysis, can be removed by providing another, preferably higher affinity, binder for the toxins, design and development of the two approaches have been largely heuristic in nature. The present work presents a thermodynamic analysis of the equilibrium limits of the two closed-loop systems in order to gain greater understanding the governing parameters that limit their ultimate ability to remove albumin-bound toxins from plasma. Better understanding of the governing parameters should result in improved systems for clinical use.