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Keywords:

  • liver failure;
  • FPSA;
  • Prometheus;
  • extracorporeal liver support therapy

Abstract

  1. Top of page
  2. Abstract
  3. Method of Prometheus®
  4. Clinical results
  5. Conclusions and future options
  6. Acknowledgements
  7. References

Fractionated plasma separation and adsorption (FPSA) is a method of albumin dialysis that is integrated into an extracorporeal liver support device (Prometheus®). This concept allows the effective removal of both protein-bound and water-soluble substances without the need for external albumin. Several studies comparing the in vivo extraction capacities of FPSA and molecular adsorbent recirculating system (MARS) concluded that detoxification by FPSA seems to be more effective than by MARS. Overall, FPSA therapy has been shown to be safe. Over the last few years, the anticoagulation protocol for FPSA therapy was optimised by using regional anticoagulation with citrate to avoid clotting of system components. Recently, the results of a large randomised-controlled multicentre trial (HELIOS) have been presented. Survival after 1 and 3 months was evaluated in 145 patients with acute-on-chronic liver failure comparing FPSA therapy with standard medical treatment versus standard medical treatment alone. There was no statistically significant survival benefit for patients undergoing FPSA therapy. However, patients with hepatorenal syndrome type I or MELD score>30 showed a significant survival benefit under FPSA in a predefined subgroup analysis. Furthermore, there have been promising results with FPSA in the treatment of refractory cholestatic pruritus. Regarding acute liver failure, only few data are currently available.

Acute-on-chronic liver failure is still associated with a high mortality. Orthotopic liver transplantation, which represents an adequate treatment for these patients, remains limited due to organ scarcity. Thus, there is a clinical demand for new therapeutic options in patients with liver failure, either of an acute or an acute-on-chronic type. One of the few extracorporeal liver support devices that have been introduced into clinical practice over the last decade is based on the method of fractionated plasma separation and adsorption (FPSA). The current results of FPSA therapy are summarised herein.

Method of Prometheus®

  1. Top of page
  2. Abstract
  3. Method of Prometheus®
  4. Clinical results
  5. Conclusions and future options
  6. Acknowledgements
  7. References

In patients with liver failure, the removal of both water-soluble and water-insoluble albumin-bound toxins is important to support detoxification. A number of techniques for liver support devices have therefore been developed during the last decades. A new technique of extracorporeal detoxification albumin was presented in 1999: FPSA (1). FPSA allows the patient's own albumin to be regenerated via passage through two adsorption matrixes in a secondary circuit (Fig. 1). In contrast to molecular adsorbent recirculating system (MARS), an albumin-permeable polysulphone membrane (AlbuFlow®, Fresenius Medical Care, Bad Homburg, Germany) is used and there is no need for external albumin. This concept was implemented into a commercially available device (Prometheus®, Fresenius Medical Care, Bad Homburg, Germany). This device also includes a high-flux haemodialyser inside the primary circuit.

image

Figure 1.  Scheme of the FPSA method. The fractionated plasma separation and adsorption system (Prometheus®) consists of a primary and a secondary circuit. Both circuits are separated by an albumin-permeable polysulphone membrane (AlbuFlow®). There, the patient's albumin fraction is filtered into the secondary circuit, where direct purification from albumin-bound toxins by different adsorbers (Prometh 01®, Prometh 02®, Fresenius Medical Care, Bad Homburg, Germany) takes place. Afterwards, conventional high-flux dialysis (FX 50®, Fresenius Medical Care, Bad Homburg, Germany) is performed inside the primary circuit.

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Clinical results

  1. Top of page
  2. Abstract
  3. Method of Prometheus®
  4. Clinical results
  5. Conclusions and future options
  6. Acknowledgements
  7. References

The pilot trial of the FPSA system included 11 patients with acute-on-chronic liver failure and concomitant renal failure (2). Blood levels of protein-bound and water-soluble toxins improved significantly after FPSA treatment. This was confirmed by subsequent studies (3, 4). In one patient with severe hepatorenal syndrome, it was demonstrated that the device may support bridging to liver transplantation for a longer period of time (>50 days) (5).

Biochemical clearance of the FPSA method has been studied in detail: the overall removal rates for bilirubin, bile acids, creatinine and urea are between 41 and 68% (3, 4). Comparisons of the detoxification efficiency of MARS and FPSA show a superiority of FPSA in comparison with MARS in terms of the removal of most protein-bound toxins as well as water-soluble substances (4, 6). Both devices lead to transient improvements of the redox state of albumin that could be beneficial in patients with liver failure (7). However, only a minor removal of different cytokines was achieved by both systems. This did not result in a significant change of serum cytokine levels possibly because of the high production rate of cytokines (8).

In general, FPSA treatment was found to be safe despite a short-term decrease of the mean arterial blood pressure in some patients. This effect is not observed in patients treated by MARS, which could be related to the removal of some vasoactive substances (e.g. renin, nitric oxide) only by the MARS system (9). Furthermore, external albumin, which is well known for its positive haemodynamic effects, is added only in MARS, while a small loss of albumin during FPSA therapy has been described (6).

Because of the large extracorporeal circuit in FPSA on the one hand and the risk of bleeding in patients with liver failure on the other, anticoagulation under FPSA therapy has been studied intensively. To avoid clotting of system components, the anticoagulation protocol for FPSA has been optimised by using regional anticoagulation with citrate (10). However, in vivo and in vitro experiments found a significant removal of clotting factors (factors II, X, protein C) by one adsorber (anion exchanger) of the FPSA system (11). However, this effect seems to be of minor clinical relevance in patients with liver failure (12). Likewise, no overt thromboses were noticed in another study that compared anticoagulation protocols using heparin or heparin with prostacyclin (13).

Just recently, the results of the HELIOS trial, a randomised-controlled European multicentre trial of FPSA therapy, have been presented (14). A total of 145 patients with acute-on-chronic liver failure were either treated with standard medical treatment and FPSA eight to 11 times over 21 days or with standard medical treatment alone. Chronic liver disease was because of alcohol in 56% of the patients. The average MELD score was 27±10 and Child Pugh Score was 12±1 points. Twenty-eight patients underwent liver transplantation during the trial. The primary end points were patient's survival after 28 days and after 3 months irrespective of liver transplantation. There was no statistically significant difference in the overall survival between both study groups. However, a significant survival benefit was observed under FPSA therapy in two predefined subgroups, namely in patients with hepatorenal syndrome type I and those with a MELD score>30. The extensive safety analysis did not show any evidence for treatment-related complications. But a further evaluation of the above-mentioned promising subgroups is necessary.

In contrast, in patients with acute liver failure, only uncontrolled data of FPSA therapy exist. One series described FPSA treatment in 18 patients, eight of them presenting with fulminant hepatitis B. Even though only one liver transplantation was performed, 50% 1-month survival after a mean of three FPSA sessions was observed (15).

In patients presenting with acute intoxication with protein-bound drugs, FPSA may be used to remove the drugs. Another possible indication for FPSA is severe refractory cholestatic pruritus (16). All patients with elevated serum bile acid levels reported a marked improvement of pruritus after three to five FPSA sessions in this series. In most patients, the benefit lasted more than 4 weeks.

Conclusions and future options

  1. Top of page
  2. Abstract
  3. Method of Prometheus®
  4. Clinical results
  5. Conclusions and future options
  6. Acknowledgements
  7. References

Fractionated plasma separation and adsorption, as an established method of albumin dialysis, offers safe extracorporeal liver support. The concept allows an effective and safe removal of both protein-bound and water-soluble substances without the need for external albumin. The detoxification by FPSA seems to be more effective than by MARS. Nevertheless, a recent large RCT did not show an overall survival benefit for patients with acute-on-chronic liver failure. However, FPSA may be a promising treatment option in subgroups of patients such as those with hepatorenal syndrome type I and MELD score of >30. Other indications for FPSA therapy comprise refractory cholestatic and intoxication with protein-bound drugs. Regarding the use of FPSA in patients with acute liver failure, the existing data are insufficient.

Future trials should focus on two points: (i) more data on treatment modalities such as when to start FPSA therapy, optimal length and frequency of treatment, etc.; (ii) more randomized-controlled data in specific patient groups such as hepatorenal syndrome.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Method of Prometheus®
  4. Clinical results
  5. Conclusions and future options
  6. Acknowledgements
  7. References

Conflicts of interest: The author received grant and research support from Fresenius Medical Care, Bad Homburg, Germany. He performed lectures sponsored by Fresenius Medical Care, Bad Homburg, Germany.

References

  1. Top of page
  2. Abstract
  3. Method of Prometheus®
  4. Clinical results
  5. Conclusions and future options
  6. Acknowledgements
  7. References
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