Modification of continuous venovenous hemodiafiltration with single-pass albumin dialysate allows for removal of serum bilirubin

CASE REPORT

Modification of Continuous Venovenous Hemodiafiltration With Single-Pass Albumin Dialysate Allows for Removal of Serum Bilirubin Lakhmir S. Chawla, MD, Florin Georgescu, MD, Bruce Abell, MD, Michael G. Seneff, MD, and Paul L. Kimmel, MD ● A 53-year-old woman was admitted to the hospital with ischemic colitis and underwent a subtotal colectomy. She developed acute renal failure, severe hyperbilirubinemia, and intense pruritus resistant to medical treatment. Extracorporeal albumin dialysis using a Molecular Adsorbent Recirculating System (MARS; Gambro Co, Lund, Sweden) has been used to treat liver failure and reduce total serum bilirubin (SB) levels. A trial of extracorporeal albumin dialysis with continuous renal replacement therapy (RRT) was instituted to achieve net removal of SB. A 25% albumin solution was mixed with conventional dialysate to yield a dialysate concentration of 1.85% or 5.0% albumin. The patient underwent 2 continuous RRT sessions using extracorporeal albumin dialysis (1.85% and 5.0% albumin dialysate). Pretreatment and posttreatment SB levels were determined, and total bilirubin concentration (TB) also was measured in each of the collection bags during conventional and albumin dialysis. Pretreatment and posttreatment SB levels were 50.4 mg/dL (862 ␮mol/L) and 39.0 mg/dL (667 ␮mol/L) with 1.85% albumin dialysate and 47.1 mg/dL (805 ␮mol/L) and 39.7 mg/dL (679 ␮mol/L) with 5.0% albumin dialysate, respectively. The collected dialysate TB level was 0.3 mg/dL (5 ␮mol/L) during nonalbumin RRT and increased to 1.37 ⴞ 0.06 mg/dL (23 ⴞ 1 ␮mol/L) with 1.85% albumin dialysis. The collected dialysate fluid TB level was 0.3 mg/dL (5 ␮mol/L) during the nonalbumin RRT and increased to 1.38 ⴞ 0.15 mg/dL (24 ⴞ 3 ␮mol/L) during 5.0% albumin RRT. Single-pass albumin dialysis with continuous RRT cleared SB better than standard continuous RRT. Single-pass albumin dialysis with continuous RRT is feasible and may be a viable alternative in centers that do not have access to MARS therapy. This modality merits additional evaluation for its efficacy in clearing albumin-bound serum toxins. Am J Kidney Dis 45: E51-E56. © 2005 by the National Kidney Foundation, Inc. INDEX WORDS: Albumin dialysis; solute-bound dialysis; bilirubin; bilirubinemia; continuous renal replacement therapy (RRT); continuous venovenous hemodialysis (CVVHD).

T

HE DEFINITIVE treatment for liver failure is liver transplantation. During the past 2 decades, different types of hepatic replacement therapies have been tested with varying success. These therapies include, but are not limited to, whole-liver ex vivo perfusion, charcoal hemoperfusion, bioartificial liver systems, and albumin dialysis. All these therapies aim to reproduce various hepatic functions to improve the patient’s clinical condition and/or bridge the patient to liver transplantation if a suitable allograft is not immediately available. One of these new therapies is albumin dialysis, which has been delivered by the Molecular Adsorbent Recycling System (MARS; Teraklin, now owned by Gambro Co, Lund, Sweden).1 MARS is a liver support system designed to support liver excretory function. Albumin dialysis is similar to standard hemodialysis, but the dialysate contains human serum albumin (HSA). One of the cardinal features of any liver replacement therapy is the ability to remove accumulated metabolites, such as bile acids, bilirubin, aromatic amino acids, endogenous benzodiaz-

epines, nitric oxide, and phenols.2-4 Most of these substances are strongly protein bound, and the most important transport protein in plasma is albumin.5 Although molecules that accumulate in liver failure are small enough to pass through normal dialysis filters, effective removal by standard dialysis or hemofiltration is prevented because they are so tightly protein bound. By placing free HSA in the dialysate, binding sites From the Department of Medicine, Division of Renal Diseases and Hypertension, and Department of Anesthesiology and Critical Care Medicine, The George Washington University Medical Center, Washington, DC. Received September 1, 2004; accepted in revised form November 24, 2004. Originally published online as doi:10.1053/j.ajkd.2004.11.023 on January 27, 2005. Address reprint requests to Lakhmir S. Chawla, MD, Department of Anesthesiology and Critical Care Medicine, The George Washington University Medical Center, 900 23rd St NW, Rm G-105, Washington, DC 20037. E-mail: [email protected] © 2005 by the National Kidney Foundation, Inc. 0272-6386/05/4503-0027$30.00/0 doi:10.1053/j.ajkd.2004.11.023

American Journal of Kidney Diseases, Vol 45, No 3 (March), 2005: E51-E56

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on the dialysate side of the circuit are open, thereby creating a gradient for these molecules to be transported onto free binding sites on the HSA in dialysate. This technique has been effective for the treatment of acute liver failure, hepatic encephalopathy, hepatorenal syndrome, and cerebral edema secondary to hepatic failure.6-9 In addition, MARS has been used successfully to treat patients with intractable cholestatic pruritus.6,10-12 MARS is an effective system for using albumin dialysis, but this system is not yet approved by the Food and Drug Administration in the United States. Also, MARS requires special training and hardware that attaches to standard hemodialysis apparatus. We successfully performed effective albumin dialysis by using a standard continuous venovenous hemodialysis (CVVHD) system. CASE REPORT A 53-year-old woman was admitted with ischemic colitis and underwent a subtotal colectomy. She developed acute renal failure, and renal replacement therapy (RRT) was initiated 1 week after admission. One month later, she developed severe hyperbilirubinemia and elevated serum transaminase levels. Her elevated serum transaminase levels resolved, but her serum bilirubin (SB) concentration remained elevated in the range of 35 to 55 mg/dL (599 to 941 ␮mol/L) for several weeks. Composition of the bilirubin indicated that almost all of it was conjugated, given that direct bilirubin made up greater than 90% of total SB. The patient underwent multiple imaging and functional evaluations of her biliary system, including 2 ultrasound evaluations, 2 computed tomographic scans, and cholescintigraphy, which failed to show ductal dilatation or obstruction. A liver biopsy showed intrahepatic cholestasis without inflammation or cirrhosis. She developed intense pruritus resistant to medical treatment that persisted over several weeks. Despite RRT for continued renal failure, both conventional intermittent hemodialysis (IHD) and continuous venovenous hemodiafiltration (CVVHDF) failed to reduce total SB levels.

Methods We obtained informed consent from the patient for the modification of her routine dialysis treatment to include albumin dialysate to treat her intractable pruritus.

Dialytic Technique Previous RRT for the patient had alternated between CVVHDF and IHD, depending on the patient’s blood pressure and overall condition. SB levels did not decrease appreciably with either IHD or CVVHDF. The patient underwent 1 session of albumin dialysate CVVHD (CVVHDa) and 1 session of albumin dialysate CVVHDF (CVVHDFa).

In each session, the first hour of the treatment was initiated with normal dialysate, and the remaining 6 hours were completed with albumin dialysate. In each session, pretreatment and posttreatment SB levels were measured, and mass balance of bilirubin was determined by weighing and sampling aliquots of the spent dialysate. We chose to assess bilirubin as our mass balance measure because it has a high affinity for serum albumin compared with other accumulated hepatotoxins (eg, bile acids).13 Session 1. The patient underwent CVVHD using a Prisma (Gambro Co) machine. The patient’s Prisma settings were blood flow of 130 mL/min, dialysate flow of 2.5 L/h, and no net ultrafiltration. Dialysate composition was as follows: sodium, 145 mEq/L (mmol/L); potassium, 2.0 mEq/L (mmol/L); chloride, 117 mEq/L (mmol/L); magnesium, 3.6 mg/dL (1.5 mmol/L); lactate, 270 mg/dL (30 mmol/L); and calcium, 3.5 mEq/L. The treatment was started immediately after a new filter and circuit had been set up. In the first hour, normal CVVHD dialysate (as described) was used. Thereafter, the dialysate was changed to an identical 5.0-L bag of dialysate spiked with 100 g of HSA (25 g/100 mL; ZLB Bioplasma AG, Berne, Switzerland), yielding a dialysate albumin concentration of 1.85%. After the switch, the patient was dialyzed using the same parameters for 6 hours. The spent ultrafiltrate for the entire session was collected. Dialysate bilirubin concentration and weight were assessed every 2 hours during the 6-hour session. Session 2. The patient underwent CVVHDF using a Prisma machine. The patient’s Prisma settings were blood flow of 130 mL/min, dialysate flow of 2.5 L/h, replacement fluid (Ringer’s lactate) of 300 mL/h, and no net ultrafiltration. Ringer’s lactate composition was as follows: sodium, 130 mEq/L (mmol/L); potassium, 4 mEq/L (mmol/L); chloride, 109 mEq/L (mmol/L); lactate, 252 mg/dL (28 mmol/L); and calcium, 2.7 mEq/L. Dialysate composition was as follows: sodium, 145 mEq/L (mmol/L); potassium, 2.0 mEq/L (mmol/L); chloride, 117 mEq/L (mmol/L); magnesium, 3.6 mg/dL (1.5 mmol/L); lactate, 270 mg/dL (30 mmol/L); and calcium, 3.5 mEq/L. The patient underwent hemodiafiltration at these settings immediately after a new filter and circuit had been set up for 1 hour. After the first hour, the dialysis bag was changed to an identical 4.0-L bag of dialysate spiked with 200 g of HSA (25 g/100 mL; ZLB Bioplasma AG), yielding a dialysate albumin concentration of 5.0%. After the switch, the patient was treated using the same settings for 6 hours. The spent ultrafiltrate was collected for the entire session. Dialysate bilirubin concentration and weight were assessed every 2 hours during the 6-hour session.

Results Figure 1 shows the change in the patient’s SB levels during 4 days when IHD, CVVHDa, CVVHDFa, and CVVHDF were used for RRT. Day 1, IHD essentially had no effect on SB levels. SB levels changed from 51 mg/dL (872 ␮mol/L) to 50 mg/dL (855 ␮mol/L), equivalent to a bilirubin reduction ratio of 1.96%. Day 2, CVVHDa (session 1) resulted in a decrease in SB levels from 50.0 mg/dL (855 ␮mol/L) to 39.0 mg/dL (667 ␮mol/L), equivalent to a bilirubin reduction ratio of 22%. There was a significant in-

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Fig 1. Plot of serum bilirubin levels after 2 sessions of RRT with albumin dialysis.

crease in SB levels in the 18 hours between the 2 sessions of albumin dialysis. At the beginning of session 2, SB level was 47.1 mg/dL (805 ␮mol/L), which decreased after CVVHDFa to 39.7 mg/dL (679 ␮mol/L), equivalent to a bilirubin reduction ratio of 15.5%. At this point, the patient and her family did not feel that the treatment was achieving symptomatic relief sufficient to justify the inconvenience of daily RRT. Day 4, the patient underwent a CVVHDF treatment for 12 hours and then was restarted on her previous thrice-weekly IHD RRT schedule. In session 1, the first hour with regular CVVHD produced a bilirubin dialysate concentration of 0.3 mg/dL (5 ␮mol/L)

compared with the 6 hours of CVVHDa, which produced a bilirubin dialysate concentration of 1.37 ⫾ 0.06 mg/dL (23 ⫾ 1 ␮mol/L). In session 2, the first hour with regular CVVHDF produced a bilirubin dialysate concentration of 0.3 mg/dL (5 ␮mol/L) compared with 6 hours of CVVHDFa, which produced a bilirubin dialysate concentration of 1.38 ⫾ 0.15 mg/dL (24 ⫾ 3 ␮mol/L). Changes in dialysate bilirubin concentrations for sessions 1 and 2 are shown in Figs 2 and 3. Mass balance removal of bilirubin for CVVHDa was 203.1 mg compared with 229.0 mg for CVVHDFa. Bilirubin removal mass balances and rates are listed in Table 1.

Fig 2. Session 1. *1.85% albumin dialysate.

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Fig 3.

DISCUSSION

Albumin dialysis using MARS has been effective in the removal of accumulated toxins in patients with hepatic failure, in the treatment of drug overdose for drugs that are highly protein bound, and in the treatment of cerebral edema in patients with acute liver failure.13-16 Since 1993, more than 400 patients have been treated with MARS for chronic hepatic failure, hepatorenal syndrome, acute hepatic failure, and primary hepatic nonfunction after liver transplantation.1 We have shown that with a modest amount of HSA added to standard CVVHDF dialysate, circulating bilirubin removal is enhanced 4-fold. We were unable to show a clinically significant increase in enhanced bilirubin transport by using 5% albumin dialysate compared with 1.85%. Table 1. Mass Bilirubin Balance and Bilirubin Removal Rate

Dialytic Modality

Bilirubin Mass Removed (mg)

Duration of Modality (min)

Rate of Bilirubin Removal (mg/min)

CVVHD CVVHDa* CVVHDF CVVHDF†

7.3 203.1 8.2 229.0

60 360 60 360

0.12 0.56 0.14 0.64

*1.85%. †5.0%.

Session 2.

MARS uses an albumin concentration of 20% in dialysate, which is 4 to 10 times greater than the albumin concentration that we used (5% and 1.85%, respectively). Despite the slow dialysate flow rates (41.67 mL/min) that we used in CVVHDa, the albumin in the dialysate was mostly unsaturated compared with the blood bilirubin concentration (50 mg/dL [855 ␮mol/L] versus 1.4 mg/dL [24 ␮mol/L], respectively). Patzer and Bane17 showed that only 0.4% albumin in the dialysate compartment is necessary for effective bound-solute dialysis. In vitro studies performed by Sauer et al18 showed that CVVHDF with single-pass albumin dialysis is similar to MARS. In that study, Sauer et al18 showed that CVVHDF with a 4% albumin dialysate concentration performed similar to or better than standard MARS and CVVHDF with a MARS dialysate system. In addition, a cost analysis performed in that study indicated that CVVHDF with single-pass albumin dialysis was less expensive than either of the MARS-based systems.18 Because MARS has been efficacious in clinical trials, we believe MARS treatment is still the gold standard with which all other types of albumin dialysis should be compared. In addition to albumin dialysate, MARS uses a special dialyzer membrane with hydrophilic/hydrophobic domains that facilitate the removal of albu-

MODIFIED CVVHDF WITH ALBUMIN DIALYSATE

min-bound toxins. In our case, we used an MF 100 Prisma hemodialyzer, which is made of polyacrylonitrite. The HF 1000, a hemodialyzer similar to that used in the MARS system, is available for the Prisma system (Hermann Goehl, Gambro, Sweden, personal communication, October 31, 2004). However, many centers around the world still do not have access to MARS. In addition, the high cost of the current MARS treatment may be prohibitive, particularly for clinicians in third-world countries. The process we describe can be adapted easily to any CVVHDF system and, potentially, any continuous arteriovenous hemodialysis system. In countries in which continuous venovenous hemodialysis systems are available, adding HSA to the dialysate during continuous arteriovenous hemodialysis is straightforward. There are several limitations to this study. First, a single case using some of the mechanics of a proven therapy (MARS) does not allow the conclusion that this modality can serve as an adequate replacement for MARS. Second, additional studies are required to determine the HSA concentration and CVVHDFa duration required to approximate a treatment using MARS. Third, although MARS treatment is expensive to perform and initiate, HSA also is expensive, and adding HSA to bag after bag of dialysate may be equally or more expensive.13 Last, adding HSA to preformed dialysate can be problematic for 3 reasons: (1) HSA contains a significant amount of sodium; (2) as more HSA is added to the dialysate, the greater the dilution effect on the dialysate; and (3) HSA in the dialysate will increase the clearance of drugs that are albumin bound and may create unpredictable changes in important drug concentrations (eg, phenytoin). We recommend that if CVVHDFa is undertaken, careful attention be given to dialysate contents, particularly sodium. Serum electrolytes and important drug levels should be checked frequently. In conclusion, albumin dialysis is an emerging dialytic technique that has a role in the treatment of acute liver failure, acute-on-chronic liver disease, Wilson’s disease, hepatorenal disease, and certain drug overdoses (eg, phenytoin).7,15,19,20 CVVHDFa is a therapy based on the same principles as MARS and allows for albumin dialysis using technical systems that many health care centers already have in place. In addition,

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CVVHDFa may be more feasible in patients with labile blood pressure and those who are critically ill. Additional studies using CVVHDFa to determine its efficacy compared with MARS are warranted. ACKNOWLEDGMENT The authors thank all the ICU nurses and support staff at the George Washington University Hospital who make clinical research possible.

REFERENCES 1. Stange J, Mitzner S, Ramlow W, Gliesche T, Hickstein H, Schmidt R: A new procedure for the removal of protein bound drugs and toxins. ASAIO J 39:M621-M625, 1993 2. Abe T, Abe T, Ageta S, Kakuta T, et al: A new method for removal of albumin-binding uremic toxins: Efficacy of an albumin-dialysate. Ther Apher 5:58-63, 2001 3. Willson RA, Webster KH, Hofmann AF, Summerskill WH: Toward an artificial liver: In vitro removal of unbound and protein-bound plasma compounds related to hepatic failure. Gastroenterology 62:1191-1199, 1972 4. Yang SS, Hughes RD, Williams R: Digoxin-like immunoreactive substances in severe acute liver disease due to viral hepatitis and paracetamol overdose. Hepatology 8:9397, 1988 5. Kragh-Hansen U: Structure and ligand binding properties of human serum albumin. Dan Med Bull 37:57-84, 1990 6. Doria C, Mandala L, Smith J, et al: Effect of molecular adsorbent recirculating system in hepatitis C virus-related intractable pruritus. Liver Transpl 9:437-443, 2003 7. Mitzner SR, Stange J, Klammt S, et al: Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: Results of a prospective, randomized, controlled clinical trial. Liver Transpl 6:277-286, 2000 8. Schmidt LE, Svendsen LB, Sorensen VR, Hansen BA, Larsen FS: Cerebral blood flow velocity increases during a single treatment with the molecular adsorbents recirculating system in patients with acute on chronic liver failure. Liver Transpl 7:709-712, 2001 9. Sen S, Mookerjee RP, Davies NA, Williams R, Jalan R: Review article: The molecular adsorbents recirculating system (MARS) in liver failure. Aliment Pharmacol Ther 16:S32-S38, 2002 (suppl 5) 10. Huster D, Schubert C, Berr F, Mossner J, Caca K: Rofecoxib-induced cholestatic hepatitis: Treatment with molecular adsorbent recycling system (MARS). J Hepatol 37: 413-414, 2002 11. Bellmann R, Graziadei IW, Feistritzer C, et al: Treatment of refractory cholestatic pruritus after liver transplantation with albumin dialysis. Liver Transpl 10:107-114, 2004 12. Mullhaupt B, Kullak-Ublick GA, Ambuhl PM, Stocker R, Renner EL: Successful use of the molecular adsorbent recirculating system (MARS) in a patient with primary biliary cirrhosis (PBC) and treatment refractory pruritus. Hepatol Res 25:442-446, 2003 13. Peszynski P, Klammt S, Peters E, Mitzner S, Stange J, Schmidt R: Albumin dialysis: Single pass vs recirculation (MARS). Liver 22:S40-S42, 2002 (suppl 2)

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14. Mitzner S, Loock J, Peszynski P, et al: Improvement in central nervous system functions during treatment of liver failure with albumin dialysis MARS—A review of clinical, biochemical, and electrophysiological data. Metab Brain Dis 17:463-475, 2002 15. Sen S, Ratnaraj N, Davies NA, et al: Treatment of phenytoin toxicity by the molecular adsorbents recirculating system (MARS). Epilepsia 44:265-267, 2003 16. Steiner C, Mitzner S: Experiences with MARS liver support therapy in liver failure: Analysis of 176 patients of the International MARS Registry. Liver 22:S20-S25, 2002 (suppl 2) 17. Patzer JF, Bane SE: Bound solute dialysis. ASAIO J 49:271-281, 2003

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18. Sauer IM, Goetz M, Steffen I, et al: In vitro comparison of the molecular adsorbent recirculation system (MARS) and single-pass albumin dialysis (SPAD). Hepatology 39: 1408-1414, 2004 19. Sen S, Felldin M, Steiner C, et al: Albumin dialysis and molecular adsorbents recirculating system (MARS) for acute Wilson’s disease. Liver Transpl 8:962-967, 2002 20. Stange J, Hassanein TI, Mehta R, Mitzner SR, Bartlett RH: The molecular adsorbents recycling system as a liver support system based on albumin dialysis: A summary of preclinical investigations, prospective, randomized, controlled clinical trial, and clinical experience from 19 centers. Artif Organs 26:103-110, 2002